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Is non-alcoholic fatty liver disease an independent predictor for macroangiopathy in Japanese type 2 diabetic patients : a cross-sectional study?
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To clarify the clinical characteristics of type 2 diabetic patients with non-alcoholic fatty liver disease (NAFLD) and to assess whether NAFLD is related to angiopathy. The study included 388 Japanese type 2 diabetic outpatients without viral hepatitis. The main outcome measures were angiopathy and NAFLD. The 388 subjects were divided into two subgroups based on alcohol consumption. Fatty liver was recognized in 36 of the 142 drinking patients (25%). There was no association of fatty liver disease with diabetic macro- or microangiopathy in these patients. Fatty liver disease (namely, NAFLD) was recognized in 77 of the 246 non-drinking patients (31%). Type 2 diabetic patients with NAFLD had a significantly younger age, higher body mass index level, higher levels of HbA1c, total cholesterol and triglyceride, lower HDL-C level, higher prevalence rates of hypercholesterolemia and obesity than counterparts without NAFLD. In addition, individuals in the elderly (≥65 years) non-drinking group with NAFLD had a significantly higher prevalence rates of diabetic macroangiopathy, coronary heart disease and thicker intima-media thickness level than their counterparts without NAFLD. The logistic regression analysis showed that NAFLD is an independent predictor of diabetic macroangiopathy.
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To investigate the role of S100A3 and the effect of S100A3 inhibition on human castration-resistant prostate cancer (CRPC) cells by using in vitro and in vivo functional assays. Using human CRPC cells (PC3 and DU145), S100A3 expression levels were assessed by reverse transcription-polymerase chain reaction and Western blot analysis. After S100A3-specific small interfering ribonucleic acid (RNA) treatment, cell viability was determined by Cell Counting Kit-8 assay, and apoptotic cell fractions were evaluated by flow cytometry. The invasive properties of these cells and the expression pattern of matrix metalloproteinases (MMPs) were assessed using transwell migration assays, reverse transcription-polymerase chain reaction, and gelatin zymography. Finally, the in vivo efficacy of S100A3 inhibition on human CRPC cells was investigated using human tumor xenograft models in nude mice. Human CRPC cells showed overexpression of S100A3, and its suppression reduced cell viability owing to apoptotic cell death. Additionally, S100A3 inhibition decreased the invasiveness of human CRPC cells. Moreover, MMP-2 and MMP-9 were downregulated in PC3, whereas only MMP-9 was downregulated in D145 after S100A3 inhibition. In human CRPC xenograft models, we noted a marked reduction in tumor growth in mice injected with S100A3 short hairpin RNA-transfected PC3 and DU145 cells.
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Does local lentiviral short hairpin RNA silencing of CCR2 inhibit vein graft thickening in hypercholesterolemic apolipoprotein E3-Leiden mice?
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Inflammatory responses to vascular injury are key events in vein graft disease and accelerated atherosclerosis, which may result in bypass failure. The monocyte chemoattractant protein-1 (MCP-1)/CC-chemokine receptor (CCR)-2 pathway is hypothesized to play a central role. A murine model for vein graft disease was used to study the effect of local application of lentiviral short hairpin RNA (shRNA) targeted against CCR2. A venous interposition was placed into the carotid artery of hypercholesterolemic apolipoprotein E3-Leiden (APOE*3-Leiden) mice to induce vein graft thickening with features of accelerated atherosclerosis. To demonstrate the efficacy of the lentiviral shRNA targeting murine CCR2 (shCCR2) in blocking vein graft disease in vivo, lentiviral shCCR2 or a control lentivirus was used to infect the vein graft locally (n = 8). Vascular CCR2 and MCP-1 messenger RNA expression levels were significantly upregulated during lesion progression in the vein graft. Infection of smooth muscle cells (SMCs) with a lentiviral shRNA targeting shCCR2 completely abolished MCP-1-induced SMC migration and inhibited SMC proliferation in vitro (n = 3 per group). Morphometric analysis of sections of grafts showed a significant 38% reduction in vein graft thickening in the shCCR2-treated mice 4 weeks after surgery (control, 0.42 +/- 0.05 mm(2); shCCR2, 0.26 +/- 0.03 mm(2); P = .007).
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To study the association between bed occupancy in psychiatric wards and rate of adverse incidents (AIs) including aggressive behavior and falls. This is a retrospective study analyzing bed occupancy and AIs' data in 4 closed wards in a state psychiatric hospital in Israel over a 20-month period. Ward-level daily records were extracted from the hospital's electronic admission-discharge and AI registries, creating a log of 609 days for each of the 4 wards. Relationships between gross and net bed occupancy and AIs rate were calculated, in general and for each ward and type of incidents. Average gross occupancy was 106±14.8% and net occupancy was 96.4±15.6%. Gross occupancy >100% was recorded in 51% of days. Net occupancy was higher on days with at least 1 incident than on no-incident days (98.6±14.8% vs. 95.7±15.7%, P<0.0001). AIs occurred in 18.6% of days in the lowest occupancy quadrant (up to 85% occupancy), compared with 26.7% of days in the highest occupancy quadrant (106% and above). Moreover, aggressive behavior-type incidents were significantly lower in the lowest occupancy quadrant days compared with the highest occupancy quadrant (8.3% vs. 14.1%, P<0.01). Evidence of a dose-response effect of bed occupancy on AIs rate was found.
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Is smoking associated with an increased risk of type 2 diabetes but a decreased risk of autoimmune diabetes in adults : an 11-year follow-up of incidence of diabetes in the Nord-Trøndelag study?
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We compared the association between smoking habits and later occurrence of type 2 diabetes on the one hand and between smoking and diabetes with autoimmunity on the other hand. We used data from a prospective study of 11-year cumulative incidence of diabetes in the Nord-Trøndelag Health Survey. Confirming previous reports, heavy smoking (>/=20 cigarettes per day) carried an increased relative risk (RR) of type 2 diabetes (n=738, RR=1.64, 95% CI: 1.12-2.39). In contrast, smoking reduced the risk of latent autoimmune diabetes in adults (LADA) and of traditional type 1 diabetes (LADA n= 81, RR=0.25, 95% CI: 0.11-0.60; type 1 diabetes, n=18, RR=0.17, 95% CI: 0.04-0.73).
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The aim of the present study was to determine the potential therapeutic value of the lazaroid U-83836E on blood brain barrier (BBB) breakdown and edema with respect to the changes in the synaptosomal Na+/K+ and Mg(2+)/Ca(2+)-adenosinetriphosphatase (ATPase) activities, tissue malondialdehyde levels and the neuronal viability in the rat brain subjected to cerebral trauma. Traumatic brain injury (TBI) was introduced by applying a 75 gm. cm force to the right parietal cortex using the weight-drop method. The first set of animals was used for determining time course changes of the synaptosomal Na+/K+ and Mg(2+)/Ca(2+)-ATPase and the malondialdehyde levels and were sacrificed 2, 6 and 24h after lesion production. A group of the animals was treated with U-83836E proir to TBI and sacrificed 24h after cerebral injury. A second set of animals was used for evaluating the alterations in BBB disruption and tissue water content and were sacrificed 2, 6 and 24h after lesion production. Two groups of animals were treated with U-83836E and sacrificed after 2 and 24h following TBI. U-83836E was given intraperitoneally thirty minutes before trauma at a dose of 10 mg/kg. Neuronal necrosis was also evaluated in the groups of U-83836E and physiological saline-treated animals. Extravasation of Evans blue into the traumatized hemisphere was maximum at 2h (p<0.001) and returned close to the control levels at 24h after TBI (p>0.05). Edema had developed progressively over time and reached the maximum degree of 2.1% (p<0.001) at 24h. U-83836E showed no effect on the BBB breakdown and the tissue water content at 2h and still had no effect on the BBB breakdown after 24h following the trauma (p>0.05), although it reduced edema after 24h (p<0.01). The losses of Na+/K+ and Mg(2+)/Ca(2+)-ATPase activities were found as 39.5% (p<0.001) and 29.4% (p<0.01) of the control value, respectively, and remained at the decreased levels throughout the experiment. Malondialdehyde level continued to increase over time reaching up to 209% (p<0.001) of the control value 24h after TBI. Both ATPase activities were improved to near control values (p>.05) by the effect of U-83836E. U-83836E inhibited the increase of lipid peroxidation (p<0.001) and also salvaged neuronal necrosis (p<0.05).
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Is retinal delivery of celecoxib several-fold higher following subconjunctival administration compared to systemic administration?
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We have previously demonstrated that celecoxib, a selective COX-2 inhibitor, reaches the retina following repeated oral administrations and inhibits diabetes-induced vascular endothelial growth factor (VEGF) mRNA expression and vascular leakage in a rat model. The aim of this study was to quantify the relative retinal bioavailability of celecoxib from the subconjunctival route compared to a systemic route. The plasma and ocular tissue distribution of celecoxib was determined in male Sprague-Dawley rats following subconjunctival and intraperitoneal administrations of drug suspension at a dose of 3 mg/rat. The animals were sacrificed at 0.5, 1, 2, 3, 4, 8, and 12 h post-dosing, the blood was collected, and the eyes were enucleated and frozen. The plasma, sclera, retina, vitreous, lens, and the cornea were isolated and celecoxib levels were determined using an HPLC method. The tissue exposure of the drug was measured as the area under the curve (AUC(0-infinity)) of the concentration vs. time profiles. The relative bioavailability was estimated as the AUC(0-infinity) ratio between subconjunctival and intraperitoneal groups. For the subconjunctivally dosed (ipsilateral) eye, the AUC(0-infinity) ratios between subconjunctival and intraperitoneal groups were 0.8 +/- 0.1, 53 +/- 4, 54 +/- 8, 145 +/- 21, 61 +/- 16, and 52 +/- 6 for plasma, sclera, retina, vitreous, lens, and cornea, respectively. For the contralateral ocular tissues, the AUC0-infinity ratios were 1.2 +/- 03, 11 +/- 0.3, 1.1 +/- 0.4, 1.0 +/- 0.3, and 1.2 +/- 0.3 in the sclera, retina, vitreous, lens, and the cornea, respectively, between the subconjunctival and the intraperitoneal groups. Assuming that the drug AUCs in contralateral eye were equal to the systemic pathway contribution to AUCs in the ipsilateral eye, the percent contribution of local pathways as opposed to systemic circulation for celecoxib delivery to the ipsilateral eye tissues was estimated to be 98% or greater.
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The purpose of this study was to describe patient satisfaction in general practice among the Sámi monolingual population, as compared with the Norwegian population. The data was collected in 2002-2004 through a health survey in communities with Sámi and Norwegian population, SAMINOR. The analyses included 15,612 men and women between 36 and 79 years, with a response rate of 60.1%. The questionnaire included questions about patients' satisfaction with primary care and what language they spoke at home. The monolingual Sámi population was less satisfied with the primary health care than the Norwegian population, RR 2.4 (95% CI 2.1-2.7) and also less satisfied with the physicians' language skills, RR 5.8 (95% CI 4.8-7.0). Frequent misunderstandings between the physician and the patient based on language difficulty were also reported, RR 3.8 (95% CI 3.3-4.3). In addition, approximately one third of the Sámi did not want to have an interpreter in on the consultation.
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Does psammaplin A induce Sirtuin 1-dependent autophagic cell death in doxorubicin-resistant MCF-7/adr human breast cancer cells and xenografts?
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Psammaplin A (PsA) is a natural product isolated from marine sponges, which has been demonstrated to have anticancer activity against several human cancer cell lines via the induction of cell cycle arrest and apoptosis. New drugs that are less toxic and more effective against multidrug-resistant cancers are urgently needed. We tested cell proliferation, cell cycle progression and autophagic cell death pathway in doxorubicin-resistant MCF-7 (MCF-7/adr) human breast cancer cells. The potency of PsA was further determined using an in vivo xenograft model.
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To investigate the effect of initial varus or valgus surgical neck alignment on outcomes of patients who sustained proximal humerus fractures treated with open reduction and internal fixation (ORIF). An institutional review board approved database of proximal humerus fractures treated with locked plates was reviewed. Of 185 fractures in the database, 101 fractures were identified and met inclusion criteria. Initial varus displacement was seen in 47 fractures (OTA types 11.A2.2, A3.1, A3.3, B1.2, B2.2, C1.2, C2.2, or C2.3) and initial valgus displacement was observed in 54 fractures (OTA types 11.A2.3, B1.1, C1.1, or C2.1). All patients were treated in a similar manner and examined by the treating physician at standard intervals. Functional outcomes were quantified via the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire and physical examination data at 12 months. Radiographs were reviewed for complications of healing. Additionally, complication rate and reoperation rate were investigated. Patients who presented with initial varus displacement had an average age of 59.3 years, while patients in the valgus group had an average age of 62.4 years. Overall, there was no statistically significant difference in age, sex distribution, BMI, fracture parts, screws used, or implant plate type between the two groups. At a minimum 12 months follow up, there was no significant difference in DASH scores between those presenting with varus versus valgus fracture patterns. In addition, no significant differences were seen in final shoulder range of motion in any plane. Overall, 30 patients included in this study developed a complication. A significantly greater number of patients in the initial varus cohort developed complications (40.4%), as compared to 20.3% of patients in the initial valgus cohort (P=0.03). Fourteen patients in this study underwent reoperation. Nine of these patients were in the varus cohort, while 5 were in the valgus cohort (P=0.15).
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Are haemorrhoids associated with internal iliac vein reflux in up to one-third of women presenting with varicose veins associated with pelvic vein reflux?
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To determine the prevalence of haemorrhoids in women with pelvic vein reflux, identify which pelvic veins are associated with haemorrhoids and assess if extent of pelvic vein reflux influences the prevalence of haemorrhoids. Females presenting with leg varicose veins undergo duplex ultrasonography to assess all sources of venous reflux. Those with significant reflux arising from the pelvis are offered transvaginal duplex ultrasound (TVS) to evaluate reflux in the ovarian veins and internal Iliac veins and associated pelvic varices in the adnexa, vulvar/labial veins and haemorrhoids. Patterns and severity of reflux were evaluated. Between January 2010 and December 2012, 419 female patients with leg or vulvar varicose vein patterns arising from the pelvis underwent TVS. Haemorrhoids were identified on TVS via direct tributaries from the internal Iliac veins in 152/419 patients (36.3%) and absent in 267/419 (63.7%). The prevalence of the condition increased with the number of pelvic trunks involved.
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We aimed to investigate the influence of oligomeric forms of β-amyloid (Aβ) and the influence of the duration of exposure on the development of tau phosphorylation. Aβ oligomers were injected intracranially either acutely into 5-month-old rTg4510 mice and tissue was collected 3 days later, or chronically into 3-month-old mice and tissue was collected 2 months later. Several forms of phosphorylated tau (p-tau), GSK3 (glycogen synthase kinase-3) and microglial and astrocyte activation were measured. Acute injections of Aβ oligomers had no effect on p-tau epitopes but did result in elevation of phosphorylated/activated GSK3 (pGSK3). Chronic infusion of Aβ oligomers into the right hippocampus resulted in 3- to 4-fold elevations in several p-tau isoforms with no changes in total tau levels. A significant elevation in pGSK3 accompanied these changes. Microglial staining with CD68 paralleled the increase in tau phosphorylation, however, CD45 staining was unaffected by Aβ. Control experiments revealed that the infusion of Aβ from the minipumps was largely complete by 10 days after implantation. Thus, the elevation in p-tau 2 months after implantation implies that the changes are quite persistent.
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Does founder Fukutin mutation cause Walker-Warburg syndrome in four Ashkenazi Jewish families?
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Walker-Warburg syndrome (WWS) is a genetically heterogeneous congenital muscular dystrophy caused by abnormal glycosylation of alpha-dystroglycan (alpha-DG) that is associated with brain malformations and eye anomalies. The Fukutin (FKTN) gene, which causes autosomal recessively inherited WWS is most often associated with Fukuyama congenital muscular dystrophy in Japan. We describe the clinical features of four nonconsanguinous Ashkenazi Jewish families with WWS and identify the underlying genetic basis for WWS. We screened for mutations in POMGnT1, POMT1, POMT2, and FKTN, genes causing WWS, by dideoxy sequence analysis. We identified an identical homozygous c.1167insA mutation in the FKTN gene on a common haplotype in all four families and identified 2/299 (0.7%) carriers for the c.1167insA mutation among normal American Ashkenazi Jewish adults.
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Granulocyte-colony stimulating factor (G-CSF) is used for the mobilization of bone marrow and endothelial progenitor cells, though G-CSF-induced inflammation may cause endothelial dysfunction. We examined the effects of G-CSF on endothelium, C-reactive protein (CRP), tumour necrosis factor-alpha (TNF-alpha) and anti-inflammatory cytokines namely interleukin 10 (IL-10). We studied 60 women with breast cancer, who were randomized to either subcutaneous G-CSF (5 microg/kg), o.d. for 5 days after adjuvant chemotherapy (n = 40) or placebo (n = 20). We measured flow-mediated dilatation (FMD%) of the brachial artery by ultrasonography, CRP, TNF-alpha, IL-10 and the ratio TNF-alpha/ IL-10 blood levels before, 2-h and 5-days after the G-CSF or placebo treatment. There was a greater increase of FMD, IL-10 and reduction of TNF-alpha/ IL-10, 2 h and 5 days after the G-CSF treatment compared to placebo. Although, CRP and TNF-alpha were higher, TNF-alpha/IL-10 was lower at the end of G-CSF treatment compared to placebo. Improvement of FMD was related to changes of IL-10 and TNF-alpha/IL-10.
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Do allergens of Epicoccum nigrum grown in different media for quality source material?
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The Epicoccum nigrum (EN) extract used in allergy disorders exhibits batch-to-batch variations in protein composition and allergenic potency. In this study, the allergens of EN grown in different media were investigated. EN was grown in five different nutrient media as stationary cultures at 25 degrees C for 5-23 days. The growth pattern was characterized by measuring dry weight, protein and carbohydrate content. The antigenic and allergenic content of EN extract was evaluated with EN-positive patients' sera and antibodies raised in rabbit. The growth of EN in Czapeck Dox medium yielded insufficient material, while Sabouraud's broth with yeast extract (SBY) gave maximum spore-mycelial mass and protein content. Potato dextrose broth (PDB) and potato dextrose agar (PDA) showed higher dry weight and protein in 7-9-day cultures. SDS-PAGE resolved 26, 22, and 21 protein bands in EN extracts from cultures of day-13 SBY, day-7 PDB, and day-9 PDA, respectively. IgE/IgG immunoblots showed more allergenic (25)/antigenic (25) bands in EN cultured in SBY than in the others. Specific IgE ELISA and intradermal tests showed EN extract from day-13 culture in SBY to be the most potent.
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Modular junctions are ubiquitous in contemporary hip arthroplasty. The head-trunnion junction is implicated in the failure of large diameter metal-on-metal (MoM) hips which are the currently the topic of one the largest legal actions in the history of orthopaedics (estimated costs are stated to exceed $4 billion). Several factors are known to influence the strength of these press-fit modular connections. However, the influence of different head sizes has not previously been investigated. The aim of the study was to establish whether the choice of head size influences the initial strength of the trunnion-head connection. Ti-6Al-4V trunnions (n = 60) and two different sizes of cobalt-chromium (Co-Cr) heads (28 mm and 36 mm; 30 of each size) were used in the study. Three different levels of assembly force were considered: 4 kN; 5 kN; and 6 kN (n = 10 each). The strength of the press-fit connection was subsequently evaluated by measuring the pull-off force required to break the connection. The statistical differences in pull-off force were examined using a Kruskal-Wallis test and two-sample Mann-Whitney U test. Finite element and analytical models were developed to understand the reasons for the experimentally observed differences. 36 mm diameter heads had significantly lower pull-off forces than 28 mm heads when impacted at 4 kN and 5 kN (p < 0.001; p < 0.001), but not at 6 kN (p = 0.21). Mean pull-off forces at 4 kN and 5 kN impaction forces were approximately 20% larger for 28 mm heads compared with 36 mm heads. Finite element and analytical models demonstrate that the differences in pull-off strength can be explained by differences in structural rigidity and the resulting interface pressures.
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Does an 8-O-4 ' norlignan exert oestrogen-like actions in osteoblastic cells via rapid nongenomic ER signaling pathway?
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Sambucus williamsii Hance (SWH), which belongs to the Caprifoliaceae family distributed in various regions of China, Korea and Japan, has been used as a folk medicine for treatment of bone and joint diseases in China for thousands of years. In previous studies, SWH was shown to possess anti-osteoporosis, healing fracture, anti-inflammatory and analgesic activities. Our previous studies showed that SWH extract effectively suppressed ovariectomy-induced increase in bone turnover and improved bone mineral density and bone biomechanical strength in rats as well as in mice. An 8-O-4' norlignan, (7R,8S)-1-(4-hydroxy-3-methoxyphenyl)-2-[4-(3-hydroxypropyl)-2-methoxyphenoxy]-1,3-propanediol (PPD) was previously isolated and identified as the bioactive ingredient in SWH. The present study aimed to characterize the bone protective effects as well as its mechanism of actions in osteoblasts. Bone protective actions of PPD on different cells were determined by proliferation assay, alkaline phosphatase (ALP) activity assay, calcium deposition as well as real-time reverse transcriptase-polymerase chain reaction (RT-PCR). In addition, estrogen receptor (ER) antagonist ICI182,780 and mitogen-activated protein kinase kinase (MEK) inhibitor U0126 blocking assays, competitive ER radioligand binding assay, ERE-dependent luciferase reporter assay and immunoblotting were used to determine if PPD activated ER and if the effects of PPD on osteoblastic functions were ER dependent. PPD exerted anabolic effects in osteoblasts and its effects were abolished by co-incubation with ICI182,780 or U0126. PPD induced mRNA expressions of Runx2, ALP, osteocalcin, and increased the ratio of osteoprotegerin/receptor activator of nuclear factor κB (OPG/RANKL). PPD failed to bind to either ERα or ERβ and did not activate ERE-luciferase activity via ER. PPD induced the phosphorylation of extracellular regulated kinases (ERK) and its effect was completely abolished by U0126. It also induced the phosphorylation of ERα at serine 118.
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The goal of this study was to compare the predictive ability of S100B, N-methyl-D-aspartate (NMDA) receptor antibodies (NR2Ab) and C-reactive protein (CRP) for neurological deficits after cardiac surgery with cardiopulmonary bypass (CPB). We investigated 557 high-risk adult patients who underwent coronary artery or valve replacement surgery using CPB as a substudy of a prospective, blinded, multicenter clinical trial. Serum concentrations of S100B (n=513 patients), NR2Ab (n=398) and CRP (n=510) were measured preoperatively, 24 and 48 hours after CPB. Neurological adverse events were assessed at baseline and postoperative days 1 and 2; neurocognitive function (mini-mental status examination) was assessed at baseline and on postoperative days 1, 7 and 28. Fifty-five (9.9%) patients had moderate or severe neurological adverse events (confusion/delirium, transient ischemic attack, or stroke) within 48 hours of CPB. Women had significantly more neurological complications than men (15.5% versus 7.8%; P=0.007). Ninety-six percent (24/25) of patients with NR2Ab concentrations > or =2.0 ng/mL preoperatively had neurological complications within 48 hours post-CPB, versus only 5.4% (20/373) of patients with NR2Ab concentrations <2.0 ng/mL, resulting in a 17.9-fold increase (95% CI, 11.6 to 27.6) in postoperative neurological complications for patients with high levels of NR2A antibodies. Preoperative serum S100B and CRP did not predict neurological complications from CPB. Decreased mini-mental status examination scores for orientation, attention and recall were associated with neurological adverse events early after CPB.
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Are standard equations accurate in assessing resting energy expenditure in patients with amyotrophic lateral sclerosis?
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To assess the utility of standard equations for calculating caloric requirements in patients with amyotrophic lateral sclerosis (ALS). Malnutrition substantially increases the risk of death in ALS. Weight loss can be stabilized and survival prolonged with early gastrostomy feeding. However the use of standard nutrition equations has not been validated in this population. We therefore compared measured caloric expenditure to 2 predictive equations in patients with varying stages of ALS. Thirty-four patients were studied. Caloric expenditure and respiratory quotient (R) were measured using indirect calorimetry. Results were compared with the Harris-Benedict equation. The prediction error for the Harris-Benedict equation was 18.6 + 14.9%. Limits of agreement showed this equation could overestimate caloric expenditure by 591 kcal/d and underestimate requirements by 677 kcal/d. R was >0.86 in 11 patients, suggesting overfeeding, and <0.8 in 15 patients, suggesting underfeeding. The difference between predicted and measured caloric expenditure did not correlate with disease severity, disease duration, or body mass index. Mechanically ventilated patients had higher than predicted energy expenditure.
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To determine whether macrophages in human reproductive tissues contain luteinizing hormone (LH)/human chorionic gonadotropin (hCG) receptor mRNA and receptor protein that can bind 125I-hCG. Macrophages isolated from term pregnancy human decidua were used for LH/hCG receptor detection by in situ hybridization for receptor mRNA and immunocytochemistry for a macrophage marker, CD68, performed alone and in combination, reverse transcription-nested polymerase chain reaction, Western and ligand blotting. The LH/hCG receptor presence in macrophages in late luteal phase human endometria and corpora lutea was determined by sequential performance of in situ hybridization and immunocytochemistry. The macrophages present in term pregnancy human decidua and late luteal phase human endometria and corpora lutea contain LH/hCG receptors.
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Do nomograms incorporating serum C-reactive protein effectively predict mortality before and after surgical treatment of renal cell carcinoma?
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To incorporate C-reactive protein into nomograms estimating survival in patients with renal cell carcinoma. Patients undergoing surgery for renal cell carcinoma from 2005-2012 were studied retrospectively. Multivariable Cox proportional hazards regression and competing risks regression models including stage, grade, C-reactive protein levels and presence of metastatic disease were constructed. Outcomes analyzed include overall mortality overall mortality and renal cell carcinoma-specific mortality. The cohort included 516 patients with a mean follow up of 1.7 years (SD 1.4 years). One- and 3-year renal cell carcinoma-specific mortality was 8.8% and 13.5%, respectively. Four nomograms were generated using overall mortality and renal cell carcinoma-specific mortality as end-points, two each for pre- and postoperative counseling. The factor with the largest effect on all nomograms was preoperative C-reactive protein. Based on the internal validation with bootstrapping, the concordance indices for renal cell carcinoma-specific mortality in the preoperative nomogram, postoperative nomogram, and the Mayo Clinic stage, size, grade and necrosis score were 0.889, 0.893, and 0.832, respectively (P = 0.005 and 0.002 comparing with stage, size, grade and necrosis scores for preoperative or postoperative nomograms). For overall mortality, the preoperative nomogram, postoperative nomogram, and stage, size, grade and necrosis score showed concordance indices of 0.866, 0.897, and 0.828, respectively (P = 0.123 and 0.008 compared with stage, size, grade and necrosis score for preoperative or postoperative nomograms).
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The onset and offset of weak low-frequency magnetic fields triggered evoked potentials in human subjects that could be detected using nonlinear analysis, but not by means of time averaging. Because the magnetic fields and their induced electric fields were both present in the brain, their respective role in producing the effect on brain activity could not be ascertained. We inquired whether a biophysical coupling mechanism involving only the electric field could explain the occurrence of the brain potentials. An external electric field capable of producing a brain electric field comparable to that induced by the magnetic stimuli was identified by finite-element analysis. The electroencephalogram from 23 subjects was measured from six scalp derivations in the presence and absence of the external electric field, and the presence of evoked potentials was assessed using nonlinear and linear analyses. Evoked potentials were observed in all but one subject (p < 0.05 in each subject); the potentials had the same latency, duration, and distribution of magnitudes as seen in the earlier studies, and were detectable only by means of nonlinear analysis. Using a realistic physical model of an ion channel, we showed that transduction of an electric field could be explained by assuming that the field exerted a force on glycocalyx molecules attached to a channel gate.
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Does co-expression network of neural-differentiation genes show specific pattern in schizophrenia?
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Schizophrenia is a neurodevelopmental disorder with genetic and environmental factors contributing to its pathogenesis, although the mechanism is unknown due to the difficulties in accessing diseased tissue during human neurodevelopment. The aim of this study was to find neuronal differentiation genes disrupted in schizophrenia and to evaluate those genes in post-mortem brain tissues from schizophrenia cases and controls. We analyzed differentially expressed genes (DEG), copy number variation (CNV) and differential methylation in human induced pluripotent stem cells (hiPSC) derived from fibroblasts from one control and one schizophrenia patient and further differentiated into neuron (NPC). Expression of the DEG were analyzed with microarrays of post-mortem brain tissue (frontal cortex) cohort of 29 schizophrenia cases and 30 controls. A Weighted Gene Co-expression Network Analysis (WGCNA) using the DEG was used to detect clusters of co-expressed genes that were non-conserved between adult cases and controls brain samples. We identified methylation alterations potentially involved with neuronal differentiation in schizophrenia, which displayed an over-representation of genes related to chromatin remodeling complex (adjP = 0.04). We found 228 DEG associated with neuronal differentiation. These genes were involved with metabolic processes, signal transduction, nervous system development, regulation of neurogenesis and neuronal differentiation. Between adult brain samples from cases and controls there were 233 DEG, with only four genes overlapping with the 228 DEG, probably because we compared single cell to tissue bulks and more importantly, the cells were at different stages of development. The comparison of the co-expressed network of the 228 genes in adult brain samples between cases and controls revealed a less conserved module enriched for genes associated with oxidative stress and negative regulation of cell differentiation.
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Coagulation FXII is activated on contact with lipoprotein particles. It has been suggested that contact with subendothelial tissue provides an alternative biological surface for FXII activation. Our aim was to investigate whether activated FXII (FXIIa) is elevated in patients with coronary atherosclerosis, and whether disease status (acute phase or stable state) affects circulating levels of FXIIa. Circulating FXIIa levels were measured in the peripheral blood of 122 patients with coronary atherosclerosis (32, stable angina; 54, unstable angina; 36, nQ myocardial infarction) and in 45 age-matched subjects (Contr). FXIIa levels (median, first and third quartiles; ng/ml) were higher in patients than in Contr: 1.61 (1.26-2.02) vs. 1.34 (1.13-1.81) (p<0.01). FXIIa levels were similar among patients with stable angina [1.66 (1.23-1.91)], unstable angina [1.53 (1.21-2.04)], and nQ myocardial infarction [1.75 (1.34-2.03)]. The three groups of patients had similar prevalence for most atherothrombotic risk factors; patients with stable angina had an increased severity of coronary disease, which did not explain the different levels of FXIIa. Fasting levels of triglycerides were the best predictor of FXIIa levels in our patients.
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Is activity of the porcine gonadotropin-releasing hormone receptor gene promoter partially conferred by a distal gonadotrope specific element ( GSE ) within an upstream enhancing region , two proximal GSEs and a retinoid X receptor binding site?
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Regulation of gonadotropin-releasing hormone (GnRH) receptor (GnRHR) numbers on gonadotropes within the anterior pituitary gland represents a critical point for control of reproductive function. Binding of GnRH to its receptor regulates follicle stimulating hormone (FSH) and luteinizing hormone (LH) release and levels of this G-protein coupled receptor on the surface of gonadotropes determines their sensitivity to GnRH pulses. While transcriptional regulation of this gene has been studied in mice, rats, humans and sheep, little is known about its regulation in the pig, an important agricultural species and human research model. We isolated 5118 bp of 5' flanking sequence for the porcine GnRHR gene and generated luciferase reporter vectors. Deletion and mutation constructs were evaluated in gonadotrope-derived alphaT3-1 cells to determine regions important for gene transcription. Additionally, electrophoretic mobility shift assays (EMSAs) were performed to identify transcription factors binding to the GnRHR promoter. Transient transfections revealed that the GnRHR promoter was functional in alphaT3-1 cells but not in cells of non-gonadotrope origin. Mutation of the highly conserved gonadotrope specific element (GSE) located at -179/-171 of proximal promoter completely ablated luciferase activity, whereas mutation of another GSE at -315/-310 reduced activity by 34%. Consistent with this, EMSAs using alphaT3-1 nuclear extracts and a steroidogenic factor (SF)1 antibody confirmed SF1 binding to both GSEs. EMSAs also demonstrated that a retinoid X receptor (RXR) binding site at -279/-274 binds RXRalpha and RXRbeta and mutation of this site eliminated promoter activity. Transient transfection of alphaT3-1 cells with reporter vectors containing selective removal of 5' flanking region for the porcine GnRHR gene indicated that the -1915/-1431 segment was important for promoter activity. Definition of this region via transfection assays and EMSAs revealed an upstream enhancing region located at -1779/-1667 that increases porcine GnRHR gene expression in alphaT3-1 cells and includes a SF1 binding site at -1760/-1753.
