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Do mathematical optimization of contrast concentration for T1-weighted spoiled gradient echo imaging? | To develop and validate closed form mathematical expressions that predict the optimal contrast agent concentration for the maximum T1-weighted spoiled gradient echo (SGRE) signal. Gadolinium and iron-based contrast agents can have significant transverse relaxivity that leads to signal dropout with increasing contrast agent concentration. A mathematical expression for the "optimal" contrast agent concentration where recovery of longitudinal magnetization is offset by increasing transverse signal decay was derived. Expressions for the maximum possible SGRE signal were also derived. Three phantoms were constructed, each with varying concentrations of one of the following three agents: gadoteridol, gadobenate dimeglumine, and ferumoxytol. After measuring the longitudinal and transverse relaxivity of the three agents, the SGRE signal was measured in the phantoms over a wide range of flip angles and echo times. Excellent qualitative agreement between the SGRE signal behavior, optimal concentration, and optimal flip angle were observed between experimental measurements and theoretical predictions. | Hepatic expression of growth hormone (GH)-inducible genes serine protease inhibitor (Spi 2.1) and insulin-like growth factor (IGF)-I are inhibited by interleukin (IL)-1. The current study examines the role of the nuclear factor kappaB (NFkappaB) pathway and suppressor of cytokine signaling (SOCS)-3 expression as potential mechanisms for IL-1-mediated GH resistance. CWSV-1 hepatocytes were cotransfected with Spi 2.1 or IGF-1 promoter luciferase constructs and empty pCMV4 vector or dominant negative inhibitor-kappaBalpha (IkappaBalpha)S/A construct. Cells were treated with or without IL-1 and then stimulated with or without recombinant human GH. Cell extracts were assayed for luciferase activity and protein, normalized and expressed as fold-induction. CWSV-1 cells transfected with pCMV4 or IkappaBalphaS/A were treated with or without IL-1 then SOCS-3 mRNA was measured. Finally, CWSV-1 cells were cotransfected with a SOCS-3 promoter construct with or without pCMV4 or IkappaBalphaS/A and then stimulated with or without IL-1 to investigate SOCS-3 promoter activity. CWSV-1 cells cotransfected with pCMV4 demonstrated a three- to fivefold induction of Spi 2.1 or IGF-1 promoter activity after GH stimulation that was almost completely inhibited by IL-1. Cotransfection with IkappaBalphaS/A increased GH-inducible Spi 2.1 and IGF-1 promoter activity, but the inhibitory effects of IL-1 on both promoters were attenuated by cotransfection with IkappaBalphaS/A. IL-1 stimulated SOCS-3 mRNA expression and promoter activity. Cotransfection with IkappaBalphaS/A increased IL-1-inducible SOCS-3 promoter activity, but not SOCS-3 mRNA or protein. |
Are signs of immune activation and local inflammation present in the bronchial tissue of patients with untreated early rheumatoid arthritis? | Events in the lungs might contribute to generation of anticitrullinated protein antibodies (ACPA) in rheumatoid arthritis (RA). We investigated if signs of immune activation are present in bronchial biopsies and bronchoalveolar lavage (BAL) of patients with early-untreated RA without clinical signs of lung involvement. Twenty-four patients with RA with symptom duration <1 year and naïve to disease-modifying antirheumatic drugs were subjected to bronchoscopy where BAL and mucosal bronchial biopsies were retrieved. For comparison, 15 bronchial biopsies and 79 BAL samples from healthy volunteers were available. Histological examination was performed to evaluate lymphocyte infiltration, presence of immune cells (T and B cells, plasma cells, dendritic cells and macrophages) and immune activation markers. Cell composition of BAL samples was analysed by differential counting and T cell subsets by flow cytometry. Lymphocyte infiltration was more frequently found in ACPA-positive patients (50%) as compared with ACPA-negative patients (17%) and controls (13%). Germinal centres, B cells and plasma cells were only found in ACPA-positive patients. The frequency of T cells in bronchial biopsies of patients with ACPA-positive RA was positively associated with expression of immune activation markers. BAL samples of patients with ACPA-positive, but not ACPA-negative, RA had significantly higher relative numbers of lymphocytes and expressed higher levels of activation markers compared with controls. | To assess the relationship between congenital uterine malformations and blood pressure in pregnancy. Twenty-four-hour automated ambulatory blood pressure monitoring (readings every 30 min) was performed in 16 normotensive, nonproteinuric, primigravidae with congenital uterine malformations (5 uterus septus, 9 uterus bicornis, 2 uterine didelphys) between 20 and 30 weeks. From the 24-hr blood pressure report, we calculated 24-hr mean, daytime and nighttime means. The results were compared with 16 primigravidae, matched for age and gestation, who were and remained normotensive throughout pregnancy, and tested for statistics with t-test; significance assessed at p < 0.001. Although they were within the normotensive range, all blood pressure measurements considered were significantly higher in pregnant women with congenital uterine malformations, compared to normal pregnant women. Namely, 24-hr, daytime, and nighttime systolic (mean +/- SD) were 121.1 +/- 8.4, 124.4 +/- 8.8, 114.0 +/- 7.7 mmHg, respectively, in women with uterine malformations and 108.0 +/- 7.4, 109.2 +/- 7.3, 102.1 +/- 8.5 mmHg, respectively, in normal pregnant women. Twenty-four-hour diastolic, daytime, and nighttime diastolic (mean +/- SD) 74.1 +/- 10.2, 77.1 +/- 10.6, 68.1 +/- 9.2 mmHg, in women with uterine malformations and 64.1 +/- 5.7, 66.0 +/- 5.7, 58.2 +/- 6.3 mmHg, in normal pregnant women (all differences p < 0.001). Fifteen of the fetuses from women with congenital uterine malformations showed intrauterine growth retardation. No differences were found 6 months after delivery. |
Does hesperetin induce the Apoptosis of Gastric Cancer Cells via Activating Mitochondrial Pathway by Increasing Reactive Oxygen Species? | Hesperetin, has been shown to exert biological activities on various types of human cancers. However, few related studies on gastric cancer are available. In this study, we sought to investigate the effect of hesperetin on gastric cancer and clarify its specific mechanism. Cell Counting Kit-8, 2',7'-dichlorofluorescin diacetate, JC-1, Hoechst 33258 staining, and western bolt were used to detect cell viability, levels of intracellular reactive oxygen species (ROS), changes in mitochondrial membrane potential (△ψ m), cell apoptosis, and expressions of mitochondrial pathway proteins, respectively. Meanwhile, xenograft tumor models in nude mice were made to evaluate the effect of hesperetin on gastric cancer in vivo. Compared with the control group, the proliferation of gastric cancer cells in hesperetin groups was significantly inhibited (P < 0.05), and dose- and time-dependent effects were observed. Pretreatment with H2O2 (1 mM) or N-acetyl-L-cysteine (5 mM) enhanced or attenuated the hesperetin-induced inhibition of cell viability (P < 0.05). Percentages of apoptotic cells, levels of intracellular ROS, and △ψ m varied with the dose and treatment time of hesperetin (P < 0.05), and hesperetin caused an increase in the levels of AIF, Apaf-1, Cyt C, caspase-3, caspase-9, and Bax and a decrease in Bcl-2 levels (P < 0.05). Meanwhile, hesperetin significantly inhibited the growth of xenograft tumors (P < 0.05). | Approximately 50% of subjects with essential hypertension (EH) are insulin resistant, and this defect in insulin action could contribute to increased cardiovascular disease (CVD) risk in these patients. To test this hypothesis, we attempted to see if there was a link between insulin resistance (IR) and carotid intimal medial thickness (IMT), an early index of CVD, in patients with essential hypertension. Ultrasound quantification of carotid IMT was performed in 79 hypertensive patients, and 63 patients (31 m and 32 f), defined as being free of plaque (IMT < 1.3 mm), were further subdivided into normal (<1.0 mm) and thickened (1-1.3 mm) IMT groups. Subjects in the thickened IMT group were older and had significantly (p < 0.05) higher plasma concentrations of fasting insulin, nitric oxide (NO(x)) and intercellular adhesion molecule 1 (ICAM-1). However, the two groups were not significantly different in terms of blood pressure, overall or regional obesity, fasting lipid levels, uric acid, concentrations of other cellular adhesion molecules or levels of C-reactive protein. There were significant (p < 0.05) correlations in the whole population between IMT and age, fasting insulin and NO(x), and multiple regression analysis identified fasting insulin as an independent predictor of IMT. |
Are circulating immunoglobulins associated with intraplaque mast cell number and other vulnerable plaque characteristics in patients with carotid artery stenosis? | Recently, we have shown that intraplaque mast cell numbers are associated with atherosclerotic plaque vulnerability and with future cardiovascular events, which renders inhibition of mast cell activation of interest for future therapeutic interventions. However, the endogenous triggers that activate mast cells during the progression and destabilization of atherosclerotic lesions remain unidentified. Mast cells can be activated by immunoglobulins and in the present study, we aimed to establish whether specific immunoglobulins in plasma of patients scheduled for carotid endarterectomy were related to (activated) intraplaque mast cell numbers and plasma tryptase levels. In addition, the levels were related to other vulnerable plaque characteristics and baseline clinical data. OxLDL-IgG, total IgG and total IgE levels were measured in 135 patients who underwent carotid endarterectomy. No associations were observed between the tested plasma immunoglobulin levels and total mast cell numbers in atherosclerotic plaques. Furthermore, no associations were found between IgG levels and the following plaque characteristics: lipid core size, degree of calcification, number of macrophages or smooth muscle cells, amount of collagen and number of microvessels. Interestingly, statin use was negatively associated with plasma IgE and oxLDL-IgG levels. | Autophagy is an evolutionarily conserved cellular process that involves the lysosomal degradation of proteins and organelles and the recycling of cellular components to ensure cellular survival under external or internal stress. Numerous data has indicated that autophagy can be successfully targeted for the treatment of multiple cancers. We have previously demonstrated that tetrandrine, a bisbenzylisoquinoline alkaloid isolated from the broadly used Chinese medicinal herb Stephaniae tetrandrae, exhibits potent antitumor effects when used either alone or in combination with other drugs. In the present study, we showed that tetrandrine is a broad-spectrum potent autophagy agonist. Although low-dose tetrandrine treatment does not affect cell viability, it can potently induce autophagy in a variety of cell lines, including cancerous cells and nontumorigenic cells. The autophagy inhibitors 3-methyladenine (3-MA) and chloroquine (CQ), effectively blocked tetrandrine-induced autophagy. Moreover, tetrandrine significantly triggered the induction of mitophagy. The underlying mechanisms are associated with the tetrandrine-induced production of intracellular reactive oxygen species (ROS), which plays a critical role in tetrandrine-induced autophagy. |
Does comorbidity influence multiple aspects of well-being of patients with ischemic heart disease? | Comorbidity is prevalent among patients with Ischemic Heart Disease (IHD) and may influence patients' subjective and objective domains of well-being. We aimed to investigate the associations between comorbidity and different measures of well-being (i.e. health related quality of life, psychological distress, sleep quality, and dyadic adjustment) among patients with IHD. In this cross-sectional study, 796 outpatients with documented IHD were enrolled from an outpatient cardiology clinic in 2006. Comorbidity (Ifudu index), quality of life (SF36), psychological distress (Hospital Anxiety Depression Scale; HADS), sleep quality (Pittsburg Sleep Quality Index; PSQI), and dyadic adjustment quality (Revised Dyadic Adjustment Scale; RDAS) were measured. Associations between comorbidity and different measures of well-being were determined. Significant correlations were found between comorbidity score and all measures of well-being. Comorbidity score was correlated with physical quality of life (r = -0.471, P < 0.001), mental quality of life (r = -0.447, P < 0.001), psychological distress (r = 0.344, P < 0.001), sleep quality (r = 0.358, P < 0.001), and dyadic adjustment (r = -0.201, P < 0.001). | To determine whether palatal medial edge epithelium (MEE) is specialized in its ability to disappear compared with other embryonic, non-palatal, epithelium. Embryonic tissues harvested from CD1 mice. Organs were cultured in 2 ml of DMEM/F12 supplemented with 300 microg/ml L-glutamine and 1% penicillin/streptomycin. Organs were cultured under various conditions including opposing other organs and opposing an inert material for a period of 6 days. Tissues were then processed for histological examination. MEE of shelves opposing nothing persisted, whereas MEE of shelves contacting another shelf disappeared. When a tail was placed against a palatal shelf the MEE disappeared, as did the epithelium from the tail, resulting in fusion between the shelf and tail. Furthermore, when palatal shelves were placed against an inert material the MEE disappeared, suggesting pressure alone is a sufficient stimulus to initiate disappearance of the MEE, and that the interaction between the two palatal shelves is not a prerequisite for the disappearance of MEE. Moreover, when two embryonic tails were cultured in close apposition they fused, as did paired limbs. Non-palatal epithelia also disappeared after contact with inert materials. Epithelial disappearance began within 24 h of contact, but there was an age limit. |
Does tLR9-Targeted STAT3 Silencing abrogate Immunosuppressive Activity of Myeloid-Derived Suppressor Cells from Prostate Cancer Patients? | Recent advances in immunotherapy of advanced human cancers underscored the need to address and eliminate tumor immune evasion. The myeloid-derived suppressor cells (MDSC) are important inhibitors of T-cell responses in solid tumors, such as prostate cancers. However, targeting MDSCs proved challenging due to their phenotypic heterogeneity. Myeloid cell populations were evaluated using flow cytometry on blood samples, functional assays, and immunohistochemical/immunofluorescent stainings on specimens from healthy subjects, localized and metastatic castration-resistant prostate cancer patients. Here, we identify a population of Lin(-)CD15(HI)CD33(LO) granulocytic MDSCs that accumulate in patients' circulation during prostate cancer progression from localized to metastatic disease. The prostate cancer-associated MDSCs potently inhibit autologous CD8(+) T cells' proliferation and production of IFNγ and granzyme-B. The circulating MDSCs have high levels of activated STAT3, which is a central immune checkpoint regulator. The granulocytic pSTAT3(+) cells are also detectable in patients' prostate tissues. We previously generated an original strategy to silence genes specifically in Toll-like Receptor-9 (TLR9) positive myeloid cells using CpG-siRNA conjugates. We demonstrate that human granulocytic MDSCs express TLR9 and rapidly internalize naked CpG-STAT3siRNA, thereby silencing STAT3 expression. STAT3 blocking abrogates immunosuppressive effects of patients-derived MDSCs on effector CD8(+) T cells. These effects depended on reduced expression and enzymatic activity of Arginase-1, a downstream STAT3 target gene and a potent T-cell inhibitor. | To study the blood-brain barrier integrity in prehepatic portal hypertensive rats induced by partial portal vein ligation,at 14 and 40 d after ligation when portal pressure is spontaneously normalized. Adult male Wistar rats were divided into four groups: Group I: Sham14d , sham operated; Group II: PH14d , portal vein stenosis; (both groups were used 14 d after surgery); Group III: Sham40d, Sham operated and Group IV: PH40d Portal vein stenosis (Groups II and IV used 40 d after surgery). Plasma ammonia,plasma and cerebrospinal fluid protein and liver enzymes concentrations were determined. Trypan and Evans blue dyes, systemically injected,were investigated in hippocampus to study blood-brain barrier integrity. Portal pressure was periodically recorded. Forty days after stricture, portal pressure was normalized, plasma ammonia was moderately high, and both dyes were absent in central nervous system parenchyma. All other parameters were reestablished. When portal pressure was normalized and ammonia level was lowered, but not normal, the altered integrity of blood-brain barrier becomes reestablished. |
Does cCR1 blockade reduce interstitial inflammation and fibrosis in mice with glomerulosclerosis and nephrotic syndrome? | CC chemokines mediate leukocyte infiltration into inflamed tissue. We have recently shown that blockade of the CC chemokine receptor CCR1 reduces interstitial inflammation and fibrosis in murine obstructive nephropathy. However, it is not known whether CCR 1 blockade is protective in progressive renal injury associated with severe proteinuria. We therefore studied the effect of the small-molecule CCR1 antagonist BX471 in a murine model of adriamycin-induced focal segmental glomerulosclerosis (FSGS) with nephrotic syndrome and progressive interstitial inflammation and fibrosis. Adriamycin nephropathy with persistent proteinuria was induced in male BALB/c mice by two intravenous injections of adriamycin (13 mg/kg) at day 0 and 14. BX471 treatment was started at day 14 when proteinuria and interstitial inflammation had developed. At 6 weeks, renal histology was studied by morphometry and immunohistochemistry. At week 6, adriamycin-treated mice showed FSGS, associated with tubulointerstitial injury consisting of tubular dilation and atrophy, interstitial leukocyte infiltration, and fibrosis. The mRNA expression of CCR1 and CC chemokines, including the CCR1 ligands CCL3 (MIP-1alpha) and CCL5 (RANTES), was up-regulated in diseased kidneys, with a prominent interstitial expression of CCL5. Compared to vehicle-treated controls BX471 significantly reduced the amount of macrophages and T lymphocytes in interstitial lesions by 51% and 22%, respectively. Markers of renal fibrosis such as interstitial fibroblasts (48%) and interstitial volume (23%) were significantly reduced by BX471 treatment. In contrast, the extent of proteinuria and glomerular sclerosis was not affected by BX471 treatment. | 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. |
Do patients With Isolated PCL Injuries Improve From Surgery as Much as Patients With ACL Injuries After 2 Years? | Reports on outcome after posterior cruciate ligament (PCL) reconstruction often contain both isolated PCL and combined knee ligament injuries. This makes it difficult to conclude on the outcome after reconstruction of isolated PCL injuries. To investigate the outcome after PCL reconstruction in patients with an isolated PCL injury and to compare this with the outcome of patients treated with reconstruction after isolated anterior cruciate ligament (ACL) injuries. Cohort study; Level of evidence, 3. Seventy-one patients with an isolated PCL injury that was reconstructed surgically and who had registered in the Norwegian Knee Ligament Registry between 2004 and 2010 were included in this study. Patients with isolated ACL reconstructions (n = 9661) who had registered in the same period were included for comparison. Knee Injury and Osteoarthritis Outcome Score (KOOS) was used as the patient-reported outcome measure. Preoperative and 2-year postoperative KOOS scores were compared. Changes in KOOS score reported by the PCL patients were compared with changes reported by the ACL patients. At the 2-year postoperative follow-up of the PCL-reconstructed patients, the patient-reported outcome was improved, measured by KOOS as follows: pain, 15.1 (95% CI, 8.5-21.8; P < .001); symptoms, 0.9 (95% CI, -6.6 to 8.3; P = .82); activities of daily living, 13.2 (95% CI, 6.6-13.9; P < .001); sports, 20.7 (95% CI, 11.8-29.4; P < .001); and quality of life, 26.6 (95% CI, 18.9-34.2; P < .001). According to the KOOS, the incremental improvements were similar for PCL and ACL patients. Time from injury to surgery was longer for the PCL patients compared with ACL patients (median, 21.5 vs 8.0 months; P < .001). | Regulation of gene expression in trypanosomatids is mainly posttranscriptional. Tight regulation of mRNA stability and access to polysomes allows Trypanosoma cruzi to adapt to different environmental conditions during its life cycle. Posttranscriptional regulation requires association between mRNAs and specific proteins to form mRNP complexes. Proteins that lack a canonical RNA-binding domain, such as eukaryotic elongation factor-1α (EF-1α), may also associate with mRNPs. EF-1α is conserved in many organisms, and it plays roles in many cellular processes other than translation, including RNA transport, the cell cycle, and apoptosis. In a previous study, EF-1α was found associated with mRNP-forming mRNAs in polysome-free fractions both in epimastigotes growing under normal conditions and in nutritionally stressed parasites. This finding suggested the possibility that EF-1α has a non-canonical function. Thus, we investigated the dynamics of EF-1α in association with T. cruzi epimastigote mRNAs under normal and stressed nutritional conditions. EF-1α is expressed throughout the parasite life cycle, but it shows a slight decrease in protein levels in the metacyclic trypomastigote form. The protein is cytoplasmically localized with a granular pattern in all forms analyzed. Following puromycin treatment, EF-1α migrated with the heaviest gradient fractions in a sucrose polysome profile, indicating that its association with large protein complexes was independent of the translation machinery. We next characterized the EF-1α-associated mRNAs in unstressed and stressed epimastigotes. We observed that specific subsets of mRNAs were associated with EF-1α-mRNPs in unstressed or stressed epimastigotes. Some mRNAs were identified in both physiological conditions, whereas others were condition-specific. Gene ontology analysis identified enrichment of gene sets involved in single-organism metabolic processes, amino acid metabolic processes, ATP and metal ion binding, glycolysis, glutamine metabolic processes, and cobalt and iron ion binding. |
Is signaling via the type I IL-1 and TNF receptors necessary for bacterially induced preterm labor in a murine model? | We have shown previously that interleukin 1 (IL-1) signaling is not necessary for bacterially induced preterm delivery in mice. We now test whether combined signaling of IL-1 and tumor necrosis factor (TNF) is critical for this process. Female mice lacking the type I receptors for IL-1 and TNF (Il1r1/Tnfrsf1a double-knockouts) and normal controls underwent intrauterine inoculation with killed Escherichia coli bacteria on day 14.5 of a 19- to 20-day gestation. Preterm delivery rates within 48 hours were recorded and gene expression was analyzed by reverse transcription-polymerase chain reaction (RT-PCR). Il1r1/Tnfrsf1a double-knockout mice had significantly lower rates of preterm delivery than controls (8% vs 69% with 7 x 10(7) bacteria, P = .002, and 52% vs 81% with 1.4 x 10(8) bacteria, P = .003) and significantly lower myometrial levels of cyclooxygenase (COX)-2, but not COX-1 mRNA. There were no genotype- or treatment-related differences in cervicovaginal and lower uterine expression of mRNAs for a variety of genes associated with cervical ripening. | The calcium-channel blocking effect of magnesium might have protective effects in patients undergoing cardiopulmonary bypass surgery. We assessed the effects of magnesium on hearts undergoing coronary artery bypass surgery with intermittent warm blood hyperkalemic cardioplegia in the antegrade fashion. Twenty patients undergoing coronary bypass surgery were randomly divided into two groups, a control group who received intermittent antegrade warm blood hyperkalemic cardioplegia for myocardial protection, and a study group who received the same solution with the addition of magnesium to the cardioplegia. Extracellular substrates (creatinine phosphokinase, creatinine phosphokinase-MB group, lactate dehydrogenase, c-reactive protein, and cardiac troponin I were measured preoperatively and postoperatively. There were significant differences in the post-operative concentrations of creatinine phosphokinase, creatinine phosphokinase-MB group, c-reactive protein, and lactate dehydrogenase after cardiopulmonary bypass (P<0.001) in the study group compared with the control subjects. Cardiac troponin I levels were also significantly lower in the study group after cardiopulmonary bypass (P<0.005). |