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CC chemokines play important roles in the pathogenesis of interstitial lung diseases. Elevated CC chemokine levels have been observed in bronchoalveolar lavage (BAL) fluid of patients with idiopathic pulmonary fibrosis (IPF). We aimed to examine whether the levels of four CC chemokines, i.e. monocyte chemoattractant protein-1 (MCP-1/CCL2), macrophage inflammatory protein-1 alpha (MIP-1 alpha/CCL3), thymus- and activation-regulated chemokine (TARC/CCL17), and macrophage-derived chemokine (MDC/CCL22), in BAL fluid are predictive of the prognosis of IPF patients. We compared the chemokine levels of patients alive 5 years after diagnosis and those who had died. Lung function data, CT scores, and serum markers were also compared. Among 39 patients (29 males, median age, 60 years), 19 patients (48%) died within 5 years after the diagnosis. Whereas percent vital capacity was not different, percent lung diffusion capacity for carbon monoxide was significantly higher in the surviving patients than in the nonsurviving patients (p < 0.01). Median CCL2 levels of surviving and nonsurviving patients were 154.3 (interquartile range, IQR: 67.3-381.8) and 427.2 (IQR: 329.2-1184.1) pg/ml, respectively (p < 0.02). CCL3 levels in BAL fluid did not differ between the surviving and nonsurviving patients. CCL17 was detected in BAL fluid of 7 patients, 6 of whom died within 5 years. CCL22 was detectable in BAL fluid of 10 patients, only 1 of whom survived. Serum levels of KL-6 and lactate dehydrogenase did not differ between the surviving and nonsurviving patients.
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Does prevalence and correlate of poor medication adherence amongst psychiatric outpatients in southwestern Nigeria?
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The aim of this study was to assess the rate of adherence to medications amongst psychiatric outpatients in Nigeria and examine factors associated with medication nonadherence amongst this group. Psychiatric outpatients (n=342) from three centres were assessed for medication adherence using the Morisky Medication Adherence Questionnaire. Details regarding sociodemographic variables (age, sex, education, religion, marital status, employment, income, medication cost), illness related variables (diagnosis, duration, number of episodes/admissions, insight, severity of symptoms, mental state, functional status), medication related variables (type, mode of administration, side effect, attitude to medication) and perception related variables (self-stigma, perceived causation and prognosis) were also obtained. There were 76 participants (22.2%) with good medication adherence, 102 (29.8%) with moderate adherence and 164 (48.0%) with poor adherence. The significant independent correlates of poor medication adherence included being employed [odds ratio (OR) 3.42, 95% confidence interval (95% CI) 2.17-5.39], poor social support (OR 5.86, 95% CI 2.87-12.17), high self-stigma (OR 4.70, 95% CI 2.24-9.96) and perceived spiritual causation of mental illness (OR 3.74, 95% CI 1.87-7.74).
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To investigate the effects of endothelin-1 (ET-1) overexpression on apoptosis of the rat pulmonary arterial microvascular smooth muscle cells (RPMC) in vitro. Primary RPMC obtained from the pulmonary artery and lung microvasculature were identified by immunofluorescence staining and electron microscope technique. The RPMC was transient transfected with the pMEXneo-ET1 and pCDNA5-FRT-TO-ET1-3'UTR plasmids as well as the empty vector respectively via lipofectamine. Flow cytometry was used to assess the cell cycle and apoptosis of RPMC. Akt and Caspase-3 expressions were detected by Western blot and real time RT-PCR. The mRNA of ET(A) expression was significantly higher than that of ET(B) receptor in primary RPMC. Flow cytometry analysis revealed significantly reduced apoptosis in ET-1 transfected RPMC compared to that in vehicle transfected RPMC. Overexpression of ET-1 in RPMC also significantly increased the phosphorylation of Akt and reduced the cleaved Caspase-3 expression.
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Is a specific KRAS codon 13 mutation an independent predictor for colorectal cancer metachronous distant metastases?
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In colorectal cancer, there are significant differences between synchronous and metachronous distant metastases. However in recent studies, synchronous and metachronous metastases were always lumped together, neglecting their clinical and molecular differences. The mechanism of the latency of metachronous metastases is still unclear. We conducted this study to reveal the relationship between EGFR pathways and metachronous metastases, and try to find efficient predictors. PCRs and pyrosequencing were used to detect KRAS, BRAF, PIK3CA and PTEN mutations in primary tumor tissues in a total of 281 patients from 2002 to 2008. Patients were identified into three groups: no-metastases group, synchronous-metastases group and metachronous-metastases group. Clinical and survival data were collected from a prospective database. KRAS codon 13 mutation was an independent predictor only for metachronous distant metastases (OR = 11.857, P < 0.001), but not for synchronous metastases. Male gender (OR = 2.233, P = 0.024), primary tumor located at rectum (OR = 0.404, P = 0.041), and primary pN2 stage (OR = 3.361, P = 0.01) were also independent predictors for metachronous distant metastases. Different SNPs in KRAS worked significantly different in determining synchronous or metachronous metastases. BRAF mutation (Univariate, OR = 11.5, P = 0.039) and > 200 ng/ml preoperative CEA (Univariate, OR = 41, P = 0.011) potentially predicted metastases within 6 months after primary tumor resection. After metachronous metastases, radical resection (HR = 0.280, P = 0.002) was the most important protective factor for long-term survival.
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Hordeum vulgare L. (HV or barley) is used by traditional healers to treat various inflammatory and cardiovascular diseases, without the knowledge of pharmacologic rationale behind its actions. This study was designed to explore the potential scientific mechanism(s) that could explain the use of Hordeum vulgare in traditional medicine as a treatment for various inflammatory and cardiovascular diseases. A crude extract and its three fractions were prepared from HV and screened for the inhibition of platelet aggregation and various metabolites of cyclooxygenase (COX), lipoxygenase (LOX) pathways of arachidonic acid (AA) metabolism as well as for its effects on certain antioxidant enzymes. Platelet aggregation was monitored using turbidometric principle, AA metabolism through radioimmunoassay and antioxidant enzymes by commercial kits using spectrophotometer. Results show that HV exhibited activities against all human platelet agonists used except adenine diphosphate, and inhibited both COX and LOX pathways of AA metabolism. It also elevated the activities of superoxide dismutase (SOD) and glutathione peroxidase (GPx). However, these activities were distributed in various fractions of HV. Aqueous fraction was most potent in elevating SOD activity; chloroform fraction had concentrated compounds responsible for COX inhibition while n-hexane seems to possess compounds responsible for LOX inhibition as well as the only fraction enhancing the activity of GPx.
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Does citrus limonoid nomilin inhibit osteoclastogenesis in vitro by suppression of NFATc1 and MAPK signaling pathways?
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Animal experiment studies have revealed a positive association between intake of citrus fruits and bone health. Nomilin, a limonoid present in citrus fruits, is reported to have many biological activities in mammalian systems, but the mechanism of nomilin on bone metabolism regulation is currently unclear. To reveal the mechanism of nomilin on osteoclastic differentiation of mouse primary bone marrow-derived macrophages (BMMs) and the mouse RAW 264.7 macrophage cell line into osteoclasts. Controlled laboratory study. Effects of nomilin on osteoclastic differentiation were studied in in vitro cell cultures. Cell viability of RAW 264.7 cells and BMMs was measured with the Cell Counting Kit. TRAP-positive multinucleated cells were counted as osteoclast cell numbers. The number and area of resorption pits were measured as bone-resorbing activity. Osteoclast-specific genes expression was evaluated by quantitative real-time PCR; and proteins expression was evaluated by western blot. Nomilin significantly decreased TRAP-positive multinucleated cell numbers compared with the control, and exhibited no cytotoxicity. Nomilin decreased bone resorption activity. Nomilin downregulated osteoclast-specific genes, NFATc1 and TRAP mRNA levels. Furthermore, nomilin suppressed MAPK signaling pathways.
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The objective of this study was to evaluate the effect of an intra-aortic filter on postoperative outcomes in high-risk cardiac surgical patients. An intra-aortic filter was used in 316 (4.9%) of 6442 cardiac surgical cases from 2003 to 2013. A retrospective analysis of the Society of Thoracic Surgeons (STS) registry data was performed for 204 patients with filter placement who underwent coronary artery bypass grafting (CABG) (n = 89), valve replacement (n = 63) or combined CABG and valve replacement (n = 52), matched with 1224 patients without filter placement by STS mortality scores based on propensity scores. Generalized linear modelling was used to compare rates of complications as well as the length of stay and time in the intensive care unit (ICU). A P-value < 0.05 was considered significant. Overall, patients with filters before matching had a significantly higher risk of death than did the patients without filters: 12.0% of patients with filters had an STS mortality risk score ≥4 vs 7.7% of patients without filters (P = 0.027). After analysis of the composite end-point of all STS major morbidities, the matched filter group had fewer overall complications (6.8 vs 13.2%, P = 0.02). The rate of postoperative respiratory failure was lower in the filter group (2.5 vs 7.0%, P = 0.01). Rates of stroke and new-onset haemodialysis, while not statistically different, were almost 50% lower in the filter group. Length of stay in the hospital and in the ICU was not significantly different; however, in patients with postoperative complications, time in the ICU (163 vs 189 h, P = 0.02) was shorter for the filter patients.
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Are polymorphisms in the DUSP10 gene associated with sex-specific colorectal cancer risk in a Han population?
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Colorectal cancer (CRC) is common, especially in developed countries. CRC is a multifactorial disease influenced by both environmental and genetic factors. In this study, we investigated the role of genetic polymorphisms in the dual specificity protein phosphatase 10 (DUSP10) gene especially in sex-specific. We selected nine DUSP10 tag single nucleotide polymorphisms (tSNPs) previously reported to be associated with colorectal cancer risk of in a case-control study from Xi'an city of China. In females, three SNPs were associated with decreased CRC risk: rs11118838, rs12724393, and rs908858. However, in males, only one SNP, rs908858, was associated with decreased CRC risk. Using a log-additive model, the rs11118838 "C" allele and the rs12724393 "G" allele were associated with decreased CRC risk in females, while the rs908858 "G" allele was associated with decreased CRC risk in both females and males. In addition, haplotype analysis also found "CG" and "CCT" were associated with the decreased CRC risk in females.
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Serum levels of tumour necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) increase during an inflammatory response and have been reported to induce a negative inotropic effect on the myocardium. Alfentanil, an opioid analgesic often used in the critical care of patients with sepsis, has been shown to enhance ventricular contractility. This study characterised the effects of TNF-alpha and IL-1beta on contraction and the Ca(2+) transient and investigated whether depressed ventricular function was ameliorated by alfentanil. Isolated rat ventricular myocytes were loaded with fura-2 and electrically stimulated at 1 Hz. Contraction and Ca(2+) transients were measured after 60, 120 and 180 min incubations in TNF-alpha (0.05 ng ml(-1)) and IL-1beta (2 ng ml(-1)). The effects of 10 microM alfentanil on contractility and Ca(2+) transients of TNF-alpha and IL-1beta treated cells were determined. After 180 min of TNF-alpha and IL-1beta treatment, the amplitude of contraction, the Ca(2+) transient and sarcoplasmic reticulum (SR) Ca(2+) content were significantly reduced. Alfentanil significantly increased contraction of TNF-alpha and IL-1beta treated cells via a small increase in the Ca(2+) transient and a larger increase in myofilament Ca(2+) sensitivity, effects that were not blocked by 10 microM naloxone, a broad spectrum opioid receptor antagonist.
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Does detection of molecular bacterascites in decompensated cirrhosis define a risk with decreased survival?
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The prognostic relevance of bacterial DNA (bactDNA) detection in ascitic fluid of patients with cirrhosis is still under debate. Using quantitative real-time PCR with broad-range primers targeting the V3 and V4 variable region of the 16S rRNA gene, we measured bactDNA concentrations in patients with and without leukocytic ascites and evaluated the impact on short-term survival. Ascites samples from 173 patients with decompensated cirrhosis were consecutively collected between February 2011 and December 2012. BactDNA-positive ascites samples were sequenced and chromatograms were identified using RipSeq. Clinical data collection and survival analyses were carried out retrospectively and correlated with ascites bactDNA levels. BactDNA was detected qualitatively with a similar frequency in both nonleukocytic and leukocytic ascites [40% (57/144) and 43.5% (10/23), respectively; P=0.724]. However, the median bactDNA level was significantly higher in leukocytic ascites than in nonleukocytic ascites (1.2×10 vs. 5.7×10 copies/ml; P=0.008). Patients' survival was associated significantly with bactDNA level. The 30-day and 180-day survival was reduced if bactDNA was above the quantification limit of 520 copies/ml (84 and 63% vs. 72 and 43%, respectively; P<0.05) and worst if bactDNA was above 5000 copies/ml. The bacterial spectrum was dominated by Gram-positive strains as shown by direct sequencing.
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Cognitive behaviour therapy (CBT) of primary insomnia is frequently combined with various pharmacological treatments, including sedative antidepressants. The present study was undertaken to evaluate the clinical efficacy of CBT, singly and combined with trazodone pharmacotherapy, for primary insomnia. Randomised, comparative clinical trial, at a single academic medical centre. Twenty outpatients (15 women, 5 men) with chronic primary insomnia were randomly assigned to CBT or CBT +100mg trazodone and treated for 8 weeks. The treatment outcome was estimated by mean changes from baseline in self-reported clinical scales, sleep continuity data and sleep architecture parameters. All patients perceived significant subjective sleep improvements. Sleep latency significantly shortened (p=0.03), sleep efficiency increased (p=0.004) and the total sleep time was significantly prolonged (p=0.006) after the CBT treatment in both groups. Sleep architecture showed that the combined approach (CBT + trazodone) resulted in a significant increase in slow wave sleep duration compared to treatment by CBT only (p=0.04).
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Is obesity associated with increased postoperative complications after operative management of tibial shaft fractures?
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To assess the association of obesity and postoperative complications after operative management of tibial shaft fractures. Patients who underwent operative management of a tibial shaft fracture were identified in a national database by Current Procedural Terminology (CPT) codes for: (1) open reduction and internal fixation (ORIF) and (2) intramedullary nailing (IMN) procedures in the setting of International Classification of Diseases, Ninth Revision (ICD-9) codes for tibial shaft fracture. These groups were then divided into non-obese, obese, and morbidly obese cohorts using ICD-9 codes. Each cohort was then assessed for grouped complications within 90 days, removal of implants within 6 months, and nonunion within 9 months postoperatively. Odds ratios and 95% confidence intervals were calculated. From 2005 to 2012, 14,638 patients who underwent operative management of tibial shaft fractures were identified, including 4425 (30.2%) ORIF and 10,213 (69.8%) IMN. Overall, 1091 patients (7.4%) were coded as obese and 820 (5.6%) morbidly obese. In each operative group, obesity and morbid obesity was associated with a substantial increase in the rate of major and minor medical complications, venous thromboembolism, infection, procedures for implant removal, and nonunion.
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The present study aims at investigating the involvement of several genes in the cell cycle distribution and apoptosis in U937 cells, a cell line lacking functional p53 protein, after combined treatment with staurosporine and irradiation. Using a DNA fragmentation assay, flow cytometry and western blot analysis, the molecular basis for the effects of staurosporine in combination with the irradiation of leukemia cells was investigated. Our results indicated that combined treatment led to an increased apoptotic cell death in U937 cells, which is correlated with the phosphorylation of the V-Jun sarcoma virus 17 oncogene homolog (c-JUN) NH(2)-terminal kinase protein (JNK), the activation of caspases, the increase in B cell leukemia/lymphoma 2 (Bcl-2) associated X protein (Bax), the decrease in Bcl xL protein (Bcl-XL) levels, the loss of mitochondria membrane potential and the release of cytochrome c.
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Is serum acid sphingomyelinase upregulated in chronic hepatitis C infection and non alcoholic fatty liver disease?
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Sphingolipids constitute bioactive molecules with functional implications in homeostasis and pathogenesis of various diseases. However, the role of sphingolipids as possible disease biomarkers in chronic liver disease remains largely unexplored. In the present study we used mass spectrometry and spectrofluorometry methods in order to quantify various sphingolipid metabolites and also assess the activity of an important corresponding regulating enzyme in the serum of 72 healthy volunteers as compared to 69 patients with non-alcoholic fatty liver disease and 69 patients with chronic hepatitis C virus infection. Our results reveal a significant upregulation of acid sphingomyelinase in the serum of patients with chronic liver disease as compared to healthy individuals (p<0.001). Especially in chronic hepatitis C infection acid sphingomyelinase activity correlated significantly with markers of hepatic injury (r=0.312, p=0.009) and showed a high discriminative power. Accumulation of various (dihydro-) ceramide species was identified in the serum of patients with non-alcoholic fatty liver disease (p<0.001) and correlated significantly to cholesterol (r=0.448, p<0.001) but showed a significant accumulation in patients with normal cholesterol values as well (p<0.001). Sphingosine, a further bioactive metabolite, was also upregulated in chronic liver disease (p<0.001). However, no significant correlation to markers of hepatic injury was identified.
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This study aimed to test single and double deviance-related modulations of the middle latency response (MLR) and the applicability of the optimum-2 multi-feature paradigm. The MLR and the MMN to frequency, intensity and double-feature deviants of an optimum-2 multi-feature paradigm and the MMN to double-feature deviants of an oddball paradigm were recorded in young adults. Double deviants elicited significant enhancements of the Nb and Pb MLR waves compared with the waves elicited by standard stimuli. These enhancements equalled approximately the sum of the numerical amplitude differences elicited by the single deviants. In contrast, the MMN to double deviants did not show such additivity. MMNs elicited by double deviants of the multi-feature and the oddball paradigm showed no significant difference in amplitude or latency.
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Does prevalence and correlate of high-quality basic pediatric preventive care?
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The list of recommended pediatric preventive services has grown considerably in the past decade, and clinician variability, clinician distribution, and other correlates of provision of these basic preventive services (BPS) are not known. To describe the proportion of high-quality basic pediatric preventive services, exclusive of immunizations, reported by parents and to identify sociodemographic and health system predictors and health service correlates of provision of these services. The study used cross-sectional data on 2041 children, 4 to 35 months of age, in the 2000 National Survey of Early Childhood Health. The BPS measure assesses the receipt of (1) developmental assessment, (2) injury prevention counseling, (3) screening for parental smoking, (4) guidance on reading to the child, and (5) guidance on 14 other topics (assessed as a composite score). The BPS scale categorizes the receipt of services as excellent, good, fair, or poor. Most children received excellent (34.9%) or good (31.5%) care, but many received fair (24.9%) or poor (8.7%) care. Sociodemographic and health care factors such as race/ethnicity, insurance, and practice setting were not associated with BPS levels. Higher BPS scores were associated with parental reports of longer well-child visits, more counseling regarding family and community risk factors, lower rates of delayed or missed care, and greater satisfaction.
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The testing of anticancer compounds in vitro is usually performed in hyperglycaemic cell cultures, although many tumours and their in vivo microenvironments are hypoglycaemic. Here, we have assessed, in cultures of tumour cells, the effects of reduced glucose levels on resistance to anticancer drugs and investigated the underlying cellular mechanisms. PIK3CA mutant (AGS, HGC27), and wild-type (MKN45, NUGC4) gastric cancer cells were cultured in high-glucose (HG, 25 mM) or low-glucose (LG, 5 mM) media and tested for sensitivity to two cytotoxic compounds, 5-fluorouracil (5-FU) and carboplatin, the PI3K/mTOR inhibitor, PI103 and the mTOR inhibitor, Ku-0063794. All cells had increased resistance to 5-FU and carboplatin when cultured in LG compared with HG conditions despite having similar growth and cell cycle characteristics. On treatment with PI103 or Ku-0063794, only the PIK3CA mutant cells displayed increased resistance in LG conditions. The PIK3CA mutant LG cells had selectively increased p-mTOR, p-S6, p-4EBP1, GLUT1 and lactate production, and reduced reactive oxygen species, consistent with increased glycolysis. Combination analysis indicated PI103 and Ku-0063794 were synergistic in PIK3CA mutant LG cells only. Synergism was accompanied by reduced mTOR signalling and increased autophagy.
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Is pre-hypertension a common phenomenon : national database study?
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Recently the Joint National Committee (7th report) introduced the term "pre-hypertension." Little is known on its prevalence in the general population. To assess the prevalence of pre-hypertension in a large national cohort. We analyzed the database of all > or = 18 year old members of Leumit Health Services, one of the four health management organizations in Israel, from which we retrieved the recorded blood pressure levels. Pre-hypertension was defined according to the JNC-7 criteria. Of the 426,033 subjects 18.6% had a diagnosis of hypertension or used antihypertensive medications. Only 40.8% of the other 346,799 subjects had had their BP measured in the preceding 2 years. BP recording rates were higher in females than in males (45.1% vs. 36.3%) and higher in elderly subjects than in young subjects (56% aged 66-75 years vs. 32% aged 18-25). Pre-hypertension was observed in 80,625 (23.2%) of the 346,799 while only 56,113 (16.2%) had normal BP records. The prevalence of pre-hypertension increased with age (13.3% aged 18-25 vs. 44.8% aged 66-75), and was more prevalent in men than in women (24.0% vs. 22.5%).
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Rheumatoid arthritis (RA) is characterized by synovial inflammation with local accumulation of mononuclear cells such as macrophages and lymphocytes. We previously demonstrated that intra-articular glucocorticoids decrease the synovial tissue (ST) T-cell population and therefore aimed to investigate whether this is mediated through modulation of apoptosis. Apoptosis and cell phenotype were evaluated by immunohistochemistry and dual-immunofluorescence in synovial biopsy sections from 12 RA patients before and after a mean of 11 days of an intra-articular triamcinolone knee injection. In vitro, RA synovial fluid (SF)-derived T cells were evaluated for Annexin V expression by multicolor flow cytometry after 24-hour exposure to dexamethasone, methylprednisolone, or triamcinolone. We also tested induction of apoptosis by dexamethasone on psoriatic arthritis SF-derived T cells using the same method. Intra-articular glucocorticoids reduced ST T cells but not macrophage number. ST apoptosis levels were unchanged following treatment, virtually absent from lymphoid aggregates, and minimal in CD3+ cells both before and after treatment. RA SF T cells were resistant to glucocorticoid-induced apoptosis when cultured in the presence of monocytes but were rendered sensitive to all three tested compounds upon SF isolation. Furthermore, transwell coculture of monocytes and T cells demonstrated that soluble factor(s) and not cellular contact are essential for T-cell resistance to glucocorticoid-mediated apoptosis. This feature is RA-specific as far as dexamethasone-induced apoptosis in nonisolated SF T cells obtained from psoriatic arthritis patients is concerned.
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Does nox4 mediate the expression of plasminogen activator inhibitor-1 via p38 MAPK pathway in cultured human endothelial cells?
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Plasminogen Activator Inhibitor-1 (PAI-1) is the most potent endogenous inhibitor of fibrinolysis which is implicated in the pathogenesis of myocardial infarction and metabolic syndrome. The formation of reactive oxygen species (ROS) plays an important role in the pathology of vascular disorders and has been shown to increase PAI-1 expression by endothelial cells. Growing evidence indicates that NADPH oxidase and in particular the constitutively active Nox4-p22(phox) complexes are major sources of ROS in endothelial cells. The aim of the present study was to characterize the role of NADPH oxidase and in particular Nox4 in the regulation of PAI-1 expression in cultured Human Umbilical Venous Endothelial Cells (HUVECs). N-acetylcysteine (NAC, scavenger of ROS), diphenylene iodonium chloride (DPI, inhibitor of flavoproteins), M40403 (superoxyde dismutase mimic) and S17834 (inhibitor of NADPH oxidase) inhibited PAI-1 release and promoter activity in HUVECs. Specific knock down of Nox4 mRNA by siRNA caused a decrease in ROS production and NADPH oxidase activity. Moreover, Nox4 silencing decreased PAI-1 expression, release and activity as well as p38 MAPK pathways and NFkappaB activation. These signalling pathways are also involved in PAI-1 release.
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There is a need to improve the prediction of outcome following acquired brain injury. The previous focus has been on specifying the relative contribution of such variables as pre-morbid intellectual ability, socioeconomic status, severity of injury and performance on neuropsychological assessments. To date, findings remain discrepant and often inconclusive. The present study examined whether dynamic assessment testing scores predict outcome. Both standard and dynamic assessment of 77 individuals with acquired brain injury was performed. Dynamic assessment identifies the learning potential of the individual, rather than measuring their statically assessed cognitive ability. The individual's potential to learn the Wisconsin Card Sorting Task (WCST), with guided instruction and feedback, was assessed and compared with standardized static measures. Using Rasch analysis, individual learning potential was determined and, unlike the standard WCST scores, was predictive of integration into the community following brain injury.
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Is hospital treatment in residential care facilities a viable alternative to hospital admission for selected patients?
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To determine if hospital treatment in residential care facilities, led by a geriatric team, might be a viable alternative to inpatient admission for selected patients. Case series with a new intervention were compared with historical controls receiving the conventional treatment. Treatment in residential care facilities (TRC) by the Residential Care Intervention Program in The Elderly (RECIPE) service was compared against the conventional treatment group, aged care unit (ACU) inpatients. A total of 95 patients in TRC and 167 patients in ACU were included. The mean Charlson Comorbidity Index score was 7 in both groups and demographics were similar, except more patients in the TRC group had dementia. Palliative care support was provided to 35.8% in the TRC group, compared with 7.8% in ACU, P < 0.001. Six-month mortality rates were similar at 30% for both groups. Rehospitalization rates at 6 months were similar at 41% for both groups. Length of care was significantly shorter for TRC (mean 2 days) compared with ACU (mean 11 days), P < 0.001.
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Although decidual natural killer (NK) cell accumulation and vascular remodeling are critical steps to ensure successful pregnancy, the molecular mechanisms controlling these events are poorly defined. Herein we analyzed whether chemerin, a recently identified chemoattractant involved in many pathophysiological processes, could be expressed in the uterine compartment and could regulate events relevant for the good outcome of pregnancy. Chemerin expression in human primary culture of stromal (ST) cells, extravillous trophoblast cells, and decidual endothelial cells (DEC) was analyzed by RT-PCR, ELISA, and Western blot. Migration through ST or DEC of peripheral blood and decidual (d) NK cells from pregnant women was performed using a transwell assay. A DEC capillary-like tube formation assay was used to evaluate endothelial morphogenesis. Chemerin is differentially expressed by decidual cells during early pregnancy being present at high levels in ST and extravillous trophoblast cells but not in DEC. Notably, ST cells from pregnant women exhibit and release higher levels of chemerin as compared with ST cells from menopausal or fertile nonpregnant women. Chemerin can support peripheral blood NK cell migration through both DEC and ST cells. Although dNK cells exhibit lower chemerin receptor (CMKLR1) expression than their blood counterpart, CMKLR1 engagement on dNK cells resulted in both ERK activation and migration through decidual ST cells. Interestingly, DEC also express CMKLR1 and undergo ERK activation and capillary-like tube structure formation upon exposure to chemerin.
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Does transcriptome analysis of Termitomyces albuminosus reveal the biodegradation of lignocellulose?
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To study whether Termitomyces albuminosus can degrade lignocelluloses and to understand the symbiotic relationship between termite mushroom and fungus-growing termite. cDNA library of T. albuminosus was sequenced by the Roche 454 GS FLX Titanium platform, and the diverse enzymes relevant to degradation of cellulose and lignin of symbiotic fungus T. albuminosus were analyzed. Eighth sequencing run resulted in a total of 82386 reads (express sequence tags, EST). After removing the vector and primer sequences, the remained 54410 reads were assembled into 3301 contigs and 3193 singletons. Comparing sequence similarity with known proteins, these sequences, representing approximately 2681 unique genes, were successfully annotated using BLAST searches (E-value < or = 1e(-10)) against the Nr, SwissProt and CDD databases. The T. albuminosus transcripts included 33 enzymes putatively involved in cellulose and hemicelluloses biodegradation. 5 enzymes could hydrolyze cellulose and others had catalytic activities for degradation of hemicelluloses, starch and glycogen and chitin. Moreover, four genes encoding laccases and a single aryl-alcohol oxidase which could degrade lignin were also identified. These results revealed symbiosis fungus T. albuminosus had many laccases and possibly decomposed phenolic compounds from plant litter.
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The balance between endothelial injury and repair in childhood is poorly understood. We examined this relationship in healthy children, in adults, and in children with familial hypercholesterolemia (FH). Circulating endothelial cells (CECs) were measured as a marker of vascular injury, with vascular repair assessed by counting colony-forming units (CFUs), also known as endothelial progenitor cells. CEC number increased with age. Children with FH had elevated CECs as compared with healthy children, with similar levels numerically to those found in healthy adults. CFU numbers were higher in healthy children than either healthy adults or children with FH. Endothelium-dependent vascular function, measured by flow-mediated dilatations, was positively associated with CFU number, even after adjustment for confounding risk variables.
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Do obese hypertensive men have plasma concentrations of C-reactive protein similar to that of obese normotensive men?
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Low-grade chronic inflammation is a characteristic feature of obesity, the most important lifestyle risk factor for hypertension. Elevated plasma concentrations of the inflammatory biomarker C-reactive protein (CRP) are associated with an increased risk of hypertension, but elevated plasma CRP concentrations are also closely associated with obesity. It is uncertain whether CRP is directly involved in the pathogenesis of hypertension or is only a marker of other pathogenic processes closely related to obesity. We studied 103 obese men (body mass index (BMI) ≥ 30.0 kg/m(2)); 63 of these men had 24-hour ambulatory blood pressure (ABP) ≥ 130/80 mm Hg and comprised the obese hypertensive (OHT) group. The 40 remaining obese men had 24-hour ABP < 130/80 mm Hg and comprised the obese normotensive (ONT) group. Our control group comprised 27 lean normotensive (LNT) men. All participants were medication-free. We measured plasma CRP concentrations with a high-sensitivity assay and determined body composition by dual energy x-ray absorptiometry scanning. There were no differences in anthropometric measures (BMI, waist circumference, or total fat mass percentage) between OHT and ONT groups (P ≥ 0.08). The obese groups had higher CRP concentrations than the LNT group (OHT: median = 2.30, interquartile range (IQR) = 1.10-4.10mg/L; ONT: median = 2.55, IQR = 1.25-4.80 mg/L; LNT: median = 0.60, IQR = 0.30-1.00 mg/L; P < 0.001), but there was no difference in CRP concentrations between OHT and ONT groups (P = 1.00). In the obese men, CRP was not correlated with either 24-hour systolic (r = 0.04; P = 0.71) or 24-hour diastolic ABP (r = -0.03; P = 0.78).
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Our objective was to determine whether paclitaxel-induced apoptosis in human lung cancer cells is Fas dependent. Human lung cancer cell lines were evaluated for morphologic evidence of apoptosis, DNA fragmentation (TUNEL positivity), and caspase-3 activation after paclitaxel treatment. Human lung adenocarcinoma, squamous cell carcinoma, undifferentiated lung carcinoma, and bronchoalveolar carcinoma cell lines were each cultured in 10 micromol/L paclitaxel. After 24 hours of culture in paclitaxel, a 22% to 69% increase in the number of apoptotic cells was evident by means of methylene blue-azure A-eosin staining with characteristic blebbing and nuclear condensation. TUNEL assay also confirmed an increase of 19.9% to 73.0% of cells with nuclear fragmentation. Caspase-3 activity, assayed by Z-DEVD cleavage, increased from 20% to 215% (P <.05). ZB4, an antagonistic anti-Fas antibody, did not block paclitaxel induction of caspase-3 activity (155.8 vs 165.8 U, not significant). Apoptotic morphologic changes were inhibited in cells cultured in the presence of paclitaxel and Ac-DEVD-CHO, a caspase-3 inhibitor.
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Does information compression exploit patterns of genome composition to discriminate populations and highlight regions of evolutionary interest?
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Genomic information allows population relatedness to be inferred and selected genes to be identified. Single nucleotide polymorphism microarray (SNP-chip) data, a proxy for genome composition, contains patterns in allele order and proportion. These patterns can be quantified by compression efficiency (CE). In principle, the composition of an entire genome can be represented by a CE number quantifying allele representation and order. We applied a compression algorithm (DEFLATE) to genome-wide high-density SNP data from 4,155 human, 1,800 cattle, 1,222 sheep, 81 dogs and 49 mice samples. All human ethnic groups can be clustered by CE and the clusters recover phylogeography based on traditional fixation index (FST) analyses. CE analysis of other mammals results in segregation by breed or species, and is sensitive to admixture and past effective population size. This clustering is a consequence of individual patterns such as runs of homozygosity. Intriguingly, a related approach can also be used to identify genomic loci that show population-specific CE segregation. A high resolution CE 'sliding window' scan across the human genome, organised at the population level, revealed genes known to be under evolutionary pressure. These include SLC24A5 (European and Gujarati Indian skin pigmentation), HERC2 (European eye color), LCT (European and Maasai milk digestion) and EDAR (Asian hair thickness). We also identified a set of previously unidentified loci with high population-specific CE scores including the chromatin remodeler SCMH1 in Africans and EDA2R in Asians. Closer inspection reveals that these prioritised genomic regions do not correspond to simple runs of homozygosity but rather compositionally complex regions that are shared by many individuals of a given population. Unlike FST, CE analyses do not require ab initio population comparisons and are amenable to the hemizygous X chromosome.
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The antiangiogenic agent cilengitide disrupts integrin binding to the extracellular matrix leading to apoptosis of activated endothelial cells. Integrins are also widely expressed in malignant glioma and integrin inhibitors may directly target tumor cells in this disease. Aim of the current study was to investigate effects of cilengitide on endothelial and glioma cells on molecular and cellular levels. Cilengitide caused dose-dependent detachment of endothelial cells from cell culture dishes. Proliferation of endothelial cells was significantly inhibited while the proportion of apoptotic cells was increased. Incubation of integrin-expressing glioma cells with cilengitide caused rounding and detachment after 24 hours as observed with endothelial cells. Cilengitide inhibited proliferation and induced apoptosis in glioma cells with methylated MGMT promotor when given alone or in combination with temozolomide. In endothelial as well as glioma cells cilengitide inhibited phosphorylation of FAK, Src and Akt. Assembly of cytoskeleton and tight junctions was heavily disturbed in both cell types.
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Does resveratrol prevent neuronal apoptosis in an early brain injury model?
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Resveratrol has been shown to attenuate cerebral vasospasm after subarachnoid hemorrhage (SAH); however, no study has explored its neuroprotective effect in early brain injury (EBI) after experimental SAH. The aim of this study was to evaluate the antiapoptotic function of resveratrol in EBI and its relationship with the PI3K/Akt survival pathway. Experimental SAH was induced in adult male rats by prechiasmatic cistern injection. Control and SAH rats were divided into six groups and treated with low (20 mg/kg) or high (60 mg/kg) concentrations of resveratrol with or without LY294002 cotreatment. Brain samples of the rats were analyzed by immunohistochemistry, immunofluorescence staining, Western blotting, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) apoptosis assays. High-concentration but not low-concentration resveratrol treatment in SAH rats led to a significant increase in phosphorylated Akt (p-Akt) protein levels compared with SAH rats without treatment. In addition, p-Akt-positive cells mainly colocalized with NeuN-positive cells. Neuronal apoptosis in SAH rat brain was attenuated by high-concentration resveratrol treatment. The antiapoptotic effect of resveratrol in SAH rats could be partially abrogated by the PI3K/Akt signaling inhibitor LY294002.
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Cadmium exposure was found to cause a decline in lung function among the general population, but these findings were limited to smokers and gender differences were not explored. To examine the relationship between cadmium and chronic obstructive pulmonary disease (COPD) according to gender and smoking status in Korea. Cross-sectional data from the Korean National Health and Nutrition Examination Survey from 2008 to 2011 were analyzed. COPD was defined by a pre-bronchodilator forced expiratory volume in 1s divided by forced vital capacity of <0.70. A logistic regression model was used to elucidate the association between blood cadmium levels and COPD according to gender and smoking status. Among 3861 eligible participants, 3622 were included in the analysis. The prevalence of COPD demonstrated an increasing trend in males (P for trend<0.001), but not in females (P for trend=0.67). After adjusting for covariates, a higher blood cadmium level, but within the normal range, was associated with COPD in males, including those who had never-smoked (P for trend <0.001 and P for trend=0.008). However, a higher blood cadmium level was not significantly associated with COPD in females, including those who had never smoked (P for trend=0.39 and P for trend=0.43).
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Does [ Inconsistency of the Epworth sleepiness scale result with the polysomnography findings in patients with sleep-disordered breathing ]?
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This study aims to investigate the consistency of Epworth sleepiness scale (ESS) results and polysomnography (PSG) findings in the patients with sleep-disordered breathing (SDB). A total of 109 patients (68 males, 41 females; mean age 48.6 years; range 20 to 77 years) who were admitted with the complaints of apnea, witnessed apnea and daytime sleepiness were included. The correlation among age, body mass index (BMI), and ESS and PSG findings were assessed. There was a positive and statistically significant correlation between the age and apnea-hypopnea index (AHI) (p<0.01). We observed that AHI figures increased with increasing age. There was also a positive and statistically significant correlation between the BMI and AHI (p<0.05). We found that AHI increased in parallel with BMI increase. There was, no statistically significant correlation among the AHI results based on the ESS assessment, the percentage of sleep under 90% of saturation, and the Arousal index (AI).
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Cell-to-cell interaction is thought to be an important feature of a variety of biological processes. As far as the proinflammatory process is concerned, the interaction between mesangial cells and monocytes/macrophages induces the expression of monocyte chemoattractant protein-1 (MCP-1), and this may play a role in glomerulonephritis. In this study, we investigated whether the cell-to-cell interaction between immune cells and renal fibroblasts induces MCP-1 gene expression, which may be involved in interstitial inflammation in the kidney. Human renal fibroblast cell lines, tNKF (from a normal kidney) and tFKIF (from a kidney with fibrosis), and peripheral blood mononuclear cells (PBMC) were used to assess the effect of cell-to-cell contact on the expression of MCP-1 mRNA in the fibroblasts. The expression of the MCP-1 gene in the fibroblasts was also examined after stimulation with tumor necrosis factor-alpha (TNF-alpha) and the culture supernatant from PBMC. RT-PCR was used to detect MCP-1 mRNA expression. Neutralizing antibodies to intercellular adhesion molecule-1 (ICAM-1) and vascular endothelial adhesion molecule-1 (VCAM-1) were used to block the cell-to-cell contact between the fibroblasts and PBMC. TNF-alpha and the culture supernatant from PBMC increased MCP-1 gene expression in tNKF cells. Contact culture with PBMC also significantly increased MCP-1 gene expression in tNKF cells. Although the basal level of MCP-1 mRNA was higher in tFKIF than tNKF cells, tFKIF cells did not respond significantly to any stimulation in this study. Following pretreatment with anti-ICAM-1 antibody, MCP-1 gene expression in tNKF cells was significantly suppressed in contact culture with PBMC. Anti-VCAM-1 antibody treatment had no effects.
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Do exosome-like Extracellular Vesicles from MYCN-amplified Neuroblastoma Cells Contain Oncogenic miRNAs?
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In recent years, evidence has accumulated indicating that both normal and cancer cells communicate via the release and delivery of macromolecules packed into extracellular membrane vesicles. We isolated nano-sized extracellular vesicles from MYCN-amplified neuroblastoma cell lines using ultracentrifugation and exosome precipitation (Exoquick) protocols. These vesicles were characterized by transmission electron microscopy (TEM), nanoparticle tracking analysis and western blotting. Exosomal miRNA profiles were obtained using a reverse transcription-polymerase chain reaction (RT-PCR) ready-to-use panel measuring a total of 742 miRNAs. In this study, we showed that MYCN-amplified neuroblastoma cell lines secrete populations of miRNAs inside small exosome-like vesicular particles. These particles were shown to be taken-up by recipient cells. By profiling the miRNA content, we demonstrated high expression of a group of established oncomirs in exosomes from two MYCN-amplified neuroblastoma cell lines. Despite the fact that other studies have demonstrated the ability of exosomal miRNAs both to repress mRNA targets and to stimulate Toll-like receptor-8 (TLR8) signaling in recipient cells, we did not observe these effects with exosomes from MYCN-amplified neuroblastoma cells. However, functional enrichment analysis reveals that mRNA targets of highly expressed exosomal miRNAs are associated with a range of cellular and molecular functions related to cell growth and cell death.
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Atherosclerosis is a complex, chronic disease that usually arises from the converging action of several pathogenic processes, including hypertension, hyperlipidemia, obesity, and the accumulation of oxidized LDL. Platelet-activating factor acetylhydrolase (PAF-AH) is a LDL- and HDL-bound enzyme that hydrolyzes and inactivates PAF and prevents LDL-cholesterol oxidation, thus delaying the onset of atherosclerotic disease. We evaluated the relationship between variants of the PAF-AH gene polymorphisms Arg92His, Ile198Thr, and Ala379Val and the presence of carotid atherosclerosis in 190 hypercholesterolemic Sicilian individuals. Carotid artery intima-media wall thickness (IMT) was measured as an indicator of early atherosclerotic disease. The participants were classified according to having normal (< or =1 mm) or abnormal (> or =1 mm) IMT and were also investigated for physical characteristics and biochemical indices, including PAF-AH activity. PAF-AH activity and LDL concentrations were significantly correlated in hypercholesterolemic patients, but plasma PAF-AH activity and HDL were not significantly correlated in either IMT group. No significant differences were detected among the PAF-AH gene polymorphisms in both groups after correction for age, sex, body mass index, plasma glucose and lipid concentrations, PAF-AH activity, blood pressure, and smoking habits. The analysis of PAF-AH genotype distribution showed no significant differences in percentage of 92, 198, and 379 genotypes in both IMT groups.
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Does multidisciplinary care improve amputation-free survival in patients with chronic critical limb ischemia?
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This study was conducted to quantify the effect of multidisciplinary care (MDC) on amputation-free survival (AFS) and wound healing within a chronic critical limb ischemia (CLI) population. We performed a retrospective, single-center cohort study of consecutive CLI patients presenting to the Vascular Surgery Service. Patients who received initial and follow-up wound care from the MDC were compared with patients who received standard wound care (SWC). The MDC team consisted of vascular, plastic, and podiatric surgeons who jointly managed wound care and directed any other consults or services as deemed necessary. SWC consisted of an inconsistent mix of providers without a defined manager, including nurses, wound care midlevel providers, general surgeons, internists, or the patients themselves. The referring physician determined the allocation of patients. The primary outcome variable was AFS, with a secondary evaluation of wound healing. The effects of baseline demographics, comorbid medical conditions, laboratory values, ischemic lesion severity and location, Rutherford classification, and participation in MDC were assessed. Significant univariate predictors (P < .10) of AFS were entered into a multivariate Cox regression model and assessed at an α = .05. Between August 2010 and June 2012, 146 CLI patients (91 male [63%]) were evaluated by the Vascular Surgery Service and were followed up for a median of 539 days (interquartile range 314-679 days). Ischemic tissue loss was present in 85 patients (38 at Rutherford category 5, and 47 at Rutherford category 6). Within this cohort, 51 (60%) had MDC, and 34 (40%) had SWC. Fifty-eight patients (68%) underwent revascularization (open in 17, endovascular in 35, and hybrid in 6), 14 (8%) were managed with primary major amputation, and 13 (15%) declined revascularization. AFS was superior for patients in the MDC arm vs the SWC arm (593.3 ± 53.5 days vs 281.0 ± 38.2 days; log-rank, P = .02). Wound-healing times favored the MDC arm over the SWC arm (444.5 ± 33.2 days vs 625.2 ± 126.5 days), although this was not statistically significant (log-rank, P = .74). Multivariate modelling revealed that independent predictors of major amputation or death, or both, were nonrevascularized patients (hazard ratio [HR], 3.76; 95% confidence interval [CI], 1.78-8.02; χ(2), P < .01), treatment by SWC (HR, 2.664; 95% CI, 1.23-5.77; χ(2), P = .012), and baseline nonambulatory status (HR, 1.89; 95% CI, 1.17-2.85; χ(2), P < .01).
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The hepatitis B virus (HBV) pol gene overlaps the S gene encoding surface antigen (HBsAg). It has been reported previously that drug-induced changes in HBsAg alter its binding to sera from humans immunized against HBV. We investigate here the changes to specific epitopes in the a determinant (the major target of neutralizing antibody) caused by a number of drug-resistant mutations. Recombinant HBsAgs, produced by transfection of Chinese hamster ovary cells with S gene plasmids into which lamivudine, adefovir and entecavir resistance and common antibody-escape mutations had been introduced, were probed with monoclonal antibodies to epitopes in the first and second loops of the a determinant. The mutations rtF166L/sF158Y (lamivudine-associated, compensatory) and rtl169T/sF161L (entecavir-associated, primary) acting alone, and the mutations rtV173L/sE164D (lamivudine-associated, compensatory) and rtSilent/sD144E (antibody escape-associated) each when combined with rtM204V/sl195M (lamivudine-associated, primary) led to decreases in antibody reactivity to epitopes in the first or second loop, or in both loops. The rtM204V/sl195M + rtV173L/sE164D mutations yielded an epitope-antibody profile similar to the rtR153Q/sG145R vaccine escape mutant. The rtM204V/sl195M mutation combined with the rtF166L/sF158Y or rtR153Q/sG145R mutation restored reactivity to second-loop epitopes previously abrogated by single mutations.
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Do wedge and needle liver biopsies show discordant histopathology in morbidly obese patients undergoing Roux-en-Y gastric bypass surgery?
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Controversy exists over whether or not single-needle liver biopsies are sufficient to compare histological parameters in patients with non-alcoholic fatty liver disease. To identify sampling variability, we biopsied four liver specimens per patient, based on biopsy size (needle vs wedge) and location (left vs right lobe), immediately prior to bariatric Roux-en-Y gastric bypass surgery. Ten prospectively enrolled, morbidly obese patients underwent 40 laparoscopy-guided biopsies; two needle and two wedge from each of 16 left and 16 right liver lobes. The Kappa coefficient for concordance compared histological parameters from left and right lobe needle- and wedge biopsies. Wedge biopsies were considered our 'Gold Standard'. Each patient had two wedge- and two needle liver biopsies. Kappa concordance between all needle and wedge biopsies from right and left lobes showed variability. Wedge- and needle liver biopsies from contralateral lobes had higher concordance with each other, compared to ipsilateral needle/wedge biopsy pairs. Contralateral wedge pairs had higher concordance than contralateral needle/needle pairs. There were no biopsy complications.
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Neurovirulent Venezuelan equine encephalitis virus (VEEV) causes lethal encephalitis in equines and is transmitted to humans by mosquitoes. VEEV is highly infectious when transmitted by aerosol and has been developed as a bio-warfare agent, making it an important pathogen to study from a military and civilian standpoint. Molecular mechanisms of VEE pathogenesis are poorly understood. To study these, the gene expression profile of VEEV infected mouse brains was investigated. Changes in gene expression were correlated with histological changes in the brain. In addition, a molecular framework of changes in gene expression associated with progression of the disease was studied. Our results demonstrate that genes related to important immune pathways such as antigen presentation, inflammation, apoptosis and response to virus (Cxcl10, CxCl11, Ccl5, Ifr7, Ifi27 Oas1b, Fcerg1,Mif, Clusterin and MHC class II) were upregulated as a result of virus infection. The number of over-expressed genes (>1.5-fold level) increased as the disease progressed (from 197, 296, 400, to 1086 at 24, 48, 72 and 96 hours post infection, respectively).
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Is lower air temperature associated with ambulance transports and death in Takamatsu area , Japan?
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The aim of this study was to investigate the linkage among ambulance transports, the number of death and air temperature in Takamatsu area, Japan. Monthly data of ambulance transports (total and acute disease) and the number of death from 2004 to 2012 were obtained from Fire Department Service in Takamatsu and Takamatsu city official website, Japan. Climate parameters for required period were also obtained from Japan Meteorological Agency. Population data in Takamatsu area were also used to adjust ambulance transports and the number of death. The linkage among ambulance transports, the number of death and climate parameters was evaluated by ecological analysis. Total ambulance transports (/a hundred thousand people/day) and ambulance transports due to acute disease (/a hundred thousand people/day) were 12.3 ± 0.9 and 6.8 ± 0.7, respectively. The number of death (/a hundred thousand people/day) was 2.5 ± 0.4. By quadratic curve, ambulance transports due to acute disease and the number of death were significantly correlated with the parameters of air temperature. However, the number of death was the highest in January and the lowest in August.
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Proliferative vitreoretinopathy (PVR) is a blinding disorder that develops after a retinal tear or detachment. Activation of the retinal pigmented epithelium (RPE) is implicated in PVR; however, the mechanisms leading to enhanced RPE proliferation, migration, and contraction remain largely unknown. This study utilized an in vitro model of PVR to investigate the role of acetylation in RPE activation and its contribution to the progression of this disease. ARPE-19 cells, primary cultures of porcine RPE, and induced pluripotent stem cell-derived RPE (iPS-RPE) were utilized for cellular and molecular analyses. Cells treated with transforming growth factor beta 2 (TGFβ2; 10 ng/mL) alone or in the presence of the broad-spectrum histone deacetylase (HDAC) inhibitor, trichostatin A (TSA; 0.1 μM), were assessed for contraction and migration through collagen contraction and scratch assays, respectively. Western blotting and immunofluorescence analysis were performed to assess α-smooth muscle actin (α-SMA) and β-catenin expression after TGFβ2 treatment alone or in combination with TSA. TGFβ2 significantly increased RPE cell contraction in collagen matrix and this effect was inhibited in the presence of TSA (0.1 μM). In agreement with these data, immunofluorescence analysis of TSA-treated iPS-RPE wounded monolayers revealed decreased α-SMA as compared with control. Scratch assays to assess wound healing revealed TSA inhibited TGFβ2-mediated iPS-RPE cell migration.
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Does human papillomavirus found in sperm head of young adult males affect the progressive motility?
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To evaluate the prevalence of human papillomavirus (HPV) sperm infection and its correlation with sperm parameters in a cohort of young adult males. Cross-sectional clinical study. Andrology and Microbiology sections at a university hospital. A cohort of 200 young adult male volunteers (18 years old), 100 with previous sexual intercourse and 100 without previous sexual intercourse. Seminal parameters, sperm culture for HPV and fluorescence in situ hybridization (FISH) analysis for HPV detection in the sperm head. Statistical analysis was performed with a two-tailed Student's t-test. Results of HPV investigation were compared to sperm parameters and results of FISH analysis. HPV infection was present in sperm cells of 10 subjects among those 100 young adults who already had unprotected intercourse and its presence was associated with reduced sperm motility. Furthermore, infected samples showed that about 25% of sperm had an HPV DNA positivity at the head site, but it is unclear whether it was integrated in the nucleus or not.
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Both in experimental colitis and in inflammatory bowel disease, colonic eicosanoid generation is enhanced and may contribute to the pathogenesis of the inflammatory response. To evaluate the effect of selective cyclo-oxygenase-2 (COX-2) inhibitors on the extent and severity of two models of experimental colitis. Colitis was induced by intra-caecal administration of 2 ml 5% acetic acid or intra-colonic administration of 0.1 ml 3% iodoacetamide. Rats were treated intra-gastrically with nimesulide 2 x 10 mg/kg/day, or once with SC-236 6 mg/kg, and killed 1 or 3 days after damage induction. The colon was isolated, weighed, macroscopic damage was measured, and mucosal samples were obtained for histology and for determination of myeloperoxidase (MPO) and nitric oxide synthase (NOS) activities and eicosanoid generation. The serum levels of thromboxane B2 (TXB2), tumour necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) were determined. Nimesulide significantly decreased the extent of colitis induced by acetic acid. Both nimesulide and SC-236 significantly decreased the extent of iodoacetamide-induced colonic damage. The decrease in the extent of colitis induced by nimesulide was accompanied by a significant decrease in mucosal MPO and NOS activities. Nimesulide and SC-236 decreased the enhanced colonic eicosanoid generation in acetic acid and iodoacetamide-induced colitis, and, in iodoacetamide-treated rats, nimesulide also decreased the elevated serum TNF-alpha and IL-1beta levels.
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Does menstrual cycle influence on pain and emotion in women with fibromyalgia?
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This study examined the influence of the menstrual cycle on pain and emotion in women with fibromyalgia (FM) as compared with women with rheumatoid arthritis (RA) and to healthy controls. One hundred and twenty-five premenopausal women (21-45 years old) participated in this study (57 with FM, 20 with RA, and 48 controls). Pain and emotion assessments were conducted during the follicular and the luteal phases of the menstrual cycle. Women with FM experienced more pain, menstrual symptoms, and negative affect than did women with RA and the controls. All women reported less positive affect during the luteal phase, although this pattern was more pronounced in women with FM and RA than in controls.
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To identify the gene responsible for autosomal dominant lamellar pulverulent cataract in a four-generation British family and characterise the functional and cellular consequences of the mutation. Linkage analysis was used to identify the disease locus. The GJA8 gene was sequenced directly. Functional behaviour and cellular trafficking of connexins were examined by expression in Xenopus oocytes and HeLa cells. A 262C>A transition that resulted in the replacement of proline by glutamine (P88Q) in the coding region of connexin50 (Cx50) was identified. hCx50P88Q did not induce intercellular conductance and significantly inhibited gap junctional activity of co-expressed wild type hCx50 RNA in paired Xenopus oocytes. In transfected cells, immunoreactive hCx50P88Q was confined to the cytoplasm but showed a temperature sensitive localisation at gap junctional plaques.
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Do intraarticular corticosteroids decrease synovial RANKL expression in inflammatory arthritis?
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Intraarticular corticosteroids are frequently used as successful adjuvant therapy for inflammatory arthritides, but little is known about their effects on molecules that regulate bone biology. We undertook this study to investigate the effect of intraarticular corticosteroids on the synovial expression of RANKL and osteoprotegerin (OPG). We evaluated RANKL, OPG, and surface marker expression by immunohistochemical methods in synovial knee biopsy samples obtained from 13 patients with inflammatory arthritis before and 2 weeks following intraarticular injection of triamcinolone hexacetonide. We further investigated the effect of dexamethasone (DEX) on RANKL expression by lymphocytes from rheumatoid arthritis synovial fluids (RA SF), using flow cytometric analysis. Finally, we evaluated the in vitro effect of DEX on RANKL and OPG expression in osteoblast-like cells, by Western blotting. Intraarticular corticosteroids induced a decrease in the number of synovial T cells without influencing the number of macrophages, evaluated as both CD68+ and CD163+ cells. This change was paralleled by a decrease of synovial RANKL expression with a concomitant reduction of the RANKL:OPG ratio. DEX down-regulated RANKL expression on lymphocytes derived from RA SF. Moreover, in vitro pretreatment of osteoblast-like cells with tumor necrosis factor favored an antiresorptive effect of DEX treatment through a similar down-regulation of RANKL expression.
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The SAH gene locus has recently been proposed to be involved in obesity-related hypertension in Japanese individuals. To replicate independently the initial findings in another ethnic group, we scanned the entire SAH gene in 190 Caucasian chromosomes. A total of 651 patients with essential hypertension and 776 controls (PEGASE Study) were genotyped for all identified variants using allele-specific oligonucleotides, and single nucleotide polymorphism as well as haplotype analyses were carried out. We also performed transient transfection experiments, northern and western blots, immunoprecipitation, and acyl-coenzyme A synthetase activity assays. We identified five polymorphisms in the promoter region (C-1808T, G-1606A, -962ins/del, G-451A, T-67C), two in introns 5 and 7 (T+9/In5C, A+20/In7T), and one missense variant (K359N). Carriage of the -1606A allele was significantly associated with hypertension [odds ratio (OR) 1.28, P = 0.049] as was 359N (OR 1.35, P = 0.048) compared with non-carriers. Conversely, for -962del, the OR for hypertension was 0.80 (P = 0.042). The SAH alleles -1606A and 359N, but not -962ins/del, displayed a raising effect on body mass index (BMI; P = 0.004 and P = 0.030, respectively) in hypertensive as well as in control individuals. After adjustment for BMI in hypertensive individuals, only the OR associated with -962ins/del remained significant (OR 0.77, P = 0.028). Functional analyses in BHK did not reveal differences for SAH 359N or 359K-containing constructs, formally excluding K359N as the functional variant.
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Is activation of microglia within paraventricular nucleus of hypothalamus involved in maintenance of established hypertension?
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Inflammation within paraventricular nucleus of the hypothalamus (PVN), a key circulatory control center in the hypothalamus, is an important pathology of sympathetic hyperactivity. Brain inflammation is mainly mediated by microglia, innate immune cells in the brain. Activated microglia produce inflammatory cytokines with alteration of their morphology. Increase in inflammatory cytokines synthesis coincides with activation of microglia within PVN of angiotensin II-induced hypertensive model and myocardial infarction-induced heart failure model. Although the increase in inflammatory cytokines and the microglial activation within PVN were also seen in spontaneously hypertensive rats (SHR), the model of essential hypertension, their involvement in blood pressure regulation has still be fully clarified. In the present study, we examined whether activated microglia within PVN were involved in maintenance of established severe hypertension with sympathoexcitation. Minocycline (25mg/kg/day), an inhibitor of microglial activation, or vehicle were orally administered to stroke-prone SHR (SHRSP) and normotensive Wistar-Kyoto (WKY) rats for 2 weeks from 15-weeks-old, the age of established hypertension. Systolic blood pressure was comparable between minocycline treated-SHRSP and vehicle treated-SHRSP, whereas morphological analysis of microglia revealed smaller cell size in minocycline treated-SHRSP than vehicle treated-SHRSP, implying that minocycline deactivated microglia within PVN.
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To present the clinical aspects and treatment outcomes of Coats disease in Saudi Arabia. A retrospective chart review was performed of 92 patients (97 eyes) diagnosed with Coats disease at King Khalid Eye Specialist Hospital from 1983 to 2010. The most common presenting complaint was decreased visual acuity followed by strabismus and then leukocoria. Snellen visual acuity was 20/20 to 20/50 in 9 eyes (9%), 20/50 to 20/160 in 11 eyes (11%), 20/200-counting fingers in 29 eyes (30%), and hand motion to no light perception in 24 eyes (25%). Telangiectasia was located in the preequatorial area in 71 eyes (73%) and most commonly involved the temporal retina in 67 eyes (69%). In eyes with clear view to the fundus, quadrant involvement by telangiectasia had the following distribution: 1) quadrant (n = 36, 37%); 2) quadrants (n = 26, 27%); 3) quadrants (n = 8, 8%); and 4 quadrants (n = 15, 15%). Total retinal detachment was present at presentation in 28 eyes (29%) and neovascular glaucoma in 8 (8%). Based on the Shields classification, the eyes were Stage 1 (n = 1, 1%), Stage 2A (n = 7, 7%), Stage 2B (n = 23, 24%), Stage 3A1 (n = 26, 27%), Stage 3A2 (n = 12, 12%), Stage 3B (n = 16, 17%), Stage 4 (n = 11, 11%), and Stage 5 (n = 5, 1%). Stage 3A was the most commonly presented stage (39%). Primary management included cryotherapy (19%), laser photocoagulation (64%), intravitreal agents (9%), and surgical drainage (4%). Combination treatment was performed in 29% of eyes. Thirteen eyes (13%) were enucleated because of clinical suspicion of retinoblastoma or the presence of glaucoma. Factors that were associated with a poor visual outcome of 20/200 or worse included age less than 10 years (relative risk: 1.27), Stages 3 and 4 disease (relative risk: 1.40), presence of subretinal fluid in all 4 quadrants including the fovea (relative risk: 14.25), and initial visual acuity of 20/200 (relative risk: 6.72) or worse (P < 0.005 for all factors).
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Is body composition associated with multisite lower body musculoskeletal pain in a community-based study?
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Population-based studies suggest that pain in the lower body is common and that pain at multiple sites is more prevalent than single-site pain. Obesity is a risk factor for multisite musculoskeletal pain, but there are limited data on the role of body composition. Therefore, we sought to determine whether body composition is associated with multisite musculoskeletal pain involving the low back, knee, and foot. A total of 133 participants were recruited for a study examining the relationship between obesity and musculoskeletal disease. Participants completed validated questionnaires that examined levels of pain at the low back, knee, and foot. Body composition was assessed using dual-energy x-ray absorptiometry. Multisite pain was common, with 26.3% of participants reporting pain at 2 sites and 31.6% at 3 sites, and only 20% were pain free. The low back was the most common site of pain (63%). Greater fat mass and fat mass index, but not fat-free mass, were associated with pain at a greater number of sites, independent of age, gender, and fat-free mass (P < .01). Longitudinal studies exploring the mechanism of action by which increased fat mass is associated with pain may provide important insights into therapeutic strategies for the prevention of multisite pain.
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Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are active in cancer therapy. Mechanisms engaged during these clinical responses need to be determined. We reported previously that epidermal growth factor stimulation markedly increased cyclin D1 protein expression in human bronchial epithelial (HBE) cells, and this was opposed by chemoprevention with all-trans-retinoic acid. The current study sought to determine whether the EGFR TKI erlotinib repressed cyclin D1 protein expression in immortalized HBE cells, lung cancer cell lines, and clinical aerodigestive tract cancers. The BEAS-2B immortalized HBE cell line was exposed to varying concentrations of erlotinib, and effects on proliferation, cell cycle distribution, G1 cyclin expression, and cyclin D1 reporter activity were measured. Non-small-cell lung cancer cell lines were also evaluated for changes in proliferation and cyclin protein expression after erlotinib treatments. A proof of principle clinical trial was conducted. During this study, patients underwent a 9-day course of erlotinib treatment. Pretreatment and posttreatment tumor biopsies were obtained, and changes in candidate biomarkers were determined by immunostaining. Plasma pharmacokinetics and tumor tissue erlotinib concentrations were measured. Erlotinib, at clinically achievable dosages, repressed BEAS-2B cell growth, triggered G1 arrest, and preferentially reduced cyclin D1 protein expression and transcriptional activation. Erlotinib also preferentially repressed proliferation and cyclin D1 protein expression in responsive, but not resistant, non-small-cell lung cancer cell lines. This occurred in the presence of wild-type EGFR sequence at exons 18, 19, and 21. Five patients were enrolled onto an erlotinib proof of principle clinical trial, and four cases were evaluable. Pharmacokinetic studies established therapeutic erlotinib plasma levels in all patients, but tissue levels exceeding 2 micromol/L were detected in only two cases. Notably, these cases had pathological evidence of response (necrosis) in posttreatment biopsies as compared with pretreatment biopsies. In these cases, marked repression of cyclin D1 and the proliferation marker Ki-67 was detected by immunohistochemical assays. Cases without pathological response to erlotinib did not exhibit changes in cyclin D1 or Ki-67 immunohistochemical expression and had much lower erlotinib tissue levels than did responding cases.
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Do an analysis of the uncertainty and bias in DCE-MRI measurements using the spoiled gradient-recalled echo pulse sequence?