Does lack of NF-kappaB1 ( p105/p50 ) attenuate unloading-induced downregulation of PPARalpha and PPARalpha-regulated gene expression in rodent heart? | Unloading of the rodent heart activates the fetal gene program, decreases peroxisome proliferator-activated receptor alpha (PPARalpha) and PPARalpha-regulated gene expression (MCAD), and induces cardiomyocyte atrophy. NF-kappaB regulates the fetal gene program and PPARalpha-regulated gene expression during cardiac hypertrophy and induces atrophy in skeletal muscle. Our objective was to test the hypothesis that NF-kappaB is the regulator for activation of the fetal gene program, for downregulation of PPARalpha and PPARalpha-regulated gene expression, and for cardiomyocyte atrophy in the heart subjected to mechanical unloading. Activation of the inhibitory kappa B kinase beta (IKKbeta)/NF-kappaB pathways were measured in the heterotopically transplanted rat heart using Western blotting of total and phospho-IKKbeta and using transcription factor ELISA's for the five members of the NF-kappaB family (p65 (Rel A), p105/p50, c-Rel, RelB, and p100/p52). In loss of function experiments, we transplanted hearts of p105/p50 knockout mice into wildtype mice and compared changes in gene expression and cardiomyocyte size with wildtype hearts transplanted into wildtype mice. Total and phospho-IKKbeta levels significantly increased in the transplanted heart seven days after surgery. The activation of IKKbeta was paralleled by increased DNA binding activity of p65 and p105/p50. Mechanical unloading induced myosin heavy chain beta expression and decreased cardiomyocyte size in hearts of both wildtype and p105/p050 knockout animals. In contrast, the downregulation of PPARalpha and MCAD was significantly attenuated or prevented in the hearts of p105/p50 knockout mice. | Headache is a common complaint for emergency visits. Common drugs used in relief of headache are opioids and their agonists and antagonists, ergot alkaloids, and nonsteroidal anti-inflammatory drugs (NSAIDs). Lack of appropriate medications or serious side effects of available drugs, motivated us to perform the study for evaluating the efficacy of intranasal lidocaine on different types of headache. A double-blind, randomized clinical trial (RCT) was performed among 90 adult patients with acute headache in Shahid Rahnemoon Emergency Center of Yazd city of Iran (45 patients in lidocaine group and 45 patients in placebo group). Patients with history of epilepsy, allergy to lidocaine, signs of skull base fracture, Glasgow Coma Scale (GCS) < 15, patients younger than 14 years and patients who had received any medication in previous 2 h were excluded. After checking vital signs and taking the demographic data, one puff of 10% lidocaine or normal saline (placebo) was sprayed into each nostril. Patients' headache severity measured by visual analog scale (VAS) before drug administration and at 1, 5, 15, and 30 min after intervention. Data were analyzed by Statistical Package for Social Sciences (SPSS) version 17 and statistical tests including t-test, repeated measures analysis of variance (ANOVA), Fisher's exact test, and Mann-Whitney test were performed. Descriptive variables were expressed by mean ± standard deviation (SD) and quantitative variables reported by frequency and percentages. P-values less than 0.05 were considered significant. 57.8% of patients were female. The mean age of patients was 35.32 years. According to sex and age, there was no significant difference between groups (P-values were 0.83 and 0.21; respectively). The mean base pain score was 6.97 in lidocaine group and 6.42 in placebo group which was not significantly different (P-value = 0.198). After intervention, the mean scores were significantly lower in lidocaine group than placebo group in all mentioned times (P-value < 0.001). The primary and secondary headaches had no significant difference in mean pain relief score in lidocaine group (P = 0.602). |
Do statin drugs decrease progression to cirrhosis in HIV/HCV co-infected individuals? | Chronic HIV/HCV co-infection carries increased risk of cirrhosis, hepatocellular carcinoma, and death. Due to anti-inflammatory properties, HMG co-A inhibitors (statins) may be useful adjunctive therapy to reduce liver disease progression. Clinical information was extracted from the Veterans Affairs HIV and HCV Clinical Case Registries (1999 - 2010). HIV-related variables included combination anti-retroviral therapy (cART) era of diagnosis, CD4 cell count, and percent time with undetectable HIV viral load. Metabolic variables included diabetes, low-HDL, and hypertension. Statin use was measured as percent time with active prescription (time-updated throughout the follow-up period). Cox proportional hazards analysis was used to determine risk factors for cirrhosis (ICD-9 or APRI>2) overall and in groups stratified by alanine aminotransferase (ALT) level above and below 40 IU/L. The cohort included 5985 HIV/HCV co-infected veterans. The majority was black race, and the mean age at index date was 45 years. Statin use was significantly protective of cirrhosis for patients with ALT ≤40 IU/L; for every 30% increase in time on statin, there was a 32% decreased risk of developing cirrhosis (HR 0.68, 95% CI 0.47 -0.98). Diabetes and low-HDL were significantly associated with cirrhosis in patients with ALT > 40 IU/L (HR 1.15, p < 0.04 and HR 1.3, p < 0.0001). | To examine whether specific neonatal factors differentially influence cerebellar subregional volumes and to investigate relationships between subregional volumes and outcomes in very preterm children at 7 years of age. Fifty-six children born very preterm (24-32 weeks gestational age) followed longitudinally from birth underwent 3-dimensional T(1)-weighted neuroimaging at median age 7.6 years. Children with severe brain injury were excluded. Cerebellar subregions were automatically segmented using the multiple automatically generated templates algorithm. The relation between cerebellum subregional volumes (adjusted for total brain volume and sex) and neonatal clinical factors were examined using constrained principal component analysis. Cognitive and visual-motor integration functions in relation to cerebellar volumes were also investigated. Higher neonatal procedural pain and infection, as well as other clinical factors, were differentially associated with reduced cerebellar volumes in specific subregions. After adjusting for clinical risk factors, neonatal procedural pain was distinctively associated with smaller volumes bilaterally in the posterior VIIIA and VIIIB lobules. Specific smaller cerebellar subregional volumes were related to poorer cognition and motor/visual integration. |
Do markers of bone remodeling predict rate of bone loss in multiple sclerosis patients treated with low dose glucocorticoids? | The aim of this study was to evaluate the clinical value of markers of bone remodeling in assessment of rate of bone loss in patients with multiple sclerosis (MS) long term treated with low dose glucocorticoids. The study involved 70 patients with MS. Motor function of the patients was evaluated using the Kurtzke Expanded Disability Status Scale (KEDSS). Bone mineral density (BMD) was determined at the lumbar spine and proximal femur at baseline and after 1.8 +/- 0.8 years. Bone remodeling was assessed using circulating concentrations of type 1 collagen cross-linked C-telopeptide (beta CTX), aminoterminal propeptide of type I procollagen, and N-MID osteocalcin (OC). A control group of 140 age-matched healthy subjects was used to compare bone-turnover markers. The plasma CTX concentration was the most significant parameter of bone remodeling which correlated with the rate of bone loss and with the KEDSS. The rate of bone loss at the proximal femur was not significantly different between tertiles of plasma OC concentrations. | Functional nicotinic acetylcholine receptors (nAChR) have been identified in airway epithelia and their location in the apical and basolateral membrane makes them targets for acetylcholine released from neuronal and non-neuronal sources. One function of nAChR in airway epithelia is their involvement in the regulation of transepithelial ion transport by activation of chloride and potassium channels. However, the mechanisms underlying this nicotine-induced activation of ion transport are not fully elucidated. Thus, the aim of this study was to investigate the involvement of adenylyl cyclases in the nicotine-induced ion current in mouse tracheal epithelium. To evaluate the nicotine-mediated changes of transepithelial ion transport processes electrophysiological Ussing chamber measurements were applied and nicotine-induced ion currents were recorded in the absence and presence of adenylyl cyclase inhibitors. The ion current changes induced by nicotine (100 μM, apical) were not altered in the presence of high doses of atropine (25 μM, apical and basolateral), underlining the involvement of nAChR. Experiments with the transmembrane adenylyl cyclase inhibitor 2'5'-dideoxyadenosine (50 μM, apical and basolateral) and the soluble adenylyl cyclase inhibitor KH7 (10 μM, apical and basolateral) both reduced the nicotine-mediated ion current to a similar extent. Yet, a statistically significant reduction was obtained only in the experiments with KH7. |
Does regulation of endothelial nitric oxide synthase and asymmetric dimethylarginine by matrine attenuate isoproterenol-induced acute myocardial injury in rats? | This study was designed to investigate the cardioprotective effects of matrine on regulation of endothelial nitric oxide synthase (eNOS) and asymmetric dimethylarginine (ADMA) in isoproterenol-induced acute myocardial ischaemic rats. Male Sprague-Dawley rats were pretreated with matrine (200, 100 and 50 mg/kg) orally for 10 days. Acute myocardial injury was induced in rats by subcutaneous injection of isoproterenol. Serum and haemodynamic parameters, histopathological variables and expression of protein levels were analysed. Oral administration of matrine (200, 100 and 50 mg/kg) significantly attenuated isoproterenol-induced cardiac necrosis and left ventricular dysfunction. Matrine treatment restored impaired ventricular Akt and eNOS protein expression with concomitant increased phosphorylation of Akt (Ser473) and eNOS (Ser1177), and also restored glycogen synthase kinase 3β activity, as indicated by increased phosphorylation at Ser 9. Moreover, treatment with matrine had no effect on the isoproterenol-induced elevated protein arginine methyltransferase 1 protein expression, but could significantly normalize the reduced dimethylarginine dimethylaminohydrolase 2 expression and attenuate the increased serum level of ADMA. The expression of catechol-o-methyltransferase and monoamine oxidase did not differ among all groups (all P > 0.05). | The 1858C/T SNP of the PTPN22 gene has been associated with many autoimmune diseases, suggesting the existence of an inflammatory process common to all of them. We studied the association of that polymorphism with immunoglobulin A deficiency (IgAD) following a double approach: a case-control and a TDT study. A total of 259 IgAD patients and 455 unrelated matched controls, and 128 families were used for each approach. Comparisons were performed using Chi-Square tests or Fisher's exact test when necessary. No association between the PTPN22 1858C/T SNP and IgA deficiency was found in any case (allelic frequencies 8% vs. 6% in patients and controls, respectively, OR= 1.14 (0.72-1.79), p= 0.56; TDT p = 0.08). |
Does cXCL13 inhibit microRNA-23a through PI3K/AKT signaling pathway in adipose tissue derived-mesenchymal stem cells? | Adipose tissue derived-mesenchymal stem cells (AMSCs) are one of the most widely used MSCs in the cell therapy for regenerative medicine. In the current study, the role of CXCL13 in AMSCs and its potential signaling pathway were investigated. AMSCs were isolated from adipose tissue of healthy subjects. After administrating the cells with CXCL13, the expression levels of miR-23a and runt-related transcription factor 2 (Runx2) were assessed by real-time PCR and western blot. The alterations of phosphoinositide-3 kinase (PI3K)/Akt, stress-activated protein kinase (SAPK)/c-jun kinase (JNK), and extracellular-signal-regulated kinase (ERK1/2) pathways were also evaluated. CXCL13 down-regulated miR-23a and up-regulated Runx2 expression in AMSCs. The inhibitor specific for PI3K/AKT, but not SAPK/JNK and ERK ERK1/2, reversed the effects of CXCL13 on miR-23a and Runx2 expression. | Vibrio parahaemolyticus is frequently isolated from environmental and seafood samples and associated with gastroenteritis outbreakes in American, European, Asian and African countries. To distinguish between different lineages of V. parahaemolyticus various genotyping techniques have been used, incl. multilocus sequence typing (MLST). Even though some studies have already applied MLST analysis to characterize V. parahaemolyticus strain sets, these studies have been restricted to specific geographical areas (e.g. U.S. coast, Thailand and Peru), have focused exclusively on pandemic or non-pandemic pathogenic isolates or have been based on a limited strain number. To generate a global picture of V. parahaemolyticus genotype distribution, a collection of 130 environmental and seafood related V. parahaemolyticus isolates of different geographical origins (Sri Lanka, Ecuador, North Sea and Baltic Sea as well as German retail) was subjected to MLST analysis after modification of gyrB and recA PCRs. The V. parahaemolyticus population was composed of 82 unique Sequence Types (STs), of which 68 (82.9%) were new to the pubMLST database. After translating the in-frame nucleotide sequences into amino acid sequences, less diversity was detectable: a total of 31 different peptide Sequence Types (pSTs) with 19 (61.3%) new pSTs were generated from the analyzed isolates. Most STs did not show a global dissemination, but some were supra-regionally distributed and clusters of STs were dependent on geographical origin. On peptide level no general clustering of strains from specific geographical regions was observed, thereby the most common pSTs were found on all continents (Asia, South America and Europe) and rare pSTs were restricted to distinct countries or even geographical regions. One lineage of pSTs associated only with strains from North and Baltic Sea strains was identified. |
Does zinc treatment ameliorate diarrhea and intestinal inflammation in undernourished rats? | WHO guidelines recommend zinc supplementation as a key adjunct therapy for childhood diarrhea in developing countries, however zinc's anti-diarrheal effects remain only partially understood. Recently, it has been recognized that low-grade inflammation may influence stunting. In this study, we examined whether oral zinc supplementation could improve weight, intestinal inflammation, and diarrhea in undernourished weanling rats. Rats were undernourished using a northeastern Brazil regional diet (RBD) for two weeks, followed by oral gavage with a saturated lactose solution (30 g/kg) in the last 7 days to induce osmotic diarrhea. Animals were checked for diarrhea daily after lactose intake. Blood was drawn in order to measure serum zinc levels by atomic absorption spectroscopy. Rats were euthanized to harvest jejunal tissue for histology and cytokine profiles by ELISA. In a subset of animals, spleen samples were harvested under aseptic conditions to quantify bacterial translocation. Oral zinc supplementation increased serum zinc levels following lactose-induced osmotic diarrhea. In undernourished rats, zinc improved weight gain following osmotic diarrhea and significantly reduced diarrheal scores by the third day of lactose intake (p < 0.05), with improved jejunum histology (p < 0.0001). Zinc supplementation diminished bacterial translocation only in lactose-challenged undernourished rats (p = 0.03) compared with the untreated challenged controls and reduced intestinal IL-1β and TNF-α cytokines to control levels. | Subarachnoid hemorrhage (SAH) is associated with cardiac injury and dysfunction. Whether aneurysm clipping versus coiling has a differential effect on the risk of troponin release and left ventricular (LV) dysfunction after SAH is unknown. It is hypothesized that aneurysm treatment does not affect the risk of developing cardiac injury and dysfunction. The study included 172 consecutive SAH patients who underwent clipping (n = 109) or coiling (n = 63) aneurysm therapy. Hemodynamic data were collected, cardiac troponin I was measured, and echocardiography was performed on the 1st, 3rd, and 6th days after enrollment. A cardiac troponin I measurement of more than 1.0 microg/L was considered abnormal. For each echocardiographic examination, a blinded observer measured LV ejection fraction (abnormal if <50%) and quantified LV regional wall motion abnormalities. The incidence of cardiac outcomes in the treatment groups was compared using odds ratios (ORs). The coiled patients were older than the clipped patients (mean age, 59 +/- 13 yr versus 53 +/- 12 yr; t test, P < 0.001) and were more likely to have posterior aneurysms (33% versus 18%; chi(2) test, P = 0.019). There were no significant between-group differences in the risk of cardiac troponin I release (coil 21% versus clip 19%; OR = 0.89, P = 0.789), regional wall motion abnormalities (33% versus 28%; OR = 0.76, P = 0.422), or LV ejection fraction lower than 50% (16% versus 17%; OR = 1.06, P = 0.892). No patient died of cardiac causes (heart failure, myocardial infarction, or arrhythmia). |
Is migraine with aura a risk factor for unprovoked seizures in children? | Migraine is associated with epilepsy, but the time order and nature of the relationship are unclear. We conducted a population based case control study to clarify the time order to determine whether migraine is a risk factor for epilepsy. Migraine symptoms were evaluated in a population-based case-control study of all incident epilepsy in Icelandic children and in matched controls (next two same sex births in the country). Migraine was associated with a fourfold increased risk for developing epilepsy, an association explained by migraine with aura (odds ratio, 8.1; 95% confidence interval, 2.7-24.3). Migraine without aura did not increase risk for epilepsy. | Recent studies have shown that mechanically unloading a failing heart may induce reverse remodeling and functional improvement. However, these benefits may be balanced by an unloading-related remodeling including myocardial atrophy that might lead to decrease in function. Using a model of heterotopic heart transplantation, we aimed to characterize the myocardial changes induced by long-term unloading. Macroscopic as well as cellular and functional changes were followed in normal hearts unloaded for a 3-month period. Microscopic parameters were evaluated with stereologic methodology. Myocardial contractile function was quantified with a Langendorff isolated, perfused heart technique. Atrophy was macroscopically obvious and accompanied by a 67% reduction of the myocyte volume and a 43% reduction of the interstitial tissue volume, thus accounting for a shift of the myocyte/connective tissue ratio in favor of noncontractile tissue. The absolute number of cardiomyocyte nuclei decreased from 64.7 +/- 5.1 x 10(7) in controls to 22.6 +/- 3.7 x 10(7) (30 days) and 21.6 +/- 3.1 x 10(7) (90 days) after unloading (P < .05). The numeric nucleic density in the unloaded myocardium, as well as the mean cardiomyocyte volume per cardiomyocyte nucleus, remained constant throughout the 90 days of observation. Functional data indicated an increase in ventricular stiffness, although contractile function was preserved, as confirmed by unaltered maximal developed pressure and increased contractility (maximum rate of left ventricular pressure development) and relaxation (minimum rate of left ventricular pressure development). |
Do [ Improving myocardial mechanics parameters of severe burn rabbits with oral fluid resuscitation ]? | To investigate the protective effect of oral fluid resuscitation on cardiac function in severe burn rabbits. One hundred and fifty rabbits were randomly divided into normal control group (NC group, n = 6, without treatment), burn group (B group, n = 42, without fluid therapy), immediate oral fluid resuscitation group (C group, n = 42), delayed oral fluid resuscitation group (D group, n = 30) and delayed and rapid oral fluid resuscitation group (E group, n = 30). The rabbits in B, C, D, E groups were subjected to 40% TBSA full-thickness burn, then were treated with fluid therapy immediately after burn (C group), at 6 hour after burn (D, E groups). The myocardial mechanics parameters including mean arterial pressure (MAP), left ventricular systolic pressure (LVSP), left ventricular end diastolic pressure (LVEDP), LV +/- dp/dt max were observed at 2, 6, 8, 12, 24, 36 and 48 post burn hour (PBH). Urine output was also examined. The level of LVSP, LV +/- dp/dt max in B roup were significantly lower than those in NC group. The level of LVSP, LV +/- dp/dt max in the C and E group were singnificantly increased during 24 hour after burn. The level of LV + dp/dt max and LV-dp/dt max in C group peaked at 8 PBH (892 +/- 116 kPa/s) and at 6PBH (724 +/- 149 kPa/s) respectively. The levels of LV +/- dp/dt max, LVSP in D group at each time point were similar to B group (P > 0.05). Both the levels of LV +/- dp/dt max in E group peaked at 8 PBH. The level of LVEDP was no obvious difference between B and other groups at each time point (P > 0.05). The changes of MAP and urine output on 24 PBH in each group were similar to above indices. | Proprotein convertase subtilisin kexin-like 9 (PCSK9) is a secreted glycoprotein that is transcriptionally regulated by cholesterol status. It modulates levels of circulating low density lipoprotein cholesterol (LDLC) by negatively regulating low density lipoprotein receptor (LDLR) levels. PCSK9 variants that result in 'gain of function' have been linked to autosomal dominant hypercholesterolemia, while significant protection from coronary artery disease has been documented in individuals who carry 'loss of function' PCSK9 variants. PCSK9 circulates in human plasma, and we previously reported that plasma PCSK9 is positively correlated with total cholesterol and LDLC in men. Herein, we report the effects of two lipid-modulating therapies, namely statins and fibrates, on PCSK9 plasma levels in human subjects. We also document their effects on endogenous PCSK9 and LDLR expression in a human hepatocyte cell line, HepG2, using immunoprecipitation and immunoblot analyses. Changes in plasma PCSK9 following fenofibrate or gemfibrozil treatments (fibric acid derivatives) were inversely correlated with changes in LDLC levels (r = -0.558, p = 0.013). Atorvastatin administration (HMGCoA reductase inhibitor) significantly increased plasma PCSK9 (7.40%, p = 0.033) and these changes were inversely correlated with changes in LDLC levels (r = -0.393, p = 0.012). Immunoblot analyses of endogenous PCSK9 and LDLR expression by HepG2 cells in response to statins and fibrates showed that LDLR is more upregulated than PCSK9 by simvastatin (2.6x vs 1.5x, respectively at 10 muM), while fenofibrate did not induce changes in either. |
Is thoracoscopic lobectomy associated with acceptable morbidity and mortality in patients with predicted postoperative forced expiratory volume in 1 second or diffusing capacity for carbon monoxide less than 40 % of normal? | A predicted postoperative (ppo) forced expiratory volume in 1 second (FEV1%) or diffusing capacity of the lung for carbon monoxide (DLCO%) of <40% has traditionally been considered to convey a high risk of lobectomy owing to elevated postoperative morbidity and mortality. These recommendations, however, were largely derived from the pre-video-assisted thoracoscopic surgical (VATS) era. We hypothesized that VATS lobectomy would be associated with acceptable morbidity and mortality at ppoFEV1% and ppoDLCO% values < 40%. PpoFEV1% and ppoDLCO% were calculated for patients undergoing open or VATS lobectomy for lung cancer in the Society of Thoracic Surgeons General Thoracic database from 2009 to 2011. Univariate comparisons, multivariate analyses, and 1:1 propensity matching were performed. A total of 13,376 patients underwent lobectomy (50.9% open, 49.1% VATS). A decreased ppoFEV1% and ppoDLCO% were each independent predictors for both cardiopulmonary complications and mortality in the open group (all P ≤ .008). In the VATS group, ppoFEV1% was an independent predictor of complications (P = .001) but not mortality (P = .77), and ppoDLCO% was an independent predictor of complications (P = .046) and mortality (P = .008). With decreasing ppoFEV1% or ppoDLCO%, complications and mortality increased at a greater rate in the open lobectomy than in a propensity-matched VATS group (n = 4215 each). For patients with ppoFEV1% < 40%, mortality was greater in the open (4.8%) than in the matched VATS group (0.7%, P = .003). Similar results were seen for ppoDLCO% < 40% (5.2% open, 2.0% VATS, P = .003). The rate of complications was significantly greater at ppoFEV1% < 40% in the open (21.9%) than in the matched VATS (12.8%, P = .005) group and similar results were seen with ppoDLCO% < 40% (14.9% open, 10.4% VATS, P = .016). | Osteomalacia (OSM) and rickets are widely prevalent in developing countries especially in females. The factors associated with such predisposition are not known. To identify nutritional, endocrine and genetic factors related to calcium and vitamin D metabolism that are associated with OSM/rickets in females. We studied 98 patients with OSM or rickets and their relatives including male and female sibs and parents (n = 221) for the presence of biochemical OSM {low serum 25-hydroxyvitamin D [25(OH)D], raised intact PTH (iPTH) and raised alkaline phosphatase} and associated nutritional and genetic factors. Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) was used for genotyping vitamin D receptor (VDR) (BsmI and FokI) and PTH gene (BstBI and DraII) single nucleotide polymorphisms (SNPs) in 74 families. The differences in the factors associated with calcium and vitamin D among the different groups were analysed by analysis of variance (ANOVA). Logistic regression analysis and the transmission disequilibrium test (TDT) were carried out to assess association between nutritional and genetic factors, and the disease, respectively. Most of the patients were female (91.8%). The mean serum 25(OH)D level of the female patients was comparable to that of the female sibs (14.4 +/- 5.7 vs. 18.3 +/- 9.7 nmol/l). The frequency of biochemical OSM was fivefold higher in female than in male sibs (24.4%vs. 4.9%). Female sibs also had significantly lower 25(OH)D, dietary calcium intake and sunshine exposure than male sibs. The frequency of biochemical OSM was comparable between mothers and fathers. The odds of biochemical OSM in the family members was reduced by 11% per 15-min daily sunshine exposure [odds ratio (OR) = 0.89, 95% confidence interval (CI) = 0.81-0.98, P = 0.02] and decreased by 20% per 100 mg dietary calcium intake (OR = 0.80, 95% CI = 0.67-0.96, P = 0.02). VDR/PTH gene SNPs showed no association with OSM/rickets on TDT analysis. |