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The pharmacokinetic parameters derived from dynamic contrast-enhanced (DCE) MRI have been used in more than 100 phase I trials and investigator led studies. A comparison of the absolute values of these quantities requires an estimation of their respective probability distribution function (PDF). The statistical variation of the DCE-MRI measurement is analyzed by considering the fundamental sources of error in the MR signal intensity acquired with the spoiled gradient-echo (SPGR) pulse sequence. The variance in the SPGR signal intensity arises from quadrature detection and excitation flip angle inconsistency. The noise power was measured in 11 phantoms of contrast agent concentration in the range [0-1] mM (in steps of 0.1 mM) and in onein vivo acquisition of a tumor-bearing mouse. The distribution of the flip angle was determined in a uniform 10 mM CuSO4 phantom using the spin echo double angle method. The PDF of a wide range of T1 values measured with the varying flip angle (VFA) technique was estimated through numerical simulations of the SPGR equation. The resultant uncertainty in contrast agent concentration was incorporated in the most common model of tracer exchange kinetics and the PDF of the derived pharmacokinetic parameters was studied numerically. The VFA method is an unbiased technique for measuringT1 only in the absence of bias in excitation flip angle. The time-dependent concentration of the contrast agent measured in vivo is within the theoretically predicted uncertainty. The uncertainty in measuring K(trans) with SPGR pulse sequences is of the same order, but always higher than, the uncertainty in measuring the pre-injection longitudinal relaxation time (T10). The lowest achievable bias/uncertainty in estimating this parameter is approximately 20%-70% higher than the bias/uncertainty in the measurement of the pre-injection T1 map. The fractional volume parameters derived from the extended Tofts model were found to be extremely sensitive to the variance in signal intensity. The SNR of the pre-injection T1 map indicates the limiting precision with which K(trans) can be calculated.
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Metabolic syndrome comprises a cluster of metabolic abnormalities leading to insulin resistance and atherosclerosis, and Helicobacter pylori is thought to be a contributing factor. We examined the association between H. pylori infection and metabolic syndrome in a large Japanese population. Consecutive asymptomatic subjects that underwent a complete medical survey in our institute between April 2006 and March 2007 were recruited, and a total of 5,488 men and 1,906 women were cross-sectionally studied. The association of H. pylori serostatus with traditional atherosclerosis risk factors was investigated by multiple linear regression analysis. Independent and significant factors affecting metabolic syndrome were determined by multiple logistic regression analysis. H. pylori seropositivity significantly increased with age in both men and women. H. pylori seropositivity was significantly higher in cases with metabolic syndrome compared with those without metabolic syndrome (P < 0.001). There was a significant and independent association between H. pylori seropositivity and metabolic syndrome (OR 1.39, 95% CI 1.18-1.62, P < 0.001) by multiple logistic regression analysis. H. pylori seropositivity was significantly associated with higher systolic blood pressure (beta coefficient = 1.03, P= 0.014), lower high-density lipoprotein (HDL)-cholesterol level (beta coefficient =-2.00, P < 0.001), and higher LDL-cholesterol level (beta coefficient = 2.21, P= 0.005) by multiple linear regression analysis.
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Do elevated Blood Lead Levels Are Associated with Reduced Risk of Malaria in Beninese Infants?
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Elevated blood lead levels (BLL) and malaria carry an important burden of disease in West Africa. Both diseases might cause anemia and they might entail long-term consequences for the development and the health status of the child. Albeit the significant impact of malaria on lead levels described in Nigeria, no evaluation of the effect of elevated BLL on malaria risk has been investigated so far. Between 2010 and 2012, blood lead levels of 203 Beninese infants from Allada, a semi-rural area 50km North from Cotonou, were assessed at 12 months of age. To assess lead levels, blood samples were analyzed by mass spectrometry. In parallel, clinical, microbiological and hematological data were collected. More precisely, hemoglobin, serum ferritin, CRP, vitamin B12, folate levels, and Plasmodium falciparum parasitemia were assessed and stool samples were also analyzed. At 12 months, the mean BLL of infants was 7.41 μg/dL (CI: 65.2; 83), and 128 infants (63%) had elevated blood lead levels, defined by the CDC as BLL>5 μg/dL. Lead poisoning, defined as BLL>10 μg/dL, was found in 39 infants (19%). Twenty-five infants (12.5%) had a positive blood smear at 12 months and 144 infants were anemic (71%, hemoglobin<110 g/L). Elevated blood lead levels were significantly associated with reduced risk of a positive blood smear (AOR = 0.38, P-value = 0.048) and P. falciparum parasite density (beta-estimate = -1.42, P-value = 0.03) in logistic and negative binomial regression multivariate models, respectively, adjusted on clinical and environmental indicators.
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Patients undergoing major orthopedic surgery experience significant postoperative pain. Failure to provide adequate analgesia may impede early physical therapy and rehabilitation, which are important factors for maintaining joint range of motion and facilitating hospital dismissal. We examined the effect of a pre-emptive, multimodal, perioperative analgesic regimen emphasizing peripheral nerve block in patients undergoing total hip (THA) and total knee (TKA) arthroplasty. Perioperative outcomes and major postoperative complications were evaluated. One hundred consecutive patients undergoing primary or revision THA or TKA using the Mayo Clinic Total Joint Regional Anesthesia (TJRA) protocol were retrospectively reviewed. The TJRA protocol is a pre-emptive, multimodal, perioperative analgesic regimen emphasizing peripheral nerve block that was jointly developed by the Departments of Anesthesiology and Orthopedic Surgery. Identified patients were matched 1:1 with historical controls undergoing identical surgical procedures with traditional anesthetic techniques. Matching criteria included patient age, gender, surgeon, date of surgery, and American Society of Anesthesiologists physical status. Patient demographics, preoperative joint range of motion, and anesthetic management were recorded for each patient. The primary study outcome was hospital length of stay. Secondary outcome variables included time to ambulation, joint range of motion, and discharge eligibility. Postoperative verbal analog pain scores (VAS), opioid requirements, side effects, and perioperative complications were also documented. One hundred patients underwent THA or TKA using the newly implemented Mayo Clinic TJRA protocol. Matched controls (n = 100) received intravenous patient-controlled analgesia with subsequent conversion to oral analgesics for postoperative pain management. TJRA patients had significantly shorter hospital lengths of stay (3.8 days v 5.0 days; P < .001), achieved discharge eligibility significantly sooner (1.7 +/- 1.9 days earlier; P < .0001), and had improved joint range of motion (90 degrees v 85 degrees ; P = .008) when compared with matched controls. TJRA patients had significantly improved postoperative analgesia, including lower VAS pain scores (postoperative day 0 through postoperative day 3; P < .001), and lower opioid requirements (postoperative day 0 to postoperative day 2; P = .04). Adverse outcomes such as postoperative urinary retention (50% v 31%; P < .001), and ileus formation (7% v 1%; P = .01) occurred more frequently among control patients.
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Does atrial natriuretic peptide help prevent late remodeling after left ventricular aneurysm repair?
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Left ventricular aneurysm repair (LVR) reduces LV wall stress and improves LV function. However, as we reported previously, the initial improvement of LVR was short-term because of LV remodeling but could be maintained longer with postoperative use of an angiotensin-converting enzyme (ACE) inhibitor. Atrial natriuretic peptide (ANP) has been used to treat patients with heart failure by natriuretic and vasodilatory actions. Recent reports have suggested that ANP inhibits the rennin-angiotensin system. In this study, the effects of ANP after LVR were evaluated. Rats that had an LV aneurysm 4 weeks after left anterior descending artery ligation underwent LVR by plicating the LV aneurysm and were randomized into 2 groups: LVR+A group was intravenously administrated with 10 microg/h of carperitide, recombinant alpha-hANP, by osmotic-pump for 4 weeks, and the LVR group was given normal saline. Echocardiography revealed better LV remodeling and function in LVR+A group than in LVR group. Four weeks after LVR, left ventricular end diastolic pressure (LVEDP) and Tau were significantly lower in LVR+A group (LVEDP: 10+/-4 in LVR+A group versus 18+/-6 mm Hg in LVR group, Tau: 13+/-2 versus 17+/-2ms). End-systolic elastance (Ees) was higher in LVR+A group (Ees: 0.34+/-0.2 versus 0.19+/-0.11 mm Hg/microL). The levels of myocardial ACE activity in LVR+A group was significantly lower than in LVR group. The mRNA expressions of brain natriuretic peptide and transforming growth factor beta1 inducing fibrosis significantly decreased in LV myocardium in LVR+A group. Histologically, myocardial fibrosis was significantly reduced in LVR+A group.
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There is controversy on the effects of the non-ionizing radiation emitted by cell phones on cellular processes and the impact of such radiation exposure on health. The purpose of this study was to investigate whether cell phone use alters cytokine expression in the saliva produced by the parotid glands. Cytokine expression profile was determined by enzyme linked immuno sorbent assay (ELISA) in the saliva produced by the parotid glands in healthy volunteers, and correlated with self-reported cell phone use and laterality. The following parameters were determined, in 83 Brazilian individuals in saliva produced by the parotid glands comparing the saliva from the gland exposed to cell phone radiation (ipsilateral) to that from the contralateral parotid: salivary flow, total protein concentration, interleukin 1 β (IL-1 β), interleukin 6 (IL-6), interleukin 10 (IL-10), interferon γ (IFN-γ), and tumor necrosis factor α (TNF-α) salivary levels by ELISA. After multiple testing correction, decreased IL-10 and increased IL-1β salivary levels in the ipsilateral side compared with the contralateral side (P < 0.05) were detected. Subjects who used cell phones for more than 10 years presented higher differences between IL-10 levels in ipsilateral versus contralateral parotids (P = 0.0012). No difference was observed in any of the tested parameters in correlation with cell phone monthly usage in minutes.
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Does crohn 's disease run a more aggressive course in young Asian patients?
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Crohn's disease is a heterogeneous inflammatory bowel disease. The impact of age at diagnosis on the clinical course of patients varies widely as reported in the Western literature. Using the Vienna Classification, we seek to determine whether young Crohn's disease patients in an Asian population followed a different clinical course than old patients. The case records of 100 Crohn's disease patients who were treated at the Inflammatory Bowel Disease Center, Singapore General Hospital, were studied retrospectively. The age group and location of disease and behavior according to the Vienna classification were determined at diagnosis. A1 group (age <40 years) defined as "young" and A2 group (age > or =40) defined as "old" contained 65 and 35 patients, respectively. Median age for the young group was 27.4 years and that for the old group was 52.6 years. Of the young patients, 66.7% flared at least once compared with 28.6% of the old patients, odds ratio of 5.0 (P < 0.001). Young patients were more likely to be steroid dependent (20.0% of A1 versus 8.6% of A2, P = 0.14), received azathioprine (38.5% of A1 versus 5.7% of A2, P < 0.001) and experienced complications (31% of A1 versus 20% of A2, P = 0.25)-numerically higher rates that did not reach statistical significance. There was no significant difference between the age groups for the location and behavior of disease as well as requirement for surgery.
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Mitochondrial permeability transition pore (mPTP) opening is a terminal event leading to mitochondrial dysfunction and cell death under conditions of oxidative stress (OS). However, mPTP blockade with cyclosporine A (CsA) has shown variable efficacy in limiting post-ischemic dysfunction and arrhythmias. We hypothesized that strong feedback between energy dissipating (mPTP) and cardioprotective (mKATP) channels determine vulnerability to OS. Guinea pig hearts (N = 61) were challenged with H2O2 (200 μM) to elicit mitochondrial membrane potential (ΔΨm) depolarization. High-resolution optical mapping was used to measure ΔΨm or action potentials (AP) across the intact heart. Hearts were treated with CsA (0.1 μM) under conditions that altered the activity of mKATP channels either directly or indirectly via its regulation by protein kinase C. mPTP blockade with CsA markedly blunted (P < 0.01) OS-induced ΔΨm depolarization and delayed loss of LV pressure (LVP), but did not affect arrhythmia propensity. Surprisingly, prevention of mKATP activation with the chemical phosphatase BDM reversed the protective effect of CsA, paradoxically exacerbating OS-induced ΔΨm depolarization and accelerating arrhythmia onset in CsA treated compared to untreated hearts (P < 0.05). To elucidate the putative molecular mechanisms, mPTP inhibition by CsA was tested during conditions of selective PKC inhibition or direct mKATP channel activation or blockade. Similar to BDM, the specific PKC inhibitor, CHE (10 μM) did not alter OS-induced ΔΨm depolarization directly. However, it completely abrogated CsA-mediated protection against OS. Direct pharmacological blockade of mKATP, a mitochondrial target of PKC signaling, equally abolished the protective effect of CsA on ΔΨm depolarization, whereas channel activation with 30 μM Diazoxide protected against ΔΨm depolarization (P < 0.0001). Conditions that prevented mKATP activation either directly or indirectly via PKC inhibition led to accelerated ΔΨm depolarization and early onset of VF in response to OS. Investigation of the electrophysiological substrate revealed accelerated APD shortening in response to OS in arrhythmia-prone hearts.
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Does airway factor XIII associate with type 2 inflammation and airway obstruction in asthmatic patients?
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Coagulation Factor XIII (FXIII) plays an important role in wound healing by stabilizing fibrin clots and cross-linking extracellular matrix proteins. FXIII is expressed in cells of the monocyte/macrophage and dendritic cell lineages in response to type 2 cytokines. We sought to determine the association between FXIII and asthma pathobiology. We analyzed the expression of FXIII mRNA and protein levels in bronchoalveolar lavage samples obtained before and after segmental allergen challenge from patients with mild asthma and in induced sputum samples collected from patients with mild-to-moderate and severe asthma. FXIII mRNA and protein levels were highly upregulated in bronchoalveolar cells and fluid after allergen challenge and mRNA levels correlated with protein levels. In sputum of asthmatic patients, FXIII expression was positively correlated with type 2 immune response and dendritic cell markers (CD209 and CD207). FXIII expression was also associated with increased airflow limitation (FEV1/forced vital capacity and residual volume/total lung capacity ratios) and greater reversibility to β-agonists.
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Minimally invasive parathyroidectomy for primary hyperparathyroidism is dependent on preoperative localization, commonly with ultrasound and sestamibi imaging. This study sought to determine if preoperative serum calcium and parathyroid hormone (PTH) levels correlate with localization sensitivity and positive predictive value (PPV). This is a retrospective analysis of a prospective database of 1,910 patients with primary hyperparathyroidism from 2002 to 2013, who had surgeon-performed ultrasound and/or sestamibi for preoperative localization. The sensitivity and PPV of ultrasound and sestamibi were analyzed by degree of preoperative serum calcium and parathyroid hormone level perturbation. In 1,910 parathyroidectomy patients, ultrasound was localizing in 1,411 of 1,644 (86%) and sestamibi in 802 of 1,165 (69%) (p < 0.01). The PPV of ultrasound was 1,135 of 1,411 (80%) and sestamibi was 705 of 802 (88%) (p < 0.01). Using logistic regression analysis, there was statistically significant positive correlation between localization and preoperative serum calcium for both sestamibi (odds ratio [OR] 1.21 [95% CI 1.00 to 1.47; p < 0.05]) and ultrasound (OR 1.29 [95% CI 1.03 to 1.60; p < 0.05]). There was a weak, but statistically significant positive correlation of PTH with sestamibi localization (OR 1.00 [95% CI 1.00 to 1.01; p < 0.05]). There was no statistically significant correlation between the PPV and serum calcium or PTH for either study. When patients were divided into quartiles of preoperative serum calcium and PTH levels, localization rates and PPV of both ultrasound and sestamibi increased with higher calcium and PTH levels. Surgeon-performed ultrasound had higher localization rates than sestamibi, with lower calcium and PTH values. Sestamibi demonstrated higher PPV values across all quartiles.
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Does minocycline prevent Abeta ( 25-35 ) -induced reduction of somatostatin and neprilysin content in rat temporal cortex?
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Tetracyclines have been demonstrated to inhibit formation of beta-amyloid (Abeta) aggregates and to disassemble preformed fibrils. Minocycline, a semi-synthetic second-generation tetracycline, can reverse Abeta-induced impairment of cognitive functions. Since somatostatin is involved in cognition and we recently showed that Abeta(25-35) lowers somatostatin expression in the rat temporal cortex, our aim here was to analyze the effects of minocycline on somatostatin immunoreactivity and mRNA levels in the temporal cortex of Abeta(25-35)-infused and healthy rats. Moreover, since brain levels of neprilysin, an Abeta-degrading enzyme, decrease with age, favoring the appearance of senile neuritic plaques, we tested whether minocyline could affect neprilysin expression. Wistar rats were thus injected with minocycline twice on the first day of treatment. On the following day, and during 14 days, Abeta(25-35) or vehicle were administered. Minocycline was injected once again on days 13 and 14. All animals were sacrificed 24 h after the last drug injection. Minocycline abrogated the Abeta(25-35)-induced decrease of somatostatin-like immunoreactive content, somatostatin mRNA levels, phosphorylated-CREB content and neprilysin levels. Minocycline alone enhanced these targets.
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Insulin resistance and hyperglycaemia are common in severe sepsis. Mitochondrial uncoupling protein 2 (UCP2) plays a role in insulin release and sensitivity. To determine if a common, functional polymorphism in the UCP2 gene promoter region (the -866 G/A polymorphism) contributes to the risk of hyperglycaemia in severe sepsis. In the prospective group 120 non-diabetic patients who were carriers of the G allele had significantly higher maximum blood glucose recordings than non-carriers (mean (SD) AA 8.5 (2.2) mmol/l; GA 8.5 (2.4) mmol/l; GG 10.1 (3.1) mmol/l; p = 0.0042) and required significantly more insulin to maintain target blood glucose (p = 0.0007). In the retrospective study 103 non-diabetic patients showed a similar relationship between maximum glucose and UCP genotype (AA 6.8 (2.3) mmol/l; GA 7.8 (2.2) mmol/l; GG 9.2 (2.9) mmol/l; p = 0.0078).
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Are differences in sitting postures associated with nonspecific chronic low back pain disorders when patients are subclassified?
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A comparative study. To investigate sitting postures of asymptomatic individuals and nonspecific chronic low back pain (NS-CLBP) patients (pooled and subclassified) and evaluate the importance of subclassification. Currently, little evidence exists to support the hypothesis that CLBP patients sit differently from pain-free controls. Although classifying NS-CLBP patients into homogeneous subgroups has been previously emphasized, no attempts have been made to consider such groupings when examining seated posture. Three angles (sacral tilt, lower lumbar, and upper lumbar) were measured during "usual" and "slumped" sitting in 33 NS-CLBP patients and 34 asymptomatic subjects using an electromagnetic measurement device. Before testing, NS-CLBP patients were subclassified by two blinded clinicians. Twenty patients were classified with a flexion motor control impairment and 13 with an active extension motor control impairment. No differences were found between control and NS-CLBP (pooled) patients during usual sitting. In contrast, analyses based on subclassification revealed that patients classified with an active extension pattern sat more lordotic at the symptomatic lower lumbar spine, whereas patients with a flexion pattern sat more kyphotic, when compared with healthy controls (F = 19.7; df1 = 2, df2 = 63, P < 0.001). Further, NS-CLBP patients had less ability to change their posture when asked to slump from usual sitting (t = 4.2, df = 65; P < 0.001).
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The airway epithelium acts as a protective barrier, separating the external environment from the underlying tissue. Daily challenges result in damage to the epithelium that, in normal individuals, is quickly and effectively repaired. In respiratory diseases, such as asthma, this repair is compromised. Following injury to the epithelium, plasma leaks into the airway lumen acting as a protective protein cap. Carbohydrates are mediators of epithelial repair, however, the associated regulatory proteins remain unknown. To identify mediators of epithelial repair based on their carbohydrate moieties using an in vitro wound repair culture model of human airway epithelial cells (1HAEo(-)). Using the lectin Allomyrina dichotoma agglutinin (AlloA) as a tool, ligands essential in the repair of damaged epithelium were characterized. AlloA was subsequently used to purify and identify a glycoprotein associated with epithelial repair. The addition of AlloA to the media of mechanically wounded monolayers inhibited repair. Fetuin, a highly glycosylated serum protein, was identified as a glycoprotein bound by AlloA. The addition of fetuin to serum starved monolayers stimulated wound closure.
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Is dystrophic epidermolysis bullosa pruriginosa associated with frequent FLG gene mutations?
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Dystrophic epidermolysis bullosa pruriginosa (DEB-Pr; OMIM 604129) is a rare manifestation of dystrophic epidermolysis bullosa (DEB), characterized by pruritus, nodular prurigo-like lesions and fragility of the skin mainly in the extremities. Fewer than 40 patients with autosomal dominant or recessive inheritance, or sporadic DEB-Pr, have been described in the literature. To disclose mutations in DEB-Pr and to elucidate the role of other pathogenic factors which may influence the pruriginous phenotype. Seven patients with typical clinical features of DEB-Pr were studied. In all patients, mutations in the gene encoding collagen VII (COL7A1) were disclosed, two of them novel (p.G2623V, p.E2736K). Three mutations were dominant, three recessive and one de novo. In the families with dominant DEB there were one or more members with DEB-Pr, but also at least one affected sibling who did not develop DEB-Pr. In six of seven patients, the clinical history revealed factors that initially induced pruritus, such as atopy, pregnancy, thyroid hormone imbalance, diabetes, infections and contact sensitization. Common filaggrin mutations were ruled out in all patients and normal filaggrin staining was found in the skin samples.
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The value of performing transthoracic echocardiography (TTE) as part of the clinical assessment of patients awaiting endovascular repair of the abdominal aorta is little evaluated. We aimed to estimate the prognostic importance of information derived from TTE on long-term all-cause mortality in a selected group of patients undergoing endovascular aneurysm repair. This was a retrospective cohort study of 273 consecutive patients selected for endovascular aneurysm repair. All patients included in the analysis underwent TTE before their procedure. Multivariable Cox regression analysis was used to estimate the effect of TTE measures on all-cause mortality. Over a mean follow-up of 3.2±1.5 years, there were 78 deaths with a mean time to death of 1.28±1.16 years. A greater tubular ascending aorta (hazard ratio [HR] 5.6, 95% confidence interval [CI] 2.77-11.33), presence of mitral regurgitation (HR 8.13, 95% CI 4.09-12.16), lower left ventricular ejection fraction (HR 0.96, 95% CI 0.93-0.98), younger age (HR 0.97, 95% CI 0.95-0.99), and presence of diabetes mellitus (HR 1.46, 95% CI 1.24-1.89) were predictors of all-cause mortality.
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Is ethanol operant self-administration in rats regulated by adenosine A2 receptors?
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Recent findings suggest that adenosine is involved in the neural and behavioral effects of ethanol (EtOH). Studies in neural cell culture show that EtOH, via activation of adenosine A2 receptors, triggers cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) signaling and CRE (cAMP regulatory element)-mediated gene expression and that this effect is blocked by inhibiting G-protein betagamma subunits. Recently, we reported that expression of a betagamma inhibitor in the nucleus accumbens (NAc) reduces EtOH drinking in rats. The NAc expresses high levels of the adenosine A2A receptor in GABAergic medium spiny neurons. If the reinforcing effects of EtOH are mediated through an A2 activation of cAMP/PKA signaling via betagamma, then A2 receptor blockade should attenuate EtOH consumption. Here we tested this hypothesis. Because adenosine A2 and dopamine D2 receptors are coexpressed in neurons of the NAc, we compared the effects of A2 blockade with those of D2 receptor blockade. Male Long-Evans rats were trained to self-administer 10% EtOH in daily 30-min sessions with an active and an inactive lever. Separate groups of rats were given the D2 antagonist eticlopride (0.005, 0.007, and 0.01 mg/kg), the A2 antagonist 3,7-dimethyl-1-propargylxanthine (DMPX; 1, 3, 5, 7, 10, and 20 mg/kg), and the A1 antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX; 0.125, 0.25, and 0.5 mg/kg) by systemic injection. Eticlopride dose-dependently reduced EtOH drinking. DMPX showed a bimodal effect: 10 and 20 mg/kg decreased, but 1 mg/kg increased, EtOH consumption. DPCPX was without effect.
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There is an increased incidence of breast cancer occurring during pregnancy. Controversy exists as to the safety of performing lymphoscintigraphy during pregnancy and no studies have reported the measured dose of uterine radiation. We performed an institutional review board (IRB)-approved prospective study of uterine radiation resulting from lymphoscintigraphy. Abdominal, perineal, and urinary radiation was measured in 14 breast cancer patients and total uterine dose was calculated. The average dose of 99m-Tc sulfur colloid was 39 +/- 20 MBq (1.04 +/- 0.53 mCi). Measured abdominal and pelvic radiation exposure demonstrated no correlation with patient age or body mass index. The average abdominal radiation exposure was 1.17 +/- 0.87 microGy. The average perineal radiation exposure was 0.23 +/- 0.17 microGy. The average dose to the uterus from bladder radioactivity determined from voided urine was 0.44 +/- 0.44 microGy. The average radiation dose to the uterus (average of abdominal and perineal doses plus contribution from bladder dose) was 1.14 +/- 0.76 microGy. One patient was 16 weeks pregnant at the time of sentinel lymph node biopsy (SLNB) and total calculated uterine dose was 1.67 microGy, suggesting that pregnancy does not significantly alter measured uterine radiation. These data were compared with the average background radiation, which is 3,000 microGy per year or 8.2 microGy per day.
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Does peanut oral immunotherapy transiently expand circulating Ara h 2-specific B cells with a homologous repertoire in unrelated subjects?
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Peanut oral immunotherapy (PNOIT) induces persistent tolerance to peanut in a subset of patients and induces specific antibodies that might play a role in clinical protection. However, the contribution of induced antibody clones to clinical tolerance in PNOIT is unknown. We hypothesized that PNOIT induces a clonal, allergen-specific B-cell response that could serve as a surrogate for clinical outcomes. We used a fluorescent Ara h 2 multimer for affinity selection of Ara h 2-specific B cells and subsequent single-cell immunoglobulin amplification. The diversity of related clones was evaluated by means of next-generation sequencing of immunoglobulin heavy chains from circulating memory B cells with 2x250 paired-end sequencing on the Illumina MiSeq platform. Expression of class-switched antibodies from Ara h 2-positive cells confirms enrichment for Ara h 2 specificity. PNOIT induces an early and transient expansion of circulating Ara h 2-specific memory B cells that peaks at week 7. Ara h 2-specific sequences from memory cells have rates of nonsilent mutations consistent with affinity maturation. The repertoire of Ara h 2-specific antibodies is oligoclonal. Next-generation sequencing-based repertoire analysis of circulating memory B cells reveals evidence for convergent selection of related sequences in 3 unrelated subjects, suggesting the presence of similar Ara h 2-specific B-cell clones.
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MicroRNAs (miRNAs), a group of small non-coding RNAs that fine tune translation of multiple target mRNAs, have been implicated in the development and progression of heart failure. The present study was undertaken to determine the roles of miR-133a on the anatomical, hemodynamic and fibrosis of heart in the chronic heart failure rats, and the downstream signaling pathway. The expression of miR-133a in the heart of chronic heart failure from patients or rats was decreased. The miR-133a mimic and miR-133a overexpression caused a decrease in the heart weight/body weight (HW/BW) and LVEDP, and an increase in the LVSP and +LV dP/dt(max) in the chronic heart failure rats. However, the miR-133a inhibitor promoted the HW/BW and LVEDP, and caused a decrease in the LVSP and LV dP/dt(max) in the chronic heart failure rats. The miR-133a mimic and miR-133a overexpression significantly caused a decrease in the fibrosis of heart in chronic heart failure rats. The Akt inhibitor TCN abolished the effects of miR-133a on the HW/BW and LVEDP decrease, LVSP and LV dP/dt(max) increase in the chronic heart failure rats. The miR-133a increased the expression of phosphorylated Akt in the heart of chronic heart failure rats.
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Do cD4 T cells mediate cardiac xenograft rejection via host MHC Class II?
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Previous studies have shown that acute CD4 T-cell-mediated cardiac allograft rejection requires donor major histocompatibility complex (MHC) Class II expression and can be independent of "indirect" antigen presentation. However, other studies suggested that indirect antigen presentation to CD4 T cells may play a primary role in cellular xenograft immunity. Thus, the relative roles of direct/indirect CD4 T cell reactivity against cardiac xenografts are unclear. In this study we set out to determine the role for indirect CD4 T cell reactivity in cardiac xenograft rejection. Rat hearts were transplanted heterotopically into wild-type and immunodeficient mice. Recipients were untreated, treated with depleting antibodies, or reconstituted with wild-type cells. Antibody depletion confirmed that rat heart xenograft rejection in C57Bl/6 mice was CD4 T-cell-dependent. Also, heart xenografts survived long term in B6 MHC Class II (C2D)-deficient mice. Graft acceptance in C2D mice was not secondary to CD4 T cell deficiency alone, because transferred B6 CD4 T cells failed to trigger rejection in C2D hosts. Furthermore, purified CD4 T cells were sufficient for acute rejection of rat heart xenografts in immune-deficient B6rag1(-/-) recipients. Importantly, CD4 T cells did not reject rat hearts in C2Drag1(-/-) hosts, in contrast to results using cardiac allografts. "Direct" xenoreactive CD4 T cells were not sufficient to mediate rejection despite vigorous reactivity to rat stimulator cells in vitro.
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We examined the effect of breast milk on plasma total antioxidant capacity (TAC), total peroxide (TP), and oxidative stress index (OSI), which are biomarkers of oxidative status. Fifty-four healthy term infants 3 to 6 mo of age were fed breast milk or a cow's milk modified formula. Plasma TAC, vitamin C, albumin, bilirubin, and uric acid levels were measured as indexes of antioxidative markers. Plasma TP levels were measured as an oxidative stress marker. The OSI was calculated to assess oxidative status. No significant differences were observed between groups with respect to growth or anthropometric measurements. Plasma uric acid, total protein, and albumin concentrations were slightly higher in the breast-fed group than in the formula-fed group. There was a positive correlation between infant's age and serum albumin levels; between TAC and plasma uric acid, albumin, and total bilirubin; and between plasma iron and TP levels in both groups (r > 0.256, P < 0.05). In addition, there was a negative correlation between plasma iron and TAC (r = -0.267, P = 0.01). Plasma TAC and vitamin C levels were significantly higher in the breast-fed group than in the formula-fed group (P < 0.05). Plasma TP levels and the OSI were higher in the formula-fed group than those in the breast-fed group (P < 0.05).
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Are elevated heat shock protein 60 levels associated with higher risk of coronary heart disease in Chinese?
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Although heat shock protein 60 (Hsp60) is implicated in the pathogenesis of atherosclerosis, its role in coronary heart disease (CHD) is uncertain. This study explored the influence of circulating Hsp60 on CHD in a large case-control study, as well as the impact of acute myocardial infarction on Hsp60 levels in a prospective study. Plasma Hsp60 and anti-Hsp60 antibody levels were determined by immunoassay. In the case-control study (1003 patients with CHD, 1003 matched control subjects), Hsp60 levels were higher in patients with CHD and were related to CHD (OR comparing extreme quartiles=4.14, P<0.0001). This association remained after adjustment for traditional risk factors (P for trend <0.0001). Individuals having high levels of Hsp60 (greater than the median of 160.24 ng/mL) and anti-Hsp60 antibody (greater than the median of 38.42 U/mL) were at a greater risk of CHD than those with low levels (OR 2.30, P<0.0001). Stronger additive effects (OR 14.04, P<0.0001) were apparent at higher Hsp60 and anti-Hsp60 antibody levels (>1000 ng/mL and greater than the median of 38.42 U/mL, respectively). The simultaneous presence of high Hsp60 and anti-Hsp60 antibody levels, current smoking, hypertension, and diabetes were cumulatively associated with CHD. Individuals who had any 4 or more of these 5 factors had an OR of 38.61 for CHD (P<0.0001) compared with individuals who had none of these factors. For the prospective study, blood was drawn from 20 patients immediately after admission for acute myocardial infarction and 2, 3, and 7 days thereafter. Hsp60 levels were significantly higher on the day of and the day after arrival than 7 days after an acute myocardial infarction (P=0.011 and P=0.026, respectively).
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To investigate if cisplatin alters vitamin status and if VR modulates cisplatin induced intestinal apoptosis and oxidative stress in Wistar/NIN (WNIN) male rats. Weanling, WNIN male rats (n = 12 per group) received adlibitum for 17 wk: control diet (20% protein) or the same with 50% vitamin restriction. They were then sub-divided into two groups of six rats each and administered cisplatin (2.61 mg/kg bodyweight) once a week for three wk or PBS (vehicle control). Intestinal epithelial cell (IEC) apoptosis was monitored by morphometry, Annexin-V binding, M30 cytodeath assay and DNA fragmentation. Structural and functional integrity of the villus were assessed by villus height/crypt depth ratio and activities of alkaline phosphatase, lys, ala-dipeptidyl amino-peptidase, respectively. To assess the probable mechanism(s) of altered apoptosis, oxidative stress parameters, caspase-3 activity, and expression of Bcl-2 and Bax were determined. Cisplatin per se decreased plasma vitamin levels and they were the lowest in VR animals treated with cisplatin. As expected VR increased only villus apoptosis, whereas cisplatin increased stem cell apoptosis in the crypt. However, cisplatin treatment of VR rats increased apoptosis both in villus and crypt regions and was associated with higher levels of TBARS, protein carbonyls and caspase-3 activity, but lower GSH concentrations. VR induced decrease in Bcl-2 expression was further lowered by cisplatin. Bax expression, unaffected by VR was increased on cisplatin treatment. Mucosal functional integrity was severely compromised in cisplatin treated VR-rats.