Does electrical pharyngeal stimulation increase substance P level in saliva? | Substance P (SP) is a neuropeptide known to enhance the swallow response. It likely acts as a neurotransmitter in the pharyngeal mucosa in response to local stimuli. It has been proposed that dysphagia after stroke may be related to reduced levels of SP, which therefore constitutes a therapeutic target. In the present pilot study, we evaluated whether electrical pharyngeal stimulation (EPS), a neuromodulation device to enhance cortical reorganization for the restoration of swallowing function after brain injury, is able to increase SP in saliva or serum. In a randomized crossover study design, 20 healthy volunteers were treated with 10 min of real (0.2-ms pulses, 5 Hz, 280 V, stimulation intensity (mA) individually adjusted to tolerance level) or sham EPS on two separate sessions. Stimulation was delivered via a pair of bipolar ring electrodes mounted on an intraluminal catheter positioned in the pharynx. Blood and saliva samples were taken prior to, during, and up to 1 h after EPS and analyzed for their SP concentration by ELISA. Following real EPS but not sham stimulation, SP levels in saliva increased immediately and significantly about 28% (p < 0.01) compared to baseline. Serum levels remained unchanged. | While ovarian carcinoma is rare in the reproductive age group, these younger patients are known to fare better than the older patients. To determine whether age is an independent prognostic factor, as well as to investigate the clinicopathologic profile and survival rate of young women with ovarian carcinoma, a retrospective analysis in a series of patients aged 40 years or younger was performed. We collected data on 74 patients with borderline or invasive ovarian carcinoma treated at the Department of Obstetrics and Gynecology at the University of Florence between 1969 and 1994. The median follow-up was 72 months (range, 11-288 months). To assess the clinicopathologic profile and survival differences according to age, the series was subdivided into "very young" (30 years or younger) and "young" (31-40 years) groups of 34 and 40 patients, respectively. Survival rates (Kaplan-Meier method) were compared by the log rank test. A multivariate analysis (Cox proportional hazards) was used to determine the independent effect of each variable on survival. The overall 5-year and 10-year survival rates were 58.2% and 46.1%, respectively. Several prognostic factors were found significant by univariate analysis, including stage (P < 0.001), grade (P < 0.001), residual disease (P < 0.001), histologic type (P < 0.05), and age (< or = 30 years vs. 31-40 years; P = 0.009). Five year survival rates for the patients age 30 years and younger and patients age 31-40 years were 71.3% and 47.1%, respectively. In the former group, low malignant potential tumors and well differentiated carcinomas were significantly more frequent (68.8% vs. 37.5%; P = 0.01). In the multivariate analysis, only stage (I vs. >I; P = 0.004), grade (0-1 vs. 2-3; P = 0.03) and residual disease (P = 0.02) were found to be significant independent prognostic factors, whereas age (< or = 30 years vs. 31-40 years) yielded no independent information (P = 0.36). |
Does resveratrol attenuate microvascular inflammation in sepsis via SIRT-1-Induced modulation of adhesion molecules in ob/ob mice? | Obesity, a sirtuin-1 (SIRT-1) -deficient state, increases morbidity and resource utilization in critically ill patients. SIRT-1 deficiency increases microvascular inflammation and mortality in early sepsis. The objective of the study was to study the effect of resveratrol (RSV), a SIRT-1 activator, on microvascular inflammation in obese septic mice. ob/ob and C57Bl/6 (WT) mice were pretreated with RSV versus dimethyl sulfoxide (DMSO) (vehicle) prior to cecal ligation and puncture (sepsis). We studied (1) leukocyte/platelet adhesion, (2) E-selectin, ICAM-1, and SIRT-1 expression in small intestine, and (3) 7-day survival. A group of RSV-treated mice received SIRT-1 inhibitor (EX-527) with sepsis induction, and leukocyte/platelet adhesion and E-selectin/ICAM-1 expression were studied. We treated endothelial (HUVEC) cells with RSV to study E-selectin/ICAM-1 and p65-acetylation (AC-p65) in response to lipopolysaccharide (LPS). RSV treatment decreased leukocyte/platelet adhesion and E-selectin/ICAM-1 expression with increased SIRT-1 expression in septic ob/ob and WT mice, decreased E-selectin/ICAM-1 expression via increased SIRT-1 expression, and decreased AC-p65 expression in HUVEC. EX-527 abolished RSV-induced attenuation of microvascular inflammation in ob/ob septic mice. Finally, ob/ob mice in the sepsis+RSV group had significantly increased 7-day survival versus the sepsis+vehicle group. | The cyclooxygenase-2 (cox-2) pathway is now recognized to be important in human cancer development and progression. The gene for cox-2 carries a common single nucleotide polymorphism, T8473C, located within a potential functional region in the 3'-UTR of cox-2 gene was identified. We have investigated the frequencies of cox-2 genotypes in Tunisian population to determine whether that polymorphism was associated with the risk of nasopharyngeal carcinoma (NPC) in Tunisian population. One hundred and eighty-nine NPC patients were compared to 237 healthy controls. The cox-2 T8473C polymorphism was significantly associated with NPC (P=0.031). The CC-genotype and C allele were more frequent in control compared to patients group [CC: OR=0.37; P=0.013; 95% CI: 0.17-0.81; C: OR=0.72; P=0.032; 95% CI: 0.53-0.97]. Multivariate logistic regression analyses revealed that the CC-genotype was associated with a significantly decreased risk of NPC (P=0.013). Tumor sizes, histologic grade, presence of primary lymph node metastases, age or sex were not associated with cox-2 genotypes. |
Are [ Interferon-inducible genes lymphocyte antigen 6 complex E and tetratricopeptide repeats 1 correlated with clinical features of patients with systemic lupus erythematosus ]? | To investigate the expression levels of lymphocyte antigen 6 complex, locus E (LY6E) and interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) genes in the peripheral blood mononuclear cells (PBMCs) of patients with systemic lupus erythematosus (SLE), and to evaluate the relations between these gene expression levels and disease activity. The clinical data of 144 SLE patients, 27 non-SLE patients with rheumatic diseases, and 59 normal controls were collected. The SLE patients were further divided into 2 subgroups: active SLE group (n = 87) and non-active SLE group (n = 57) according to SLEDAI scores. Specimens of peripheral blood were drawn; total RNA was extracted and transcribed into cDNA. Sybr green dye based real-time quantitative PCR method was used to compare the expression levels (indicated as-DeltaDeltaCT value) of LY6E and IFIT1 in patients with SLE and those in the controls. (1) The-DeltaDeltaCT value of LY6E expression level of the SLE patients was 5.4760 +/- 1.9806, significantly higher than those of the non-SLE patients (3.4323 +/- 1.7456) and normal controls (4.5198 +/- 1.6359, both P = 0.001). (2) The-DeltaDeltaCT value of LY6E and IFIT1 mRNA expression of the active SLE patients were 6.1960 +/- 1.7729 and 6.4997 +/- 2.6297 respectively, significantly higher than those observed in the inactive SLE patients (4.3770 +/- 1.7764 and 4.1327 +/- 2.6044 respectively, both P = 0.000). The-DeltaDeltaCT values of LY6E and IFIT1 mRNA of the SLE patients were correlated with the SLEDAI scores, and with the numbers of matched criteria used in the diagnosis of SLE (P < 0.001). | Tetrodotoxin (TTX) is a neurotoxin found in puffer fish and other marine animals. New clinical studies suggest that low-dose TTX can safely relieve severe, treatment-resistant cancer pain. The therapeutic potential of TTX in addiction is supported by studies in laboratory animals. The purpose of this double-blind, placebo-controlled study was to assess the effect of a single intramuscular dose of TTX on cue-induced craving and anxiety in abstinent heroin addicts. Forty-five abstinent heroin addicts were randomly assigned to three treatment groups: placebo, 5 microg TTX, or 10 microg TTX. Participants were exposed to a neutral video or a heroin-related video. Craving, anxiety, blood pressure, and heart rate were measured pre- and post-exposure. Heroin-related cues increased both craving and anxiety and had no effect on blood pressure and heart rate. A single dose of TTX dose-dependently attenuated the increases in craving and anxiety while having no effect on blood pressure or heart rate. |
Is esophageal Mucosal Impedance Pattern Distinct in Patients With Extraesophageal Reflux Symptoms and Pathologic Acid Reflux? | Current diagnostic tests for gastroesophageal reflux disease (GERD) do not consistently measure chronicity of reflux. Mucosal impedance (MI) is a minimally invasive measurement to assess esophageal conductivity changes due to GERD. We aimed to investigate MI pattern in patients with symptoms of extraesophageal reflux (EER) in a prospective longitudinal cohort study. Patients with potential symptoms of EER undergoing esophagogastroduodenoscopy (EGD) with wireless pH monitoring were studied. Participants included those with erosive esophagitis (E+), normal EGD/abnormal pH (E-/pH+), and normal EGD/normal pH (E-/pH-). MI was measured from the site of injury in patients with E+, as well as at 2, 5, and 10 cm above the squamocolumnar junction (SCJ) in all participants. Forty-one patients with symptoms of EER were studied. MI measurements at 2 cm above the SCJ were significantly (P = 0.04) different among the three groups, with MI lowest for E+ and greatest for E-/pH- patients. Although not statistically significant, there is a graded increase in median (interquartile range) MI axially along the esophagus at 5 cm (P = 0.20) and at 10 cm (P = 0.27) above the SCJ, with those with reflux (E+ and E-/pH+) having a lower MI than those without. | Circadian rhythms are known to influence a variety of biological phenomena such as cell cycle, sleep-wake rhythm, hormone release and other important physiological functions. Given that cell cycle entry of hibernating hematopoietic stem cells (HSCs) plays a critical role in controlling hematopoiesis, we asked functional significance of the clock gene Bmal1, which plays a central role in regulating circadian rhythms as a transcription factor. Here we investigated the necessity of Bmal1 for HSC functions using Bmal1 deficient (Bmal1⁻/⁻) mice. Using colony-forming assays in vitro, we found that the frequency of mixed colony formation between Bmal1⁺/⁺ and Bmal1⁻/⁻ CD34-KSL cells does not differ significantly. Competitive bone marrow assays also revealed that Bmal1⁻/⁻ bone marrow cells competed normally with wild-type cells and displayed long-term multi-hematopoietic lineage reconstitution. In addition, there were no significant differences in the frequencies and hibernation state of bone marrow HSCs between Bmal1⁺/⁺ and Bmal1⁻/⁻ mice, suggesting that they are independent of circadian rhythms. |
Is the ventricular epicardial fat related to the myocardial mass in normal , ischemic and hypertrophic hearts? | The purpose of the present study was to evaluate the extent of the ventricular epicardial fat and its relationship with the underlying myocardium, neither of which is still completely understood. A total of 117 autoptic human hearts was subdivided into four groups: normals (N), ischemics (I), hypertrophics (H) and hypertrophic-ischemics (HI). In each heart, the ventricular myocardial and epicardial fat weights were measured. On the basis of these data, the epicardial fat percentage within the ventricles was calculated. The left, right and total ventricular fat weights were greater in H and HI than in N and I (P<.05, P<.05, P<.01, respectively). No differences were detected in the epicardial fat weights in comparing H versus HI and N versus I. Moreover, the fat percentage in each ventricle did not vary between the four groups. However, if compared with the right ventricle, the left ventricle showed an epicardial fat percentage consistently lower (P<.0001). In nonhypertrophied hearts (N and I), the body mass index and the total epicardial fat weight were correlated (P<.05), whereas in hypertrophied hearts (H and HI), they were not. | Resistance to cisplatin-centered chemotherapy is a major cause of treatment failure in human ovarian cancer. Whereas PTEN, a tumor suppressor gene product, is believed to promote apoptosis primarily via inactivation of the PI3K/Akt cell survival pathway, recent evidence suggests that PTEN may function independently of this pathway. Activation of p53 is a key determinant of sensitivity to cisplatin-induced apoptosis. Whether PTEN can facilitate cisplatin sensitivity, and this involves the activation of p53, remains unclear. In this study, we determined whether and how PTEN over-expression sensitizes ovarian cancer cells to CDDP-induced apoptosis. Using pairs of chemosensitive and chemoresistant ovarian cancer cell lines (OV20028 vs. C13* and A2780-s vs. A2780-cp) as an in vitro model, we have examined the influence of PTEN over-expression in regulation of cisplatin-induced apoptosis. Apoptosis was assessed morphologically by Hoechst staining and confirmed by the detection of cleaved products of caspase-3 and PARP by Western blot. Over-expression of PTEN by PTEN cDNA transfection up-regulates p53 content and increases the sensitivity of chemoresistant cells to cisplatin-induced apoptosis without detectable changes in the levels of phosphorylated Akt and FKHR as well as FasL mRNA abundance as determined by Western blot and RT-PCR, respectively. PTEN-mediated chemosensitization was attenuated by p53 down-regulation by siRNA in C13*, a chemoresistant wild-type p53 cell. Moreover, PTEN over-expression failed to sensitize the chemoresistant p53 mutant ovarian cancer cell line A2780-cp to cisplatin-induced apoptosis, unless wild-type p53 was reconstituted by adenoviral p53 infection. |
Is decreased plasma CXCL16/SR-PSOX concentration associated with coronary artery disease? | To investigate for the first time whether the plasma CXCL16 concentration is altered in coronary artery disease (CAD) patients. Accumulating evidence suggests that the novel chemokine/scavenger receptor CXCL16/SR-PSOX is involved in the development of atherosclerosis and CAD. Using ELISA we assessed the plasma CXCL16 concentration in 40 stable angina pectoris (SAP) patients, 17 unstable angina pectoris/non-ST-elevation myocardial infarction (UAP/non-STEMI) patients, 387 survivors of a first myocardial infarction (MI) and healthy control subjects (44 controls for SAP and UAP/non-STEMI patient groups and 387 controls for post-MI patients). SAP patients exhibited significantly lower median CXCL16 levels (2111 pg/ml) than the corresponding control subjects (2678 pg/ml) (P=0.0012). UAP/non-STEMI patients also appeared to have lower CXCL16 levels (2192 pg/ml) compared with controls (NS). Patients investigated 3 months after MI tended (P=0.07) to have lower CXCL16 levels (2529 pg/ml) than the corresponding controls (2638 pg/ml). There were no significant correlations between CXCL16 levels and different measures of CAD severity determined by quantitative coronary angiography in post-MI patients. Neither patients nor controls exhibited significant correlations between CXCL16 levels and plasma lipoprotein fractions, inflammatory cytokines, C-reactive protein or numbers of inflammatory cells in peripheral blood. | This pilot study, the first of its type, was conducted to determine the clinical outcome of glaucoma drainage implant (GDI) surgery supplemented with injectable crosslinked hyaluronic acid (HA) in patients with severe glaucoma. This was a retrospective chart study involving 10 eyes of 10 patients with severe glaucoma (glaucomatous visual field loss worse than -20 dB) who had previously undergone GDI surgery supplemented with crosslinked HA with a 2-year follow-up. Surgical success was defined as intraocular pressure (IOP) <21 mm Hg with a reduction of ≥40% (definition A) or ≥50% (definition B) from baseline IOP on 2 consecutive follow-up visits, IOP >5 mm Hg on 2 consecutive follow-up visits, and neither reoperation of glaucoma nor loss of light perception vision. The mean ± SD baseline IOP before GDI was 38.5 ± 10.7 mm Hg, and the mean IOP at the last follow-up visit was 13.0 ± 5.0 mm Hg, with a mean pressure drop of 24.4 ± 10.9 mm Hg (62%; p = 0.005). According to definition A, life-table analysis showed an overall success rate of 80%, while according to definition B, the success rate was 50% after 24 months of follow-up. Complications were infrequent and not serious. No complications resulting from the reticulated HA therapy itself were observed. |
Does obesity increase risk of anticoagulation reversal failure with prothrombin complex concentrate in those with intracranial hemorrhage? | Not all patients with warfarin-related acute intracranial hemorrhage (ICH) achieve full reversal of international normalized ratio (INR) after the first dose of weight-based prothrombin complex concentrate (PCC). We sought to identify factors associated with anticoagulation reversal failure after the first dose of PCC. Consecutive patients who were hospitalized with warfarin-related acute ICH at a tertiary center between 1 January 2010 and 31 December 2012 were studied. Anticoagulation reversal failure was defined as INR ≥ 1.5 after the first dose of PCC. Logistic regression was performed to determine the predictors of anticoagulation reversal failure. Fifty-one patients with acute ICH received PCC for warfarin reversal using a weight-based protocol. Overall, 23 (45%) patients did not achieve full reversal of INR after the first dose. Those with anticoagulation reversal failure were obese (body mass index > 30 kg/m(2)) (41% vs. 14%, p = 0.03), had a higher initial INR (3.0 ± 1.4 vs. 2.0 ± 0.7, p = 0.001), and had a higher prevalence of initial INR >2.0 (22% vs. 67%, p = 0.001), compared with those who were successfully reversed. Multivariable logistic regression identified obesity (odds ratio 7.88, 95% CI 1.12 to 55.68) and initial INR >2.0 (odds ratio 12.49, 95% CI 2.27 to 68.87) as independent predictors of anticoagulation reversal failure. | Stomatal guard cells monitor and respond to environmental and endogenous signals such that the stomatal aperture is continually optimised for water use efficiency. A key signalling molecule produced in guard cells in response to plant hormones, light, carbon dioxide and pathogen-derived signals is hydrogen peroxide (H(2)O(2)). The mechanisms by which H(2)O(2) integrates multiple signals via specific signalling pathways leading to stomatal closure is not known. Here, we identify a pathway by which H(2)O(2), derived from endogenous and environmental stimuli, is sensed and transduced to effect stomatal closure. Histidine kinases (HK) are part of two-component signal transduction systems that act to integrate environmental stimuli into a cellular response via a phosphotransfer relay mechanism. There is little known about the function of the HK AHK5 in Arabidopsis thaliana. Here we report that in addition to the predicted cytoplasmic localisation of this protein, AHK5 also appears to co-localise to the plasma membrane. Although AHK5 is expressed at low levels in guard cells, we identify a unique role for AHK5 in stomatal signalling. Arabidopsis mutants lacking AHK5 show reduced stomatal closure in response to H(2)O(2), which is reversed by complementation with the wild type gene. Over-expression of AHK5 results in constitutively less stomatal closure. Abiotic stimuli that generate endogenous H(2)O(2), such as darkness, nitric oxide and the phytohormone ethylene, also show reduced stomatal closure in the ahk5 mutants. However, ABA caused closure, dark adaptation induced H(2)O(2) production and H(2)O(2) induced NO synthesis in mutants. Treatment with the bacterial pathogen associated molecular pattern (PAMP) flagellin, but not elf peptide, also exhibited reduced stomatal closure and H(2)O(2) generation in ahk5 mutants. |
Is heart-type fatty acid binding protein a novel prognostic marker in patients with non-ischaemic dilated cardiomyopathy? | To determine whether concentrations of heart-type fatty acid binding protein (H-FABP) measured before hospital discharge predict critical cardiac events in patients with idiopathic dilated cardiomyopathy (DCM). 92 consecutive patients with DCM were enrolled and followed up for four years. Serum concentrations of H-FABP, brain natriuretic peptide (BNP), cardiac troponin T before hospital discharge and survival rate. 23 patients died of cardiac causes, received a left ventricular assist device or underwent heart transplantation during the four-year follow up. Univariate analyses showed that New York Heart Association functional class, heart rate, ejection fraction, serum H-FABP and plasma BNP were significant variables. According to multivariate analysis, serum H-FABP and plasma BNP concentrations were independent predictors of critical cardiac events. Cardiac troponin T before hospital discharge was not a predictor. The area under the receiver operating characteristic curve for death from critical cardiac events was similar between H-FABP and BNP. Patients with an H-FABP concentration at or above the median (> or = 5.4 ng/ml) had a significantly lower survival rate than those below the median, according to analysis by log rank test (p < 0.0001). When combined with BNP concentration at or above the median (> or = 138 pg/ml), H-FABP below the median predicted the worst prognosis among the combinations. | To explore an effective approach for the treatment of patients with uveal melanomas, we designed a strategy that combines HtrA2 gene therapy and radiation therapy. pIRES-Egr1-Omi/HtrA2 (pEgr1-HtrA2) recombinant plasmids were constructed and transfected into human uveal melanoma cells (OCM-1) in vitro. The transfected cells were exposed to irradiation. HtrA2 messenger RNA and protein level was detected by quantitative reverse transcription polymerase chain reaction and Western blot, respectively. Combined with radiation, assays that evaluated the apoptotic inducibility caused by HtrA2 gene therapy was performed by flow cytometry. Followingly, the effects of HtrA2 overexpression on the in vitro radiosensitivity of uveal melanoma cells were investigated by clonogenic formation assay. The in vivo effects of HtrA2 gene therapy combined with radiation therapy were evaluated in different groups. The recombinant plasmids could be successfully transferred into OCM-1 cells, and transfection of pEgr1-HtrA2 plasmids combined with radiotherapy caused dramatically elevation of HtrA2 compared with non-irradiated cells in messenger RNA and protein levels, which was associated with increased apoptosis. Furthermore, we observed that the transfection of pEgr1-HtrA2 could significantly enhance radiosensitivity of OCM-1 cell in vitro. In mice bearing xenograft tumours, pEgr1-HtrA2 combined with radiation therapy significantly inhibited tumour growth compared with the other treatment groups (P < 0.01). |
Is polymorphisms of rs174616 in the FADS1-FADS2 gene cluster associated with a reduced risk of type 2 diabetes mellitus in northern Han Chinese people? | Several studies have shown associations between the composition of polyunsaturated fatty acids (PUFAs) in various tissues and type 2 diabetes mellitus (T2DM) development in European populations. Genetic variants of fatty acid desaturase (FADS) contribute to the variations of PUFA composition. Here we have explored whether similar correlations are also true among Chinese Han people. A case-control study was employed to examine this correlation in Han Chinese people. The study included 421 healthy adults and 331 T2DM patients. The ratio of arachidonic acid/linoleic acid (AA/LA), which reflects Δ6 desaturase activity, was significantly increased in T2DM patients. Furthermore, the ratio of eicosapentaenoic acid/α-linolenic acid (EPA/ALA), which reflects Δ5 desaturase activity, was markedly decreased in T2DM patients. Importantly, among four single nucleotide polymorphisms (rs174545, rs2072114, rs174602 and rs174616) in the FADS1-FADS2 gene cluster, only minor allele (T) of rs174616 was associated with decreased risk of T2DM in both codominant and dominant models after adjustment for age, gender and BMI. Furthermore, the ratio of AA/LA in both controls and T2DM was reduced in T carriers while an increased proportion of LA was seen in T2DM patients compared with control patients. | Sublethal doses of photon irradiation (IR) are suspected to increase tumor cell migration and support locoregional recurrence of disease, which has already been shown in other cell lines. This manuscript describes the effect of photon and carbon-ion IR on WHO class I meningioma cell migration and provides an approach to the underlying cellular mechanisms. Meningioma cells were gained operatively at the university hospital in Homburg/Saar, Germany. For migration, membranes (8-µm pore sizes) were coated with collagen I, with collagen IV, and with fibronectin. Cells were analyzed in migration experiments with or without serum stimulation, with or without photon and carbon IR 24 h prior to experiments, and with or without integrin antibodies. Fluorescence-activated cell sorting (FACS) analyses of the integrins ανβ1, ανβ3, and ανβ5 were performed without IR and 6, 12 and 24 h after IR. Enzyme-linked immunosorbent assay (ELISA) analyses of matrix metalloproteinases (MMP)-2 and MMP-9 were realized with and without IR after cells were cultured on collagen I, collagen IV, or fibronectin for 24 h. Cells and supernatants for FACS and ELISA were stored at - 18 °C. The significance level was set at 5 % using both Student's t test and two-way ANOVA. Migration of meningioma cells was serum-inducible (p < 0.001). It could be increased by photon IR (p < 0.02). The integrins ανβ1 and ανβ5 showed a 21 and 11 % higher expression after serum stimulation (not significant), respectively, and ανβ1 expression was raised by 14 % (p = 0.0057) after photon IR. Antibody blockage of the integrins ανβ1 and ανβ5 inhibited serum- and photon-induced migration. Expression of MMP-2 and MMP-9 remained unchanged after both IR and fetal bovine serum (FBS). Carbon-ion IR left both integrin expression and meningioma cell migration unaffected. |
Does levodopa availability improve with progression of Parkinson 's disease? | Previous pharmacokinetic trials with standard levodopa formulations showed a different behaviour of levodopa degradation in plasma of patients with Parkinson's disease (PD) in various stages. To investigate associations between levodopa plasma levels in relation to the scored intensity of PD. We administered water soluble 100 mg levodopa and 25 mg benserazide to 50 PD patients, taken off medication for at least 12 hours, and assessed the levodopa plasma concentrations during an 180 minutes period under standardised conditions. The computed area under the curve (AUC) values of levodopa plasma levels were significant higher in advanced PD patients. PD rating scores significantly correlated to the AUC outcomes and the maximum levodopa plasma concentration. | Recently, we have shown that intraplaque mast cell numbers are associated with atherosclerotic plaque vulnerability and with future cardiovascular events, which renders inhibition of mast cell activation of interest for future therapeutic interventions. However, the endogenous triggers that activate mast cells during the progression and destabilization of atherosclerotic lesions remain unidentified. Mast cells can be activated by immunoglobulins and in the present study, we aimed to establish whether specific immunoglobulins in plasma of patients scheduled for carotid endarterectomy were related to (activated) intraplaque mast cell numbers and plasma tryptase levels. In addition, the levels were related to other vulnerable plaque characteristics and baseline clinical data. OxLDL-IgG, total IgG and total IgE levels were measured in 135 patients who underwent carotid endarterectomy. No associations were observed between the tested plasma immunoglobulin levels and total mast cell numbers in atherosclerotic plaques. Furthermore, no associations were found between IgG levels and the following plaque characteristics: lipid core size, degree of calcification, number of macrophages or smooth muscle cells, amount of collagen and number of microvessels. Interestingly, statin use was negatively associated with plasma IgE and oxLDL-IgG levels. |
Do glucocorticoids upregulate FOXP3 expression and regulatory T cells in asthma? | T regulatory (T reg ) cells are characterized by expression of suppressive cytokines and the transcription factor FOXP3. They play a key role in balancing immune responses and maintain peripheral tolerance against antigens and allergens. The loss of peripheral tolerance against allergens causes diseases that can be therapeutically controlled with glucocorticoids. The present study investigates whether glucocorticoids affect the activity of T reg cells on the basis of FOXP3 and cytokine expression. CD4 + T cells from healthy donors and glucocorticoid-treated asthmatic patients were isolated, and expression of FOXP3, along with IL-10 and TGF-beta1, was determined. The effect of glucocorticoids on T reg cells was measured in vivo before and after GC treatment and in in vitro cultures. FOXP3 mRNA expression was significantly increased in asthmatic patients receiving inhaled glucocorticoid treatment, systemic glucocorticoid treatment, or both. FOXP3 tightly correlated with IL10 mRNA expression. No correlation of FOXP3 mRNA expression was observed in relation to a (GT)n microsatellite promoter polymorphism on chromosome Xp11.23 or total IgE level. The frequency of CD25 + memory CD4 + T cells and transient FOXP3 mRNA expression by CD4 + T cells significantly increased after systemic glucocorticoid treatment, whereas TGFB1 expression did not change. Furthermore, glucocorticoids induced IL10 and FOXP3 expression in short-term and long-term cultures in vitro. | To examine the accuracy of HistoScanning (HS) in detecting seminal vesicle (SV) invasion (SVI) within prostate cancer (PCa) patients. We relied on our prospective institutional database. Patients who received HS before radical prostatectomy were included in the study cohort. An experienced HS examiner retrospectively reanalyzed the HS data blinded to patient characteristics and pathologic results. The HS results for every single SV were compared with the corresponding findings from the final pathologic report after radical prostatectomy. An area under the receiver operating characteristic curve for the prediction of SVI by HS was calculated. Depending on HS signal volume cut-offs (>0, >0.2, and >0.5 mL), the sensitivity, specificity, positive predictive value, and negative predictive value for the prediction of SVI were assessed. Overall, 131 patients and 262 SVs were assessable. Of those, 23 (17.5%) men had SVI, and 39 (14.9%) single SVs were infiltrated by tumor overall. The area under the receiver operating characteristic curve for predicting SVI by HS was 0.54. Depending on the HS signal volume cut-offs (>0, >0.2, and >0.5 mL), the sensitivity, specificity, positive predictive value, and negative predictive value for predicting SVI were 76.9%, 10.8%, 13.1%, and 72.7%; 61.5%, 24.2%, 12.4%, and 78.3%; and 46.2%, 50.2%, 14.0%, and 84.2%, respectively. |
Does image subtraction facilitate assessment of volume and density change in ground-glass opacities in chest CT? | To study the impact of image subtraction of registered images on the detection of change in pulmonary ground-glass nodules identified on chest CT. A cohort of 33 individuals (25 men, 8 women; age range 51-75 years) with 37 focal ground-glass opacities (GGO) were recruited from a lung cancer screening trial. For every participant, 1 to 3 follow-up scans were available (total number of pairs, 84). Pairs of scans of the same nodule were registered nonrigidly and then subtracted to enhance differences in size and density. Four observers rated size and density change of the GGO between pairs of scans by visual comparison alone and with additional availability of a subtraction image and indicated their confidence. An independent experienced chest radiologist served as an arbiter having all reader data, clinical data, and follow-up examinations available. Nodule pairs for which the arbiter could not establish definite progression, regression, or stability were excluded from further evaluation. This left 59 and 58 pairs for evaluation of size and density change, respectively. Weighted kappa statistics (kappa w) were used to assess interobserver agreement and agreement with the arbiter. Statistical significance was tested with a kappa z-test. When the subtraction image was available, the average interobserver kappa w improved from 0.52 to 0.66 for size change and from 0.47 to 0.57 for density change. Average agreement with the arbiter improved from 0.61 to 0.76 for size change and from 0.53 to 0.64 for density change. The effect was more pronounced when observer confidence without the subtraction image was low: agreement improved from 0.26 to 0.57 and from 0.19 to 0.47 in those cases. | Patients with diabetes are at increased risk of ischemic events. Suv39h1 is a histone methyltransferase that catalyzes the methylation of histone 3 lysine 9, which is associated with the suppression of inflammatory genes in diabetes. However, the role of Suv39h1 in myocardial ischemia/reperfusion (I/R) injury under diabetic condition has not been evaluated. To generate diabetic model, male SD rats were fed with 60% fat diet followed by intraperitoneal injection with 40mg/kg streptozotocin. Adenovirus encoding Suv39h1 gene was used for Suv39h1 overexpression. Each rat received injections of adenovirus at five myocardial sites. Three days after gene transfection, each rat was subjected to left main coronary artery occlusion and reperfusion. After 30 min ischemia and reperfusion for 4 h, the rats were euthanized for real-time PCR, Western blot, immunohistochemical staining, and morphometric analysis. Delivery of Ad-Suv39h1 into the hearts of diabetic rats could markedly increase Suv39h1 expression. Up-regulation of Suv39h1 significantly reduced infarct size and tissue damage after I/R injury, which was associated with protection from apoptosis of cardiac myocytes and reduction of inflammatory response. In addition, compared with injury group, Ad-Suv39h1 led to a decreased activity of mitogen-activated protein kinase family and its down-steam transcriptional factor NF-κB. |
Are human placenta-derived neurospheres susceptible to transformation after extensive in vitro expansion? | The cancer stem cell model links neoplastic cells with normal stem cell biology, but little is known on how normal stem cells are transformed into cancer stem cells. To investigate the processes underlying the transformation of normal stem cells we developed in vitro a cancer stem cell model from human amniotic and chorionic placenta membranes. In this model we studied the expression of specific stem cell molecules by flow cytometry, and genes, by real time RT-PCR. Microscopy immunfluorescence was employed to investigate the proliferative and differentiation patterns. Fluorescence microscopy and FACS were employed to investigate the proliferative and differentiation patterns. To evaluate the tumorigenic potential of our model we injected the cells into NOD.CB17-Prkdcscid/NCrHsd mice. Normal human stem cells from amniotic and chorionic placenta membranes were converted into neural cell lineages, under specific conditions, to form secondary neurospheres with a capacity for self-renewal. After extensive in vitro culture, these cells underwent spontaneous transformations and acquired a neuroblastoma (NB)-like phenotype with an elevated proliferative potential that is comparable to established neuroblastoma cell lines. The ability of these cells to transform their phenotype was evidenced by increased clonogenic ability in vitro; by augmented expression level of certain proliferation- and transformation-related genes (e.g., CCNA2, MYCN, ENPP2, GRIA3, and KIT); by the presence of multinucleated and hyperdiploid cells. We further demonstrated that the transformed phenotype is an NB by measuring the expression of NB-specific markers, disialoganglioside GD2 and N-Myc proteins. | The impact of psychosocial states, such as depression or anxiety, and social support on the outcomes of stable outpatients with mild heart failure (HF) has not been evaluated in the "real world" clinical practice. In the present study, 139 patients with a prior history of admission for HF provided the baseline demographic, clinical, socio-environmental, and psychosocial information. Cardiac death or re-admission because of worsening of HF was monitored during the follow-up period of 1 year. The prevalence of depression and anxiety were 37% and 37%, respectively, in HF patients. Depression was independently associated with male (sbeta=-0.36, P=0.01), social ties (sbeta=0.22, P=0.04) and low social support (sbeta=-0.39, P<0.01). Anxiety was associated with alcohol drinking (sbeta=0.22, P=0.04), brain natriuretic peptide > or =200 pg/dl (sbeta=0.35, P<0.01), and low social support (sbeta=-0.28, P=0.01). Kaplan-Meier analysis demonstrated that patients with anxiety (log-lank test; P<0.01) and lower scores of social support (P<0.01) had a higher rate of HF-related re-admission. |
Is optimal dairy intake predicated on total , cardiovascular , and stroke mortalities in a Taiwanese cohort? | Dairy foods help achieve essential nutrient adequacy. This role may be conflicted where so-called chronic diseases prevail. We have examined associations between dairy intake and mortality where dairy foods have not been traditional. A representative Taiwanese cohort of 3810 subjects, aged 19-64 years, derived from the Nutrition and Health Survey in Taiwan (NAHSIT, 1993-1996) was linked to death registration (1993-2008). Participants were categorized by 4 dairy weekly intake frequencies from 0 to >7 times. Mortality hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using Cox proportional-hazards models. Nonconsumers of dairy products included 30.7% of the men and 22.1% of the women. Adverse sociodemographic and personal behaviors were generally significantly associated with lower dairy consumption. After adjustment for covariates, together with body mass index (BMI) and supplement use, those with 3-7 times/week intakes had an HR (95% CI) for all-cause mortality of 0.61 (0.39-0.96) with a significant dose-response trend (p = 0.043). Similarly, the HR for cardiovascular disease (CVD) mortality with dairy weekly intake frequency >7 was 0.14 (0.02-0.97) with a significant linear trend (p = 0.007). For stroke, the corresponding HR (95% CI) was 0.03 (0.00-0.28) with a linear trend. By age and with adjustment for dietary quality, food, and calcium or vitamin D intake, significance and dose-response relationships remained. Dairy intake and cancer mortality were not associated. | To test the hypothesis that subarachnoid bupivacaine blockade decreases hypnotic requirements for thiopental sodium and midazolam. Randomized, double-blind, placebo-controlled study. Teaching hospital. 53 nonpremedicated ASA physical status I and II adult male patients scheduled for elective lower abdominal, pelvic, or lower limb surgery. Intravenous injections of midazolam or thiopental were administered with or without subarachnoid bupivacaine blockade (12.5 mg) at the L3-L4 level. Thiopental or midazolam hypnotic requirements were determined using loss of ability to open eyes in response to verbal command as an endpoint. The thiopental requirements were determined by titration; the midazolam requirements were determined from dose-response curves obtained with bolus injections of predetermined doses of the drug. Subarachnoid bupivacaine blockade decreased the hypnotic dose of thiopental from 3.40 +/- 0.68 mg/kg (mean +/- SD) with a dose range of 2.3 to 4.5 mg/kg (intramuscular saline) to 2.17 +/- 0.48 mg/kg with a dose range of 1.3 to 2.8 mg/kg (p < 0.005 for the difference). The ED50 value of midazolam decreased with the bupivacaine blockade, from 0.23 mg/kg (95% confidence limits: 0.08 to 0.38 mg/kg) to 0.06 mg/kg (0.01 to 0.14 mg/kg), with p < 0.0001 for the difference. |
Does gene expression identify heterogeneity of metastatic behavior among gastrointestinal stromal tumors? | Adjuvant imatinib is useful in patients with gastrointestinal stromal tumors (GIST) at high risk of recurrence. At present, the risk of recurrence is determined based on tumor size, mitotic rate, tumor site, and tumor rupture. Previous studies using various biochemical pathways identified gene expression patterns that distinguish two subsets of aggressive fibromatosis (AF), serous ovarian carcinoma (OVCA), and clear cell renal cell carcinoma (RCC). These gene sets separated soft tissue sarcomas into two groups with different probabilities of developing metastatic disease. The present study used these gene sets to identify GIST subgroups with different probabilities of developing metastatic disease. We utilized these three gene sets, hierarchical clustering, and Kaplan-Meier analysis, to examine 60 primary resected GIST samples using Agilent chip expression profiling. Hierarchical clustering using both the combined and individual AF-, OVCA-, and RCC- gene sets identified differences in probabilities of developing metastatic disease between the clusters defined by the first branch point of the clustering dendrograms (p = 0.029 for the combined gene set, p = 0.003 for the AF-gene set, p < 0.001 for the OVCA-gene set, and p = 0.003 for the RCC-gene set). | Patients suffering from post-polio syndrome still contribute significantly to the number of patients with chronic respiratory failure requiring home mechanical ventilation (HMV). Many of these patients are treated either with invasive (tracheostomy) or non-invasive (nasal mask) controlled mechanical ventilation i.e. volume-controlled ventilation (VCV). In this group of patients, we have previously shown that bi-level pressure support ventilation (bi-level PSV) decreases the oxygen cost of breathing. The aim of this study was to compare the effect of bi-level PSV, with special regard to the adequacy of ventilation and the oxygen cost of breathing, during the patients' ordinary VCV and spontaneous breathing. Eight post-polio patients on nocturnal VCV were investigated. Five of them were tracheostomized and three of them used a nasal mask. Work of breathing was analysed by assessing differences in oxygen consumption (VO2) using indirect calorimetry. Blood gases were obtained regularly to assess adequacy of ventilation. Bi-level PSV decreases the oxygen cost of breathing in post-polio patients with respiratory failure without decreasing ventilation efficiency. Furthermore, PaCO2 decreased significantly using this mode of ventilation (P < 0.05). |
Do lymph node metastases impact survival in follicular variant papillary thyroid cancer? | Follicular variant of papillary thyroid cancer (FVPTC) is the most common and fastest growing subtype of papillary thyroid cancer (PTC) with features of both PTC and follicular thyroid cancer (FTC). The purpose of this study was to determine the patient and tumor features associated with lymph node metastases (LNM) in FVPTC. This was a retrospective review of adult (≥18) patients with histologically confirmed diagnoses of FVPTC within the SEER database between 1988 and 2009. LNM were defined by at least two lymph nodes with metastatic disease. To determine factors associated with LNM, we constructed a multivariate logistic regression model from significant variables (p < 0.05) identified on univariate analysis. Similarly, we used a Cox proportional hazards model to understand the relative importance of LNM in determining disease-specific mortality (DSM). Of the 20,357 cases of FVPTC with lymph node data available, 1,761 (8.7%) had LNM; 61.1% of these LNM were located in the central neck and 38.9% were in the lateral neck. Extrathyroidal extension (odds ratio [OR] 2.6, 95% confidence interval [CI] 2.2-3.0, p < 0.01) and multifocality (OR 3.0, 95% CI 2.5-3.6, p < 0.01) were the strongest predictors of LNM. Importantly, LNM did not independently predict DSM (p = 0.52). Tumor size >4 cm (hazards ratio [HR] 5.3, 95% CI 2.2-12.8, p < 0.01) and extrathyroidal extension (HR 8.2, 95% CI 3.0-22.0, p < 0.01) were the strongest predictors of DSM. | Lipopolysaccharide (LPS) is closely associated with the development of infection-induced deleterious pulmonary reactions. In this study, we investigated the enhancement effects of LPS on tachykinin-mediated plasma exudation in the lungs of guinea pigs. The role of oxidants was also explored. Intravenous LPS (100 mu kg-1) or its vehicle was administered 0 to 3 hours prior to bilateral electrical or sham stimulation of the cervical vagus nerves in animals anesthetized with urethane and artificially ventilated. Plasma exudation into the lungs was assessed by measurement of extravasated 125I-albumin which had been intravenously administered before stimulation. The plasma exudation in the lungs increased after bilateral cervical vagal stimulation. LPS alone did not induce significant plasma exudation. The vagally-mediated plasma exudation was enhanced by LPS with the peak effect 1 hour after LPS administration. LPS also enhanced exogenous substance P (10(-8) mol kg-1, i.v.)-induced plasma exudation. The vagally-induced plasma exudation was abolished by a specific neurokinin-1 (NK-1) receptor antagonist, L-732,138. The LPS-induced enhancement response was also attenuated by L-732,138. The vagally-induced plasma exudation was not affected by superoxide dismutase (SOD, 5000 U kg-1, i.p.) pretreatment. However, SOD significantly inhibited the LPS-enhanced neurogenic plasma leakage. The LPS-induced enhancement was not completely abolished by either L-732,138 or SOD pretreatment alone, but by a combination of both. |
Are patients with chronic heart failure encountered in daily clinical practice different from the `` typical '' patient enrolled in therapeutic trials? | The aim of this study was to compare the clinical characteristics of patients enrolled in randomized clinical trials on congestive heart failure treatment with those of real-world patients encountered in daily clinical practice. We searched the Cochrane review methodology, Medline and SilverPlatter databases to obtain the clinical characteristics of both patients enrolled in therapeutic clinical trials and real-world patients with heart failure. We selected 27 clinical trials, and 8 prospective epidemiological studies or registries published between 1987 and 2001 which enrolled 53,859 and 18,207 patients, respectively. On average, compared to real-world heart failure patients, patients enrolled in clinical trials were younger (63 +/- 10 vs 75 +/- 11 years respectively, p < 0.0001), and more likely to be male (72 vs 54% respectively, p < 0.0001). Clinical trial patients showed a lower ejection fraction (26 +/- 7 vs 38 +/- 15% respectively, p < 0.0001) but a lower prevalence of NYHA functional class III-IV (62 vs 75% respectively, p < 0.0001) than real-world patients. In clinical trial patients, the prevalence of ischemic heart disease (67 vs 42% respectively, p < 0.0001) and a history of previous myocardial infarction (62 vs 42% respectively, p < 0.0001) were higher than in real-world patients. Conversely, the prevalence of chronic atrial fibrillation (12 vs 31% respectively, p < 0.0001) and of diabetes (22 vs 24% respectively, p < 0.02) was lower in trial patients than in real-world patients. | Gene expression in tumours is regulated by environmental as well as genetic/epigenetic factors. This study assessed the environmental factors in intestinal expression of gastric cancers. We immunohistochemically examined intratumoural heterogeneity in the expression of Cdx2, MUC2, MUC5AC and MUC6 in 39 intramucosal and 49 extramucosally invasive undifferentiated-type gastric carcinomas (UGCs), consisting of signet ring cell carcinomas showing a layered structure (LS) in the mucosa and dedifferentiated tubular adenocarcinomas without LS and with minor tubular components (TC). The LS retains mucosal vertical polarity with superficial MUC5AC expression. Loss of this polarity was independent of intestinal expression and associated with extramucosal invasion. In LS(+) UGCs, intestinal expression was enhanced as the size of mucosal spread increased and was significantly reduced with deeper extramucosal invasion, whereas, in LS(-)/TC(+) UGCs, intestinal expression was frequent and predominant in the mucosa and was insignificantly reduced with deeper extramucosal invasion. |
Is exclusion of pH artifacts essential for hypopharyngeal pH monitoring? | Published yields of pH monitoring for suspected laryngopharyngeal reflux (LPR) vary greatly. Hypopharyngeal pH artifacts may be responsible for these inconsistencies. To determine the impact of potential artifacts on pH monitoring of the hypopharynx and esophagus. Patients with suspected LPR were prospectively studied. Single-catheter, triple-sensor pH monitoring was performed off antireflux therapy. Subjects recorded meal times and marked liquid swallows outside of meals on the data recorder. Results were analyzed by excluding six potential pH artifacts individually and all together. Positive pH test was defined as three or more reflux episodes in hypopharynx, total percent of time pH less than 4 was 1.0% or greater in the proximal esophagus, and total percent of time pH less than 4 was 4.2% or greater in the distal esophagus. Wilcoxon rank sum and chi-square tests were used. Thirty-eight subjects (24 females; median age, 47 yr) completed the study. A total of 2,225 hypopharyngeal pH drops less than 4 were identified; 48% were short pH drops at less than 5 seconds, 17% within meal periods, 16% liquid swallows outside of meals, 16% isolated proximal pH drops, 12% pH out of range, and 5% pH drift. Eighty percent of the hypopharyngeal pH drops were at least one of the potential pH artifacts. The yield of the hypopharyngeal sensor was reduced by 45% (from 92% to 47%) after all potential pH artifacts were excluded. Yields of proximal and distal esophageal pH sensors were reduced by 19% and 8%, respectively, significantly less than the hypopharyngeal sensor (P < .01). | During the engraftment process of transplanted HPC, the beta 1 integrins play an important role. An increased expression and adhesive function of these integrins has been shown in hematopoietic cell lines and peripheral blood-derived HPC after stimulation with SCF. In this study, we investigated the influence of SCF on the engraftment capability and tissue distribution of cord blood (CB) cells transplanted into NOD/SCID mice. CB-derived mononuclear cells were injected i.v. into 40 sublethally irradiated NOD/SCID mice with or without the addition of 10 microg SCF/ mouse. Six weeks later, BM, liver, kidneys, brain and testicular tissue were analyzed for the prevalence of human cells. The mean proportion of human CD45+ CD71+ cells within the BM of all engrafted mice receiving SCF in addition to the cells was 1.7-fold higher than in the respective controls. By immunohistochemical staining, human cells were found in liver and kidneys of the engrafted animals, but not in neural tissues or testicles. In the kidneys, the proportion of human cells rose significantly from 0.07 +/- 0.3% to 0.24 +/- 0.05% with treatment with SCF, compared with untreated controls. Single human cells in the liver additionally stained positive for human albumin, indicating organ-specific differentiation of the transplanted cells. |
Do self-control and parental control mediate the relationship between negative emotions and emotional eating among adolescents? | The study was conducted to simultaneously investigate the mediating effects of parental control and adolescents' self-control on the relationship between adolescents' negative emotions and emotional eating, and to determine pathways with the greatest effect among these variables. Negative emotions, emotional eating, parental control, and self-control were investigated in 594 high school students (average age=16.70, SD=1.09) in Changsha City, China. High levels of negative emotions and parental control and low levels of self-control were strongly related to high levels of emotional eating in adolescents. In addition to the direct relationship between negative emotions and emotional eating, there was a mediating effect observed through low self-control and high parental control. The mediational effect of parental control was non-significant in adolescent boys. Furthermore, negative emotions related to emotional eating through the effect of parental control on adolescents' self-control. The degree to which both mediators explained the relationship between negative emotions and emotional eating ranged from 52.6% to 66.8%, and self-control had a stronger mediational effect than did parental control. | Synovial sarcoma (SS) is an aggressive soft-tissue tumor. Despite being considered as a chemosensitive disease, the real impact of perioperative chemotherapy on metastasis-free survival (MFS) is controversial. We have shown that metastatic relapse of SS is strongly associated with genomic complexity. There are no data regarding the potential correlation between genomic complexity and response to chemotherapy. The study population included 65 SS patients diagnosed between 1991 and 2013 and with available tissue material. Genomic profiling was carried out by using array-CGH. Forty-five SS out of the 65 patients were treated with neoadjuvant anthracycline/ifosfamide-based chemotherapy. Radiological response was assessed according to RECIST criteria. Histological response was defined by the percentage of recognizable tumor cells on the surgical specimen. Genomic complexity was significantly associated with MFS. However, there was no statistically significant association between radiological or histological response and genomic complexity. |