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Is obesity associated with a poorer prognosis in women with hormone receptor positive breast cancer?
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Whether moderate to severe obesity (body mass index (BMI)≥30 to <40kg/m(2)) contributes to breast cancer recurrence and mortality remains uncertain. 1199 women, recruited within 12 months of their diagnosis of hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) invasive breast cancer completed an enrolment questionnaire and an annual follow-up questionnaire every 12 months for another 5 years. The impact of obesity on time to either local or distant recurrence or new breast cancer, or death due to breast cancer was determined by Cox regression. Women in the most extreme categories of BMI (<18.5 and ≥40) were excluded from the analysis. Of the 1155 included women, mean age, 58.4±11.6 years, 53.8% had Stage 1 disease and 88.9% received oral adjuvant endocrine therapy (OAET) within 2 years of diagnosis. The likelihood of an event was significantly associated with moderate to severe obesity (HR=1.71, 95%CI, 1.12-2.62, p=0.014), disease beyond Stage 1 (HR=2.87, 95% CI 1.73-4.75, p<0.001), OAET (HR=0.26, 95%CI 0.14-0.46, p<0.001), mastectomy (HR=3.28, 95%CI 1.98-5.44, p<0.001) and radiotherapy (HR=2.12, 95%CI 1.24-3.63, p=0.006). For Stage 1 disease, only moderate to severe obesity (HR 3.23, 95%CI 1.48-7.03, p=0.003) and OAET use (HR 0.41, 95%CI 0.17-0.98, p=0.046) were significantly associated with an event.
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Neonatal arterial ischemic stroke occurs in > or =1:4000 births. Many children experience motor deficits but acute predictors of outcome are lacking. Diffusion-weighted MRI changes in descending corticospinal tracts remote from arterial ischemic stroke may represent pre-Wallerian degeneration. We verify and quantify this signal and correlate it with motor outcome. Fourteen neonates with acute arterial ischemic stroke and > or =12 months follow-up with the Pediatric Stroke Outcome Measure were included. Quantitative measurements of descending corticospinal tracts diffusion-weighted MRI signal were developed using Image J software. Ipsilesional descending corticospinal tract diffusion-weighted MRI signal was abnormal in 10 neonates with decreased apparent diffusion coefficients (P<0.001). Poor outcome correlated with: (1) percentage of peduncle (P=0.002); (2) length of descending corticospinal tracts P<0.001); and (3) volume of descending corticospinal tracts (P=0.002). None of: (1) any peduncle; (2) any posterior limb of the internal capsule; or (3) infarct volume correlated with outcome. All children without descending corticospinal tracts signal had normal outcome. Chronic Wallerian degeneration was seen in all children with hemiparesis. Software-assisted analysis was superior to visual inspection with excellent reliability (intra-class correlation coefficient > or =0.9).
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Does helicobacter pylori vacuolating cytotoxin inhibit duodenal bicarbonate secretion by a histamine-dependent mechanism in mice?
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The pathogenic mechanisms involved in Helicobacter pylori-induced duodenal mucosal injury are incompletely understood. In the present study, we sought to investigate the effect of H. pylori vacuolating cytotoxin (VacA) on duodenal mucosal bicarbonate (HCO3-) secretion. Concentrated bacterial culture supernatants from an H. pylori wild-type strain producing VacA with s1/m1 genotypes (P12) and from an isogenic mutant lacking VacA (P12DeltavacA) were used. HCO3- secretion by murine duodenal mucosa was examined in vitro in Ussing chambers. Duodenal mucosal histamine release was measured using enzyme-linked immunosorbent assay. The expression of histamine H2 receptor was examined by immunohistochemical analysis. In a dose-dependent manner, the VacA-positive supernatant P12 reduced prostaglandin E2 (PGE2)-stimulated duodenal mucosal HCO3- secretion to a maximum of 49% (P<.0001), whereas P12DeltavacA did not result in significant inhibition (P>.05). Purified VacA had a similar effect. Histamine H2 receptor antagonists attenuated the effect of P12 on PGE2-induced HCO3- secretion. P12 stimulated duodenal histamine release in a dose-dependent manner, and exogenous histamine inhibited PGE2-stimulated duodenal HCO3- secretion. H2 receptor expression was found in duodenal epithelial cells, the enteric nerve plexus, and lymphocytes in Peyer's patch.
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To examine whether the elevated preoperative plasma D-dimer levels show correlation with chemoresistance and poor prognosis in serous ovarian cancer patients. Preoperative plasma D-dimer levels were measured in 125 patients with primary serous ovarian cancer (SOC).The correlations of plasma D-dimer levels with clinicopathological features, chemotherapeutic response, and survival outcome were further analyzed. Kaplan-Meier estimates were used to compute the survival functions and were compared using log-rank tests. Cox proportional-hazard regression analysis was used to evaluate the effects of D-dimer on progression-free survival (PFS) and overall survival (OS), controlling for potential confounding factors. The median follow-up period was 49 (range 5-85) months. Elevated plasma D-dimer levels were positively associated with advanced FIGO stage (P = 0.010), residual tumor size (P = 0.017), the presence of malignant ascites (P = 0.028), increased serum CA125 level (P = 0.014), and neo-adjuvant chemotherapy (P = 0.008). The patients with elevated plasma D-dimer levels had significantly higher chemoresistance rates (56.41 %) compared to the normal plasma D-dimer levels (20.93 %). Additionally, it was found by the univariate analysis that elevated plasma D-dimer levels were closely related with a low 5-year PFS rate (28.21 vs 52.33 %, P = 0.002) and a poor 5-year OS (30.77 vs 63.95 %, P < 0.001). However, after adjustment for other factors, high plasma D-dimer levels were only closely correlated with a poor 5-year OS (HR 1.901, 95 % CI 1.021-3.540; P = 0.043).
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Does sympathetic vasomotor tone determine blood pressure response to long-term sibutramine treatment?
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The serotonin and norepinephrine transporter inhibitor sibutramine is a widely used antiobesity drug. In acute studies, the peripheral sympathomimetic effect of sibutramine was counteracted by a central sympatholytic action. The objective was to test the hypothesis that blood pressure responses to long-term sibutramine therapy may be related to sympathetic nerve traffic before treatment in a prospective open-label study in an academic clinical research center. This study comprised 20 obese subjects (body mass index, 30-40 kg/m2; age, 30-57 yr) receiving 5 d of placebo treatment followed by open-label 15 mg/d sibutramine and hypocaloric diet over 12 wk. Body weight, blood pressure, heart rate, muscle sympathetic nerve activity (MSNA) (microneurography), plasma catecholamines, and adipose tissue gene expression were measured. Open-label sibutramine treatment decreased body weight 4.1 kg (P<0.01) and MSNA 17 bursts per minute (P=0.001), and increased diastolic blood pressure 3 mm Hg (P<0.05) and heart rate 8 bpm (P<0.01). The change in blood pressure with sibutramine treatment was inversely correlated with initial MSNA (r2=0.34; P<0.01). Chronic sibutramine treatment increased adrenoreceptor gene expression and plasma catecholamines.
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The shape of the ionizing radiation response curve at very low doses has been the subject of considerable debate. Linear-no-threshold (LNT) models are widely used to estimate risks associated with low-dose exposures. However, the low-dose hyperradiosensitivity (HRS) phenomenon, in which cells are especially sensitive at low doses but then show increased radioresistance at higher doses, provides evidence of nonlinearity in the low-dose region. HRS is more prominent in the G2 phase of the cell cycle than in the G0/G1 or S phases. Here we provide the first cytogenetic mechanistic evidence of low-dose HRS in human peripheral blood lymphocytes using structural chromosomal aberrations. Human peripheral blood lymphocytes from 2 normal healthy female donors were acutely exposed to cobalt 60 γ rays in either G0 or G2 using closely spaced doses ranging from 0 to 1.5 Gy. Structural chromosomal aberrations were enumerated, and the slopes of the regression lines at low doses (0-0.4 Gy) were compared with doses of 0.5 Gy and above. HRS was clearly evident in both donors for cells irradiated in G2. No HRS was observed in cells irradiated in G0. The radiation effect per unit dose was 2.5- to 3.5-fold higher for doses ≤0.4 Gy than for doses >0.5 Gy.
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Does patient 's ethnicity influence utilization of effective therapies in rheumatoid arthritis?
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Biological agents have revolutionized the treatment of rheumatoid arthritis (RA). Given the previously documented ethnic disparity in the health service literature, we sought to determine if ethnic difference exists in the lag time between the diagnosis of RA and use of first biological agent. RADIUS 1 and 2 are observational studies designed to document how rheumatologists treat RA across the United States. The sample analyzed here included early patients with RA who entered RADIUS with the initiation of the first biological agent. Ethnic status was categorized as White (W), African American (AA), and Hispanic (H). Lag time (months from RA diagnosis to initiation of the first biological agent) was the principal outcome variable. Compared to W (n=1616), AA (n=147) and H (n=116) were more likely to be female, younger, and have less than a high school education. Despite similar swollen and tender joint counts, AA and H had more active disease on the basis of Health Assessment Questionnaire and patient global assessments. Almost 97% of patients had some type of insurance coverage. On multivariable analysis, ethnic affiliation was not associated with lag time (14.5 months W vs 14.9 AA vs 14.3 H; p=NS). Similarly, there were also no significant ethnic differences in time to first DMARD (e.g., methotrexate) initiation.
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Claudin-5, claudin-9, and claudin-11 are expressed in endothelial cells to constitute tight junctions, and their deficiency may lead to hyperpermeability, which is the initiating process and pathological basis of cardiovascular disease. Although tongxinluo (TXL) has satisfactory antianginal effects, whether and how it modulates claudin-5, claudin-9, and claudin-11 in hypoxia-stimulated human cardiac microvascular endothelial cells (HCMECs) have not been reported. In this study, HCMECs were stimulated with CoCl2to mimic hypoxia and treated with TXL. First, the messenger RNA (mRNA) expression of claudin-5, claudin-9, and claudin-11 was confirmed. Then, the protein content and distribution of claudin-9, as well as cell morphological changes were evaluated after TXL treatment. Furthermore, the distribution and content histone H3K9 acetylation (H3K9ac) in the claudin-9 gene promoter, which guarantees transcriptional activation, were examined to explore the underlying mechanism, by which TXL up-regulates claudin-9 in hypoxia-stimulated HCMECs. We found that hypoxia-suppressed claudin-9 gene expression in HCMECs (F = 7.244; P = 0.011) and the hypoxia-suppressed claudin-9 could be reversed by TXL (F = 61.911; P = 0.000), which was verified by its protein content changes (F = 29.142; P = 0.000). Moreover, high-dose TXL promoted the cytomembrane localization of claudin-9 in hypoxia-stimulated HCMECs, with attenuation of cell injury. Furthermore, high-dose TXL elevated the hypoxia-inhibited H3K9ac in the claudin-9 gene promoter (F = 37.766; P = 0.000), activating claudin-9 transcription.
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Is the uniform chest compression depth of 50 mm or greater recommended by current guidelines appropriate for all adults?
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This study was conducted to evaluate the appropriateness of the chest compression (CC) depth recommended in the current guidelines and simulated external CCs, and to characterize the optimal CC depth for an adult by body mass index (BMI). Adult patients who underwent chest computed tomography as a screening test for latent pulmonary diseases in the health care center were enrolled in this study. We calculated the internal anteroposterior (AP) diameter (IAPD) and external AP diameter (EAPD) of the chest across BMIs (<18.50, 18.50-24.99, 25.00-29.99, and ≥30.00 kg/m(2)) for simulated CC depth. We also calculated the residual chest depths less than 20 mm for simulated CC depth. There was a statistically significant difference in the chest EAPD and IAPD measured at the lower half of the sternum for each BMI groups (EAPD: R(2) = 0.638, P < .001; IAPD: R(2) = 0.297, P < .001). For one-half external AP CC, 100% of the patients, regardless of BMI, had a calculated residual internal chest depth less than 20 mm. For one-fourth external AP CC, no patients had a calculated residual internal chest depth less than 20 mm. For one-third external AP CC, only 6.48% of the patients had a calculated residual internal chest depth less than 20 mm.
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SERPINA3K, an extracellular serine proteinase inhibitor (serpin), has been shown to have decreased levels in the retinas of diabetic rats, which may contribute to diabetic retinopathy. The function of SERPINA3K in the retina has not been investigated. The present study identified a novel function of SERPINA3K, i.e. it protects retinal cells against oxidative stress-induced cell death including retinal neuronal cells and Müller cells. Flow-cytometry showed that the protective effect of SERPINA3K on Müller cells is via reducing oxidation-induced necrosis. Measurements of intracellular calcium concentration showed that SERPINA3K prevented the intracellular calcium overload induced by H(2)O(2). A similar protective effect was observed using a calcium chelator (BAPTA/AM). Further, SERPINA3K inhibited the phosphorylation of phospholipase C (PLC)-gamma1 induced by H(2)O(2). Likewise, a specific PLC inhibitor showed similar protective effects on Müller cells exposed to H(2)O(2). Furthermore, the protective effect of SERPINA3K was attenuated by a specific PLC activator (m-3M3FBS). Finally, in a binding assay, SERPINA3K displayed saturable and specific binding on Müller cells.
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Does cholesterol efflux capacity of high-density lipoprotein correlate with survival and allograft vasculopathy in cardiac transplant recipients?
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Cardiac allograft vasculopathy (CAV) is a major cause of mortality after cardiac transplantation. High-density lipoprotein (HDL) cholesterol efflux capacity (CEC) is inversely associated with coronary artery disease. In 2 independent studies, we tested the hypothesis that reduced CEC is associated with mortality and disease progression in CAV. We tested the relationship between CEC and survival in a cohort of patients with CAV (n = 35). To determine whether reduced CEC is associated with CAV progression, we utilized samples from the Clinical Trials in Organ Transplantation 05 (CTOT05) study to determine the association between CEC and CAV progression and status at 1 year (n = 81), as assessed by average change in maximal intimal thickness (MIT) on intravascular ultrasound. Multivariable Cox proportional hazard models demonstrated that higher levels of CEC were associated with improved survival (hazard ratio 0.26, 95% confidence interval 0.11 to 0.63) per standard deviation CEC, p = 0.002). Patients who developed CAV had reduced CEC at baseline and 1-year post-transplant. We observed a significant association between pre-transplant CEC and the average change in MIT, particularly among patients who developed CAV at 1 year (β = -0.59, p = 0.02, R
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Epilepsy is a neural disorder in which abnormal plastic changes during short and long term periods lead to increased excitability of brain tissue. Kindling is an animal model of epileptogenesis which results in changes of synaptic plasticity due to repetitive electrical or chemical sub-convulsive stimulations of the brain. Lateral hypothalamus, as the main niche of orexin neurons with extensive projections, is involved in sleep and wakefulness and so it affects the excitability of the brain. Therefore, we investigated whether lateral hypothalamic area (LHA) inactivation or orexin-A receptor blocking could change convulsive behavior of acute and kindled PTZ treated animals and if glutamate has a role in this regard. Kindling was induced by 40 mg/kg PTZ, every 48 hours up to 13 injections to each rat. Three consecutive stages 4 or 5 of convulsive behavior were used to ensure kindling. Lidocaine was injected stereotaxically to inactivate LHA, unilaterally. SB334867 used for orexin receptor 1 (OX1R) blocking administered in CSF. We demonstrated that LHA inactivation prevented PTZ kindling and hence, excitability evolution. Hippocampal glutamate content was decreased due to LHA inactivation, OX1R antagonist infusion, lidocaine injection and kindled groups. In accordance, OX1R antagonist (SB334867) and lidocaine injection decreased PTZ single dose induced convulsive behavior. While orexin-A i.c.v. infusion increased hippocampal glutamate content, it did not change PTZ induced convulsive intensity.
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Is the need for epidural analgesia related to birthweight - a population-based register study?
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To investigate the relation between use of epidural analgesia (EDA) and maternal and fetal characteristics. Population-based register study. Nationwide study in Sweden. All 106,775 primiparous women who in 2002-2005 delivered a singleton infant vaginally at term. Register study with data from the Medical Birth Registry and the Swedish Register of Education. Use of EDA during vaginal delivery. A total of 47,810 women (45%) received EDA during labor. EDA was used more often in women who were either young or short, had a high body mass index or a short education, or gave birth to an infant with high birthweight. After adjustment, the positive correlation with birthweight persisted. The use of EDA was twice as high in women with infant birthweight >4,500 g, 60% higher in those with infants weighing between 4,000 and 4,500 g and 25% lower when infants weighed <3,000 g, when compared to those with newborns weighing between 3,000 and 3,500 g.
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Sirtuin 3 (Sirt3), one of the seven Sirtuins family members, plays critical roles in the progression of multiple cancer types. However, its role in the prognosis of hepatocellular carcinoma (HCC) has not yet been investigated systematically. The correlation of Sirtuins expression with prognosis of HCC was determined by immunohistochemistry (IHC) in a large HCC patient cohort (n = 342). Expression of Sirt3 in tumoral and peritumoral tissues of HCC patients were further determined by western blotting (WB). IHC and WB studies both showed a decreased expression of Sirt3 in tumoral tissues compared with peritumoral tissues (P = 0.003 for IHC, P = 0.0042 for WB). Decreased expression of Sirt3 in both tumoral and peritumoral tissues was associated with increased recurrence probability and decreased overall survival rate by univariate analyses (intratumoral Sirt3: P = 0.011 for TTR, P = 0.001 for OS; peritumoral Sirt3: P = 0.017 for TTR, P = 0.023 for OS), the prognostic value was strengthened by multivariate analyses (intratumoral Sirt3: P = 0.031 for TTR, P = 0.001 for OS; peritumoral Sirt3: P = 0.047 for TTR, P = 0.031 for OS). Intratumoral Sirt3 also showed a favorable prognostic value in patients with BCLC stage A (TTR, P = 0.011; OS, P < 0.001). In addition, we found that IHC studies of other sirtuin members showed a decreased expression of Sirt2, Sirt4 and Sirt5 and an increased expression of Sirt1, Sirt6 and Sirt7 in intratumoral tissues compared with peritumoral tissues. In contrast to Sirt3, other members did not showed a remarkable correlation with HCC prognosis.
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Are human SA gene polymorphisms associated with non-high-density lipoprotein cholesterol in postmenopausal women : a pilot study?
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The purpose of the study is to evaluate the associations between polymorphisms of the human SA (SAH) gene, an acyl-CoA synthetase gene, with dyslipidemia and phenotypes of the insulin resistance syndrome in postmenopausal women. One hundred and forty-two postmenopausal women were recruited for the study. Each subject received anthropometric and blood pressure measurements, fasting sampling for lipids, and a 75-g oral glucose tolerance test for insulin resistance. Genotypes of two polymorphisms in the promoter region (c.-962ins/del, c.-451G>A), one missense variant (c.1077G>C, p.K359N) in exon 8, and one in intron 12 (A>G) of the SAH gene, were determined. There were significant differences in genetic distribution of the SAH gene promoter I/D polymorphism between the two groups of subjects by non-high-density lipoprotein cholesterol (non-HDL-C) levels (p=0.004). The subjects with the DD genotype was associated with high levels of non-HDL-C (>160 mg/dL) as compared with the ID or II genotypes (p=0.002). Furthermore, three haplotypes were constructed based on the promoter I/D and the exon 8 G/C polymorphisms. Homozygosity for SAH haplotype 3 was associated with increased adiposity, insulin resistance, and elevated levels of non-HDL-C in the post menopausal women. The subjects with haplotype 3 had double the risk to have higher non-HDL-C levels than those with haplotype 1.
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Direct hemoperfusion with a polymyxin B-immobilized column (PMX-DHP) adsorbs endotoxin and has been used for the treatment of septic shock. Yet, the mechanisms by which PMX-DHP acts on acute kidney injury are only partially understood. Rats were anesthetized, tracheostomized, and placed on mechanical ventilation. The animals were randomized to three groups: a cecal ligation and puncture (CLP) + dummy-DHP group (n = 10), a CLP + PMX-DHP group (n = 10), and a sham group (n = 4). Four hours after CLP, a dummy-DHP or PMX-DHP was performed for 1 h. The heart rate, mean arterial pressure, arterial blood gases, and plasma concentrations of creatinine, lactate, potassium, interleukin (IL)-6, and IL-10 were measured at 0 h and 8 h. Eight hours after CLP, the kidney was harvested, and histopathologic examination was performed. The expressions of cleaved poly (ADP-ribose) polymerase (PARP) and nuclear factor (NF)-κB p65 were examined by immunohistochemistry. A terminal deoxynucleotide transferase dUTP nick-end labeling assay was performed to detect apoptotic nuclei in kidney sections. PMX-DHP maintained hemodynamics and the acid-base balance and significantly (P < 0.05) decreased the plasma concentrations of lactate, creatinine, potassium, IL-6, and IL-10 compared with dummy-DHP. PMX-DHP significantly (P < 0.001) attenuated the expressions of cleaved PARP and NF-κB p65 in renal tubular cells and renal tubular cell apoptosis compared with dummy-DHP.
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Do noradrenergic terminals regulate L-DOPA-derived dopamine extracellular levels in a region-dependent manner in Parkinsonian rats?
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Serotonin (5-HT) neurons mediate the ectopic release of dopamine (DA) induced by L-DOPA in the Parkinsonian brain. We hypothesized that the participation of noradrenalin transporters (NET) in the clearance of DA may account for the lower effect of L-DOPA in extrastriatal regions compared with the striatum. Using a multisite intracerebral microdialysis approach, we tested the influence of the pharmacological blockade of NET and/or the destruction of noradrenalin (NE) fibers on DA and 5-HT release in the striatum, hippocampus (HIPP), substantia nigra pars reticulata (SNr) and prefrontal cortex (PFC) of 6-hydroxydopamine-lesioned rats. L-DOPA (12 mg/kg, i.p.) increased DA extracellular levels to a lesser extent in the SNr, PFC and HIPP compared with the striatum. The NET blockers desipramine (10 mg/kg, i.p.) and reboxetine (3 mg/kg, i.p.) potentiated L-DOPA effect in the PFC, SNr and HIPP but not in the striatum. The NE neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (50 mg/kg, i.p. 1 week before dialysis experiment) potentiated L-DOPA effect in the SNr and HIPP. 5-HT extracellular levels were enhanced only when L-DOPA was combined to NET blockers.
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Based on large genomic sequence polymorphisms, several haplotypes belonging to two major lineages of the human pathogen Mycobacterium ulcerans could be distinguished among patient isolates from various geographic origins. However, the biological relevance of insertional/deletional diversity is not understood. Using comparative genomics, we have investigated the genes located in regions of difference recently identified by DNA microarray based hybridisation analysis. The analysed regions of difference comprise approximately 7% of the entire M. ulcerans genome. Several different mechanisms leading to loss of functional genes were identified, ranging from pseudogenization, caused by frame shift mutations or mobile genetic element interspersing, to large sequence polymorphisms. Four hot spot regions for genetic instability were unveiled. Altogether, 229 coding sequences were found to be differentially inactivated, constituting a repertoire of coding sequence variation in the rather monomorphic M. ulcerans.
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Is global leukocyte DNA methylation altered in euthymic bipolar patients?
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Bipolar disorder is a complex disorder hypothesized to involve an interaction of multiple susceptibility genes and environmental factors. The environmental factors may be mediated via epigenetic mechanisms such as DNA methylation. Since a different extent of DNA methylation has recently been reported in lymphoblastoid cells derived from monozygotic twins discordant for bipolar disorder, we hypothesized that bipolar patients exhibit a different extent of leukocyte global DNA methylation compared with healthy controls. DNA was extracted from peripheral blood leukocytes of 49 euthymic bipolar patients and 27 matched healthy controls. Percent of global genome DNA methylation was measured using the cytosine-extension method. Plasma homocysteine levels were measured by HPLC. Leukocyte global DNA methylation did not differ between bipolar patients [62.3%+/-18.0 (S.D)] and control subjects (63.9%+/-14.6), p=0.70. Bipolar patients' plasma homocysteine levels (11.5 microM+/-4.8) did not differ from those of healthy controls (11.4+/-2.9), p=0.92.
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Injury to the saphenous vein endothelium during harvest impacts patency after coronary artery bypass graft surgery. Many centers are adopting endoscopic saphenous vein harvest (ESVH) instead of using the traditional open saphenous vein harvest (OSVH) technique. Our objective was to compare the effects of ESVH and OSVH on the structural and functional viability of saphenous vein endothelium using multiphoton imaging, immunofluorescence, and biochemical techniques. Ten patients scheduled for coronary artery bypass graft surgery were prospectively identified. Each underwent ESVH for one portion and OSVH for another portion of the saphenous vein. A 1-cm segment from each portion was immediately transported to the laboratory for processing. The vessel segments were labeled with fluorescent markers to quantify cell viability (esterase activity), calcium mobilization, and generation of nitric oxide. Samples were also labeled with immunofluorescent antibodies to visualize caveolin, endothelial nitric oxide synthase, von Willebrand factor, and cadherin, and extracted to identify these proteins using Western blot techniques. All labeling, imaging, and image analysis was done in a blinded fashion. Esterase activity was significantly higher in the OSVH group (p < 0.0001). Similarly, calcium mobilization and nitric oxide production were significantly greater in the OSVH group (p = 0.0209, p < 0.0001, respectively). Immunofluoresence and Western blot techniques demonstrated an abnormal alteration in distribution of caveolin and endothelial nitric oxide synthase in the ESVH group.
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Do activation conditions determine susceptibility of murine primary T-lymphocytes to retroviral infection?
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Genetically modified T-lymphocytes are potential therapeutic agents for the treatment of various disorders. Successful retroviral infection of primary murine T-lymphocytes is a prerequisite to the study of adoptive cell therapies in a small animal model. The definition of factors controlling retroviral infection of T-lymphocytes would also be useful to better understand retroviral diseases. However, retroviral-mediated gene transfer into murine primary T-cells has remained elusive. In order to define the requirements for stable and efficient gene transfer in primary murine T-lymphocytes, we investigated factors capable of affecting retroviral infection. These include activation conditions (using mitogens or monoclonal antibodies), culture conditions (including media composition and cytokine addition), timing of viral exposure, retroviral receptor selection (ecotropic, amphotropic, or vesicular stomatitis virus G (VSV-G) glycoprotein receptor), and viral titer. We show that efficient gene transfer can be achieved in murine T-lymphocytes, provided that a number of favorable conditions are met, in particular optimized T-cell activation conditions, optimal timing of infection, adequate interleukin-2 concentration and T-cell density, and a high viral titer. On a particulate basis, we find that ecotropic particles are more effective than amphotropic or VSV-G-pseudotyped particles, and recommend the use of a specifically selected retroviral packaging cell line. CD4+ T-cells are equally or more infectible than CD8+ lymphocytes, depending on the activation conditions. The Th1 and Th2 subsets are comparably susceptible to retroviral infection, in contrast to what has been reported in some instances of human T-cell infection by human immunodeficiency virus (HIV).
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In patients undergoing elective partial pancreatectomy, our aim was to evaluate the effect of metabolic syndrome (MS) on postoperative mortality, morbidity, and utilization of hospital resources. Our hypothesis was that MS is associated with worse surgical outcomes after pancreatectomy. Fifteen thousand eight hundred thirty-one patients undergoing elective pancreatectomy from 2005 to 2012 were identified in the Participant User File of the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP). Univariable and multivariable analyses were performed examining the association of MS (defined as body mass index ≥30 kg/m(2), hypertension requiring medications, and diabetes requiring medications and/or insulin) and risk of 30-day mortality, morbidity, and utilization of hospital resources (risk of blood transfusion in the first 72 h after pancreatectomy and prolonged hospital stay, defined as ≥13 days, which was the 75th percentile of this cohort). Multivariable logistic regression models controlled for age, sex, race, pancreatectomy type (distal versus proximal), smoking status, alcohol consumption, functional status, dyspnea, cardiovascular disease, hematocrit, INR, serum albumin, bilirubin, and creatinine. Stratified analyses were conducted by type of pancreatectomy and indication for pancreatectomy (benign versus malignant). On univariate analysis, 1070 (6.8%) patients had MS. MS was associated with increased postoperative morbidity, major morbidity, surgical site infection, septic shock, cardiac event, respiratory failure, pulmonary embolism, blood transfusion, and prolonged duration of hospital stay (P < 0.05 for all analyses). After controlling for potentially confounding variables, there was a 26% increased odds of postoperative morbidity (P < 0.001), 17% increased odds of major morbidity (P = 0.034), 32% increased odds of surgical site infection (P < 0.001), 34% increased odds of respiratory failure (P = 0.023), 68% increased odds of pulmonary embolism (P = 0.045), 26% increased odds of blood transfusion (P = 0.018), and 21% increased odds of prolonged hospital stay (P = 0.011) in patients with MS compared to patients without MS. MS was not associated with 30-day mortality after elective pancreatectomy (P = 0.465). When stratified by distal versus proximal pancreatectomy and benign versus malignant disease, the effect of MS on outcomes appears to be modified by type of pancreatectomy and indication with poorer outcomes observed for distal pancreatectomies and benign indications for resection.
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Is same-day intrauterine device placement rarely complicated by pelvic infection?
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To compare rates of pelvic inflammatory disease (PID) among women who did and did not receive an intrauterine device (IUD) the day they sought emergency contraception (EC) or pregnancy testing. Women, 15 to 45 years of age, who sought EC or pregnancy testing from an urban family planning clinic completed surveys at the time of their clinic visit (August 22, 2011, to May 30, 2013) and 3 months after their clinic visit. The surveys assessed contraceptive use and symptoms, testing, and treatment for sexually transmitted infections (STI) and PID. We reviewed the medical records of participants who reported IUD placement within 3 months of enrollment and abstracted de-identified electronic medical record (EMR) data on all women who sought EC or pregnancy testing from the study clinic during the study period. During the study period, 1,060 women visited the study clinic; 272 completed both enrollment and follow-up surveys. Among survey completers with same-day IUD placement, PID in the 3 months after enrollment was not more common (1/28 [3.6%]; 95% CI, 0%-10.4%) than among women who did not have a same-day IUD placed (11/225 [4.9%]; 95% CI, 2.7%-8.6%; p = .71). Chart review and EMR data similarly showed that rates of PID within 3 months of seeking EC or pregnancy testing were low whether women opted for same-day or delayed IUD placement.
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Radiation therapy after surgical resection is the approved treatment of gliomas, and survival benefits are reported with taxane-based chemotherapy. We investigated whether these regimes could be augmented with blood-brain barrier permeable drugs, N and D. Noscapine is an opioid antitussive, which acts anti cancer via blocking microtubule dynamics. Diltiazem is a calcium channel-blocking cardiac antiarrythmic, which also blocks tumor growth and P-glycoprotein. Effects of N (11.1 micromol/L), D (11.1 micromol/L), and T (11.7 micromol/L) were monitored in C6 glioma cells via S phase, colony formation, and fine structure analysis. Taxol depleted S phase from 35.2% to 12.2%. Both N and D synergistically augmented T-mediated S-phase depletion, and they also effectively reduced colonies, which were more potent by N by 49%. Taxol reduced colonies by 98%, and there were almost no surviving colonies in copresence of T with either N or D. Colony reduction by radiotherapy was increased strongly by T and significantly by N. Taxol and radiation profoundly increased number of mitochondria. Both D and N suppressed this increase via myelinosis and autophagy.
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Does pretreatment of rocuronium reduce the frequency and severity of etomidate-induced myoclonus?
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To investigate the effect of pretreatment with a low dose of rocuronium on the occurrence of etomidate-induced myoclonus. Prospective, randomized, double-blinded study. Medical center in South Korea. 110 ASA physical status I, II, and III patients scheduled for elective cardiac or pulmonary surgery with general anesthesia. All patients were randomized to pretreatment with a low dose of rocuronium (0.06 mg/kg; Group R) or placebo (saline; Group S), followed three minutes later by etomidate (0.3 mg/kg). Patients were monitored for myoclonic movements and pain on a scale of 0-3. Bispectral index (BIS) and electromyographic (EMG) activity were recorded continuously throughout the procedure. Frequency of myoclonus was significantly lower in Group R (25%) than in Group S (63%). In the latter group, there was no difference in the frequency of male (59%) and female (68%) patients experiencing myoclonus. In Group S, EMG activity and BIS were significantly increased in patients who experienced severe myoclonus, and BIS was well correlated with EMG activity.
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To explore lipocalin-2 (LCN-2) expression and its possible role and mechanism(s) of production in rat models of diet-inducible fatty liver. Fatty liver was triggered in male Sprague-Dawley rats fed either with liquid Lieber-DeCarli (LDC) or LDC + 70% cal fructose (L-HFr) diet for 4 or 8 wk. Chow-nourished animals served as controls. Hepatic expression of LCN-2 and other metabolic and inflammatory mediators was assessed by quantitative reverse transcription polymerase chain reaction and Western blotting. Serum LCN-2, fasting leptin, and lipid profile were evaluated via Enzyme-Linked Immunosorbent Assay, Radioimmunoassay, and colorimetric assays, respectively. The localization of LCN-2 in the liver was detected by using immunofluorescence staining. Furthermore, HE stain was used to evaluate hepatic fat degeneration and inflammation. Both LDC-fed and L-HFr-fed rat histologically featured fatty liver. In the liver, mRNA transcriptions of Mcp-1, a2-m, Il-8 and Glut5 were increased in the L-HFr group at both time points (P < 0.001), while the transcription of Tlr4, Inos, and Tnf-α was significantly up-regulated at week 4. Interestingly, hepatic Lcn-2 expression was 90-fold at week 4 and 507-fold at week 8 higher in L-HFr-subjected rats vs control (P < 0.001). In contrast to HDL-cholesterol, systemic levels of LCN-2, fasting leptin and triglycerides were elevated in the L-HFr regimen (P < 0.001). Moreover, protein expression of hepatic LCN-2, CD14, phospho-MAPK, caspase-9, cytochrome c and 4-hydroxynonenal was increased in the L-HFr group. Conversely, the hepatic expression of PGC-1α (a mitochondrial-biogenic protein) was reduced in the L-HFr category at week 8. The localization of LCN-2 in the liver was predominantly restricted to MPO⁺ granulocytes.
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Does hostility differentially predict cardiovascular risk factors in African American and White young adults?
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Hostility may influence racial disparities in cardiovascular disease through differential associations with cardiovascular risk factors. This study explored racial variations in relations between hostility and selected cardiovascular risk factors. Cook-Medley Hostility (Ho) scores and 11 risk factors were examined among 66 healthy, White and African American young adults. Controlling for age, gender, and body mass index, the interaction of hostility and race yielded significant (or marginal) associations with resting systolic and diastolic blood pressure (SBP, DBP), cardiac index (CI; i.e. cardiac output adjusted for body size), total peripheral resistance (TPR), insulin (INS), triglycerides (TG) and percent body fat (PBF). Contributing substantial variance, hostility was positively associated with SBP, DBP, TPR, TG and INS, and negatively associated with CI among African Americans. Conversely, hostility was negatively associated with TPR and PBF among Whites.
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Wee1-like kinase (Wee1) is a tyrosine kinase which negatively regulates entry into mitosis at the G2 to M-phase transition and has a role in inhibition of unscheduled DNA replication in S-phase. The present study investigated the clinical role of Wee1 in advanced-stage (FIGO III-IV) ovarian serous carcinoma. Wee1 protein expression was analyzed in 287 effusions using immunohistochemistry. Expression was analyzed for association with clinicopathologic parameters, including survival. Forty-five effusions were additionally studied using Western blotting. Wee1 was further silenced in SKOV3 and OVCAR8 cells by siRNA knockdown and proliferation was assessed. Nuclear expression of Wee1 in tumor cells was observed in 265/287 (92%) and 45/45 (100%) effusions by immunohistochemistry and Western blotting, respectively. Wee1 expression by immunohistochemistry was significantly higher in post-chemotherapy disease recurrence compared to pre-chemotherapy effusions obtained at diagnosis (p=0.002). Wee1 silencing in SKOV3 and OVCAR8 cells reduced proliferation. In univariate survival analysis of the entire cohort, a trend was observed between high (>25% of cells) Wee1 expression and poor overall survival (p=0.083). Survival analysis for 109 patients with post-chemotherapy effusions showed significant association between Wee1 expression and poor overall survival (p=0.004), a finding which retained its independent prognostic role in Cox multivariate analysis (p=0.003).
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Is dose escalation of infliximab therapy in arthritis patients related to diagnosis and concomitant methotrexate treatment : observational results from the South Swedish Arthritis Treatment Group register?
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To study frequency of dose escalation in infliximab-treated patients and to identify possible predictors thereof. Patients with chronic arthritis initiating their first course of anti-TNF treatment with infliximab at Lund University Hospital were included in a structured clinical follow-up protocol. Information on diagnosis, drug dosage, disease duration, previous and ongoing DMARDs, treatment start and cessation were prospectively collected during the period March 1999 through February 2007. All patients were started on a dose of 3 mg/kg at time 0, week 2, week 6 and then every eighth week independent of diagnosis and were followed for a period of 2 yrs. A total of 206 patients were included in the study. Thirty-two of the patients had PsA, 25 had AS and 149 patients had RA. A minor dose escalation, defined as less than doubling of the dosage, was observed for 53, 48 and 42% of the patients with PsA, AS and RA, respectively. The corresponding values for major dose escalation was observed for 19, 8 and 15% of the patients, respectively. Regression analysis showed that patients with a diagnosis of PsA (P = 0.03), longer follow-up period (P < 0.01), and lack of concomitant MTX treatment (P = 0.03) were significantly associated with risk of dose escalation.
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Atrial natriuretic peptide (ANP) is a hormone that has both antihypertrophic and antifibrotic properties in the heart. We hypothesized that myocyte-derived ANP inhibits endothelin (ET) gene expression in fibroblasts. We have investigated the mechanism(s) involved in the antiproliferative effect of ANP on cardiac fibroblasts in a cell culture model. We found that cardiac myocytes inhibited DNA synthesis in co-cultured cardiac fibroblasts as did treatment with the ET-1 antagonist BQ610. The effect of co-culture was reversed by antibody directed against ANP or the ANP receptor antagonist HS-142-1. ANP inhibited the expression of the ET-1 gene and ET-1 gene promoter activity in cultured fibroblasts. The site of the inhibition was localized to a GATA-binding site positioned between -132 and -135 upstream from the transcription start site. GATA4 expression was demonstrated in cardiac fibroblasts, GATA4 bound the ET-1 promoter both in vitro and in vivo, and siRNA-mediated knockdown of GATA4 inhibited ET-1 expression. ET-1 treatment resulted in increased levels of phospho-serine(105) GATA4 in cardiac fibroblasts and this induction was partially suppressed by co-treatment with ANP.
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Does prenatal zinc reduce stress response in adult rat offspring exposed to lipopolysaccharide during gestation?
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Previous investigations by our group have shown that prenatal treatment with lipopolysaccharide (LPS; 100 μg/kg, intraperitoneally) on gestation day (GD) 9.5 in rats, which mimics infections by Gram-negative bacteria, induces short- and long-term behavioral and neuroimmune changes in the offspring. Because LPS induces hypozincemia, dams were treated with zinc after LPS in an attempt to prevent or ameliorate the impairments induced by prenatal LPS exposure. LPS can also interfere with hypothalamic-pituitary-adrenal (HPA) axis development; thus, behavioral and neuroendocrine parameters linked to HPA axis were evaluated in adult offspring after a restraint stress session. We prenatally exposed Wistar rats to LPS (100 μg/kg, intraperitoneally, on GD 9.5). One hour later they received zinc (ZnSO4, 2 mg/kg, subcutaneously). Adult female offspring that were in metestrus/diestrus were submitted to a 2 h restraint stress session. Immediately after the stressor, 22 kHz ultrasonic vocalizations, open field behavior, serum corticosterone and brain-derived neurotrophic factor (BDNF) levels, and striatal and hypothalamic neurotransmitter and metabolite levels were assessed. Offspring that received prenatal zinc after LPS presented longer periods in silence, increased locomotion, and reduced serum corticosterone and striatal norepinephrine turnover compared with rats treated with LPS and saline. Prenatal zinc reduced acute restraint stress response in adult rats prenatally exposed to LPS.
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Bilateral lower extremity venous duplex scanning for acute deep venous thrombosis (DVT) has been advocated because of the high incidence of occult contralateral leg involvement. We investigated the clinical necessity of such a policy. The results from 2996 venous duplex studies performed during the past 2 years were retrospectively reviewed. A total of 1694 of these scans were performed on patients with symptoms, of whom 248 (15%) were found to have an acute DVT. Symptoms were limited to one side in 198 patients, whereas bilateral complaints were noted in 50 patients. Among the patients with symptoms of acute DVT, 72 (29%) had bilateral involvement. Bilaterality was more likely in patients with bilateral symptoms than in those with only unilateral symptoms (56% vs 22%; p < 0.005). Of the patients with unilateral symptoms and bilateral DVT, all of them had either acute (80%) or acute and chronic (20%) thrombosis in the symptomatic leg. The contralateral asymptomatic limb had fewer acute and more chronic DVT (41% and 55%, respectively). No patient from the entire group admitted with symptoms had an acute DVT in the asymptomatic limb without a concomitant acute DVT in the symptomatic leg. Unilateral scanning would decrease the examination time by 21% and potentially increase total reimbursement for symptomatic venous scans by 9% compared with routine bilateral duplex scanning.
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Does association Between Presence of Virulence Genes and Antibiotic Resistance in Clinical Klebsiella Pneumoniae isolate?
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To investigate the presence of rmpA and wcaG virulence genes and Class 1, 2, and 3 integrons, and to evaluate a relationship between antibiotic resistance and virulence in Klebsiella pneumoniae METHODS: We collected a total of 200 K. pneumoniae isolates from hospitals in Tehran, Iran. Antibiotic susceptibility was determined using the disk diffusion method. The extended-spectrum β-lactamase (ESBL) producers were detected using the combination disk method. We detected the rmpA and wcaG genes and class 1, 2, and 3 integrons via polymerase chain reaction (PCR). The χ Of 200 isolates, 115 (57.5%) were ESBL producers; 74.0% carried the class 1 integron, and 1.0% carried the class 2 integron. The gene rmpA was detected in 7% of isolates and the gene wcaG in 23.5% of isolates. Integron-positive isolates showed a higher prevalence of wcaG compared with to integron-negative isolates (P <.05).
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Existing dogma that a female is born with fixed number of eggs was challenged by the detection of stem cells in adult mammalian ovary. Data has accumulated in support of ovarian stem cells (OSCs) proliferation, maintenance in culture, formation of germ cell nests and differentiation into oocytes and primordial follicle assembly using different strategies. Flow cytometry analysis identified >8 μm OSCs which are DDX1 positive and are considered equivalent to spermatogonial stem cells (SSCs) in testis. Analysis of both ovarian and testicular smears obtained after enzymatic digestion has led to the identification of an additional stem cell population termed very small embryonic-like stem cells (VSELs). VSELs and OSCs/SSCs differ from each other in their size and OCT-4 expression. VSELs express pluripotent markers including nuclear OCT-4 whereas OSCs/SSCs express cytoplasmic OCT-4 suggesting a differentiated state. VSELs can be studied by flow cytometry as small sized cells which are LIN-/CD45-/Sca-1+. We have reported 0.02 ± 0.008, 0.03 ± 0.017 and 0.08 ± 0.03 % of total cells as VSELs in normal, chemoablated and after FSH treatment to chemoablated mouse ovary.
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Does acetyl-Ile-Gly-Leu protect neurons from Abeta ( 1-42 ) induced toxicity in vitro and in V337M human tau-expressing mice?
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We previously reported that the neurotoxicity of amyloid beta protein (Abeta(1-42), 10 nM) was blocked by an Abeta-derived tripeptide, Abeta(32-34) (Ile-Gly-Leu, IGL), suggesting that IGL may be a lead compound in the design of Abeta antagonists. In the present study, three stable forms of IGL peptide with acetylation of its N-terminal and/or amidation of its C-terminal (acetyl-IGL, IGL-NH(2) and acetyl-IGL-NH(2)) were synthesized and examined for their effects on Abeta-induced neurotoxicity. Phosphatidylinositol 4-kinase type II (PI4KII) activity was measured using recombinant human PI4KIIalpha kinase and cell viability was assessed in primary cultured hippocampal neurons. To test effects in vivo, 1.5 microl of 100 nM Abeta and/or 100 nM acetyl-IGL was injected into the hippocampal CA1 region of right hemisphere in transgenic mice expressing V337M human tau protein. Four weeks later, behavior performance in the Morris water maze was tested and after another 2 weeks, sections of brain were prepared for immunohistochemistry. Among the three modified tripeptides, acetyl-IGL attenuated the Abeta-induced inhibition of PI4KII activity as well as enhancement of glutamate neurotoxicity in primary cultured rat hippocampal neurons. Injection of Abeta into the hippocampus of mice impaired spatial memory and increased the number of degenerating neurons in bilateral hippocampal regions. Co-injection of acetyl-IGL prevented the learning impairment as well as the neuronal degeneration induced by Abeta.
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Serum cystatin C has been established as a predictor of cardiovascular events. The aim of this study was to evaluate the role of cystatin C in determining the presence and the severity of patients with coronary artery disease (CAD). A total of 936 subjects without overt renal disease were included in this cross-sectional study. Among them were 714 patients with CAD and 222 without based on coronary angiography. Subjects were further divided into four groups according to cystatin C quartile. Serum cystatin C was measured using particle-enhanced immunoassay method. The study analyzed the relationship of cystatin C levels with the presence and severity of CAD, including the number of stenotic vessels involved and Gensini score. Serum cystatin C levels were significantly higher in patients with CAD than those without (P<0.001), and significantly increased as the involvement of coronary vessels increased (P<0.001). The prevalence of CAD and its severity assessed by Gensini score were also significantly greater in the highest quartile of cystatin C (P<0.001). Moreover, cystatin C levels were independently correlated with the presence of CAD in a multivariate logistic regression model (P=0.023) and were positively correlated with Gensini score by linear regression analysis (standardized β=0.083, P=0.010).
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Does endotoxin preconditioning prevent cellular inflammatory response during ischemic neuroprotection in mice?
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Tolerance to ischemic brain injury is induced by several preconditioning stimuli, including lipopolysaccharide (LPS). A small dose of LPS given systemically confers ischemic protection in the brain, a process that appears to involve activation of an inflammatory response before ischemia. We postulated that LPS preconditioning modulates the cellular inflammatory response after cerebral ischemia, resulting in neuroprotection. Mice were treated with LPS (0.2 mg/kg) 48 hours before ischemia induced by transient middle cerebral artery occlusion (MCAO). The infarct was measured by 2,3,5-triphenyltetrazolium chloride staining. Microglia/macrophage responses after MCAO were assessed by immunofluorescence and flow cytometry. The effect of MCAO on white blood cells in the brain and peripheral circulation was measured by flow cytometry 48 hours after MCAO. LPS preconditioning induced significant neuroprotection against MCAO. Administration of low-dose LPS before MCAO prevented the cellular inflammatory response in the brain and blood. Specifically, LPS preconditioning suppressed neutrophil infiltration into the brain and microglia/macrophage activation in the ischemic hemisphere, which was paralleled by suppressed monocyte activation in the peripheral blood.
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Colorectal cancer mortality has started to decrease in several developed countries in Asia. The current study aimed to present the long-term trends in colorectal cancer mortality in Korea using joinpoint analysis and age-period-cohort modeling. The number of colorectal cancer deaths and the population for each 5-year age group were obtained from Statistics Korea for the period 1984-2013 for adults 30 years and older. Joinpoint regression analysis was conducted to determine changes in trends in age-standardized mortality rates, and age-period-cohort analysis was performed to describe trends in colorectal cancer mortality using the intrinsic estimator method. In men, the age-standardized mortality rate for colorectal cancer increased from 1984 to 2003, and the mortality rates stabilized thereafter, whereas the mortality rate of colorectal cancer in women has decreased since 2004. The age-specific mortality rate of colorectal cancer increased in both men and women over time, whereas decreases in the age-specific mortality rate in younger cohorts were observed. In the age-period-cohort analysis, old age and recent period were associated with higher mortality for both men and women. The birth cohort born after 1919 showed reduced colorectal cancer mortality in both men and women.
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Is prealbumin a more sensitive marker than albumin to assess the nutritional status in patients undergoing radiotherapy for head and neck cancer?
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The aim of this prospective study was to determine the prevalence of malnutrition and to evaluate a more sensitive marker to assess the nutritional status in patients undergoing RT for head and neck cancer. The prospective study included 51 (mean age of 57.6 ±11.2 years) patients undergoing RT for head and neck cancer. Malnutrition was defined as weight loss > 5% of baseline. Forty-six (90.2%) of 51 patients were male. Malnutrition developed in 33 (64.7%) patients during RT. Mean prealbumin level was significantly lower in patients with malnutrition than in those without malnutrition (17 ±5 g/dl vs. 22 ±5 g/dl, respectively, p = 0.004). On the other hand, there was no significant difference between the two groups in terms of other nutrition parameters including total protein, albumin, total cholesterol, triglyceride, and glucose (p > 0.05). The percentage of weight loss negatively correlated with prealbumin (r = -0.430, p = 0.002), but not with other nutrition parameters including total protein, albumin, triglyceride, total cholesterol, HDL cholesterol, LDL cholesterol, and glucose (p > 0.05).
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Preeclampsia (PE) is one of the most important complications of pregnancy that is associated with significant mortality and morbidity in mother and fetus. Since the etiologic factors in its development are still unclear, we aimed to examine the intercellular adhesion molecule-1 (ICAM-1) gene K469E polymorphism in preeclamptic and control healthy women. Genetic polymorphism was analyzed in 192 PE and 186 healthy control women. PCR-RFLP method was used to identify K469E polymorphism. The frequency of KK, KE, and EE genotypes of ICAM-1 gene was not different between PE patients and healthy pregnant women. Whereas, the frequency of KE and EE genotypes was significantly higher in severe PE than mild PE women and control group, and the risk of severe PE was 2.4-fold higher in subjects with KE genotype (OR, 2.4 [95% CI, 1 to 5.9]; P = 0.03) and 3.3-fold higher in subjects with EE genotype (OR, 3.3 [95% CI, 1.2 to 9]; P = 0.015) compared to individuals with KK genotype.
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Is hippocampal and prefrontal atrophy in patients with early non-demented Parkinson 's disease related to cognitive impairment?
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Early stage patients with Parkinson's disease (PD) show cognitive impairment in frontal lobe functions and memory tests. Hippocampal atrophy is seen in medicated patients with advanced PD. To examine whether prefrontal or hippocampal atrophy are already present in early stage PD, and whether such atrophy is associated with cognitive impairment. Twenty non-medicated, non-demented patients with early stage PD and 22 neurologically healthy age matched controls were studied. All subjects underwent magnetic resonance imaging to study hippocampal and prefrontal atrophy. Atrophy was evaluated by a neuroradiologist using a five point scale. In addition, the patients underwent a neuropsychological test battery sensitive to frontal lobe functions and memory. Patients with PD had atrophy in the right and the left prefrontal cortex. In the right hippocampus, the mean atrophy score was 1.15 in PD and 0.45 in controls. Corresponding figures for the left hippocampus were 1.05 for PD and 0.64 for controls. In PD, the left hippocampus atrophy correlated with verbal memory and prefrontal atrophy correlated with impaired performance in a test measuring vigilance.
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The interactions of selectins and their ligands initiate the process of leukocyte migrating into inflamed tissue. P-selectin glycoprotein ligand 1 (PSGL-1) is the best characterized ligand of selectins, and has been demonstrated to mediate the adhesion of leukocytes to all three selectins in vivo. PSGL-1 not only functions as an anchor molecule to capture the leukocytes to the activated endothelial cells by its interaction with selectins, but also transduces the signals to activate leukocytes. Our present work aimed to investigate the mechanism by which PSGL-1-mediated signal activates neutrophils and enhances the adhesion to the endothelial cells. We detected the effects of the engagement of PSGL-1 with monoclonal antibodies (mAb) or P-selectin on the adhesion of neutrophils to the recombinant intercellular adhesion molecule-1 (ICAM-1), and on the expression of beta(2)-integrin. Additionally, the role of cytoskeleton in these process was studied by using inhibitor cytochalasin B. The engagement of PSGL-1 increased the expression of beta(2)-integrin on the surface of neutrophils and enhanced the adhesion of neutrophils to the recombinant ICAM-1. mAb against CD18 impaired the adhesion of PSGL-1-engaged neutrophils to ICAM-1. Moreover, the inhibitor cytochalasin B largely blocked the increase of CD18 expression as well as the adhesion of PSGL-1-engaged neutrophils to ICAM-1.
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Is collagen degradation by interleukin-1beta-stimulated gingival fibroblasts accompanied by release and activation of multiple matrix metalloproteinases and cysteine proteinases?
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Several collagenolytic matrix metalloproteinases (MMPs) have recently been identified in gingival fibroblasts, while secreted cysteine proteinases could also participate in connective tissue destruction in periodontitis. To clarify their involvement, we examined enzyme release during collagen breakdown by cultured cytokine-stimulated fibroblasts. Gingival fibroblasts were derived from four chronic periodontitis patients and cultured on collagen gels in serum-free medium for 1-4 days. Collagenolysis was measured by hydroxyproline release into the medium. Proteinases were assessed by electrophoresis and immunoblotting. Adding interleukin-1beta resulted in progressive gel breakdown. This was associated particularly with a shift in MMP-1 band position from proenzyme to active enzyme and the appearance of active as well as proenzyme forms of cathepsin B. There was also partial processing of pro-MMP-13 and increased immunoreactivity for active cathepsin L. In addition, both pro-forms and active forms of MMP-8, membrane-type-1-MMP and MMP-2 were present in control and treated cultures.
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Compared with standard donors, kidneys recovered from donors after cardiac death (DCD) exhibit higher rates of delayed graft function (DGF), and DCD livers demonstrate higher rates of biliary ischemia, graft loss, and worse patient survival. Current practice limits the use of these organs based on time from donor extubation to asystole, but data to support this is incomplete. We hypothesized that donor postextubation parameters, including duration and severity of hemodynamic instability or hypoxia might be a better predictor of subsequent graft function. We performed a retrospective examination of the New England Organ Bank DCD database, concentrating on donor factors including vital signs after withdrawal of support. Prolonged, severe hypotension in the postextubation period was a better predictor of subsequent organ function that time from extubation to asystole. For DCD kidneys, this manifested as a trend toward increased DGF. For DCD livers, this manifested as increased rates of poor outcomes. Maximizing the predictive value of this test in the liver cohort suggested that greater than 15 min between the time when the donor systolic blood pressure drops below 50 mm Hg and flush correlates with increased rates of diffuse biliary ischemia, graft loss, or death. Donor age also correlated with worse outcome.
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Is microcoagulation of junctional dorsal root entry zone effective treatment of brachial plexus avulsion pain : long-term follow-up study?
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To analyze long-term clinical results of coagulation lesions of the dorsal root entry zone (DREZ) in patients with deafferentation pain due to brachial plexus avulsion and to correlate the pain relief after DREZ coagulation with pain duration before the DREZ coagulation. Twenty-six patients with intractable deafferentation pain after brachial plexus avulsion lesion were treated for pain at the Department of Neurosurgery. Junctional coagulation lesion was made with bipolar forceps along the DREZ. The patients assessed post-operative analgesic effect using a visual analog scale at 1 week, 1 year, 3 years, and 5 years after the surgery. The greatest pain relief was reported immediately after the DREZ procedure. Over the 5-year follow-up period, the pain relief effect gradually and significantly decreased. There were no significant differences between the pain relief evaluated at 1 week and after 1 year and between the pain relief evaluated at 1 week and after 3 years. There was a correlation between the pain duration before the surgery and pain relief after the surgery, with best correlation found between pain duration before surgery and pain relief 5 years after DREZ procedure (r = 0.623, P = 0.007).
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Increased circulating methylarginines (MA) have been linked to the metabolic syndrome to explain endothelial dysfunction and cardiovascular disease risk. Proteins that contain MA are regulatory and release them during catabolism. We hypothesised that increased protein turnover in insulin-resistant states contributes to an increase in circulating MA. MATWERIALS AND METHODS: We performed hyperinsulinaemic, euglycaemic, and isoaminoacidaemic experiments on 49 lean, obese and elderly subjects, with measurements of the kinetics of glucose and protein metabolism. Plasma MA, i.e. asymmetrical dimethylarginine (ADMA), symmetrical dimethylarginine (SDMA), and N -monomethyl-L-arginine (NMMA), lipids and body composition were measured. Insulin resistance of glucose and protein metabolism occurred in obese and elderly subjects. ADMA concentrations were 29 to 120% higher in obese and 34% higher in elderly than in lean subjects. SDMA were 34 and 20% higher in obese than in lean and than in elderly subjects, respectively. NMMA were 32% higher in obese than in lean subjects. ADMA differed by sex, being higher in men, namely by 1.75x in obese men and by 1.27x in elderly men. Postabsorptive ADMA (r=0.71), SDMA (r=0.46), and NMMA (r=0.31) correlated (all p<0.05) with rates of protein flux. All three MA correlated negatively with clamp glucose infusion rates and uptake (p<0.001). ADMA and SDMA correlated negatively with net protein synthesis and clamp amino acid infusion rates (p<0.05). All MA also correlated with adiposity indices and fasting insulin and triglycerides (p<0.05).
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Does alternative first exon splicing regulate subcellular distribution of methionine sulfoxide reductases?
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Methionine sulfoxide reduction is an important protein repair pathway that protects against oxidative stress, controls protein function and has a role in regulation of aging. There are two enzymes that reduce stereospecifically oxidized methionine residues: MsrA (methionine-S-sulfoxide reductase) and MsrB (methionine-R-sulfoxide reductase). In many organisms, these enzymes are targeted to various cellular compartments. In mammals, a single MsrA gene is known, however, its product is present in cytosol, nucleus, and mitochondria. In contrast, three mammalian MsrB genes have been identified whose products are located in different cellular compartments. In the present study, we identified and characterized alternatively spliced forms of mammalian MsrA. In addition to the previously known variant containing an N-terminal mitochondrial signal peptide and distributed between mitochondria and cytosol, a second mouse and human form was detected in silico. This form, MsrA(S), was generated using an alternative first exon. MsrA(S) was enzymatically active and was present in cytosol and nucleus in transfected cells, but occurred below detection limits in tested mouse tissues. The third alternative form lacked the active site and could not be functional. In addition, we found that mitochondrial and cytosolic forms of both MsrA and MsrB in Drosophila could be generated by alternative first exon splicing.
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It has been argued that carotid intima-media thickness (IMT) could better reflect an adaptive response of the vessel wall rather than being a marker of atherosclerosis. We explore this hypothesis by analyzing the ARTICO data. The ARTICO study was designed to evaluate the prognostic value of the pathological ankle-brachial index (ABI) for the emergence of new vascular events in patients who have suffered a noncardioembolic stroke. Collected variables were as follows: vascular risk factors, mean waist perimeter, quantification of carotid IMT, characteristics of carotid plaques, ABI, and presence of microalbuminuria. A total of 591 patients with a complete carotid evaluation were available. There was no correlation between ABI and IMT (Spearman's, p NS). Logistic regression revealed that pathological ABI correlated significantly only with internal carotid artery stenosis greater than or equal to 50% (OR [odds ratio] 2.80, 1.66-4.71, P < .01) and peripheral artery disease (OR 3.33, 1.63-6.78, P < .01). However, multivariate regression analysis demonstrated that carotid IMT was independently associated with age (OR 1.05, 95% confidence interval [CI] 1.02-1.09, P < .01), hypertension (OR 1.83, 95% CI 1.02-3.26, P = .04), waist circumference (OR 1.03, 95% CI 1.01-1.05, P < .01), and microalbuminuria (OR 2.02, 95% CI 1.22-3.35, P < .01).
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Is [ Coding single nucleotide polymorphism an ideal marker for detecting gene imprinting by 5 ' nuclease assay ]?
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To establish a novel approach for quick and high throughput verification of human gene imprinting. By use of a pair of dye-labeled probes, 5' nuclease assay was combined with reverse transcriptase-PCR(RT-PCR) to genotype a coding single nucleotide polymorphism (cSNP), rs705(C/T) of a known imprinted gene, small nuclear ribonucleotide protein N (SNRPN), on both genomic DNA and cDNA of human lymphoblast cell lines. Allele discrimination showed a clear monoallelic expression pattern of SNRPN, which was confirmed by RT-PCR based restriction fragment length polymorphisms. Pedigree analysis verified the paternal origin of expressed allele, which is in consistency with previous report.
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To identify the cost to the Medicare program for patients with either stable or progressive vision loss and to estimate the impact on eye-related and non-eye related care. Retrospective cohort study. The study population was Medicare beneficiaries included in the standard 5% analytic sample and continuously enrolled from 1999 to 2003, excluding Medicare managed-care enrollees. Vision loss was categorized as moderate loss, severe loss, and blindness, based on International Classification of Diseases 9, Clinical Modification codes. Average yearly cost of eye-related and non-eye related medical care during 1999 to 2003, in 2003 dollars. (1) depression, (2) injury, (3) skilled nursing facility (SNF) utilization, and (4) long-term care facility (LTC) admission. Compared with patients with normal vision, excess adjusted mean eye-related costs were 345 dollars, 407 dollars, and 237 dollars annually for those with moderate loss, severe loss, and blindness, respectively; annual excess non-eye related costs were 2193 dollars, 3301 dollars, and 4443 dollars, respectively. At each level of vision loss, those progressing from a presumably normal state at baseline incurred higher Medicare costs than those with that level of vision loss at baseline. Any degree of progressive vision loss was associated with an increased risk of depression, injury, SNF utilization, and LTC admission. Identifiable costs attributable to these complications explained 27% to 41% of the excess costs associated with vision loss.
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Do african American Patients with Chronic Rhinosinusitis Have a Distinct Phenotype of Polyposis Associated with Increased Asthma Hospitalization?
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Chronic rhinosinusitis (CRS) is a common inflammatory disease of the upper airways that is often categorized into subtypes including "with" and "without" nasal polyps. However, the influence of multiple important epidemiologic factors, including race, on CRS has not been investigated. The present study assessed various phenotypic characteristics of CRS in patients, living in the United States, with different racial backgrounds. We performed a large retrospective cohort study of patients with CRS treated at a large urban tertiary care referral center in Chicago. African American (AA) patients with CRS living in Chicago were more likely to report hyposmia as a symptom of CRS. Furthermore, AA patients with CRS who failed medical therapy and required surgical intervention had a significantly higher frequency of nasal polyposis and aspirin-exacerbated respiratory disease, and a higher disease severity index on computed tomography imaging than did white patients with CRS. The increased polyposis in AAs was associated with increased hospitalization for asthma. There were no differences in the prevalence of atopy, asthma, atopic dermatitis, food allergy, duration of disease, or number of surgeries between different races.
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To investigate how affects electrical-conduction function following myocardial infarction (MI) in rats. Thirty SD rats of either sex (220-250 g) were anesthetized using chlorine hydrate and were randomly divided into three groups: control group, MI group and transplantation group. The field potential (FP) morphology and activation-conduction duration were recorded with microeletrode array techniques. The MEA recorded clear FP morphology. Activation-conduction duration was (6.5 ± 2.12) ms in the control group, (17.5 ± 3.54) ms in the MI group, and (9.13 ± 1.31) ms in the transplantation group.
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Do a prospective study of the diagnostic utility of sputum Gram stain in pneumonia?