Does interleukin-10 inhibit inducible nitric oxide synthase in an animal model of necrotizing enterocolitis? | Nitric oxide (NO) and its role in surgical inflammation are well documented; demonstrating the role of NO in necrotizing enterocolitis (NEC) and ways in which it may be suppressed may provide avenues for immune modulation in the treatment of NEC. We sought to demonstrate an increase in inducible nitric oxide synthase (iNOS) mRNA and nitric oxide in an experimental model of necrotizing enterocolitis. In addition, we hypothesized that interleukin-10 (IL-10) would attenuate this response. Newborn rats were treated with 25 microliters intraperitoneal IL-10 or vehicle prior to laparotomy, 1 h superior mesenteric artery (SMA) occlusion, 50 micrograms/kg intraluminal platelet activating factor administration, and SMA reperfusion. iNOS mRNA and nitric oxide levels were measured in the liver, small bowel, and serum and compared using Student's t-test. Small bowel iNOS mRNA increased after NEC induction from 0.058 +/- 0.02 to 0.144 +/- 0.05 relative intensity units (RIU) at 2 h (p < 0.01) and from 0 to 0.09 +/- 0.02 RIU at 6 h (p < 0.03). Liver mRNA increased from 0.026 +/- 0.002 to 0.485 +/- 0.09 RIU (p < 0.002) and from 0 to 0.069 +/- 0.02 RIU (p < 0.0001) at 2 and 6 h, respectively. Serum nitric oxide increased in NEC induced animals at 2 h from 28.04 +/- 10.5 to 45.18 +/- 6.8 microM (p < 0.001). IL-10 suppressed iNOS mRNA and nitric oxide expression at 2 h in small bowel, liver, and serum by 60%, 89%, and 11%, respectively. | In a population-based sample of women (45, 50, or 55 years old), behavioral data and blood serum were collected concurrently, enabling us (1) to investigate cognitive differences among premenopausal, perimenopausal, and postmenopausal groups of women and (2) to evaluate the relationship between blood estrogen levels and cognitive performance. Groups of premenopausal (n = 129), perimenopausal (n = 58), and postmenopausal (n = 55) women were tested on tasks assessing episodic and semantic memory, verbal fluency, visuospatial performance, and face recognition. Blood serum was collected concurrently for analyses of estrogen levels. With inclusion of controls for age and education, results showed that there were no differences in cognitive performance among premenopausal, perimenopausal, and postmenopausal groups of women. In addition, there were no associations between blood estrogen levels and cognitive performance. |
Does factor V Leiden have a role in cryptogenic ischemic stroke among Iranian young adults? | Different risk factors have been suggested for ischemic stroke in young adults. In a group of these patients despite of extensive diagnostic work-up, the primary cause remains unknown. Coagulation tendency is accounted as a possible cause in these patients. Previous studies on factor V Leiden (FVL) as the main cause of inherited thrombophilia for clarifying the role of FVL in stroke have resulted in controversial findings. The current study investigates the role of this factor in ischemic stroke among Iranians. This case-control study was performed between September 2007 and December 2008 in Isfahan, Iran. The case group comprised of 22 patients of which 15 were males and 7 were females with age range of ≤50 years, diagnosed as ischemic stroke without classic risk factors and the control group consisted of 54 healthy young adults. After filling consent form, venous blood samples were obtained and sent to the laboratory for genetic examination. No FVL mutation was found in the case group. There was one carrier of the mutation as heterozygous in the control group (relative frequency = 1.85%). | Conditioned place aversion (CPA) is known to be a sensitive measure of the aversive motivational state produced by opioid withdrawal in rats made chronically dependent on opioids. The purpose of the present study was to examine the sensitivity of the CPA model in detecting a possible aversive state associated with naloxone-precipitated withdrawal from acute treatment with morphine. Doses of morphine and naloxone, as well as number of conditioning trials, were systematically varied to determine the minimum conditions that would result in a detectable CPA in male Wistar rats. Naloxone (0.003-16.7 mg/kg) was administered 4 h after an injection of vehicle or morphine (1.0, 3.3, or 5.6 mg/kg) and immediately prior to confinement to one compartment of the conditioning apparatus; rats received either one or two such naloxone-conditioning trials (separate by 48 h). Morphine (5.6 mg/kg) followed 4 h later by vehicle produced no significant preference or aversion. In morphine-naive rats, 10 mg/kg naloxone was required to produce a significant CPA with two cycles of conditioning. When increasing doses of morphine were administered (1.0, 3.3, 5.6 mg/kg), significant increases in naloxone potency to elicit a CPA were observed (16-, 211-, and 1018-fold potency shifts, respectively). Naloxone potency after two pretreatments with 5.6 mg/kg morphine was comparable to its potency to elicit a CPA after chronic exposure to morphine. Although naloxone was still effective in producing a CPA after a single conditioning cycle (and hence a single morphine exposure), its effects were dramatically reduced relative to those seen with two conditioning cycles. |
Are procedure Delays and Time of Day Associated With Reductions in Quality of Screening Colonoscopies? | There have been conflicting results from studies to determine whether factors unrelated to endoscopist skill, such as fatigue, affect the quality of screening colonoscopy. We studied the effects of human and system factors on screening colonoscopy withdrawal time and likelihood of detecting an adenoma in a large cohort of patients. We performed a retrospective analysis of operation and quality improvement data in colonoscopies performed at single academic medical center from November 2012 through February 2014. We collected data from the Northwestern Medicine Enterprise Data Warehouse on endoscopy procedure reports, patient demographics, and pathology reports of all patients undergoing endoscopy. We identified all screening colonoscopies during the study period and determined whether an adenoma was identified in each screening colonoscopy procedure. Our study included data from 7004 screening colonoscopies of patients 50-75 years old performed by endoscopists who performed at least 100 screening colonoscopies during the study period (n = 18). Approximately 27% of procedures began on time; the median colonoscope insertion time was 5.9 minutes (interquartile range, 4.0-8.6). In multivariable logistic regression analysis adjusting for covariates and endoscopist-level clustering, adenoma detection was not associated with procedure delay (P = .48), hour of day (P = .40), or performing the second of 2 colonoscopy blocks in 1 day (P = .88). Adenoma detection was associated with insertion time overall (P = .006), but there was no consistent directional relationship across insertion quintiles. | Cerebral ischemia upregulates aquaporin-4 expression, increases blood-brain barrier (BBB) permeability, and induces brain edema. Mesenchymal stem cells (MSCs) can repress inflammatory cytokines and show great potential for ischemic stroke therapy. However, the effect of MSCs regarding the protection of ischemia-induced BBB break down is unknown. We test whether MSCs therapy protects BBB integrity and explore the molecular mechanisms of aquaporin-4 on BBB integrity. Two hundred and twenty-eight adult CD1 male mice underwent 90 minutes transient middle cerebral artery occlusion and received 2 × 10(5) MSCs intracranial transplantation. The neurological severity score was improved and both ischemia-induced brain edema and BBB leakage were reduced in MSC-treated mice. MSCs therapy reduced astrocyte apoptosis and inhibited ischemia-induced aquaporin-4 upregulation. In addition, small-interfering RNA knockdown of aquaporin-4 after cerebral ischemia effectively reduced aquaporin-4 expression, brain edema, BBB leakage, and astrocyte apoptosis. Conditional medium from lipopolysaccharide (LPS)-activated microglia enhanced aquaporin-4 expression, p38 and JNK phosphorylation, and apoptosis of cultured astrocytes. MSC treatment reduced the expression of inflammatory cytokines in LPS-activated microglia, and subsequently reduced aquaporin-4 expression and apoptosis of astrocytes. Knockdown of aquaporin-4 in cultured astrocytes also reduced apoptosis. Treatment with p38 and JNK inhibitors showed that p38, but not the JNK signaling pathway, was responsible for the aquaporin-4 upregulation. |
Does maternal undernutrition induce premature reproductive senescence in adult female rat offspring? | To determine the effects of maternal undernutrition (MUN) on the reproductive axis of aging offspring. Animal (rat) study. Research laboratory. Female Sprague-Dawley rats. Food restriction during the second half of pregnancy in rats. Circulating gonadotropins, antimüllerian hormone (AMH), ovarian morphology, estrous cyclicity, and gene expression studies in the hypothalamus and ovary in 1-day-old (P1) and aging adult offspring. Offspring of MUN dams had low birth weight (LBW) and by adult age developed obesity. In addition, 80% of adult LBW offspring had disruption of estrous cycle by 8 months of age, with the majority of animals in persistent estrous. Ovarian morphology was consistent with acyclicity, with ovaries exhibiting large cystic structures and reduced corpora lutea. There was an elevation in circulating T, increased ovarian expression of enzymes involved in androgen synthesis, an increase in plasma LH/FSH levels, a reduction in E2 levels, and no changes in AMH in adult LBW offspring compared with in control offspring. Hypothalamic expression of leptin receptor (ObRb), estrogen receptor-α (ER-α), and GnRH protein was altered in an age-dependent manner with increased ObRb and ER-α expression in P1 LBW hypothalami and a reversal of this expression pattern in adult LBW hypothalami. | Hospital readmissions for pneumonia occur often and are difficult to predict. For fiscal year 2013, the Centers for Medicare & Medicaid Services readmission penalties have been applied to acute myocardial infarction, heart failure, and pneumonia. However, the overall impact of pneumonia pathogen characterization on hospital readmission is undefined. This was a retrospective 6-year cohort study (August 2007 to September 2013). We evaluated 9,624 patients with a discharge diagnosis of pneumonia. Among these patients, 4,432 (46.1%) were classified as having culture-negative pneumonia, 1,940 (20.2%) as having pneumonia caused by antibiotic-susceptible bacteria, 2,991 (31.1%) as having pneumonia caused by potentially antibiotic-resistant bacteria, and 261 (2.7%) as having viral pneumonia. The 90-day hospital readmission rate for survivors (n = 7,637, 79.4%) was greatest for patients with pneumonia attributed to potentially antibiotic-resistant bacteria (11.4%) followed by viral pneumonia (8.3%), pneumonia attributed to antibiotic-susceptible bacteria (6.6%), and culture-negative pneumonia (5.8%) (P < .001). Multiple logistic regression analysis identified pneumonia attributed to potentially antibiotic-resistant bacteria to be independently associated with 90-day readmission (OR, 1.75; 95% CI, 1.56-1.97; P < .001). Other independent predictors of 90-day readmission were Charlson comorbidity score > 4, cirrhosis, and chronic kidney disease. Culture-negative pneumonia was independently associated with lower risk for 90-day readmission. |
Is dual oxidase 2 in lung epithelia essential for hyperoxia-induced acute lung injury in mice? | Acute lung injury (ALI) induced by excessive hyperoxia has been employed as a model of oxidative stress imitating acute respiratory distress syndrome. Under hyperoxic conditions, overloading quantities of reactive oxygen species (ROS) are generated in both lung epithelial and endothelial cells, leading to ALI. Some NADPH oxidase (NOX) family enzymes are responsible for hyperoxia-induced ROS generation in lung epithelial and endothelial cells. However, the molecular mechanisms of ROS production in type II alveolar epithelial cells (AECs) and ALI induced by hyperoxia are poorly understood. In this study, we show that dual oxidase 2 (DUOX2) is a key NOX enzyme that affects hyperoxia-induced ROS production, particularly in type II AECs, leading to lung injury. In DUOX2 mutant mice (DUOX2(thyd/thyd)) or mice in which DUOX2 expression is knocked down in the lungs, hyperoxia-induced ALI was significantly lower than in wild-type (WT) mice. DUOX2 was mainly expressed in type II AECs, but not endothelial cells, and hyperoxia-induced ROS production was markedly reduced in primary type II AECs isolated from DUOX2(thyd/thyd) mice. Furthermore, DUOX2-generated ROS are responsible for caspase-mediated cell death, inducing ERK and JNK phophorylation in type II AECs. To date, no role for DUOX2 has been defined in hyperoxia-mediated ALI despite it being a NOX homologue and major ROS source in lung epithelium. | This study's objective was to determine whether junior medical students' end-of-rotation shelf exam scores varied by the preceptorship county's rurality. Student learning during rural preceptorship experiences, 1999 to 2005, was assessed using the students' scores on the National Board of Medical Examiners family medicine subject examination. Rurality was measured using both population density and the rural-urban continuum (RUC) codes. Exam scores were collected between January 1999 and May 2005 for 734 students. Mean scores did not vary significantly by rurality, although they did vary significantly by semester. Test scores of students in rural locations were not statistically significantly different from those of students in urban preceptorships. |
Does manganese protect against the effects of alcohol on hypothalamic puberty-related hormones? | Since manganese (Mn) is capable of stimulating the hypothalamic-pituitary unit and advancing female puberty, we assessed the possibility that this element might overcome some of the detrimental effects of prepubertal alcohol (ALC) exposure on the hypothalamic control of pituitary function. Rats received either saline or Mn (10mg/kg) daily by gastric gavage from day 12 to day 31. After weaning, all rats were provided Lab Chow diet ad libitum until day 27 when they began receiving either the Bio Serv control or ALC diet regime. On day 31, the medial basal hypothalamus (MBH) was collected to assess luteinizing hormone-releasing hormone (LHRH) and cyclooxygenase 2 (COX2) protein levels. Release of prostaglandin-E2 (PGE2), LHRH and serum luteinizing hormone (LH) were also assessed. Other animals were not terminated on day 31, but remained in study to assess timing of puberty. Short-term ALC exposure caused elevated hypothalamic LHRH content, suggesting an inhibition in peptide release, resulting in a decrease in LH. Both actions of ALC were reversed by Mn supplementation. COX2 synthesis, as well as PGE2 and LHRH release were suppressed by ALC exposure, but Mn supplementation caused an increase in COX2 synthesis and subsequent PGE2 and LHRH release in the presence of ALC. Mn supplementation also ameliorated the action of ALC to delay puberty. | High-resolution CT (HRCT) scanning is part of the management of severe asthma, but its application varies between centers. We sought to describe the HRCT scan abnormalities of a large severe asthma cohort and to determine the utility of clinical features to direct the use of HRCT scanning in this group of patients. Subjects attending our Difficult Asthma Clinic (DAC) between February 2000 and November 2006 (n = 463) were extensively re-characterized and 185 underwent HRCT scan. The HRCT scans were analyzed qualitatively and the interobserver variability was assessed. Using logistic regression we defined clinical parameters that were associated with bronchiectasis (BE) and bronchial wall thickening (BWT) alone or in combination. HRCT scan abnormalities were present in 80% of subjects and often coexisted with BWT (62%), BE (40%), and emphysema (8%). The interobserver agreement for BE (kappa = 0.76) and BWT (kappa = 0.63) was substantial. DAC patients who underwent HRCT scanning compared with those who did not were older, had longer disease duration, had poorer lung function, were receiving higher doses of corticosteroids, and had increased neutrophilic airway inflammation. The sensitivity and specificity of detecting BE clinically were 74% and 45%, respectively. FEV(1)/FVC ratio emerged as an important predictor for both BE and BWT but had poor discriminatory utility for subjects who did not have airway structural changes (FEV(1)/FVC ratio, >or= 75%; sensitivity, 67%; specificity, 65%). |
Do contextual predictors of mental health service use among children open to child welfare? | Children involved with child welfare systems are at high risk for emotional and behavioral problems. Many children with identified mental health problems do not receive care, especially ethnic/minority children. To examine how patterns of specialty mental health service use among children involved with child welfare vary as a function of the degree of coordination between local child welfare and mental health agencies. Specialty mental health service use for 1 year after contact with child welfare was examined in a nationally representative cohort of children aged 2 to 14 years. Predictors of service use were modeled at the child/family and agency/county levels. Child- and agency-level data were collected between October 15, 1999, and April 30, 2001. Ninety-seven US counties. A total of 2823 child welfare cases (multiple informants) from the National Survey of Child and Adolescent Well-being and agency-level key informants from the participating counties. Specialty mental health service use during the year after contact with the child welfare system. Only 28.3% of children received specialty mental health services during the year, although 42.4% had clinical-level Child Behavior Checklist scores. Out-of-home placement, age, and race/ethnicity were strong predictors of service use rates, even after controlling for Child Behavior Checklist scores. Increased coordination between local child welfare and mental health agencies was associated with stronger relationships between Child Behavior Checklist scores and service use and decreased differences in rates of service use between white and African American children. | Cancer is one of the devastating neovascular diseases that incapacitate so many people the world over. Recent reports from the National Cancer Institute indicate some significant gain therapy and cancer management as seen in the increase in the 5-year survival rate over the past two decades. Although near-perfect cure rate have been reported in the early-stage disease, these data reveal high recurrence rate and serious side effects including second malignancies and fatalities. Most of the currently used anticancer agents are only effective against proliferating cancer cells. Thus attention has been focused on potential anti-cancer agents capable of killing cancer cells independent of the cell cycle state, to ensure effective elimination of most cancer cells. The objective of this study was to test the chemosensitivity and potential mechanism of action of a novel cancer drug, CytoregR, in a panel of human cancer cells. the study was performed using a series of bioassays including Trypan blue exclusion, MTS Growth inhibition, LDH-cytotoxicity, TUNEL-Terminal DNA fragmentation Apoptosis Assay, and the Caspase protease CPP32 activity assays. CytoregR induced significant dose- and time-dependent inhibition of growth in all the cells; with significant differences in chemosensitivity (P < 0.05) between the target cells becoming more apparent at 48 hr exposure. CytoregR showed no significant effect on normal cells relative to the tumor cells. Growth inhibition in all the cells was due to induction of apoptosis at lower concentrations of cytoregR (> 1:300). CytoregR-induced caspase protease-3 (CPP32) activation significantly and positively correlated with apoptosis induction and growth inhibition; thus implicating CPP32 as the principal death pathway in cytoregR-induced apoptosis. |
Does selenite enhance and prolongs the efficacy of cisplatin treatment of human ovarian tumor xenografts? | Our earlier studies on ovarian tumor xenografts provide evidence that co-treatment with selenite prevents the development of resistance to single-treatment using the drug cisplatin. However, these studies did not reflect the repetitive schedule of clinical chemotherapy. We hypothesized that selenite can enhance the effectiveness of cisplatin during the course of repeated treatments, reflecting clinical practices. Multiple i.p. injections of cisplatin (5.2 mg/kg) alone, or with selenite (1.5 mg/kg), were administered to mice bearing subcutaneous xenografts of human ovarian tumor (A2780) cells and the tumor volume was recorded. Selenite increased and prolonged the efficacy of multiple cisplatin treatments, although selenite was not an effective inhibitor by itself. In the absence of selenite, the effectiveness of cisplatin decreased. | To determine whether concentrations of heart-type fatty acid binding protein (H-FABP) measured before hospital discharge predict critical cardiac events in patients with idiopathic dilated cardiomyopathy (DCM). 92 consecutive patients with DCM were enrolled and followed up for four years. Serum concentrations of H-FABP, brain natriuretic peptide (BNP), cardiac troponin T before hospital discharge and survival rate. 23 patients died of cardiac causes, received a left ventricular assist device or underwent heart transplantation during the four-year follow up. Univariate analyses showed that New York Heart Association functional class, heart rate, ejection fraction, serum H-FABP and plasma BNP were significant variables. According to multivariate analysis, serum H-FABP and plasma BNP concentrations were independent predictors of critical cardiac events. Cardiac troponin T before hospital discharge was not a predictor. The area under the receiver operating characteristic curve for death from critical cardiac events was similar between H-FABP and BNP. Patients with an H-FABP concentration at or above the median (> or = 5.4 ng/ml) had a significantly lower survival rate than those below the median, according to analysis by log rank test (p < 0.0001). When combined with BNP concentration at or above the median (> or = 138 pg/ml), H-FABP below the median predicted the worst prognosis among the combinations. |
Do spinal manipulation force and duration affect vertebral movement and neuromuscular responses? | Previous study in human subjects has documented biomechanical and neurophysiological responses to impulsive spinal manipulative thrusts, but very little is known about the neuromechanical effects of varying thrust force-time profiles. Ten adolescent Merino sheep were anesthetized and posteroanterior mechanical thrusts were applied to the L3 spinous process using a computer-controlled, mechanical testing apparatus. Three variable pulse durations (10, 100, 200 ms, force = 80 N) and three variable force amplitudes (20, 40, 60 N, pulse duration = 100 ms) were examined for their effect on lumbar motion response (L3 displacement, L1, L2 acceleration) and normalized multifidus electromyographic response (L3, L4) using a repeated measures analysis of variance. Increasing L3 posteroanterior force amplitude resulted in a fourfold linear increase in L3 posteroanterior vertebral displacement (p < 0.001) and adjacent segment (L1, L2) posteroanterior acceleration response (p < 0.001). L3 displacement was linearly correlated (p < 0.001) to the acceleration response over the 20-80 N force range (100 ms). At constant force, 10 ms thrusts resulted in nearly fivefold lower L3 displacements and significantly increased segmental (L2) acceleration responses compared to the 100 ms (19%, p = 0.005) and 200 ms (16%, p = 0.023) thrusts. Normalized electromyographic responses increased linearly with increasing force amplitude at higher amplitudes and were appreciably affected by mechanical excitation pulse duration. | Reducing ultraviolet radiation exposure may decrease melanoma risk in the hereditary melanoma setting. It is unknown whether genetic counseling and test reporting of CDKN2A/p16 mutation status promote long-term compliance with photoprotection recommendations, especially in unaffected mutation carriers. This study evaluated changes 2 years following melanoma genetic testing in self-reported practice of sun protection (sunscreen, photoprotective clothing, and ultraviolet radiation avoidance) among 37 members of two CDKN2A/p16 kindreds (10 unaffected carriers, 11 affected carriers, and 16 unaffected noncarriers; response rate = 64.9% of eligible participants). Multivariate profile analysis indicated that all three participant groups reported increased daily routine practice of sun protection 2 years following melanoma genetic testing (P < 0.02), with 96.9% reporting that at least one sun protection behavior was part of their daily routine, up from 78.1% at baseline (P < 0.015). Unaffected carriers (P < 0.024) and unaffected noncarriers (P < 0.027) reported significantly more frequent use of photoprotective clothing. Affected carriers maintained adherence to all sun protection behaviors. Reported sunburns in the past 6 months decreased significantly (P < 0.018). |
Does modified Mandibular Inferior Border Sagittal Split Osteotomy reduce Postoperative Risk for Developing Inferior Border Defects? | The purpose of this study was to evaluate the impact of a modified sagittal split osteotomy (SSO) surgical technique on the incidence of persisting inferior border defects. The secondary aim was to identify risk factors associated with the development of these complications. The patient charts and radiographs of 276 consecutive patients who underwent bilateral SSO, performed by a single surgeon in 2 different centers from July 2012 to September 2014, were retrospectively examined. The predictor variable was length of advancement. The outcome variable was the presence or absence of an inferior border defect. Other variables included age and side of the jaw. In all cases the same surgical technique was used. All statistical analyses were performed using SAS software, version 9.4 (SAS Institute, Cary, NC). The analysis included 408 operation sites in 204 patients (132 female and 72 male patients; median age, 22 years; age range, 13 to 66 years). In 5.1% of operation sites an osseous defect at the lower border of the mandible was observed. Age at the time of surgery (P < .0001) and length of advancement (P = .0111) were identified as risk factors for the development of a persisting osseous defect at the inferior border of the osteotomy gap after SSO. | Although local tissue activation of the endothelin (ET) system contributes to the development of pulmonary hypertension, the impact of isolated chronic plasma hyperendothelinemia on the pulmonary circulation is unknown. Mini-osmotic pumps were implanted in rats to deliver ET-1 during 7 or 28 days. After in vivo hemodynamics, the lungs were isolated to derive pressure-flow relations. Small pulmonary arteries ( approximately 250 microm) were mounted on an isometric myograph to study their reactivity. Plasma ET-1 approximately doubled (p < 0.05) after 7 and 28 days. Lung tissue ET-1 level increased fourfold after 7 days (p < 0.001) but was no longer significantly elevated after 28 days. Right ventricular systolic pressure was unaffected. The pulmonary pressure-flow relation shifted upward with a steeper slope (p < 0.05) at 7 days, but not after 28 days. Maximum dilatations to both acetylcholine (p < 0.01) and sodium nitroprusside (p < 0.001) were greatly reduced by approximately 50% after 28 days and were normalized by the addition of the nitric oxide synthase inhibitor L-NNA and the antioxidant N-acetyl-L-cysteine, respectively. |
Does lipopolysaccharide suppress albumin expression by activating NF-kappaB in rat hepatocytes? | The severity of hypoalbuminemia has been shown to be related to morbidity and mortality in critical illness, illustrating the need for better understanding of the molecular mechanism of hypoalbuminemia. Lipopolysaccharide(LPS) is a key mediator which induces hypoalbuminemia in sepsis and septic shock. The present studies were performed to identify whether the reduction of albumin expression induced by LPS was mediated by activating nuclear factor kappa B(NF-kappaB) in cultured rat hepatocytes. Primary rat hepatocytes were divided into five groups treated with normal saline or 1 ng/ml, 0.01 microg/ml, 0.1 microg/ml, or 1 microg/ml of LPS for 24 h. The albumin level in the supernatant and NF-kappaB activity in hepatocytes were measured. Hepatocytes were pretreated for 30 min with SN50 (a highly selected inhibitor of NF-kappaB) at different concentrations (10, 30, and 50 microg/ml). After 24 h of treatment with 1 microg/ml of LPS, the culture medium was measured for albumin level. Meanwhile, NF-kappaB activity in hepatocytes was assayed. LPS dramatically decreased albumin expression and enhanced NF-kappaB activity in rat hepatocytes, especially in the 1 microg/ml LPS group. This reduction in albumin expression induced by LPS can be completely inhibited by SN50 in different concentrations, and the maximal increase in albumin was observed at a SN50 dosage of 30 microg/ml. | To determine the effect of participation in clinical trials on survival of women with ovarian cancer. Disease-specific factors and demographics were also examined. A total of 158 women were treated for ovarian cancer at a regional cancer center. All patients were offered treatment with surgery/chemotherapy and were screened at diagnosis for participation in clinical research. Progression-free and overall survival, as well as demographic- and treatment-related data, were recorded. Fifty-three participated in clinical trials and 105 did not. On-study versus off-study subjects were similar in age (64.1 vs 63.5 years), ethnicity (87% vs 85% white), performance status (100% 0-1 Gynecologic Oncology Group scale), and urban versus rural lifestyle (58% vs 55% urban). Stage of disease, histologic subtype, and type/amount of therapy were also similar. Kaplan-Meier analysis showed superior overall survival for on-study subjects (median, 46 vs 25 months, 95% confidence interval, 1.0299-2.1505 months, P = 0.0343). A trend toward improved progression-free survival approached significance for on-study subjects (median, 23 vs 9 months, 95% confidence interval, 0.9545-2.0022 months, P = 0.0866). |
Are cerebrospinal fluid corticotropin-releasing hormone levels elevated in monkeys with patterns of brain activity associated with fearful temperament? | Asymmetric patterns of frontal brain activity and brain corticotropin-releasing hormone (CRH) systems have both been separately implicated in the processing of normal and abnormal emotional responses. Previous studies in rhesus monkeys demonstrated that individuals with extreme right frontal asymmetric brain electrical activity have high levels of trait-like fearful behavior and increased plasma cortisol concentrations. In this study we assessed cerebrospinal fluid (CSF) CRH concentrations in monkeys with extreme left and extreme right frontal brain electrical activity. CSF was repeatedly collected at 4, 8, 14, 40, and 52 months of age. Monkeys with extreme right frontal brain activity had increased CSF CRH concentrations at all ages measured. In addition, individual differences in CSF CRH concentrations were stable from 4 to 52 months of age. | We reviewed our experience with preoperative chemoradiotherapy in patients with adenocarcinoma of the distal esophagus and pretreatment endoscopic ultrasonography-identified celiac adenopathy. One hundred eighty-six patients with adenocarcinoma of the distal esophagus were staged with endoscopic ultrasonography before treatment from 1997 through 2004. All patients were treated with concurrent chemoradiotherapy (CRT group) and surgical intervention or induction chemotherapy followed by concurrent chemoradiotherapy (C-->CRT group) and surgical intervention. Survival analysis (excluding operative mortality) evaluated various pretreatment factors. Multivariable Cox regression analysis showed that pretreatment endoscopic ultrasonography-identified celiac adenopathy was a significant predictor of decreased long-term survival (P = .03). Median and 3-year survivals were 49 months and 54% in the endoscopic ultrasonography-identified cN0 M0 group (n = 65), 45 months and 56% in the endoscopic ultrasonography-identified cN1 M0 group (n = 96), and 19 months and 12% in the endoscopic ultrasonography-identified celiac adenopathy (cM1a) group (n = 18; P = .03). Increased systemic relapse was noted in the endoscopic ultrasonography-identified cM1a group (44% vs 22%, P = .07). The only factor associated with increased survival in the endoscopic ultrasonography-identified cM1a group (27 vs 15 months, P = .02) was the addition of induction chemotherapy before concurrent chemoradiotherapy and surgical intervention. |
Is cortical and subcortical neurodegeneration associated with HIV neurocognitive impairment? | To determine the association of markers of regional neurodegeneration (ND) at autopsy to degree of neurocognitive impairment in persons with HIV. In a prospectively followed cohort of HIV-infected individuals we examined the relationship between antemortem neuropsychological (NP) abilities and postmortem neuropathological data. Twenty-seven HIV-infected individuals with both neuropsychological and neuropathological data were identified. Laser confocal scanning microscopy was used to determine the degree of ND based on: (1) microtubule-associated protein (MAP2; reflecting neuronal cell bodies and dendrites) and (2) synaptophysin (SYN; a measure of presynaptic terminals). A regional combined score, based on the distribution of percentage neuropil occupied by MAP2 and SYN and emphasizing severity of ND, was created for each brain region: midfrontal cortex, hippocampus, and putamen. The regional combined scores from each brain region studied were better correlated with level of global NP impairment than measures of SYN and MAP2 individually. In a regression, hippocampal and putamen regional combined scores were independent predictors of degree of antemortem NP impairment (F(3,23) = 6.17; P < 0.01; R2 = 0.45). The correlations among regional ND measures demonstrated that ND is unevenly distributed across multiple brain regions. | To physiologically test the durability of a sutureless aortic stent-graft based on nitinol bonded to polyhedral oligomeric silsesquioxane (POSS) and poly(carbonate-urea) urethane (PCU) for 10 years according to Food and Drug Administration guidelines. Aortic stent-grafts (n = 4) were tested in 37°C distilled water using simulated in vivo hydrodynamic pulse loading. After 400 million cycles, surface topography was assessed by scanning electron microscopy (SEM) and Fourier transform infrared (FTIR) spectroscopy. Dynamic compliance was measured using a pulsatile flow phantom. Mechanical and elastic properties were determined by stress-strain studies and elastic deformation tests. Dynamic scanning calorimetry (DSC) and thermomechanical analysis (TMA) were used to assess thermal resistance. Comparison was made with a zero-cycled control. All stent-grafts successfully completed accelerated pulsatile fatigue at 94±14-mmHg pulse pressure. SEM images confirmed uniform surface topography without any fractures. FTIR showed increased intensity of -NHCO- bonds, but there was no significant sign of biodegradation. Tensile stress of fatigue-tested polymer compared favorably with the zero-cycled control at 50% to 500% strain (p = 0.69). At a mean pressure range of 60 to 120 mmHg, overall compliance of the fatigue-tested grafts was 3.48±1.27%mmHg(-1)×10(-2) with no significant difference compared to control (3.26±0.65%mmHg(-1)×10(-2); p = 0.47). DSC and TMA showed comparable thermotropic transition. |
Does addition of cladribine to induction/consolidation regimen impair peripheral blood stem cell mobilization and bone marrow harvest for autotransplantation in acute myeloid leukemia patients? | The previous study by the Polish Adult Leukemia Group has demonstrated that addition of cladribine to standard DNR+AraC induction potentiates the antileukemic activity. The goal of this study was to compare the efficacy of bone marrow or peripheral blood hematopoietic cell collection in patients who obtained remission after daunorubicine plus cytarabine induction with cladribine (DAC-7) or without addition of cladribine (DA-7) in preparation for autotransplantation. Sixty-six patients aged 41 years (range, 17-58 years) were included in this study: 33 cases in the DAC-7 and 33 in the DA-7 arm. Hematopoietic cells were collected from the bone marrow (ABMT, n = 29) or from the peripheral blood (ABCT, n = 37) using cytopheresis after administration of AraC (2 x 2 g/m2) on days 1, 3, 5 and subsequent G-CSF (10 microg/kg) from day 7 as mobilization therapy. The numbers of harvested CD34+ cells were similar in the DAC-7 and DA-7 pretreated patients both after harvesting from peripheral blood (2.55 x 10(6)/kg vs 2.5 x 10(6)/kg) and from bone marrow (1.62 x 10(6)/kg vs 1.55 x 10(6)/kg), respectively. The proportion of patients with sufficient material for autologous bone marrow transplantation was higher in the DAC-7 compared with the DA-7 arm. All patients engrafted; hematopoietic recovery was similar in both subgroups. | Growing evidence implicates hypothalamic inflammation in the pathogenesis of diet-induced obesity and cognitive dysfunction in rodent models. Few studies have addressed the association between obesity and hypothalamic damage in humans and its relevance. This study aimed to determine markers of obesity-associated hypothalamic damage on diffusion tensor imaging (DTI) and to determine whether DTI metrics are associated with performance on cognitive testing. This cross-sectional study analyzed DTI metrics (primary [λ(1)], secondary [λ(2)], and tertiary [λ(3)] eigenvalues; fractional anisotropy; and mean diffusivity) in the hypothalamus of 24 consecutive middle-age obese subjects (13 women; 49.8 ± 8.1 y; body mass index [BMI], 43.9 ± 0.92 kg/m(2)) and 20 healthy volunteers (10 women; 48.8 ± 9.5 y; BMI, 24.3 ± 0.79 kg/m(2)). measures: Hypothalamic damage assessed by DTI metrics and cognitive performance evaluated by neuropsychological test battery. λ(1) values in the hypothalamus were significantly lower in obese subjects (P < .0001). The sensitivity, specificity, and positive and negative predictive values for obesity-associated hypothalamic damage by λ(1) < 1.072 were 75, 87.5, 83.3, and 80.7%, respectively. Patients with hypothalamic λ(1) < 1.072 had higher values of BMI, fat mass, inflammatory markers, carotid-intima media thickness, and hepatic steatosis and lower scores on cognitive tests. Combined BMI and alanine aminotransferase had the strongest association with hypothalamic damage reflected by λ(1) < 1.072 (area under the curve = 0.89). |
Does pREPL deficiency with or without cystinuria cause a novel myasthenic syndrome? | To investigate the genetic and physiologic basis of the neuromuscular symptoms of hypotonia-cystinuria syndrome (HCS) and isolated PREPL deficiency, and their response to therapy. We performed molecular genetic, histochemical, immunoblot, and ultrastructural studies, investigated neuromuscular transmission in vitro in a patient with isolated PREPL deficiency, and evaluated the effect of pyridostigmine in this patient and in 3 patients with the HCS. HCS is caused by recessive deletions involving the SLC3A1 and PREPL genes. The major clinical features of HCS are type A cystinuria, growth hormone deficiency, muscle weakness, ptosis, and feeding problems. The proband with isolated PREPL deficiency had myasthenic symptoms since birth and a positive edrophonium test but no cystinuria. She and 1 of 3 patients with HCS responded transiently to pyridostigmine during infancy. The proband harbors a paternally inherited nonsense mutation in PREPL and a maternally inherited deletion involving both PREPL and SLC3A1; therefore, the PREPL deficiency determines the phenotype. We detected no PREPL expression in the patient's muscle and endplates. Electrophysiology studies revealed decreased quantal content of the endplate potential and reduced amplitude of the miniature endplate potential without endplate acetylcholine receptor deficiency or altered endplate geometry. | Clinical observations are suggesting accelerated granulation tissue formation in traumatic wounds treated with vacuum-assisted closure (VAC). Aim of this study was to determine the impact of VAC therapy versus alternative Epigard application on local inflammation and neovascularization in traumatic soft tissue wounds. Thirty-two patients with traumatic wounds requiring temporary coverage (VAC n = 16; Epigard n = 16) were included. At each change of dressing, samples of wound fluid and serum were collected (n = 80). The cytokines interleukin (IL)-6, IL-8, vascular endothelial growth factor (VEGF), and fibroblast growth factor-2 were measured by ELISA. Wound biopsies were examined histologically for inflammatory cells and degree of neovascularization present. All cytokines were found to be elevated in wound fluids during both VAC and Epigard treatment, whereas serum concentrations were negligible or not detectable. In wound fluids, significantly higher IL-8 (p < 0.001) and VEGF (p < 0.05) levels were detected during VAC therapy. Furthermore, histologic examination revealed increased neovascularization (p < 0.05) illustrated by CD31 and von Willebrand factor immunohistochemistry in wound biopsies of VAC treatment. In addition, there was an accumulation of neutrophils as well as an augmented expression of VEGF (p < 0.005) in VAC wound biopsies. |
Do large-diameter total hip arthroplasty modular heads require greater assembly forces for initial stability? | 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. | To develop a method for quick identification of sun-dried and sulfur-fumigated Cimicifugae Rhizoma by Fourier transform infrared spectroscopy (FTIR). The alcoholic and aqueous extracts of sun-dried and sulfur-fumigated Cimicifugae Rhizoma were analyzed and compared by FTIR combined with second derivative infrared spectroscopy. FTIR spectra showed that there were some differences in the positions of infrared absorption peaks and the relative intensities in the alcoholic and aqueous extracts of sun-dried and sulfur-fumigated Cimicifugae Rhizoma, and the second derivative IR spectra clearly enhanced the spectral resolution of their differences. FTIR spectra showed that the new absorption peaks of Cimicifugae Rhizoma appeared and a part of original absorption peaks disappeared after sulfur-fumigation in aqueous extracts, while a lot of new absorption peaks appeared and the intensities of almost all absorption peaks significantly decreased after sulfur-fumigation in alcoholic extracts. Second derivative IR spectra showed that both sun-dried and sulfur-fumigated Cimicifugae Rhizoma extracted by water differed significantly from each other ranging from about 3 950 to 3 940 cm(-1), 3 850 to 3 800 cm(-1), 1 800 to 1 750 cm(-1), as well as from 1 400 to 1 350 cm(-1); Differences also existed between sun-dried and sulfur-fumigated Cimicifugae Rhizoma extracted by ethanol ranging from about 3 980 to 3 960 cm(-1), 3 850 to 3 800 cm(-1), and 1 500 to 1 460 cm(-1). |
Does group B streptococcal beta-hemolysin/cytolysin directly impair cardiomyocyte viability and function? | Group B Streptococcus (GBS) is a leading cause of neonatal sepsis where myocardial dysfunction is an important contributor to poor outcome. Here we study the effects of the GBS pore-forming beta-hemolysin/cytolysin (Bh/c) exotoxin on cardiomyocyte viability, contractility, and calcium transients. HL-1 cardiomyocytes exposed to intact wild-type (WT) or isogenic Deltabeta h/c mutant GBS, or to cell-free extracts from either strain, were assessed for viability by trypan blue exclusion and for apoptosis by TUNEL staining. Functionality of exposed cardiomyocytes was analyzed by visual quantitation of the rate and extent of contractility. Mitochondrial membrane polarization was measured in TMRE-loaded cells exposed to GBS beta h/c. Effects of GBS beta h/c on calcium transients were studied in fura-2AM-loaded primary rat ventricular cardiomyocytes. Exposure of HL-1 cardiomyocytes to either WT GBS or beta h/c extracts significantly reduced both rate and extent of contractility and later induced necrotic and apoptotic cell death. No effects on cardiomyocyte viability or function were observed after treatment with Deltabeta h/c mutant bacteria or extracts. The beta h/c toxin was associated with complete and rapid loss of detectable calcium transients in primary neonatal rat ventricular cardiomyocytes and induced a loss of mitochondrial membrane polarization. These effects on viability and function were abrogated by the beta h/c inhibitor, dipalmitoyl phosphatidylcholine (DPPC). | This study aimed to compare the symptoms, unmet needs, and QoL reported by women at 6 months to <2 years and 2 to 5 years following surgery and adjuvant treatment for breast cancer. It also evaluated the relationships among symptoms, unmet needs, and QoL using structural equation modeling. In this study, 113 and 137 survivors following breast cancer treatment 6 months to <2 years and 2 to 5 years, respectively, completed the Memorial Symptom Assessment Scale, the Supportive Care Needs Survey-34, and the Medical Outcomes Study 12-item Short Form Health Survey version 2.0 during their medical follow-up. The mean numbers of symptoms and unmet needs were 5.43 and 3.0, respectively, for survivors at <2 years, and 5.24 and 2.42, respectively, for survivors at 2 to 5 years following treatment. The most common reported symptoms were related primarily to physical domains. No significant differences were found between the two survivor groups on the MSAS scores. Survivors at <2 years reported significantly higher scores in Psychological and Health Care System/Information needs (p < 0.01), and lower composite scores in physical and mental QoL (p < 0.05) than those at 2 to 5 years post-treatment. Significant direct and indirect effects were found of symptom burden through unmet needs on survivors' physical and mental QoL after adjustment for survival time, and the models showed a good fit. |
Are postoperative medical complications the main cause of early death after emergency surgery for colonic cancer? | Only a few small studies have evaluated risk factors related to early death following emergency surgery for colonic cancer. The aim of this study was to identify risk factors for death within 30 days after such surgery. Some 2157 patients who underwent emergency treatment for colonic cancer from May 2001 to December 2005 were identified from the national colorectal cancer registry. Thirty-day mortality rates were calculated and risk factors for early death were identified using logistic regression analysis. The overall 30-day mortality rate was 22.1 per cent. The strongest risk factor for early death was postoperative medical complications (cardiopulmonary, renal, thromboembolic and infectious), with an odds ratio of 11.7 (95 per cent confidence interval 8.8 to 15.5). Such complications occurred in 24.4 per cent of patients, of whom 57.8 per cent died. Other independent risk factors were age at least 71 years, male sex, American Society of Anesthesiologists grade III or more, palliative outcome, tumour perforation, splenectomy and adverse intraoperative surgical events. Postoperative surgical complications were noted in 20.4 per cent of the patients but had no statistically significant influence on mortality. | We have described cerebrospinal fluid (CSF) myeloid microvesicles (MVs) as a marker of microglia activation during neuroinflammation in Alzheimer disease (AD), and characterized their ability to produce toxic amyloid β1-42 (Aβ1-42 ) oligomers from aggregated or soluble substrate. The aim of this study is to investigate the association of CSF myeloid MVs with neuroimaging, clinical, and paraclinical data in AD and mild cognitive impairment (MCI). We collected CSF from 106 AD patients, 51 MCI patients, and 29 neurologically healthy controls. We examined CSF myeloid MV content and AD markers. A subgroup of 34 AD and 21 MCI patients underwent structural and diffusion tensor MRI. Higher levels of myeloid MVs were found in the CSF of AD patients and MCI patients converting within 3 years relative to controls, but also, at a lower level, in MCI patients not converting to AD. CSF myeloid MVs were associated with Tau but not with Aβ1-42 CSF levels. CSF MVs levels correlated with white matter (WM) tract damage in MCI, and with hippocampal atrophy in AD. |
Do age and violent-content labels make video games forbidden fruits for youth? | To protect minors from exposure to video games with objectionable content (eg, violence and sex), the Pan European Game Information developed a classification system for video games (eg, 18+). We tested the hypothesis that this classification system may actually increase the attractiveness of games for children younger than the age rating. Participants were 310 Dutch youth. The design was a 3 (age group: 7-8, 12-13, and 16-17 years) x 2 (participant gender) x 7 (label: 7+, 12+, 16+, 18+, violence, no violence, or no label control) x 2 (game description: violent or nonviolent) mixed factorial. The first 2 factors were between subjects, whereas the last 2 factors were within subjects. Three personality traits (ie, reactance, trait aggressiveness, and sensation seeking) were also included in the analyses. Participants read fictitious video game descriptions and rated how much they wanted to play each game. Results revealed that restrictive age labels and violent-content labels increased the attractiveness of video games for all of the age groups (even 7- to 8-year-olds and girls). | Treatment resistance and metastasis are the major causes of death among patients with colorectal cancer (CRC). Approximately 20% of surgically treated patients ultimately develop metastases during the follow-up period. Currently, the TNM system is the only available prognostic test. Therefore, the identification of new markers for CRC remains important. Thrombomodulin (TM), a glycoprotein, is involved in angiogenesis and has been linked to many malignant diseases. However, the function of TM in CRC remains unclear. A total of 170 patients with CRC participated in this study. TM expression was analyzed via immunohistochemistry. Univariate (Kaplan-Meier) analysis was used to analyze patient outcomes, including overall survival (OS) and disease-free survival (DFS). TM expression was manipulated using shRNA or an overexpression system. Transwell migration assays, wound healing migration assays, and the xCELLigence biosensor system were used to detect cell proliferative and migratory capacities. TM expression in the tumor tissues significantly and positively correlated with the DFS and OS of non-metastatic patients with CRC (ps = 0.036 and 0.0218, respectively). Suppression of TM expression increased the proliferation and migration of DLD-1 cells. TM overexpression reduced the cells' proliferative and migratory capacities. Cyclooxygenase (COX)-2 expression was up-regulated following TM silencing. Furthermore, the association between the migration of colon cancer cells and the levels of TM and epithelial-to-mesenchymal transition (EMT) markers (fibronectin, vimentin and ezrin) was confirmed in HT29 and DLD-1 cells. |