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Sputum Gram stain and culture have been said to be unreliable indicators of the microbiological diagnosis of bacterial pneumonia. The etiological diagnosis of pneumonia is surrounded by great degree of uncertainty. This uncertainty should be and can be calculated and incorporated in the diagnosis and treatment. To determine the diagnostic accuracy and diagnostic value of sputum Gram stain in etiological diagnosis and initial selection of antimicrobial therapy of bacterial community acquired pneumonia (CAP). DESIGN-METHOD: Prospective study of 1390 patients with CAP admitted January 2002-June 2008, to our institutions. Of the 1390 patients, 178 (12.8%) fulfilled the criteria for inclusion into this study (good-quality sputa and presence of the same microorganism in blood and sputum cultures which was used as gold standard for assessing the diagnostic accuracy and diagnostic value of sputum Gram stain). The sensitivity of sputum Gram stain was 0.82 for Pneumococcal pneumonia, 0.76 for Staphylococcal pneumonia, 0.79 for Haemophilus influenzae pneumonia and 0.78 for Gram-negative bacilli pneumonia. The specificity of sputum Gram stain was 0.93 for Pneumococcal pneumonia, 0.96 for Staphylococcal pneumonia, 0.96 for H. influenzae pneumonia and 0.95 for Gram-negative bacilli pneumonia. The positive likelihood ratio (LR+) was 11.58 for Pneumococcal pneumonia, 19.38 for Staphylococcal pneumonia, 16.84 for H. influenzae pneumonia, 14.26 for Gram-negative bacilli pneumonia. The negative likelihood ratio (LR-) was 0.20 for Pneumococcal pneumonia, 0.25 for Staphylococcal pneumonia, 0.22 for H. influenzae pneumonia, and 0.23 for Gram-negative bacilli pneumonia.
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Increased consumption of a high-fat (HF) diet is a salient contributor to obesity; however, how diminished satiation signaling contributes to overconsumption and obesity development remains poorly understood. Using obese-prone (OP) and obese-resistant (OR) rats, we tested feeding responses to intragastric liquid meal replacement, prior and after HF feeding. Next, chow- and HF-fed OP and OR rats were tested for sensitivity to intraduodenal glucose, intralipid, and meal replacement loads. To examine the role of glucagon-like peptide-1 (GLP-1) and vagal signaling, animals were treated with exendin-9, GLP-1 receptor antagonist, prior to meal replacement infusion, and Fos-like immunoreactivity (Fos-Li) in the dorsal hindbrain was examined after infusion. OP and OR rats reduced chow intake equally following gastric liquid meal; however, after 2 weeks of HF feeding, intragastric meal replacement reduced food intake less in OP than OR. Similarly, HF feeding, but not chow, diminished the suppressive effects of intraduodenal meal replacement, glucose, and intralipid in OP compared to OR. This effect was associated with lower Fos-Li expression in the dorsal hindbrain of OP rats. Finally, exendin-9 failed to attenuate reduction of food intake by meal replacement in OP rats during HF feeding.
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Is lymphopenia at presentation associated with increased risk of infections in patients with systemic lupus erythematosus?
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Patients with systemic lupus erythematosus (SLE) frequently suffer from infections, but the predisposing risk factors, as well as the exact frequency and nature of such infections, are not fully understood. To describe the frequency, types and risk factors for infections in a group of Chinese patients in the early stage of SLE in Hong Kong. Retrospective record study. We reviewed the case records of 91 Chinese SLE patients, presenting <12 months after SLE diagnosis. Details of major infections (requiring intravenous antimicrobial therapy, or any confirmed mycobacterial infection) and minor infections were reviewed. Clinical and laboratory features, the systemic lupus erythematosus disease activity index (SLEDAI) at presentation and drug treatment were recorded and analysed. There were 48 major infections and 62 minor infections during 260 patient-years of follow-up. A lymphocyte count < or =1.0 x 10(9)/l at presentation was independently associated with an increased risk for major infection: hazard ratio 4.7 (95%CI 1.6-13.7), p = 0.005. SLEDAI, use of corticosteroids and immunosuppressive therapy were all not associated with increased risk of infection.
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Preconditioning neurons with noninjurious hypoxia (hypoxic preconditioning, HPC) or the anesthetic isoflurane (APC) induces tolerance of severe ischemic stress. The mechanisms of both types of preconditioning in the hippocampus require moderate increases in intracellular Ca and activation of protein kinase signaling. The authors hypothesized that the expression of signal transduction genes would be similar after APC and HPC. Hippocampal slice cultures prepared from 9-day-old rats were preconditioned with hypoxia (5 min of 95% nitrogen/5% carbon dioxide) or 1% isoflurane in air/5% carbon dioxide for 1 h. A day later, cultures were subjected to 10 min oxygen and glucose deprivation (simulated ischemia). Intracellular Ca, measured in CA1 neurons at the completion of preconditioning, and cell death in CA1, CA3, and dentate regions was assessed 48 h after simulated ischemia. Message RNA encoding 119 signal transduction genes was quantified with rat complimentary DNA microarrays from pre-oxygen-glucose deprivation samples. Both APC and HPC increased intracellular Ca approximately 50 nm and decreased CA1, CA3, and dentate neuron death by about 50% after simulated ischemia. Many signaling genes were increased after preconditioning, with hypoxia increasing more apoptosis/survival genes (8 of 10) than isoflurane (0 of 10). In contrast, isoflurane increased more cell cycle/development/growth genes than did hypoxia (8 of 14 genes, vs. 1 of 14).
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Is population-based stepwise screening for unrecognised Type 2 diabetes ineffective in general practice despite reliable algorithms?
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The yield of screening programmes for Type 2 diabetes in the existing healthcare setting might be lower than anticipated from tests of screening algorithms in data from epidemiological surveys. Our aims were to evaluate the reliability of the algorithms and the effectiveness of a proposed stepwise screening programme for Type 2 diabetes in general practice. The screening programme had four steps: (i) mail-distributed self-administered risk-chart; (ii) screening tests: random blood glucose (RBG) and HbA(1)c; (iii) diagnostic procedure 1 for fasting blood glucose (FBG) (if RBG >/=5.5 mmol/l or HbA(1)c >/=6.1%); and (iv) OGTT as diagnostic procedure 2 (if 5.6</=FBG<6.1 mmol/l or HbA(1)c >/=6.1%). Abnormalities of glucose metabolism were classified according to the WHO 1999 criteria, based on capillary whole blood. The subjects were all patients between 40 and 69 years of age ( n=60,926) who were registered in 88 general practices and had not been previously diagnosed with diabetes. A total of 11,263 individuals had a high-risk risk-score and attended the screening consultation (step 1 test-positive). Of these, 30.1% needed diagnostic tests (step 2 test-positive) and 27.2% of these needed an OGTT (step 3 test-positive). The test-positive proportions were equal to the proportions obtained in data from a population-based survey from Step 2 onwards, and the algorithms were thus reliable. The identification rate was only 19% of all prevalent undiagnosed diabetes according to a recently published prevalence estimate. This was due to a large dropout rate among high-risk individuals prior to entry into the programme.
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Improper mechanical ventilation can exacerbate acute lung damage, causing a secondary ventilator-induced lung injury (VILI). We hypothesized that VILI can be reduced by modifying specific components of the ventilation waveform (mechanical breath), and we studied the impact of airway pressure release ventilation (APRV) and controlled mandatory ventilation (CMV) on the lung micro-anatomy (alveoli and conducting airways). The distribution of gas during inspiration and expiration and the strain generated during mechanical ventilation in the micro-anatomy (micro-strain) were calculated. Rats were anesthetized, surgically prepared, and randomized into 1 uninjured control group (n = 2) and 4 groups with lung injury: APRV 75% (n = 2), time at expiration (TLow) set to terminate appropriately at 75% of peak expiratory flow rate (PEFR); APRV 10% (n = 2), TLow set to terminate inappropriately at 10% of PEFR; CMV with PEEP 5 cm H2O (PEEP 5; n = 2); or PEEP 16 cm H2O (PEEP 16; n = 2). Lung injury was induced in the experimental groups by Tween lavage and ventilated with their respective settings. Lungs were fixed at peak inspiration and end expiration for standard histology. Conducting airway and alveolar air space areas were quantified and conducting airway micro-strain was calculated. All lung injury groups redistributed inspired gas away from alveoli into the conducting airways. The APRV 75% minimized gas redistribution and micro-strain in the conducting airways and provided the alveolar air space occupancy most similar to control at both inspiration and expiration.
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Does d1 dopamine receptor signaling involve caveolin-2 in HEK-293 cells?
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Dopamine receptors in the kidney, especially those belonging to the D1-like receptor family, are important in the regulation of renal function and blood pressure. Because of increasing evidence that G protein-coupled receptors (GPCRs) are associated with caveolae and lipid rafts, we tested the hypothesis that the D1 dopamine receptor (D1R) and signaling molecules are regulated by caveolin in caveolae or lipid rafts. Six experimental approaches were used: (1) construction of tagged human D1Rs (hD1Rs) and transfectants; (2) cell culture [human embryonic kidney (HEK)-293 and immortalized rat renal proximal tubule cells] and biotinylation; (3) cell fractionation by sucrose gradient centrifugation; (4) immunoprecipitation and immunoblotting; (5) immunofluorescence and confocal microscopy; and (6) adenylyl cyclase assays. hD1Rs, heterologously expressed in HEK-293 cells, formed protein species with molecular mass ranging from 50 to 250 kD, and were localized in lipid rafts and nonraft plasma membranes. The hD1Rs cofractionated with caveolin-2, G protein subunits, and several signaling molecules. Both exogenously expressed hD1Rs and endogenously expressed rat D1Rs colocalized and coimmunoprecipitated with caveolin-2. A D1R agonist (fenoldopam) increased the amount of caveolin-2beta associated with hD1Rs and activated adenylyl cyclase to a greater extent in lipid rafts than in nonraft plasma membranes. Reduction in the expression of caveolin-2 with antisense oligonucleotides attenuated the stimulatory effect of fenoldopam on cyclic adenosine monophosphate (cAMP) accumulation.
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Locally advanced colorectal cancer often requires extended resection to radically remove all tumor. This is the only chance for cure in these patients, but a higher complication rate would be expected. To evaluate the overall benefit for the patient, this study assesses morbidity and mortality as well as long-term survival of patients who underwent extended resection for a T3-T4 carcinoma. Two hundred twenty patients with locally advanced adenocarcinoma of the colorectum were included. One hundred fifty presented with a T3 and 70 with a T4 tumor. Eighty-three patients underwent extended resection. In 38 patients extended en bloc resection was performed because of inflammatory adherence mimicking infiltration. Thirty-three patients who underwent extended resections were over 70 years of age. There were no significant differences between the groups that underwent extended or nonextended resections in age, sex, stage, or grading. pT4 lesions were significantly more frequent in the extended resection group than in the nonextended resection group. Mean survival was 44 months after extended resections and 45 months after nonextended resections. In the extended resection group there was no significant difference in mean survival between pT3 and pT4 stage patients within 46 and 38 months, respectively. In patients who underwent nonextended resections, however, there was a significant difference in mean survival within 48 months for pT3 and 28 for pT4 patients (P < 0.05). Postoperative morbidity and mortality were comparable between the extended resection group and the non-extended resection group. The presence of residual tumor influenced prognosis of patients significantly; R0 resections fared significantly better than patients who underwent R1 or R2 resections (55 and 51 to 14/12 and 23/8 months) (P < 0.01). Nodal stage and International Union Against Cancer stage were also significant determinants of prognosis. After extended resections mean survival morbidity and 30-day mortality in patients more than 70 years was similar to those less than 70 years.
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Do patients with colorectal cancer associated with Lynch syndrome and MLH1 promoter hypermethylation have similar prognoses?
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Mismatch repair-deficient (dMMR) colorectal cancer (CRC) is caused by Lynch syndrome (LS) in 3% and sporadic inactivation of MLH1 by hypermethylation (MLH1-hm) in 12% of cases. It is not clear whether outcomes between LS-associated and MLH1-hm CRC differ. The objective of this study was to explore differences in clinical factors and outcomes in these two groups. Patients with dMMR CRC identified by immunohistochemistry staining and treated at a single institution from 1998 to 2012 were included. MLH1-hm was established with BRAF mutational analysis or hypermethylation testing. Patients' charts were accessed for information on pathology, germ-line MMR mutation testing, and clinical course. A total of 143 patients had CRC associated with LS (37 patients, 26%) or MLH1-hm (106 patients, 74%). Patients with LS were younger, more often male, presented more often with stage III disease, and had more metachronous disease than patients with MLH1-hm tumors. There was no difference in cancer-specific survival (CSS) between the groups; overall survival was longer in patients with LS, but this difference was minimal after adjusting for age and stage at diagnosis.
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To evaluate nitric oxide and interleukin (IL)-6, IL-8 and IL-13 in the exhaled breath of children with allergic rhinitis (AR), before and after intranasal allergen exposure. A total of 49 children with AR – comprising 20 who also had episodic asthma (AR+A) and 29 without asthma (AR) – were compared with 34 healthy controls. Nitric oxide concentrations in exhaled air (eNO) and IL-6, IL-8 and IL-13 in exhaled breath condensates (EBC) were measured in winter, outside the natural allergen exposure season, before and after an intranasal allergen challenge. The mean concentrations of eNO, IL-6 and IL-13 were significantly higher in the two AR groups. The concentration of IL-8 was below the assay detection limit in all EBC samples. The intranasal allergen challenge increased IL-13/EBC levels in both AR groups, but did not influence mean concentrations of eNO, IL-6 or IL-8. No challenge-related changes in IL-13/EBC were observed in the allergen-exposed controls or placebo-exposed children.
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Do an intricate network of conserved DNA upstream motifs and associated transcription factors regulate the expression of uromodulin gene?
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Uromodulin is a kidney specific glycoprotein whose expression can modulate kidney homeostasis. However, the set of sequence specific transcription factors that regulate the uromodulin gene UMOD and their upstream binding locations are not well characterized. We built a high resolution map of its transcriptional regulation. We applied in silico phylogenetic footprinting on the upstream regulatory regions of a diverse set of human UMOD orthologs to identify conserved binding motifs and corresponding position specific weight matrices. We further analyzed the predicted binding motifs by motif comparison, which identified transcription factors likely to bind these discovered motifs. Predicted transcription factors were then integrated with experimentally known protein-protein interactions available from public databases and tissue specific expression resources to delineate important regulators controlling UMOD expression. Analysis allowed the identification of a reliable set of binding motifs in the upstream regulatory regions of UMOD to build a high confidence compendium of transcription factors that could bind these motifs, such as GATA3, HNF1B, SP1, SMAD3, RUNX2 and KLF4. ENCODE deoxyribonuclease I hypersensitivity sites in the UMOD upstream region of the mouse kidney confirmed that some of these binding motifs were open to binding by predicted transcription factors. The transcription factor-transcription factor network revealed several highly connected transcription factors, such as SP1, SP3, TP53, POU2F1, RARB, RARA and RXRA, as well as the likely protein complexes formed between them. Expression levels of these transcription factors in the kidney suggest their central role in controlling UMOD expression.
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Platelet transfusion is accompanied by febrile nonhemolytic transfusion reactions. The generation of cytokines (like IL-1 beta, IL-6, IL-8, and TNF-alpha) in platelet concentrates by white cells is suggested to be responsible for febrile nonhemolytic transfusion reactions. The number of white cells in the platelet concentrates is crucial to cytokine generation. This study was performed to determine whether WBC reduction in platelet concentrates by prestorage leukodepletion filters or inactivation by gamma radiation reduced the levels of these cytokines during storage for 3 days. Each of the platelet concentrates (n = 54) was prepared from a single random donor by platelet-rich plasma. This was then divided into four groups: 1) unfiltered, nonirradiated random-donner platelet concentrates (n = 13); 2) unfiltered, gamma-irradiated random-donner platelet concentrates (n = 16); 3) filtered, nonirradiated random-donner platelet concentrates (n = 14); and 4) filtered, gamma-irradiated random-donner platelet concentrates (n = 11). Cytokine levels in platelet concentrates supernatants were measured by ELISA kits according to the manufacturer's recommendations. Our results showed that IL-8 was detected in unfiltered, nonirradiated, and gamma-irradiated random-donner platelet concentrates but not in the filtered random-donner platelet concentrates. TNF-alpha was only detected in unfiltered, nonirradiated units. Compared with unfiltered platelet concentrates, prestorage filtration prevented a rise in the IL-8 and TNF-alpha on day 3 of storage. The concentration of IL-1 beta was lower than the minimum concentration value of the kit used for this purpose. IL-6 was detected only in 7 units of all filtered platelet concentrates on day 3.
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Does pancreatic neuropathy result in `` neural remodeling '' and altered pancreatic innervation in chronic pancreatitis and pancreatic cancer?
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Chronic pancreatitis (CP) and pancreatic cancer (PCa) are characterized by intrapancreatic neuropathic alterations, including increased neural density and hypertrophy, pancreatic neuritis and neural invasion (NI) by cancer cells in PCa. The aim of this study was to identify the influence of these neuropathic changes on the quality of pancreatic innervation, intrapancreatic glia, and visceral pain. Pancreatic nerve fiber qualities were characterized by immunohistochemical visualization of various markers, including those for sympathetic (tyrosine hydroxylase, TH) and cholinergic innervation (choline acetyltransferase, ChAT), as well as the glial transcription factor, Sox10, and the neuroepithelial progenitor cell marker, Nestin, in normal pancreas (NP, n=16), CP (n=20), and PCa (n=20) patients. The neural immunoreactivity scores of these markers were correlated with the severity of intrapancreatic neuropathic changes and with abdominal pain sensation of patients. Pancreatic sympathetic innervation was significantly reduced in CP and PCa, whereas parasympathetic innervation did not show major changes. Nestin neuro-immunoreactivity was stronger, and Sox10-immunoreactivity was weaker in CP and PCa than in NP. Pancreatic sympathetic and cholinergic innervation was noticeably decreased in patients with severe pancreatic neuritis, NI by cancer cells, or abdominal pain. Moreover, the neural immunoreactivity for Sox10 and Nestin also varied with intrapancreatic neuropathic alterations and abdominal pain.
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Hair concentrations are a noninvasive measure of cumulative antiretroviral exposure and the strongest predictor of viral suppression in large cohorts of nonpregnant patients. We examined hair concentrations of antiretrovirals in relation to virologic outcomes in pregnant and breastfeeding women for the first time. The Prevention of Malaria and HIV Disease in Tororo trial (NCT00993031) enrolled HIV-infected pregnant Ugandan women at 12-28 weeks gestation who were randomized to lopinavir or efavirenz-based antiretroviral therapy (ART). Small hair samples were collected at 30-34 weeks gestation and 10-25 weeks postpartum. Efavirenz and lopinavir hair concentrations were measured via liquid chromatography/tandem mass spectrometry. Multivariate logistic regression models examined predictors of viral suppression (HIV-1 RNA ≤400 copies/ml) at delivery and 24 weeks postpartum. Among 325 women, median CD4 cell count was 366 cells/μl (interquartile range 270-488) at ART initiation. Mean self-reported 3-day adherence was greater than 97% in each arm. Viral suppression was achieved by 98.0% (efavirenz) and 87.4% (lopinavir) at delivery. At 24 weeks postpartum, 92.5% (efavirenz) and 90.6% (lopinavir) achieved viral suppression; 88% of women were breastfeeding. In multivariate models including self-reported adherence and pretreatment HIV-1 RNA, antiretroviral hair concentrations were the strongest predictor of viral suppression at delivery [efavirenz: adjusted odds ratio (aOR) 1.86 per doubling in concentration, 95% confidence interval (CI) 1.14-3.1, P = 0.013; lopinavir: aOR 1.90, 95% CI 1.33-2.7, P = 0.0004] and 24 weeks postpartum (efavirenz: aOR 1.81, 95% CI 1.22-2.7, P = 0.003; lopinavir: aOR 1.53, 95% CI 1.05-2.2, P = 0.026).
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Does glucose control predict 2-year change in lipid profile in youth with type 1 diabetes?
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To test the hypothesis that a change in glycated hemoglobin (A1c) over a follow-up interval of approximately 2 years would be associated with concomitant changes in fasting lipids in individuals with type 1 diabetes (T1D). All subjects with T1D diagnosed in 2002-2005 in the SEARCH for Diabetes in Youth study with at least 2 study visits ∼12 and ∼24 months after an initial visit were included (age at initial visit, 10.6 ± 4.1 years; 48% female; diabetes duration, 10 ± 7 months; 76% non-Hispanic white; A1c = 7.7% ± 1.4%). Longitudinal mixed models were fit to examine the relationship between change in A1c and change in lipid levels (total cholesterol [TC], high-density lipoprotein-cholesterol [HDL-c], low-density lipoprotein-cholesterol [LDL-c], log triglycerides [TG], and non-HDL-c) with adjustment for possible confounders. Change in A1c over time was significantly associated with changes in TC, HDL-c, LDL-c, TG, and non-HDL-c over the range of A1c values. For example, for a person with an A1c of 10% and then a 2% decrease in A1c 2 years later (to 8%), the model predicted concomitant changes in TC (-0.29 mmol/L, -11.4 mg/dL), HDL-c (0.03 mmol/L, 1.3 mg/dL), LDL-c (-0.23 mmol/L, -9.0 mg/dL), and non-HDL-c (-0.32 mmol/L, -12.4 mg/dL) and an 8.5% decrease in TG (mmol/L).
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Phosphoinositide-3 kinase (PI3K) inhibition attenuates proliferation and survival in B-cell malignancies. Celecoxib induces endoplasmic reticulum (ER) stress-induced apoptosis via a cyclo-oxgenase-2 (COX2)-independent manner in certain types of cancer cells. In the present study, we assessed the effects of combinations of drugs with a p110δ-specific inhibitor, CAL-101, and celecoxib to induce apoptosis in Epstein-Barr virus (EBV)-transformed B-cells and non-Hodgkin's lymphoma (NHL) cells. The apoptotic effect of combination treatment with CAL-101 and celecoxib on B-cell malignancies was determined by flow cytometry and immunoblotting. Exposure to CAL-101 and celecoxib significantly increased apoptosis, which was accompanied by the inactivation of AKT, Ras homolog gene family, member A (RHOA), Rho-associated coiled-coil containing protein kinase 1 (ROCK1), and ROCK2 as well as up-regulation of Phosphatase and tensin homolog (PTEN). Co-treatment with CAL-101 and celecoxib triggered the ER stress response and the down-regulation of BCL2 and BCL-XL. SB203580, SP600125, and salubrinal effectively inhibited apoptosis and attenuated expression of phosphorylated protein kinase RNA-like endoplasmic reticulum kinase (PERK) and CCAAT-enhancer-binding protein homologous protein (CHOP). Levels of apoptosis signal-regulating kinase 1 (ASK1) were also increased after treatment with CAL-101 and celecoxib.
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Does recipient T cell TIM-3 and hepatocyte galectin-9 signalling protect mouse liver transplants against ischemia-reperfusion injury?
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By binding to T cell immunoglobulin mucin-3 (TIM-3) on activated Th1 cells, galectin-9 (Gal-9) negatively regulates Th1-type alloimmunity. Although T cells contribute to hepatic ischemia-reperfusion injury (IRI), it is unknown whether negative T cell-dependent TIM-3 co-stimulation may rescue IR-stressed orthotopic liver transplants from innate immunity-driven inflammation. We used wild type (WT) and TIM-3 transgenic (Tg) mice (C57BL/6) as liver donors and recipients in a clinically-relevant model of hepatic cold storage (20 h at 4°C in UW solution) and syngeneic orthotopic liver transplantation (OLT). Orthotopic liver transplants in WT or TIM-3Tg→TIM-3Tg groups were resistant against IR-stress, evidenced by preserved hepatocellular function (serum ALT levels) and liver architecture (Suzuki's score). In contrast, orthotopic liver transplants in WT or TIM-3Tg→WT groups were susceptible to IRI. TIM-3 induction in circulating CD4+ T cells of the recipient: (1) depressed T-bet/IFN-γ, while amplifying GATA3 and IL-4/IL-10 expression in orthotopic liver transplants; (2) promoted T cell exhaustion (PD-1, LAG-3) phenotype; and (3) depressed neutrophil and macrophage infiltration/function in orthotopic liver transplants. In parallel studies, we documented for the first time that Gal-9, a natural TIM-3 ligand, was produced primarily by and released from IR-stressed hepatocytes, both in vivo and in vitro. Moreover, exogenous recombinant Gal-9 (rGal-9) potentiated liver resistance against IRI by depressing T cell activation and promoting apoptosis of CD4+ T cells.
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Focal cortical dysplasia (FCD) is able to generate an intrinsic pathological EEG activity characterized by a continuous or near-continuous spiking. Different patterns of discharge were described. We examined quantitatively the distribution of the intracerebral FCD patterns in relation to sleep in order to investigate whether this activity is independent of thalamocortical influences. We analyzed the first sleep cycle of 5 patients with a diagnosis of FCD type II who underwent combined scalp-intracranial electroencephalography (EEG), and showed an intracranial EEG pattern typical for FCD. Three patterns of FCD intracranial EEG activity were identified in all 5 patients, and visually marked for a maximum of 30min of each stage (wake, N1, N2, N3, REM): spike or polyspike exceeding 2Hz (pattern 1), spike or polyspike interrupted by flat periods below 2Hz (pattern 2) and discharges of >15Hz low-voltage rhythmic activity with regular morphology (pattern 3). After marking, the percentages of the three patterns across the different stages were calculated. The three patterns of FCD were present between 45% and 97% of the total time analyzed. Pattern 1 was the predominant pattern in wakefulness (73-100%), N1 (76-97%) and N2 (58-88.5%) in all patients, and in REM in 4 of 5 patients (91-100%). During N2 and N3, there was an increase in pattern 2 in all patients, becoming the predominant pattern in 3 of the 5 patients during N3 (63-89%). Pattern 3 was rare and only sporadically observed during N2 and N3. Wakefulness and REM sleep showed a similar pattern (pattern 1) with a slight amplitude reduction in REM sleep.
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Is sucrase-isomaltase an independent prognostic marker for colorectal carcinoma?
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Expression of disaccharidase sucrase-isomaltase (SI) is significantly enhanced during neoplastic transformation of colonic epithelium. Our study was designed to determine whether expression of SI within primary tumors was significantly associated with survival in patients with colorectal carcinoma (CRC). SI expression was analyzed by immunohistochemistry in paraffin sections from 182 Stage I to III CRC that had been resected for cure at the New England Deaconess Hospital between 1965 and 1977. Expression was scored as absent or present in 1 to 50 percent or more than 50 percent of tumor cells. Associations were explored among SI expression, other clinical or pathologic variables, and overall survival. The data set is mature, with 91 (56 percent) patients who had died of CRC at a median follow-up of 96 months. Fifty-five percent of primary CRC expressed SI. When the multivariate Cox analysis was performed, nodal status, T stage, primary site, grade, and SI expression were independent covariates. SI expression was not associated with the expression of other clinicopathologic variables but increased the risk of death from colorectal carcinoma by 1.83-fold.
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To describe the prevalence of prolonged fatigue, chronic fatigue syndrome (CFS)-like illness, and associated symptom patterns in adolescents attending primary care. The design was cross-sectional. A questionnaire designed by the authors assessing fatigue and associated symptoms was administered to 901 adolescents (aged 11-18 years) attending 12 primary care clinics in the Chicago area. Prevalence rates for prolonged fatigue and CFS-like illness were calculated. Univariate comparisons involving sociodemographic data and fatigue severity were made between adolescents with and without prolonged fatigue, and sociodemographic and symptom predictors of prolonged fatigue were identified using logistic regression analysis. Prolonged fatigue (> or = 1 month) occurred at a rate of 8.0% and CFS-like illness occurred at a rate of 4.4%. Adolescents with prolonged fatigue were significantly older and also reported greater fatigue severity than those without fatigue. Findings from logistic regression indicated that, in addition to increasing age, headaches, muscle pains, fever, and fatigue made worse by exercise were significantly associated with prolonged fatigue.
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Does macrophage metalloelastase accelerate the progression of atherosclerosis in transgenic rabbits?
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Macrophage metalloelastase (matrix metalloproteinase [MMP]-12) is upregulated in atherosclerotic lesions and aneurysm; thus, increased MMP-12 activity may play an important role in the pathogenesis of atherosclerosis. However, the pathological roles of MMP-12 in the initiation and progression of atherosclerosis have not been defined. We compared the susceptibility of MMP-12 transgenic (Tg) rabbits to cholesterol-rich diet-induced atherosclerosis with that of non-Tg littermate rabbits. The rabbits were maintained at either relatively lower levels of hypercholesterolemia for shorter periods or higher levels of hypercholesterolemia for longer periods through a diet containing different amounts of cholesterol. We found no significant difference in the aortic atherosclerotic lesion size or quality between Tg and non-Tg rabbits at lower hypercholesterolemia. At higher hypercholesterolemia for longer periods, however, Tg rabbits developed more extensive atherosclerosis in the aortas and coronary arteries than did non-Tg rabbits. Histological examinations revealed that atherosclerotic lesions of Tg rabbits contained prominent macrophage infiltration associated with marked disruption of the elastic lamina in the tunica media with occasional formation of aneurysm-like lesions. Furthermore, increased expression of MMP-12 derived from macrophages was associated with elevated expression of MMP-3, suggesting that MMP-12 may play a pivotal role in the cascade activation of other MMPs, thereby exacerbating extracellular matrix degradation during the progression of atherosclerosis.
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CXC motif chemokine 10 (CXCL10), known as interferon-γ-induced protein 10, is an inflammatory cytokine secreted by various cells in response to interferon-γ. CXCR3, the receptor of CXCL10, is predominantly expressed on activated T, B, natural killer, and dendritic cells, as well as macrophages. CXCR3 promotes chemotaxis upon binding CXCL10. Serum CXCL10 levels have recently attracted attention as a post-transplantation biomarker for graft rejection. However, the correlation between the degree of T cell response to allostimulation and CXCL10 levels remains unclear. In this study, we investigated the serum and bile CXCL10 levels of patients who underwent living donor liver transplantation (LDLT) and compared them with the T cell responses to allostimulation. Between February 2009 and August 2012, 41 patients underwent LDLT at Hiroshima University Hospital. Serum and bile CXCL10 levels were measured weekly for 4 weeks after surgery, while the T cell responses to allostimulation were evaluated using a mixed lymphocyte reaction with an intracellular carboxyfluorescein diacetate succinimidyl ester-labeling technique that we regularly use to monitor the immune response to anti-donor and anti-third-party stimulation after liver transplantation. The stimulation index (SI) and CD25 expression of the CD4+ and CD8+ T cell subsets in response to allostimulation were then analyzed using flow cytometry. Serum CXCL10 levels were significantly correlated with the SI values for CD8+ T cells in response to both types of allostimulation. Bile CXCL10 levels were significantly correlated with CD25 expression of CD8+ T cell subsets, especially in response to anti-donor stimulation. Patients with higher bile CXCL10 levels suffered from severe acute cellular rejection that was refractory to steroid pulse.
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Do the use of theraputic plasma exchange ( TPE ) in the setting of refractory burn shock?
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This study examines the physiologic effects of theraputic plasma exchange (TPE) in the setting of refractory burn shock and attempts to identify variables that correlate with the eventual need for TPE. A retrospective analysis was conducted of 40 patients over 24 months with >20% TBSA burns who experienced complicated resuscitations. TPE was utilized in 21 patients when the patients' total resuscitation volumes exceeded 1.2 times the amount predicted by the modified Baxter formula (3 cm(3) LR/kg/%TBSA). Nineteen matched, contemporaneous patients served as controls. Demographic, injury severity, and acute clinical variables were abstracted for comparison between the two groups. Additionally, the TPE group was analyzed for blood lactate levels, mean arterial pressure (MAP) and urine output (UOP) before and after TPE. Univariate and multivariate statistical analyses were used for comparisons, where appropriate. In response to TPE, MAP increased by 24% (p<0.0001), UOP increased by >400% (p=<0.0001), IVF rates were reduced by 25% (p=0.01), and lactate levels decreased by almost 50% (p=0.0006). On univariate analysis, admission lactate (p=0.0006) and %TBSA (p=0.01) were found to be significantly increased in the TPE group compared to controls, while there was no difference in age, gender, weight, admission HCT, incidence of acute renal failure, or mortality between the groups. However, on multivariate logistic regression analysis, only elevated admission lactate was independently associated with the eventual need for TPE (OR 2.23, 95% CI=1.30-3.84, p=0.004).
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To investigate the independent relationship of individual- and area-level socio-economic status (SES) with the presence and severity of visual impairment (VI) in an Asian population. Cross-sectional data from 9993 Chinese, Malay and Indian adults aged 40-80 years who participated in the Singapore Epidemiology of eye Diseases (2004-2011) in Singapore. Based on the presenting visual acuity (PVA) in the better-seeing eye, VI was categorized into normal vision (logMAR≤0.30), low vision (logMAR>0.30<1.00), and blindness (logMAR≥1.00). Any VI was defined as low vision/blindness in the PVA of better-seeing eye. Individual-level low-SES was defined as a composite of primary-level education, monthly income<2000 SGD and residing in 1 or 2-room public apartment. An area-level SES was assessed using a socio-economic disadvantage index (SEDI), created using 12 variables from the 2010 Singapore census. A high SEDI score indicates a relatively poor SES. Associations between SES measures and presence and severity of VI were examined using multi-level, mixed-effects logistic and multinomial regression models. The age-adjusted prevalence of any VI was 19.62% (low vision = 19%, blindness = 0.62%). Both individual- and area-level SES were positively associated with any VI and low vision after adjusting for confounders. The odds ratio (95% confidence interval) of any VI was 2.11(1.88-2.37) for low-SES and 1.07(1.02-1.13) per 1 standard deviation increase in SEDI. When stratified by unilateral/bilateral categories, while low SES showed significant associations with all categories, SEDI showed a significant association with bilateral low vision only. The association between low SES and any VI remained significant among all age, gender and ethnic sub-groups. Although a consistent positive association was observed between area-level SEDI and any VI, the associations were significant among participants aged 40-65 years and male.
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Is modulation of hypoxic pulmonary vasoconstriction time and nitric oxide dependent in a peritonitis model of sepsis?
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This study assessed modulation of hypoxic pulmonary vasoconstriction (HPV) in isolated perfused rat lungs during sepsis induced by cecal ligation and perforation (CLP) at different times and its relationship to nitric oxide synthases (NOS). Prospective controlled trial in a university research laboratory. 102 male Sprague-Dawley rats. Groups 1-3 received sham laparotomy 6 h before lung isolation: group 1, only laparotomy; group 2, concurrently L- N6-(1-iminoethyl)-lysine (L-NIL, 3 mg/kg); group 3, concurrently N(Omega)-nitro-L-arginine methylester (L-NAME, 5 mg/kg). Groups 4-6 received CLP 6 h before lung isolation: group 4, only CLP; group 5, concurrently L-NIL; group 6, concurrently L-NAME. The same experiments were carried out with sham and CLP treatment for 24 h (groups 7-12). Exhaled NO from rats' lungs was measured after anesthesia and tracheostomy. After the pulmonary circuit was isolated and perfused, angiotensin II (0.1 microg) was injected into the inflow tract. The lungs were ventilated with the hypoxic mixture (HPV, 3% O2) for 10 min and then again with the normoxic mixture (21% O2) for an equal period. Changes in perfusion pressure were measured. Endothelial (eNOS) and inducible NOS (iNOS) expression of the lungs was determined. Treatment with L-NAME but not L-NIL increased HPV in sham lungs. HPV was unaltered after CLP 6 h and decreased after CLP 24 h compared to sham. In CLP animals eNOS protein expression was reduced whereas iNOS expression was increased compared to sham animals. Exhaled NO, reflecting NOS activity was twice as high in the CLP 24 h group than in the CLP 6 h group.
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The single-nucleotide polymorphism (SNP) rs11761231 on chromosome 7q has been reported to be sexually dimorphic marker for rheumatoid arthritis (RA) susceptibility in a British population. We sought to replicate this finding and to better characterize susceptibility alleles in the region in a North American population. DNA from 2 North American collections of RA patients and controls (1,605 cases and 2,640 controls) was genotyped for rs11761231 and 16 additional chromosome 7q tag SNPs using Sequenom iPlex assays. Association tests were performed for each collection and also separately, contrasting male cases with male controls and female cases with female controls. Principal components analysis (EigenStrat) was used to determine association with RA before and after adjusting for population stratification in the subset of the samples for which there were whole-genome SNP data (772 cases and 1,213 controls). We failed to replicate an association of the 7q region with RA. Initially, rs11761231 showed evidence for association with RA in the North American Rheumatoid Arthritis Consortium (NARAC) collection (P=0.0073), and rs11765576 showed association with RA in both the NARAC (P=0.038) and RA replication (P = 0.0013) collections. These markers also exhibited sex differentiation. However, in the whole-genome subset, neither SNP showed significant association with RA after correction for population stratification.
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Does tyrosine phosphatase beta regulate angiopoietin-Tie2 signaling in human endothelial cells?
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The endothelial cell (EC)-selective receptor tyrosine kinase, Tie2, and its ligands angiopoietin Ang-1 and Ang-2, are essential for blood vessel maintenance and repair. Ang-1 is an agonist of Tie2 receptor activation, whereas Ang-2 is a context-dependent antagonist/agonist. Therefore, we investigated the role of the EC-selective phosphatase, human protein tyrosine phosphatase beta (HPTPbeta), in regulating Tie2 activity. siRNA silencing of HPTPbeta enhanced Ang-1 and Ang-2-induced Tie2 phosphorylation at 10 min (2.5-fold, P < 0.001; and 1.8-fold, P < 0.05, respectively). The cell survival response to Ang-1, but not Ang-2, was enhanced by HPTPbeta silencing as measured by flow cytometry (0.85-fold to 0.66-fold, P < 0.05) and ELISA (0.88-fold to 0.53-fold, P < 0.01). Hypoxia, which upregulated HPTPbeta expression in endothelial cells, impaired Ang-1-induced Tie2 phosphorylation.
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Malnutrition impairs host immunity, resulting in high mortality and morbidity, secondary to infections. Nuclear factor kappaB (NFkappaB) plays a critical role in host defense, but how quickly refeeding normalizes the impaired NFkappaB activity in peritoneal resident cells (PRCs) is unknown. Our aim was to investigate the effects of 1-day ad libitum refeeding on severe diet restriction-induced NFkappaB activity in PRCs. Mice received chow, 146 g/kg per day (ad libitum) or 36.5 g/kg per day (severe diet restriction), for 7 days. One-half the mice in the diet-restricted group were then fed ad libitum for 1 day (refeeding). PRCs were harvested by peritoneal lavage. After incubation with tumor necrosis factor-alpha (TNF-alpha), nuclear translocation of NFkappaB in PRCs was investigated using laser scanning cytometry. The main subpopulation of PRCs was macrophages in all groups. Mean fluorescence intensity over the nuclear area at 0 or 100 ng/mL of TNF-alpha was 16 +/- 2 or 31 +/- 8* in the ad libitum, 20 +/- 4 or 19 +/- 3 in the severe diet-restricted, and 20 +/- 4 or 30 +/- 5* in the refeeding group, respectively (*p < .05 versus 0 ng/mL of TNF-alpha in each group versus 100 ng/mL of TNF-alpha in diet-restricted group). Cytoplasmic accumulation of NFkappaB was significantly increased after TNF-alpha stimulation in the refed group but not in the ad libitum group.
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Is evidence-based medicine affordable : the cost-effectiveness of current compared with optimal treatment in rheumatoid and osteoarthritis?
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To determine the cost-effectiveness of averting the burden of disease. We used secondary population data and metaanalyses of various government-funded services and interventions to investigate the costs and benefits of various levels of treatment for rheumatoid arthritis (RA) and osteoarthritis (OA) in adults using a burden of disease framework. Population burden was calculated for both diseases in the absence of any treatment as years lived with disability (YLD), ignoring the years of life lost. We then estimated the proportion of burden averted with current interventions, the proportion that could be averted with optimally implemented current evidence-based guidelines, and the direct treatment cost-effectiveness ratio in dollars per YLD averted for both treatment levels. The majority of people with arthritis sought medical treatment. Current treatment for RA averted 26% of the burden, with a cost-effectiveness ratio of dollar 19,000 per YLD averted. Optimal, evidence-based treatment would avert 48% of the burden, with a cost-effectiveness ratio of dollar 12,000 per YLD averted. Current treatment of OA in Australia averted 27% of the burden, with a cost-effectiveness ratio of dollar 25,000 per YLD averted. Optimal, evidence-based treatment would avert 39% of the burden, with an unchanged cost-effectiveness ratio of dollar 25,000 per YLD averted.
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To explore if the hypoxia/reoxygenation-induced increased activity and expression of PTP-1B in neonatal rat cardiomyocytes are mediated by nitric oxide (NO). Neonatal rat cardiomyocytes were isolated and randomly divided into 4 groups: normal group (N group); hypoxia/reoxygenation group (H/R group); N(omega)-nitro-l-arginine methylester treated group (L-NAME group); hypoxia/reoxygenation plus L-NAME group (L-NA + H/R group). PTP-1B activity in cardiomyocytes was determined spectrophotometrically at 405 nm, PTP-1B expression in cardiomyocytes was detected by Western blot.NO and LDH concentrations in cell medium were also assayed. PTP-1B activity and expression in cardiomyocytes was significantly higher in the H/R group as compared to the N group and this increase could be blocked by cotreatment with L-NAME. As compared to H/R group, nitric oxide and LDH concentrations in cell medium were significantly decreased in the L-NA + H/R group (NO concentration: H/R group, 368% +/- 13% and L-NA + H/R group, 61% +/- 7%, P < 0.005; LDH concentration: H/R group, 41.2 +/- 6.7 and L-NA + H/R group, 23.6 +/- 4.8, P < 0.05).
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Is dietary counseling associated with an improved lipid profile in children with familial hypercholesterolemia?
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Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C). Guidelines recommend cholesterol-lowering medication from 8 to 10 years of age and dietary recommendations. Little is known about the diet of FH children and the effect of dietary counseling. The aim of the study was to describe the diet of FH children with respect to fat quality, and to investigate if dietary counseling improved lipid profile. Fifty-four FH children (5-18 years) were included in the study and dietary intake was recorded with a pre-coded food diary for four days. Information about plasma lipid levels was obtained. Median intake of total fat, monounsaturated fat, polyunsaturated fat (PUFA) and saturated fat (SFA) was 30.8, 10.4, 5.9 and 12.0 E %, respectively. Among non-statin treated FH children, SFA intake was significantly correlated with TC, LDL-C and apolipoprotein (apo) B (rsp = 0.55; p = 0.004, rsp = 0.46; p = 0.02, and rsp = 0.45; p = 0.02, respectively), and PUFA/SFA ratio significantly inversely correlated with TC (rsp = -0.42; p = 0.03). Compared to the first visit, non-statin and non-plant sterol treated FH children (n = 10) had significantly reduced levels of TC (p < 0.01), LDL-C (p = 0.01), high-density lipoprotein cholesterol (p = 0.02), apo B (p = 0.05) and apo A-1 (p = 0.02) levels at a later visit.
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The prognosis of patients with apparently localized, operable, muscle-invasive bladder cancer depends to a large extent on the presence or absence of subclinical, microscopic distant metastases at the time of surgery. Expression of the S100A4 protein has been shown to correlate with the risk of metastasis in both animal tumour-model systems and clinical investigations in other tumour types. The purpose of the present study was to investigate the prognostic potential of S100A4 protein expression for predicting distant metastatic relapse in muscle-invasive bladder cancer. We analyzed 108 consecutive patients, treated for transitional cell bladder cancer with preoperative radiotherapy and cystectomy. Pretherapeutic biopsies of the bladder tumours were investigated for immunohistochemical expression of S100A4 protein and results, along with clinical and histopathological data, compared with the pattern of relapses over a 10+ yr follow-up period. Focal S100A4 protein expression emerged as the only significant independent predictor of distant metastatic relapse and distant metastasis-free survival in multivariate analysis.
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Is pre-eclampsia associated with increased risk of stroke in the adult offspring : the Helsinki birth cohort study?
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Women who develop pre-eclampsia in pregnancy are at increased risk of cardiovascular disease. The offspring from pregnancies complicated by pre-eclampsia have higher blood pressures during childhood, but little is known about their long-term health. We hypothesized that pre-eclampsia would lead to an increased risk of cardiovascular disease in the offspring. We traced 6410 babies born in Helsinki, Finland, from 1934 to 1944. We used the mothers' blood pressure levels and the presence of proteinuria during pregnancy to define pre-eclampsia and gestational hypertension without proteinuria according to modern criteria. Two hundred eighty-four of the pregnancies were complicated by pre-eclampsia (120 with nonsevere and 164 with severe disease) and 1592 by gestational hypertension. The crude hazard ratio for all forms of stroke among people whose mothers had pre-eclampsia was 1.9 (1.2 to 3.0; P=0.01); among people whose mothers had gestational hypertension, it was 1.4 (1.0 to 1.8; P=0.03). There was no evidence that these pregnancy disorders were associated with coronary heart disease in the offspring. Pre-eclampsia, in particular severe disease, was associated with a reduced mean head circumference at birth, whereas gestational hypertension was associated with an increased head circumference in relation to body length.
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The interaction between Siglec-10 and its ligand, CD24, selectively represses tissue damage-caused immune responses. However, the nature of Siglec-10 and CD24 in human hepatocellular carcinoma (HCC) is still poorly defined. Hereon, the expression, function, and regulation of CD24 and Siglec-10 in HCC were investigated in the present study. Flow cytometry was performed to examine the expression of Siglec-10 in HCC tissues and adjacent non-tumor tissues of HCC patients. To further determine whether Siglec-10 expression is associated with the clinical characteristics and survival, conventional immunohistochemistry was performed in 96 HCC patients. Additionally, the role of Siglec-10 in the regulation of natural killer (NK) cell dysfunction was evaluated. Finally, CD24 expression in HCC was also assessed. Siglec-10 was expressed most on NK cells in HCC (40.7 ± 4.5%). Compared with surrounding non-tumor tissues, tumor tissues had higher Siglec-10 expression (31.0 ± 1.7% versus 40.7 ± 4.5%, n = 10, P < 0.05), and the expression was negatively associated with patient survival. Siglec-10(+)CD56(+) NK cells exhibited reduced effector function, as shown by decreased granules and cytokine expressions compared with Siglec-10(-)CD56(+) NK cells. Moreover, the number of CD24(+)CD45(-) cells in HCC tissues was higher than that in adjacent non-tumor tissues (9.4 ± 0.9% versus 3.1 ± 0.9%, n = 15, P < 0.05).
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Is high density lipoprotein positively correlated with the changes in circulating total adiponectin and high molecular weight adiponectin during dietary and fenofibrate treatment?
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The investigation of the relationship between high density lipoprotein (HDL) and adiponectin. Thirty-seven obese or overweight [body mass index ≥27 Kg/m(2)], hypertriglyceridemic patients underwent one of the following interventions for 3 months: 1) Low-calorie diet (n=19), 2) Low-calorie diet plus fenofibrate (n=18). Circulating total adiponectin did not change significantly in the low-calorie diet group. However, in the subgroup of patients whose high density lipoprotein cholesterol (HDL-C) decreased over the first month of diet, a statistically significant reduction of the circulating total adiponectin was observed (p=0.010), while in the subgroup of patients whose HDL-C increased over the latter 2 months of the diet, an increase in circulating total adiponectin over the 2 months was found (p=0.043). The percentage change of HDL-C over the first month of diet was positively correlated with the percentage change of circulating total adiponectin (r=0.579, p=0.019). The percentage change of HDL-C over the 3 months of diet was positively correlated with the percentage changes of circulating total adiponectin (r=0.527, p=0.030) and high molecular weight (HMW) adiponectin (r=0.524, p=0.031). The change in circulating total adiponectin over the first month of diet was positively correlated with the HDL-C at 1 month (r=0.606, p=0.013). The change in HMW adiponectin over the 3 months of diet was positively correlated with the HDL-C at 3 months (r=0.602, p=0.011). The percentage change of circulating HMW adiponectin over the first month of fenofibrate treatment was positively correlated with the percentage change of HDL-C (r=0.594, p=0.012).
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The aim of this study was to investigate whether mRNA expression of the apoptosis-associated genes, XAF1 and XIAP, in bladder cancer patients correlates with response to neoadjuvant treatment. Gene expression was analyzed by a real-time quantitative PCR method in paired samples from 14 bladder cancer patients treated with a combination of neoadjuvant gemcitabine and cisplatin. The prognostic significance of XAF1 and XIAP mRNA expression as well as the correlation with several clinical and pathological findings were evaluated. The clinical response in the XAF1-high subset (n = 5) was remarkably higher compared with the XAF1-low subset (n = 9) (100% vs. 44.4%; P = 0.038). These results translated into a notably improvement of progression-free survival (PFS) in the XAF1-high subset (log-rank P = 0.012). In addition, patients in the XAF1-high subset had a 3.9-fold decreased chance of dying from the disease (hazard ratio for death (HR), 0.257; (CI 95%), 0.043-1.536, P = 0.036). When we evaluated the expression of XIAP, although an inverse correlation was found between expression and pathological response, there were no statistically significant associations with the clinical response, the length of PFS, and OS.
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Does high Proportion of Nuclear Phenotype identify Aggressive Cutaneous Squamous Cell Carcinoma?
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To develop a quantitative histopathology algorithm to predict which patients with cutaneous squamous cell carcinoma (cSCC) were likely to experience recurrence or metastases. This retrospective study of cSCC lesions compared patients with aggressive disease (n = 40) and those with nonaggressive disease (n = 35). Based on a previous study using nuclear karyometry, we determined that aggressive lesions had a high proportion of a specific nuclear phenotype. The proportion of those nuclei was used to derive an aggressiveness score for each lesion. The mean age of patients was similar in both groups, as were the locations of index lesions. The mean aggressiveness scorefor cases with aggressive lesions was 0.60 ± 0.21 and was 0.28 ± 0.35 for those with nonaggressive lesions. The overall accuracy in properly characterizing lesions was 72%. The area under the receiver operating characteristic curve was 0.80 ± 0.05. In general, the aggressive nuclear phenotype is represented by elevated levels of chromatin clumps and short linear segments of dark chromatin/intense pixels.
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There is now evidence that an increased translocation of LPS from gram negative bacteria with subsequent gut-derived inflammation, i.e. induction of systemic inflammation and oxidative & nitrosative stress (IO&NS), is a new pathway in chronic fatigue syndrome (CFS). The present study examines the serum concentrations of IgA and IgM to LPS of gram-negative enterobacteria, i.e. Hafnia Alvei; Pseudomonas Aeruginosa, Morganella Morganii, Pseudomonas Putida, Citrobacter Koseri, and Klebsielle Pneumoniae in CFS patients both before and after intake of natural anti-inflammatory and anti-oxidative substances (NAIOSs), such as glutamine, N-acetyl cysteine and zinc, in conjunction with a leaky gut diet during 10-14 months. We measured the above immune variables as well as the Fibromyalgia and Chronic Fatigue Syndrome Rating Scale in 41 patients with CFS before and 10-14 months after intake of NAIOSs. Subchronic intake of those NAIOSs significantly attenuates the initially increased IgA and IgM responses to LPS of gram negative bacteria. Up to 24 patients showed a significant clinical improvement or remission 10-14 months after intake of NAIOSs. A good clinical response is significantly predicted by attenuated IgA and IgM responses to LPS, the younger age of the patients, and a shorter duration of illness (< 5 years).
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Does whole exome sequencing of a dominant retinitis pigmentosa family identify a novel deletion in PRPF31?
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Mutations at some retinitis pigmentosa (RP) loci are associated with variable penetrance and expressivity, exacerbating diagnostic challenges. The purpose of this study was to dissect the genetic underpinnings of nonsyndromic RP with variable age of onset in a large Mexican family. We ascertained members of a large, multigenerational pedigree using a complete ophthalmic examination. We performed whole exome sequencing on two affected first cousins, an obligate carrier, and a married-in spouse. Confirmatory sequencing of candidate variants was performed in the entire pedigree, as well as genotyping and mRNA studies to investigate expression changes in the causal locus. We identified a 14-base pair (bp) deletion in PRPF31, a gene implicated previously in autosomal dominant (ad) RP. The mutation segregated with the phenotype of all 10 affected females, but also was present in six asymptomatics (two females and four males). Studies in patient cells showed that the penetrance/expressivity of the PRPF31 deletion allele was concordant with the expression levels of wild-type message. However, neither the known PRPF31 modulators nor cis-eQTLs within 1 Mb of the locus could account for the variable expression of message or the clinical phenotype.
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Diabetes mellitus is a risk factor for death after coronary artery bypass grafting. Its relative risk may be related to the level of perioperative hyperglycemia. We hypothesized that strict glucose control with a continuous insulin infusion in the perioperative period would reduce hospital mortality. All patients with diabetes undergoing coronary artery bypass grafting (n = 3554) were treated aggressively with either subcutaneous insulin (1987-1991) or with continuous insulin infusion (1992-2001) for hyperglycemia. Predicted and observed hospital mortalities were compared with both internal and external (Society of Thoracic Surgeons 1996) multivariable risk models. Observed mortality with continuous insulin infusion (2.5%, n = 65/2612) was significantly lower than with subcutaneous insulin (5.3%, n = 50/942, P <.0001). Likewise, glucose control was significantly better with continuous insulin infusion (177 +/- 30 mg/dL vs 213 +/- 41 mg/dL, P <.0001). For internal comparison, multivariable analysis showed that continuous insulin infusion was independently protective against death (odds ratio 0.43, P =.001). Conversely, cardiogenic shock, renal failure, reoperation, nonelective operative status, older age, concomitant peripheral or cerebral vascular disease, decreasing ejection fraction, unstable angina, and history of atrial fibrillation increased the risk of death. For external comparison, observed mortality with continuous insulin infusion was significantly less than that predicted by the model (observed/expected ratio 0.63, P <.001). Multivariable analysis revealed that continuous insulin infusion added an independently protective effect against death (odds ratio 0.50, P =.005) to the constellation of risk factors in the Society of Thoracic Surgeons risk model.
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Do staphylococcus aureus antigens induce IgA-type glomerulonephritis in Balb/c mice?
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Staphylococcus aureus (S. aureus) is a common, normal pathogenic flora that colonizes mucosal tissues. We previously reported that glomerulonephritis occurs during methicillin-resistant S. aureus infection, and demonstrated polyclonal elevation of serum immunoglobulin A (IgA) and IgG levels and various histological findings, such as mesangial extracapillary and endocapillary proliferation. To investigate the pathogenic roles of S. aureus antigens, we induced IgA-type glomerulonephritis in mice by immunization with antigens derived from S. aureus, as a model of human IgA nephropathy (IgAN). Balb/c mice (Th2 dominant type) and C57BL/6 mice (Th1 dominant type) were immunized biweekly for 4 months with antigens derived from S. aureus mixed with Freund's incomplete adjuvant. Mesangial proliferative glomerulonephritis with IgA, IgG and complement 3 (C3) depositions were observed in all Balb/c mice. Although C3 depositions and cell proliferation in the mesangial area were also seen in C57BL/6 mice, they were not correlated with urinary findings. In Balb/c mice, S. aureus antigens were detected in glomeruli using affinity-purified human anti-S. aureus antibodies, but there was no staining in C57BL/6 mice. The antibodies reacted with several S. aureus antigens, based on Western blot analysis, and the main 30-35 kDa band differed in intensity in Balb/c and C57BL/6 mice. In addition, increased transforming growth factor beta (TGF-beta) messenger RNA (mRNA) expression was seen in Balb/c mice compared to C57BL/6 mice.
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Long-term results of a study investigating potential prognostic factors for treatment outcomes in patients with stage III esophageal cancer are presented. In 64 patients, the impact of tumor cell expression of erythropoietin (EPO) and erythropoietin-receptor (EPO-R) and ten additional factors (age, gender, performance status, tumor length, tumor stage (T-stage), nodes (N-stage), histology/grading, hemoglobin levels during radiotherapy, surgery) on survival and loco-regional control was evaluated up to 10 years following radio-chemotherapy. On multivariate analysis, improved survival was associated with low EPO-R expression (p=0.034) and hemoglobin levels during radiotherapy ≥ 12 g/dl (p=0.026). Low EPO expression was associated with survival on univariate (p=0.010) but not on multivariate analysis (p=0.42). On multivariate analysis, improved loco-regional control was significantly associated with hemoglobin levels during radiotherapy ≥ 12 g/dl (p<0.001).
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Does a novel mutation confirm MFRP as the gene causing the syndrome of nanophthalmos-renititis pigmentosa-foveoschisis-optic disk drusen?
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To describe the clinical and genetic characteristics of the second family with a recently described recessive syndrome characterized by posterior microphthalmos, retinitis pigmentosa, foveoschisis, and optic disk drusen. Observational case report. Three affected subjects and one healthy sibling from a consanguineous marriage from Spain were studied. Complete ophthalmologic examinations including A- and B-mode ultrasonography (US), electroretinography (ERG), fluorescein retinal angiography (FA), and optical coherence tomography (OCT) were performed in each individual. Genetic analysis included polymerase chain reaction amplification and direct nucleotide sequencing of the complete MFRP gene. All three affected siblings had bilateral shortening of the posterior ocular segment associated with high hyperopia and normal anterior segment dimensions. Best-corrected visual acuity ranged from 20/200 to 20/60. Funduscopy, ERG, and FA were compatible with retinitis pigmentosa, and B-mode ultrasound showed optic disk drusen. OCT analysis revealed outer retinal layer schisis with absence of foveal pit. Inheritance of this syndrome followed an autosomal recessive pattern. Molecular analysis revealed a novel homozygous 1-bp deletion (c.498delC) in exon 5 of MFRP, predicting a prematurely truncated protein (P166fsX190). A healthy sister demonstrated to be a carrier of the mutation.
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To estimate the sensitivity and specificity of emergency department (ED) ultrasound for the detection of solid organ injury following blunt abdominal trauma. A prospective cohort study performed in the ED of an urban Level I trauma center on patients who sustained blunt abdominal trauma. Following initial standard trauma evaluation, patients underwent a secondary ultrasound examination performed specifically to identify injury to the liver or spleen, followed by computed tomography (CT) scan of the abdomen. Ultrasound examinations were performed by emergency medicine residents or attending physicians experienced in the use of ultrasound for detecting hemoperitoneum. Ultrasonographers prospectively determined the presence or absence of liver or spleen injury. CT findings were used as the criterion standard to evaluate the ultrasound results. From July 1998 through June 1999, 152 patients underwent secondary ultrasound examination and CT. Of the 152 patients, nine (6%) had liver injuries and 10 (7%) had spleen injuries. Ultrasound correctly detected only one of the liver injuries for a sensitivity of 11% (95% CI: 0%-48%) and a specificity of 98% (95% CI: 94%-100%). Ultrasound correctly detected eight spleen injuries for a sensitivity of 80% (95% CI: 44%-98%) and a specificity of 99% (95% CI: 95%-100%).
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Does sustained delivery of IL-1Ra from pluronic F127-based thermosensitive gel prolong its therapeutic potentials?
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Pluronic F-127 (PF127) has previously shown to prolong the sustained release of various proteinous drugs and their serum half-lives. Subsequently, we have extended this approach to look at in vitro release, in vivo efficacy and pharmacokinetics of interleukin-1 receptor antagonist (IL-1Ra). Various concentrations of PF127 gels were prepared using cold method. In vitro drug release kinetic studies were performed using membraneless dissolution method. Stability of IL-1Ra was assessed by SDS-PAGE. In vivo studies and in vivo bioactivity of IL-1Ra were also performed on wistar rats. IL-1Ra loaded PF127 gels showed in vitro sustained release of IL-1Ra, depending on the concentration of gel used. SDS-PAGE confirmed the stability of protein during its in vitro release. PF127 gel also exhibited prolonged release of IL-1Ra in rats as compared to that of IL-1Ra aq. solution. In vivo bioactivity of IL-1Ra loaded in gel was confirmed by its ability to inhibit IL-1β-stimulated induction of IL-6.
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Clusterin (CLU) /Apolipoprotein J is a protein biosensor of oxidative stress and inflammation, which is upregulated in many pathological processes including atherosclerosis. Previous studies have shown that in aortic tissue, CLU expression increases with atherosclerotic lesion progression and it has been coupled with vascular damage and coronary artery disease. A few studies enter into CLU and carotid atherosclerosis while the apolipoprotein's expression on human carotid tissue and its association with parameters related to the disease development has not been examined. The present study was designed to reveal the relationships between the degree of CLU immunolocalization on carotid artery and demographic characteristics, blood parameters and pharmacological treatment of patients underwent internal carotid artery endarterectomy. CLU expression was detected by immunohistochemistry in 42 carotid endarterectomy specimens. Patients' serum levels of tumor necrosis factor-a (TNF-a), interleukin-6 (IL-6), high sensitive C-reactive protein (hsCRP) and classical parameters related to atherosclerosis such as lipid profile, as well as thrombosis related parameters such as fibrinogen, antithrombin III, protein C and protein S were determined. Demographic characteristics, smoking habits and the use of medications were recorded. Comparisons between groups were performed by students't-test and analysis of variance. Independent associations with CLU expression on carotid tissue were denoted by linear regression analysis. CLU imuunolocalization was denser in smokers than in non-smokers (p = 0.041) while it was rarefied in specimens of patients on cropidogrel treatment (p = 0.045) compared to the rest not taking this medication. Clopidogrel intake was independent predictor of lower CLU expression on carotid artery (p =0.045). CLU was positively correlated with serum TNF-a concentration (r = 0.33, p = 0.040) that was independent predictor of higher expression of the apolipoprotein (p = 0.001). IL-6, hsCRP and classical parameters related to atherosclerosis and thrombosis were not associated with CLU immunolocalization.
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Is serum dipeptidyl peptidase-4 associated with multiple vertebral fractures in type 2 diabetes mellitus?
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Patients with type 2 diabetes mellitus (T2DM) have a high risk of fracture although they have slightly higher bone mineral density (BMD). There is no evidence that dipeptidyl peptidase-4 (DPP-4) is involved in the bone fragility of the patients. The aim of this study was to investigate the association between serum DPP-4 levels and vertebral fractures (VFs) in men with T2DM. We conducted a cross-sectional study and investigated the relationships between serum DPP-4 levels vs BMD at lumbar spine, femoral neck and radius, bone turnover markers and presence of VFs in 204 Japanese male patients. Multiple regression analyses adjusted for confounders such as age, duration of diabetes, body mass index, serum creatinine, HbA1c, serum albumin, log(alanine transaminase), and log(C-reactive protein) showed that serum DPP-4 was positively associated with bone formation markers (bone-specific alkaline phosphatase and osteocalcin) as well as a bone resorption marker [tartrate-resistant acid phosphatase 5b (TRACP-5b)] (β = 0·25, P < 0·01; β = 0·17, P < 0·05; and β = 0·30, P < 0·01, respectively), but not BMD at each site. Multivariate logistic regression analyses adjusted for the confounders described above revealed that serum DPP-4 levels were associated with the presence of multiple VFs (odds ratio 1·61, 95% confidential interval 1·05-2·49 per SD increase, P < 0·05). This association was still significant after additional adjustment for any sites of BMD or bone turnover markers except for TRACP-5b.
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Pulmonary hypertension after cardiopulmonary bypass is a common problem in pediatric cardiac operations. This study tested the hypothesis that there is a difference between adult and immature pulmonary artery constrictor and dilator responses. Reactivity of pulmonary artery ring segments from 22 mature (15 to 19 weeks) and 15 immature pigs (4 to 5 weeks) was tested in a vessel myograph. Potassium as a receptor-independent vasoconstrictor and phenylephrine as an alpha-receptor-mediated vasoconstrictor were used to assess smooth-muscle vasoconstriction. To assess endothelial cell function (nitric oxide production and secretion), we used increasing concentrations of bradykinin or acetylcholine. Sodium nitroprusside was used to produce maximum smooth-muscle relaxation at the end of each experiment. The data demonstrated maturation-independent endothelium and smooth-muscle-mediated vasodilation. Pulmonary artery ring segments from immature pigs had significantly less KCl constriction compared with mature pigs (p < 0.05). In contrast, pulmonary ring segments from immature pigs demonstrated enhanced alpha-receptor-mediated constriction compared with mature pigs.
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