Are sR proteins and the nonsense-mediated decay mechanism involved in human GLB1 gene alternative splicing? | The human GLB1 gene is known to give rise to two alternatively spliced mRNAs, which encode two different proteins: lysosomal beta-galactosidase (beta-gal) and elastin-binding protein (EBP). The beta-gal transcript includes the 16 exons of the GLB1 gene. In the EBP transcript, exons 3, 4 and 6 are skipped, while exon 5 has a different reading frame. However, little is known on how this alternative splicing is regulated. Cycloheximide treatment of HeLa cells and human fibroblasts revealed the presence of new transcripts that are otherwise degraded by nonsense-mediated decay (NMD). A minigene carrying the exons involved in the alternative splicing of GLB1 was constructed. Improving the acceptor-site scores of exons 3 or 4 increased the relative inclusion of these exons, but did not stop them being skipped in some transcripts. Overexpression of different SR proteins altered the relative proportion of the different transcripts produced by the minigene, indicating a possible mechanism for the regulation of the alternative splicing of GLB1. Finally, a comparison of this gene among different species was performed. | Smoking, largely through increased oxidative stress, causes endothelial dysfunction which is an early key event in atherosclerosis. Smoking cessation and antioxidant vitamin therapy are shown to have beneficial role by restoring altered endothelial physiology. The present study was aimed to determine whether Terminalia arjuna, an Indian medicinal plant with potent antioxidant constituents, would improve endothelial dysfunction in smokers. Eighteen healthy male smokers (age 28.16+/-9.45 years) and equal number of age-matched non-smoker controls participated in the study. The baseline brachial artery reactivity studies were performed using high frequency ultrasound according to standard protocol under identical conditions to determine endothelium-dependent, flow-mediated dilation and endothelium-independent nitroglycerine-mediated dilation. The two groups were matched regarding age, body mass index, blood pressure, serum cholesterol, mean resting vessel diameters and post-occlusion flow velocities (all p=NS). While flow-mediated dilation was significantly impaired amongst smokers compared to controls (4.71+/-2.22 v. 11.75+/-5.94%, p <0.005), the nitroglycerine-mediated dilation was similar in the two groups (20.35+/-3.89 v. 19.68+/-3.74%, p=NS). Subsequently the smokers were given Terminalia arjuna (500 mg q8h) or matching placebo randomly in a double blind cross-over design for two weeks each, followed by repetition of brachial artery reactivity studies to determine various parameters including flow-mediated dilation after each period. There was no significant difference as regards vessel diameter and flow velocities between the two therapies. However, the flow-mediated dilation showed significant improvement from baseline values after Terrminalia arjuna therapy but not with placebo (9.31+/-3.74 v. 5.17+/-2.42%, p <0.005). |
Does a common UCP2 polymorphism predispose to stress hyperglycaemia in severe sepsis? | 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). | The reconstruction of large facial bony defects using microvascular transplants requires extensive surgery to achieve full rehabilitation of form and function. The purpose of this study is to measure the agreement between virtual plans and the actual results of maxillofacial reconstruction. This retrospective cohort study included 30 subjects receiving maxillofacial reconstruction with a preoperative virtual planning. Parameters including defect size, position, angle and volume of the transplanted segments were compared between the virtual plan and the real outcome using paired t test. A total of 63 bone segments were transplanted. The mean differences between the virtual planning and the postoperative situation were for the defect sizes 1.17 mm (95 % confidence interval (CI) (-.21 to 2.56 mm); p = 0.094), for the resection planes 1.69 mm (95 % CI (1.26-2.11); p = 0.033) and 10.16° (95 % CI (8.36°-11.96°); p < 0.001) and for the planes of the donor segments 10.81° (95 % CI (9.44°-12.17°); p < 0.001) The orientation of the segments differed by 6.68° (95 % CI (5.7°-7.66°); p < 0.001) from the virtual plan; the length of the segments differed by -0.12 mm (95 % CI (0.89-0.65 mm); not significant (n.s.)), respectively, while the volume differed by 73.3 % (95 % CI (69.4-77.6 %); p < 0.001). The distance between the transplanted segments and the remaining bone was 1.49 mm (95 % CI (1.24-1.74); p < 0.001) and between the segments 1.49 mm (95 % CI (1.16-1.81); p < 0.001). |
Are isolated tumor cells in stage I & II colon cancer patients associated with significantly worse disease-free and overall survival? | Lymph node (LN) involvement represents the strongest prognostic factor in colon cancer patients. The objective of this prospective study was to assess the prognostic impact of isolated tumor cells (ITC, defined as cell deposits ≤ 0.2 mm) in loco-regional LN of stage I & II colon cancer patients. Seventy-four stage I & II colon cancer patients were prospectively enrolled in the present study. LN at high risk of harboring ITC were identified via an in vivo sentinel lymph node procedure and analyzed with multilevel sectioning, conventional H&E and immunohistochemical CK-19 staining. The impact of ITC on survival was assessed using Cox regression analyses. Median follow-up was 4.6 years. ITC were detected in locoregional lymph nodes of 23 patients (31.1%). The presence of ITC was associated with a significantly worse disease-free survival (hazard ratio = 4.73, p = 0.005). Similarly, ITC were associated with significantly worse overall survival (hazard ratio = 3.50, p = 0.043). | Chronic cerebral hypoperfusion is a critical causative factor for the development of cognitive decline and dementia in the elderly, which involves many pathophysiological processes. Consequently, inhibition of several pathophysiological pathways is an attractive therapeutic strategy for this disorder. Rutin, a biologically active flavonoid, protects the brain against several insults through its antioxidant and anti-inflammatory properties, but its effect on cognitive deficits and brain damage caused by chronic cerebral hypoperfusion remains unknown. Here, we investigated the neuroprotective effect of rutin on cognitive impairments and the potential mechanisms underlying its action in rats with chronic cerebral hypoperfusion. We used Sprague-Dawley rats with permanent bilateral common carotid artery occlusion (BCCAO), a well-established model of chronic cerebral hypoperfusion. After rutin treatment for 12 weeks, the neuroprotective effect of rutin in rats was evaluated by behavioural tests, biochemical and histopathological analyses. BCCAO rats showed marked cognitive deficits, which were improved by rutin treatment. Moreover, BCCAO rats exhibited central cholinergic dysfunction, oxidative damage, inflammatory responses and neuronal damage in the cerebral cortex and hippocampus, compared with sham-operated rats. All these effects were significantly alleviated by treatment with rutin. |
Are new users of metformin at low risk of incident cancer : a cohort study among people with type 2 diabetes? | The antidiabetic properties of metformin are mediated through its ability to activate the AMP-activated protein kinase (AMPK). Activation of AMPK can suppress tumor formation and inhibit cell growth in addition to lowering blood glucose levels. We tested the hypothesis that metformin reduces the risk of cancer in people with type 2 diabetes. In an observational cohort study using record-linkage databases and based in Tayside, Scotland, U.K., we identified people with type 2 diabetes who were new users of metformin in 1994-2003. We also identified a set of diabetic comparators, individually matched to the metformin users by year of diabetes diagnosis, who had never used metformin. In a survival analysis we calculated hazard ratios for diagnosis of cancer, adjusted for baseline characteristics of the two groups using Cox regression. Cancer was diagnosed among 7.3% of 4,085 metformin users compared with 11.6% of 4,085 comparators, with median times to cancer of 3.5 and 2.6 years, respectively (P < 0.001). The unadjusted hazard ratio (95% CI) for cancer was 0.46 (0.40-0.53). After adjusting for sex, age, BMI, A1C, deprivation, smoking, and other drug use, there was still a significantly reduced risk of cancer associated with metformin: 0.63 (0.53-0.75). | Elite throwing athletes have increased proximal humeral retrotorsion (HRT) and glenoid retroversion (GRV) in their throwing shoulders compared with their nonthrowing shoulders. These adaptive morphologic changes are thought to be independently protective against shoulder injury; however, their relationship to each other is poorly understood. To determine if an association exists between HRT and GRV within the same shoulders of professional pitchers. Cross-sectional study; Level of evidence, 3. The HRT and GRV measurements were determined using published techniques in asymptomatic bilateral shoulders of 32 professional pitchers (mean age, 23 years). Three measurements for each variable were averaged, and the reliability of the techniques was verified. The relationship between HRT and GRV within the same shoulders was determined with Pearson correlation coefficients. Paired t tests were used to compare HRT and GRV between the throwing and nonthrowing shoulder. Simple ratios were calculated between HRT and GRV. Humeral retrotorsion and GRV were both significantly greater on the throwing side compared with the nonthrowing side (HRT: throwing = 9.0° ± 11.4° and nonthrowing = 22.1° ± 10.7°, P < .001; GRV: throwing = 8.6° ± 6.0° and nonthrowing = 4.9° ± 4.8°, P = .001). Within the same shoulders, there was a statistically significant positive association between HRT and GRV on the throwing side (r = 0.43, P = .016) but not on the nonthrowing side (r = -0.13, P = .50). The HRT:GRV ratio was 2.3:1 for throwing shoulders and 7:1 for nonthrowing shoulders. |
Is tumor necrosis factor inhibitor therapy but not standard therapy associated with resolution of erosion in the sacroiliac joints of patients with axial spondyloarthritis? | Radiography is an unreliable and insensitive tool for the assessment of structural lesions in the sacroiliac joints (SIJ). Magnetic resonance imaging (MRI) detects a wider spectrum of structural lesions but has undergone minimal validation in prospective studies. The Spondyloarthritis Research Consortium of Canada (SPARCC) MRI Sacroiliac Joint (SIJ) Structural Score (SSS) assesses a spectrum of structural lesions (erosion, fat metaplasia, backfill, ankylosis) and its potential to discriminate between therapies requires evaluation. The SSS score assesses five consecutive coronal slices through the cartilaginous portion of the joint on T1-weighted sequences starting from the transitional slice between cartilaginous and ligamentous portions of the joint. Lesions are scored dichotomously (present/absent) in SIJ quadrants (fat metaplasia, erosion) or halves (backfill, ankylosis). Two readers independently scored 147 pairs (baseline, 2 years) of scans from a prospective cohort of patients with SpA who received either standard (n = 69) or tumor necrosis factor alpha (TNFα) inhibitor (n = 78) therapy. Smallest detectable change (SDC) was calculated using analysis of variance (ANOVA), discrimination was assessed using Guyatt's effect size, and treatment group differences were assessed using t-tests and the Mann-Whitney test. We identified baseline demographic and structural damage variables associated with change in SSS score by univariate analysis and analyzed the effect of treatment by multivariate stepwise regression adjusted for severity of baseline structural damage and demographic variables. A significant increase in mean SSS score for fat metaplasia (P = 0.017) and decrease in mean SSS score for erosion (P = 0.017) was noted in anti-TNFα treated patients compared to those on standard therapy. Effect size for this change in SSS fat metaplasia and erosion score was moderate (0.5 and 0.6, respectively). Treatment and baseline SSS score for erosion were independently associated with change in SSS erosion score (β = 1.75, P = 0.003 and β = 0.40, P < 0.0001, respectively). Change in ASDAS (β = -0.46, P = 0.006), SPARCC MRI SIJ inflammation (β = -0.077, P = 0.019), and baseline SSS score for fat metaplasia (β = 0.085, P = 0.034) were independently associated with new fat metaplasia. | Whether extremely low birth weight (ELBW) infants are at risk of cerebral hypoperfusion is uncertain because key issues concerning their cerebral blood flow (CBF) and mean arterial pressure (MAP) are unresolved: (1) whether CBF is pressure-passive or autoregulated; (2) the normal level of MAP; and (3) whether inotropic drugs used to increase MAP might inadvertently impair CBF. We addressed these issues in ELBW infants undergoing intensive care. CBF (measured by near-infrared spectroscopy) and MAP were measured in 17 infants aged 1.5 to 40.5 hours. Five infants remained normotensive (MAP 37 +/- 2 mm Hg, [mean +/- SEM]); twelve became hypotensive (MAP 25 +/- 1 mm Hg) and were treated with dopamine (10-30 mug x kg(-1) per min). CBF of hypotensive infants (14 +/- 1 mL x 100 g(-1) per min) was lower than the CBF of normotensive infants (19 +/- mL x 100 g(-1) per min). After commencement of dopamine in hypotensive infants, MAP increased (29 +/- 1 mm Hg) and CBF also increased (18 +/- 1 mL x 100g(-1) per min). CBF was correlated with MAP in hypotensive infants before (R = 0.62) and during (R = 0.67) dopamine, but not in normotensive infants. A breakpoint was identified in the CBF versus MAP autoregulation curve of untreated infants at MAP = 29 mm Hg; no breakpoint was evident in dopamine-treated infants. |
Do vitamin D and glucocorticoids differentially modulate chemokine expression in human airway smooth muscle cells? | Chemokines play a critical role in the pathogenesis of asthma and facilitate the recruitment of inflammatory cells in the airways. Evidence now suggests that airway smooth muscle (ASM) may serve as a source of chemokines in inflamed airways. Although vitamin D has potent anti-inflammatory properties in vitro in some cell types, its effects on ASM cells remain unclear. Here, we investigated whether 1alpha, 25-dihydroxy vitamin D3 (calcitriol) modulated chemokine production in ASM. Human ASM cell cultures were derived from tracheal samples taken during surgery. ASM cells were treated with tumour necrosis factor alpha (TNFalpha) and/or interferon gamma (IFNgamma) for 24 h in the presence of calcitriol and/or the glucocorticoid fluticasone added 2 h before. RANTES (regulated upon activation, normal T-cell expressed and secreted), interferon-inducible protein 10 (IP-10) and fractalkine (FKN) levels in cell supernatants were measured by ELISA. In TNFalpha-treated cells, calcitriol inhibited RANTES and IP-10 secretion in a concentration-dependent manner. FKN levels were negligible. In TNFalpha/IFNgamma-treated cells, whereas fluticasone or calcitriol alone partially inhibited RANTES secretion (by 38 and 20%, respectively), the combination of both drugs additively inhibited RANTES secretion (by 60%). No effect was observed on IP-10 secretion. Whereas fluticasone enhanced FKN secretion (by 50%), calcitriol significantly decreased FKN levels (by 50%). Interestingly, calcitriol blocked the stimulatory effect of fluticasone on FKN secretion, which was inhibited by 60% with the combination of calcitriol and fluticasone. | To find permanent prostate implant (PPI) pre-plan dosimetric parameters that predict post-implant D90 ≥ 140 Gy. Pre-plans were evaluated for 504 patients undergoing PPI with (125)I seeds for low or intermediate risk prostate cancer. Baseline patient and disease factors, numbers of seeds, ratios of number of seeds to available positions (occupancy proportion), and distances between the 100% isodose line and edge of the prostate (margin) planned for the whole prostate (WP), superior (S), inferior (I), anterior (A), and posterior (P) halves, SA, SP, IA, and IP quarters, and superior (ST), inferior (IT), and middle (MT) thirds, and anterior (AT) and posterior (PT) middle one-sixth segments were analyzed by post-implant D90 subset (≥ 140 Gy vs. < 140 Gy). 20% had post-implant D90 < 140 Gy (mean: 128.0 Gy, range: 97.5-139.2) vs. ≥ 140 Gy (mean: 154.4 Gy, range: 140.0-193.5). The D90 ≥ 140 Gy subset had larger AT and IA segment mean numbers of seeds (p = 0.01, 0.046), larger WP, S, A, SA, ST, AT, and MT segment mean margins (p = 0.01, 0.01, 0.001, 0.0001, 0.03, 0.005, 0.02), and lower PT segment occupancy proportion (p = 0.004). On multivariate analysis, independent predictors of post-implant D90 ≥ 140 Gy were increased SA mean margin, no pre-implant 5-α-reductase inhibitor, higher pre-plan D90, decreased P occupancy proportion, no pre-implant hormone therapy, and decreased SP mean margin. |
Are polymorphisms -1082 G/A and -819 C/T in the interleukin-10 gene associated with gout susceptibility in the Chinese Han male population? | Gout is caused by monosodium urate crystal-induced inflammation of the joints and periarticular tissues. Interleukin 10 (IL-10) is an important immunoregulatory cytokine, levels of which can be influenced by functional single-nucleotide polymorphisms in the promoter. To investigate the association of -1082 G/A and -819 C/T polymorphisms in the IL-10 promoter with gout susceptibility in the Chinese Han male population. A case-control study was performed in 302 patients and 284 controls. Genotyping of IL-10 -1082 G/A and -819 C/T polymorphisms was performed by DNA sequencing techniques. An association analysis was analyzed by the χ(2) test. No significant differences were found in -819T/C and -1082 A/G genotypic and allelic frequencies between gout cases and controls (for -819T/C, χ(2)=0.212, df=1, p=0.645 by genotype; χ(2)=0.079, df=1, p=0.779 by allele; for -1082 A/G, χ(2)=2.116, df=1, p=0.146 by genotype; χ(2)=1.854, df=1, p=0.173 by allele). | Plasma VEGF levels increase after minimally invasive colorectal resection (MICR) and remain elevated for 2-4 weeks. VEGF induces physiologic and pathologic angiogenesis by binding to endothelial cell (EC) bound VEGF-Receptor-1 (VEGFR1) and VEGFR2. Soluble forms of these receptors sequester plasma VEGF, decreasing the amount available to bind to EC-bound receptors. Ramifications of surgery-related plasma VEGF changes partially depend on plasma levels of sVEGFR1 and sVEGFR2. This study assessed perioperative sVEGFR1 and sVEGFR2 levels after MICR in patients with colorectal cancer. Forty-five patients were studied; blood samples were taken from all patients preoperatively (preop) and on postoperative days (POD) 1 and 3; in most a fourth sample was drawn between POD 7-30. Late samples were bundled into two time points: POD 7-13 and POD 14-30. sVEGFR1 and sVEGFR2 levels were measured via ELISA. sVEGFR2 data are reported as mean +/- SD and were assessed with the paired samples t test. sVEGFR1 data were not normally distributed. They are reported as median and 95% confidence interval (CI) and were assessed with the Wilcoxon signed-Rank test (p < 0.05). Preoperatively, the mean plasma sVEGFR2 level (7583.9 pg/ml) was greater than the sVEGFR1 result (98.3 pg/ml). Compared with preop levels, sVEGFR2 levels were significantly lower on POD 1 (6068.2 pg/ml, +/-2034.5) and POD 3 (6227.6 pg/ml, +/-2007.0), whereas sVEGFR1 levels were significantly greater on POD 1 (237.5 pg/ml; 95% CI, 89.6-103.5), POD 3 (200.2 pg/ml; 95% CI, 159-253), and POD 7-13 (102.9 pg/ml; 95% CI, 189.7-253). No differences were found on POD 7-13 for sVEGFR2 or POD 14-30 for either protein. |
Is the programmable adult Codman Hakim valve useful even in very small children with hydrocephalus . A 7-year retrospective study with special focus on cost/benefit analysis? | Ventriculo-peritoneal shunting is the most commonly used method for the treatment of paediatric hydrocephalus. The programmable valve with the ability to adjust the opening pressure non-invasively has made it easier to find exactly the right opening pressure for each child and reduce the risk of over- or under-drainage. The aim of this investigation was to study our clinical experience with the adult Codman Hakim programmable valve in children, with reference to complications and economic impact. A seven-year retrospective study of 122 hydrocephalic children (aged from children born prematurely to 15 years old) shunted with the adult Codman Hakim programmable valve was performed. The programmable valve was the first shunt in 76 children and in 14 after prior ventricular drainage. The remaining 46 had different non-programmable systems as their first shunt. The most common reason for changing to a programmable valve was over-drainage. With the programmable valve, catheter-related complications, e.g. proximal (36%) or distal obstructions (30%), were the main reasons for surgical revision. Non-invasive pressure adjustment was performed in 73% of the children. Among the children with the programmable valve as their first shunt, 57 (75%) were adjusted, 12 (21%) had severe symptoms of over-drainage and would have required urgent surgical change of the valve if it had not been adjustable. A resetting of the opening pressure after MRI was found in 38% and accidental resetting occurred in 4%. Programmable valves are about twice as expensive as non-programmable valves. We estimated the increased cost of the valve and compared it with the savings from a reduction in the number of re-operations. The total cost for the programmable valve (as the primary shunt) in our study was less than that for expected re-operations due to over- or under-drainage when using non-programmable valves. | IL-17A is a key driver of human autoimmune diseases, particularly psoriasis. We sought to determine the role of IL-17A in psoriasis pathogenesis and to identify a robust and measurable biomarker of IL-17A-driven pathology. We studied 8 healthy subjects and 8 patients with psoriasis before and after administration of secukinumab, a fully human anti-IL-17A mAb, and used a combination of classical techniques and a novel skin microperfusion assay to evaluate the expression of 170 proteins in blood, nonlesional skin, and lesional skin. For validation, we also tested stored sera from 601 patients with a variety of autoimmune diseases. IL-17A was specifically expressed in lesional compared with nonlesional psoriatic skin (9.8 vs 0.8 pg/mL, P < .001). Proteomic and gene transcription analyses revealed dysregulated antimicrobial peptides, proinflammatory cytokines, and neutrophil chemoattractants, levels of which returned to normal after treatment with secukinumab. β-Defensin 2 (BD-2) was identified as a biomarker of IL-17A-driven pathology by comparing protein expression in patients with psoriasis versus that in healthy subjects (5746 vs 82 pg/mL in serum, P < .0001; 2747 vs <218 pg/mL in dermis, P < .001), responsiveness to secukinumab therapy, and synergistic induction by IL-17A and TNF-α in epidermal keratinocytes. In a validation set of sera from 601 patients with autoimmune diseases thought to be IL-17A driven, we found that BD-2 levels are most highly increased in patients with psoriatic skin lesions, and in patients with psoriasis, BD-2 levels correlated well with IL-17A levels (r = 0.70, n = 199, P < .001) and Psoriasis Area and Severity Index scores (r = 0.53, n = 281, P < .001). |
Does active workstation allow office workers to work efficiently while sitting and exercising moderately? | To determine the effects of a moderate-intensity active workstation on time and error during simulated office work. The aim of the study was to analyse simultaneous work and exercise for non-sedentary office workers. We monitored oxygen uptake, heart rate, sweating stains area, self-perceived effort, typing test time with typing error count and cognitive performance during 30 min of exercise with no cycling or cycling at 40 and 80 W. Compared baseline, we found increased physiological responses at 40 and 80 W, which corresponds to moderate physical activity (PA). Typing time significantly increased by 7.3% (p = 0.002) in C40W and also by 8.9% (p = 0.011) in C80W. Typing error count and cognitive performance were unchanged. | N-acetylglucosaminyltransferase V (GnT-V) is an enzyme that catalyzes beta1-6 branching of N-acetylglucosamine on asparagine (N)-linked oligosaccharides (N-glycan) of cell proteins. We examined the relationship between GnT-V expression and clinicopathologic features of the patients with bladder cancer. We immunohistochemically examined GnT-V expression in paraffin-embedded bladder cancer specimen using anti-GnT-V monoclonal antibody. We compared GnT-V expression with cause-specific survival of the patients with bladder cancer treated by radical cystectomy. Kaplan-Meier survival curves were generated to show the cause-specific survival. Univariate and multivariate analyses were carried out to compare GnT-V expression with other clinical and pathologic variables. We also evaluated mRNA expression of GnT-V and N-linked oligosaccharide structure in bladder cancer specimens. Immunohistochemistry revealed that GnT-V expression inversely correlated with tumor grade and stage. The incidence of positive GnT-V expression in bladder cancer was significantly higher in low-grade/superficial cancer than in high-grade/invasive cancer. The patients whose tumor was positive for GnT-V survived significantly longer than those whose tumor was negative for GnT-V. Univariate and multivariate analyses revealed that GnT-V expression was an independent predictor of prognosis of the patient. The expression of GnT-V mRNA determined by reverse transcription-PCR was consistent with the results with immunohistochemistry for tumor samples. Carbohydrate structural analysis revealed that superficial bladder cancer is rich in branched N-linked oligosaccharides, for which biosynthesis GnT-V is responsible. |
Is bOLD quantified renal pO2 sensitive to pharmacological challenges in rats? | Blood oxygen level-dependent (BOLD) MRI has been effectively used to monitor changes in renal oxygenation. However, R2* (or T2*) is not specific to blood oxygenation and is dependent on other factors. This study investigates the use of a statistical model that takes these factors into account and maps BOLD MRI measurements to blood pO2. Spin echo and gradient echo images were obtained in six Sprague-Dawley rats and R2 and R2* maps were computed. Measurements were made at baseline, post-nitric oxide synthase inhibitor (L-NAME), and post-furosemide administration. A simulation of each region was performed to map R2' (computed as R2*-R2) to blood pO2. At baseline, blood pO2 in the outer medulla was 30.5 ± 1.2 mmHg and 51.9 ± 5.2 mmHg in the cortex, in agreement with previous invasive studies. Blood pO2 was found to decrease within the outer medulla following L-NAME (P < 0.05) and increase after furosemide (P < 0.05). Blood pO2 in the cortex increased following furosemide (P < 0.05). | There is little information in the literature regarding the use of health care services by workers with occupational contact dermatitis. The objective of the study was to describe the use of health care services by workers with occupational contact dermatitis. One hundred workers with hand dermatitis were enrolled and observed for 6 months after assessment at St. Michael's Hospital (Toronto, ON, Canada). Information was collected at the time of diagnosis and 6 months after the assessment. Questionnaires were administered to collect information about clinical presentation and the use of health services. A diagnosis of occupational contact dermatitis was made for 78 of the workers. By the time of assessment at the Occupational Health Clinic at St. Michael's Hospital, almost all of the workers had seen their family doctor for their skin problem, and 71% had seen a dermatologist. Although family doctors and dermatologists asked the workers to identify their occupation, they rarely asked about workplace exposures, and the physicians provided minimal advice about job change or modification on return to work. During the 6 months following diagnosis, 62% of the workers saw their family physicians in follow-up, but rarely was advice about job change or modification provided at these follow-up visits. |
Do glycosaminoglycans inhibit the antibacterial activity of LL-37 in biological fluids? | The antibacterial activity of antimicrobial peptides is influenced by various factors such as salt content, pH and the presence of proteins. In this study, we explored the antibacterial action of the human cathelicidin LL-37 in physiologically relevant conditions, i.e. various human wound fluids, human plasma fractions and serum. Radial diffusion assays using Staphylococcus aureus and Escherichia coli were employed for the study of antibacterial effects of LL-37 in the presence of 12 different wound fluids, citrate-, heparin- or EDTA-plasma, or human serum. Glycosaminoglycan content of wound fluids was determined by an Alcian Blue-binding assay. Protein content of wound fluids was measured by the Bradford method. A slot-binding assay was used to study the effects of inhibitors on the interaction between LL-37 and glycosaminoglycans. Five of twelve wound fluids derived from acute wounds showed marked inhibitory effects on the antibacterial action of LL-37. The inhibition was significantly correlated with high glycosaminoglycan content in wound fluid. Analogous to these findings, heparin-plasma strongly inhibited the antibacterial effect of LL-37. The interaction between LL-37 and glycosaminoglycans was abrogated by the cationic polymers DEAE-dextran and chitosan, yielding increased activity of LL-37. | Although obesity is associated with gonadal dysfunction in the general population, gonadotoxic treatment might diminish the impact of obesity in childhood cancer survivors (CCS). The aim was to evaluate whether altered body composition is associated with gonadal dysfunction in male CCS, independent of gonadotoxic cancer treatment. Three hundred fifty-one male CCS were included. Median age at diagnosis was 5.9 years (0-17.8) and median age at follow-up 25.6 years (18.0-45.8). Total and non-SHBG-bound testosterone, sex hormone-binding globulin, inhibin B, and follicle-stimulating hormone (FSH) were studied. Potential determinants were BMI, waist circumference, waist-hip ratio, and body composition measures (dual energy X-ray absorptiometry). Non-SHBG-bound testosterone was significantly decreased in survivors with BMI ≥ 30 kg/m(2) (adjusted mean 9.1 nmol/L vs. 10.2 nmol/L, P = 0.015), high fat percentage (10.0 vs. 11.2, P = 0.004), and high waist circumference (>102 cm) (9.0 vs. 11.0, P = 0.020). Survivors with high fat percentage (≥25%) had significantly lower inhibin B/FSH ratios (inhibin B/FSH ratio: β -34%, P = 0.041). |
Does stakeholder attitudes and need regarding cell-free fetal DNA testing? | To explore stakeholder views on cell-free DNA testing and highlight findings important for successful implementation and the provision of best practice in counseling. Noninvasive tests based on the analysis of cell-free fetal DNA are now widely available in clinical practice and applications are expanding rapidly. It is essential that stakeholder views are considered in order to identify and address any ethical and social issues. We provide an overview of stakeholder viewpoints and then focus on the key issues of informed decision making, test uptake, service delivery and information sources. | The endoplasmic reticulum (ER) is a major intracellular Ca(2+) store in endothelial cells (ECs). The Ca(2+) concentration in the ER greatly contributes to the generation of Ca(2+) signals that regulate endothelial functions. Many proteins, including stromal interaction molecule 1/2 (STIM1/2), Orai1/2/3, and sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase 3 (SERCA3), are involved in the ER Ca(2+) refilling after store depletion in ECs. This study is designed to examine the role of Ca(2+) in the ER in coronary endothelial dysfunction in diabetes. Mouse coronary ECs (MCECs) isolated from diabetic mice exhibited (1) a significant decrease in the Ca(2+) mobilization from the ER when the cells were treated by SERCA inhibitor, and (2) significant downregulation of STIM1 and SERCA3 protein expression in comparison to the controls. Overexpression of STIM1 restored (1) the increase in cytosolic Ca(2+) concentration due to Ca(2+) leak from the ER in diabetic MCECs, (2) the Ca(2+) concentration in the ER, and (3) endothelium-dependent relaxation that was attenuated in diabetic coronary arteries. |
Does genome-wide association study in mice identify loci affecting liver-related phenotypes including Sel1l influencing serum bile acids? | Using publicly available data from inbred mouse strains, we conducted a genome-wide association study to identify loci that accounted for liver-related phenotypes between C57BL/6J and A/J mice fed a Paigen diet. We confirmed genome-wide significant associations for hepatic cholesterol (chromosome 10A2) and serum total bile acid concentration (chromosome 12E) and identified a new locus for liver inflammation (chromosome 7C). Analysis of consomic mice confirmed that chromosome 12 A/J alleles accounted for the variance in serum total bile acid concentrations and had pleiotropic effects on liver mass, serum cholesterol, and serum alanine aminotransferase activity. Using an affected-only haplotype analysis among strains, we refined the chromosome 12E signal to a 1.95 Mb linkage disequilibrium block containing only one gene, sel-1 suppressor of lin-12-like (Sel1l). RNA sequencing and immunoblotting demonstrated that the risk allele locally conferred reduced expression of SEL1L in liver and distantly down-regulated pathways associated with hepatocyte nuclear factor 1 homeobox A (Hnf1a) and hepatocyte nuclear factor 4A (Hnf4a), known modifiers of bile acid transporters and metabolic traits. Consistent with these data, knockdown of SEL1L in HepG2 cells resulted in reduced HNF1A and HNF4A and increased bile acids in culture media; it further captured multiple molecular signatures observed in consomic mouse livers with reduced SEL1L. Finally, dogs harboring a SEL1L mutation and Sel1l(+/-) mice fed a Paigen diet had significantly increased serum total bile acid concentrations, providing independent confirmation linking SEL1L to bile acid metabolism. | The purpose of the study is to investigate the influence of cardiopulmonary resuscitation (CPR) time before the first defibrillation. The present study retrospectively analyzed the Utstein template records from April 1, 2002, to June 30, 2005. Patients who had out-of-hospital-witnessed cardiac arrest caused by cardiac disease and who presented with ventricular fibrillation (VF) as the initial cardiac rhythm were included in the study. Before April 1, 2003, the emergency medical technician (EMT) needed to obtain telephone permission before attempting defibrillation, and CPR was continued until permission was received (CPR first). On and after April 1, 2003, the EMT was immediately able to attempt a defibrillation without obtaining permission (shock first). In 143 patients who had out-of-hospital-witnessed VF, 43 patients and 100 patients were treated with the CPR-first strategy and the shock-first strategy, respectively. The duration of CPR before the first defibrillation was longer in the CPR-first group than that in the shock-first group. The CPR-first group showed a higher rate of favorable neurologic outcome 30 days after (28% vs 14%; P = .048) and 1 year after cardiac arrest (26% vs 11%; P = .033) than those of the shock-first group. In the patients with witnessed VF, a stepwise multiple logistic regression analysis showed the CPR-first strategy to improve the neurologic outcome. |
Does ten years of growth hormone ( GH ) replacement normalize muscle strength in GH-deficient adults? | GH replacement for 1-5 yr improves, but does not fully normalize, muscle strength. OBJECTIVE, DESIGN, AND PATIENTS: In this single-center, open-labeled, prospective study, the effects of 10 yr of GH replacement on muscle strength and neuromuscular function were followed in 109 consecutive adults (61 men; mean age 50.0 yr; range 22-74 yr) with adult-onset GH deficiency. The mean initial GH dose of 0.88 mg/d was gradually lowered to 0.47 mg/d. The mean IGF-I sd score increased from -1.54 at baseline to 1.12 at study end. GH replacement induced a sustained increase in lean mass and isometric knee flexor strength (60 degrees). In most other measures of upper leg and handgrip strength, there were transient increases during the first half of the study (0-5 yr), whereas during the second half (5-10 yr), the absolute values of muscle strength decreased and returned to or even below the baseline values. However, after correction for age and gender using observed/predicted value ratios, there were sustained and, until 7 yr, even progressive increases in the measures of muscle strength. At study end, knee flexor strength had increased to 104-110% of predicted, knee extensor strength to 93-108%, and handgrip strength to 88-93%. Measurements of neuromuscular function showed reduced voluntary motor unit activation after 10 yr. | Activation of NF-kappaB signaling pathway plays a critical role in the initiation and progression of carcinogenesis. However, the role of NF-kappaB pathway in esophageal squamous cell carcinoma (ESCC) has not been fully elucidated. Studies have shown that curcumin possesses anti-infection and anti-oxidation effects. This study was to evaluate whether curcumin could induce apoptosis through inhibition of NF-kappaB signaling pathway in ESCC cells. Expressions of pIkappaBalpha and Bcl-2 were detected using Western blott after incubation of ESCC cells with curcumin (50 micromol/L) at different time points. Apoptosis and the number of viable ESCC cells were analyzed using flow cytometry and MTT, respectively, after the treatment of curcumin, 5-FU, or the combination of curcumin and 5-FU. In two ESCC cell lines, EC9706 and Eca109,curcumin inhibited IkappaBalpha phosphorylation and Bcl-2 in a time-dependent manner; curcumin alone increased cell apoptosis (P<0.05), and the effect became more prominent when it was combined with 5-FU (P<0.05); curcumin plus 5-FU exerted a stronger inhibition effect on cell proliferation than curcumin alone (P<0.05) or 5-FU alone (P<0.05). |
Does evaluation of a new device to prevent fall in persons with Parkinson 's disease? | To compare walking characteristics of individuals with Parkinson's disease (PD) using a new walking aid, the WalkAbout, with usual walking. Fifteen subjects with PD were recruited. Subjects walked in their usual fashion and then walked again in the WalkAbout. Gait parameters, 5-min walk, and oxygen consumption were recorded. Stride lengths were shorter when using the WalkAbout. On an average, the distance walked in 5 min and the oxygen uptake was not different when walking with the WalkAbout compared with the usual walk. Eight subjects (responders) walked further with the WalkAbout compared to their usual walk (164.90 +/- 55.72 m vs. 140.82 +/- 55.94 m). Seven subjects (non-responders) walked a shorter distance while using the WalkAbout compared to their usual walk (241.79 +/- 73.06 m vs. 281.24 +/- 82.83 m). Compared to non-responders, responders were older, had more severe disability, and were more likely to use an assistive device for walking. Responders walked more slowly, had a shorter stride length, and walked shorter distances in 5 min than non-responders. | H3K9 methylation is one of the essential histone post-translational modifications for heterochromatin formation and transcriptional repression. Recently, several studies have demonstrated that H3K9 methylation negatively regulates the type I interferon response. We report the application of EHMT1 and EHMT2 specific chemical inhibitors to sensitize CML cell lines to interferon and imatinib treatments. Inhibition of EHMT1 and EHMT2 with BIX01294 enhances the cytotoxicity of IFNα2a in four CML cell lines, K562, KCL22, BV173 and KT1 cells. Chromatin immunoprecipitation assay shows that BIX01294 treatment enhances type I interferon response by reducing H3K9me2 at the promoters of interferon-stimulated genes. Additionally, BIX01294 treatment augments IFNα2a- and imatinib-mediated apoptosis in CML cell lines. Moreover, our data suggest that the expression level of EHMT1 and EHMT2 inversely correlates with the type I interferon responsiveness in CML cell lines. |
Is elevated mean platelet volume associated with silent cerebral infarction? | The presence of silent cerebral infarction (SCI) increases the risk of transient ischaemia attack, symptomatic stroke, cardiovascular disease and dementia. Mean platelet volume (MPV) is a surrogate marker of activated platelets and is considered a link between inflammation and thrombosis. In addition, MPV is a risk predictor for cardiovascular disease, stroke and overall vascular mortality. The purpose of the study was to assess the MPV levels in SCI patients. A cross-sectional study was conducted to evaluate the association between MPV and SCI in 2215 subjects (1385 men and 830 women). The participants with SCI had higher MPV levels than those without SCI (10.4 ± 1.3 fL vs. 9.2 ± 1.2 fL; P < 0.001). Moreover, the subjects with a high MPV had a higher prevalence of SCI. Multivariate logistic regression analyses revealed that the odds ratios and 95% confidence intervals for SCI according to MPV quartiles were 1.000, 2.131 (1.319-3.444), 3.015 (1.896-4.794), 7.822 (4.874-12.554) respectively (P < 0.001). | To compare the rate of parastomal hernia in patients undergoing anterior fascial fixation of the ileal conduit with that in patients without fascial fixation. Limited data exist on whether anterior fascial fixation of the ileal conduit impacts the rate of parastomal hernia. A total of 496 consecutive patients undergoing radical cystectomy and ileal conduit reconstruction from 1995 to 2012 were retrospectively evaluated for parastomal hernia. All patients had a 2-fingerbreadth aperture and the ileal conduit brought through the rectus muscle and sheath. Patients were divided into 1 of 3 groups based on stoma fixation and/or reinforcement: anterior fascial fixation, posterior reinforcement, or no fascial fixation. A parastomal hernia was defined as a palpable bulge at the stoma site. Multivariate logistic regression was conducted for the primary end point of parastomal hernia, controlling for other patient- and treatment-related factors that might affect the rate of parastomal hernia. Median follow-up was 16 months (range, 1-189 months). The parastomal hernia rate was significantly greater in the anterior fascial suture group (43 of 281; 15.3%) than the no fascial suture group (12 of 164; 7.3%; P=.02). Multivariate logistic regression analysis modeled for the occurrence of a parastomal hernia demonstrated that anterior fascial fixation was an independent predictor of the development of parastomal hernia (odds ratio, 2.3; 95% confidence interval, 1.03-5.14; P=.04). |
Are soluble vascular cell adhesion molecule-1 and soluble E-selectin associated with micro- and macrovascular complications in Type 1 diabetic patients? | There are no large studies in Type 1 diabetic patients that have examined the relation between soluble adhesion molecules and micro- and macrovascular outcomes, although the risks of such complications are high. Therefore, the main objective is to examine the relationship between soluble (s) vascular cell adhesion molecule-1 (sVCAM-1) and sE-selectin and retinopathy, albuminuria, and cardiovascular disease (CVD) in Type 1 diabetic patients. Cross-sectional data on 540 Type 1 diabetic patients, with a mean age of 40 years and diabetes duration of 22 years, from the EURODIAB Prospective Complications Study (PCS) were analysed. Retinopathy was assessed by centrally graded retinal photographs. Albumin excretion rate (AER) was used to define micro- and macroalbuminuria. CVD was defined as having physician diagnosed myocardial infarction (MI), stroke, coronary artery bypass graft (CABG) or angina, or Minnesota coded ischaemic electrocardiograms (ECGs). Unadjusted, there was a positive relationship between sVCAM-1 and sE-selectin with nonproliferative and proliferative retinopathy, micro- and macroalbuminuria, and CVD. After adjustment for age, sex, duration of diabetes, systolic blood pressure (BP), LDL-cholesterol, fasting triglycerides (TGs), smoking, body mass index (BMI), and glycated haemoglobin, as well as other complications, the strongest significant associations were shown between sVCAM-1 and macroalbuminuria, with an odds ratio of 1.83 (1.33-2.53) for every 100 ng/ml increase in sVCAM-1. | Hepatocyte nuclear factor 4α (HNF4α) is a liver enriched transcription factor and is indispensable for liver development. However, the role of HNF4α in hepatocellular carcinoma (HCC) progression remains to be elucidated. We report that reduced HNF4α expression correlated well with the aggressive clinicopathological characteristics of HCC and predicted poor prognosis of patients. HNF4α levels were even lower in metastatic HCCs, and ectopic HNF4α expression suppressed the metastasis of hepatoma cells both in vitro and in vivo. Forced HNF4α expression attenuated the expression and nuclear translocation of RelA (p65) and impaired NF-κB activation through an IKK-independent mechanism. Blockage of RelA robustly attenuated the suppressive effect of HNF4α on hepatoma cell metastasis. MicroRNA (miR)-7 and miR-124 were transcriptionally up-regulated by HNF4α, which repressed RelA expression by way of interaction with RelA-3' untranslated region (UTR). In addition, nuclear factor kappa B (NF-κB) up-regulated the expression of miR-21 in hepatoma cells, resulting in decreased HNF4α levels through down-regulating HNF4α-3'UTR activity. |
Do extracellular vesicles participate in the transport of cytokines and angiogenic factors in diabetic patients with ocular complications? | Extracellular vesicles (EVs), including circulating microvesicles (MVs) or mi- croparticles (MPs) and exosomes, derived from cells or platelets are present in the peripheral blood and are important elements involved in the activation of the coagulation system, transport of macromolecules and intercellular communication. In patients with vascular complications (including diabetes), the number of EVs is significantly increased during the acute phase of the disease. However, less is known about EVs release in the chronic state of diabetes. To analyse the profile of inflammatory cytokines and angiogenic factors in EVs in diabetic patients with ocular and vascular complications. The study included patients with diabetes and varying degrees of ocular complications including retinopathy (n = 48) and the control group (n = 13). EV-enriched and EV-depleted fractions were obtained from platelet-poor plasma by means of the centrifugation method (16 000 g, for 90 min). In screening, the profile of cytokines with pro-angiogenic effects was preliminary assessed using the protein microarray technology for controlled diabetic patients - CD, uncontrolled diabetic patients - UD and for the control group. In all patients, concentrations of cytokines: RANTES (Regulated on Activation, Normal T-cell Expressed and secreted) and Ang-2 (angiopoietin-2) were assayed using the ELISA method. Common blood and biochemical tests were performed. In patients with diabetes, analysis of supernatant revealed significantly increased concentrations of basic fibroblast growth factor (bFGF) and soluble receptor for vascular endothelial growth factor 2 (V-EGFR2) when compared to the control group: 49 (10.5-122) vs. 24 (2-72.5) SD (p = 0.03) and 260 (195.5-351) vs. 360 (256-461.5) SD (p = 0.01). In UD patients, concentrations of RANTES, angiostatin, tumor necrosis factor-α (TNF), and tissue inhibitors of metalloproteinase 1 and 2 (TIMP1 and TIMP2) were relatively higher in the EV-enriched fraction when compared to the EV-depleted fraction. Post hoc analysis revealed significant differences between UC patients and the control group in RANTES (16.73 (14.41-18.93) vs. 14.62 (12.37-15.28) mg/ml; p = 0.0235) and Ang-2 (2.76 (2.23-4.64) ng/ml vs. 1.74 (1.54-1.93); p = 0.0316) concentrations. These analyses did not reveal any significant differences in RANTES and Ang-2 concentrations between CD patients and the control group. | Studies performed in Andean populations living in high altitude, indicate that the reduced availability of oxygen could be associated to both a fetal growth retardation and a lower birth weight. These variables are predictive of morbidity and mortality during the first year of life. To study perinatal variables of newborns of mothers living at contrasting altitudinal levels, harboring different degrees of Aymara ancestry. Review of medical records of 5,295 women whose deliveries occurred between February 2004 and August 2010. Information was obtained on place of residence, grouped into two categories: coast (150 to 3,000 m) and high plateau (3,000 to 4,300 m), ancestry was estimated using number of Aymara surnames that were homologated to percentages of Amerindian admixture, gestational age, birth weight, height, head circumference and obstetric variables. Gestational age showed a tendency to increase and birth weight, height and head circumference to decrease with altitude of residence. Only weight reached statistical significance. Women with Aymara ancestry gave birth to children with a significantly higher gestational age, weight and cranial circumference. |
Is medical comorbidities at admission predictive for 30-day in-hospital mortality in patients with acute myocardial infarction : analysis of 5161 cases? | The present study investigated the prognostic value of medical comorbidities at admission for 30-day in-hospital mortality in patients with acute myocardial infarction (AMI). A total of 5161 patients with AMI were admitted in Chinese PLA General Hospital between January 1, 1993 and December 31, 2007. Medical comorbidities including hypertension, diabetes mellitus, previous myocardial infarction, valvular heart disease, chronic obstructive pulmonary disease (COPD), renal insufficiency, previous stroke, atrial fibrillation and anemia, were identified at admission. The patients were divided into 4 groups based on the number of medical comorbidities at admission (0, 1, 2, and ≥ 3). Cox regression analysis was used to calculate relative risk (RR) and 95% confidence intervals (CI), with adjustment for age, sex, heart failure and percutaneous coronary intervention (PCI). The mean age of the studied population was 63.9 ± 13.6 years, and 80.1% of the patients were male. In 74.6% of the patients at least one comorbidity were identified. Hypertension (50.7%), diabetes mellitus (24.0%) and previous myocardial infarction (12%) were the leading common comorbidities at admission. The 30-day in-hospital mortality in patients with 0, 1, 2, and ≥ 3 comorbidities at admission (7.2%) was 4.9%, 7.2%, 11.1%, and 20.3%, respectively. The presence of 2 or more comorbidities was associated with higher 30-day in-hospital mortality compared with patients without comorbidity (RR: 1.41, 95% CI: 1.13-1.77, P = 0.003, and RR: 1.95, 95% CI: 1.59-2.39, P = 0.000, respectively). | Normal tissue radiosensitivity is the major limiting factor in radiotherapy of cancer. The use of phytochemicals may reduce the adverse effects of radiation in normal tissue. The effect of ethyl acetate fraction of Aphanamixis polystachya (EAP) was investigated on the radiation-induced chromosome damage in the bone marrow cells of Swiss albino mice exposed to various doses of gamma-radiation. The mice were divided into two groups, one group was exposed to 0, 1, 2, 3, 4 or 5 Gy of gamma-radiation, while another group received 7.5 mg/kg body weight (BW) of EAP 1 h before exposure to 0, 1, 2, 3, 4 or 5 Gy of gamma-radiation. Various asymmetrical chromosome aberrations were studied in the bone marrow cells of mice at 12, 24 or 48 h post-irradiation. To understand the mechanism of action of the free radical scavenging activity of 0, 5, 10, 20, 30, 40, 50, 60 or 70 microg/ml EAP, assays were carried out in vitro. Irradiation of mice to different doses of gamma radiation caused a dose dependent elevation in the frequency of aberrant cells and chromosome aberrations like chromatid breaks, chromosome breaks, dicentrics, acentric fragments and total aberrations at all the post-irradiation times studied. The maximum asymmetrical aberrations were scored at 24 h post-irradiation except chromatid breaks that were highest at 12 h post-irradiation. A maximum number of polyploid and severely damaged cells (SDC) were recorded at 24 h post-irradiation in the SPS+irradiation group. Treatment of mice with 7.5 mg/kg BW of EAP before exposure to 1-5 Gy of whole body gamma-radiation significantly reduced the frequencies of aberrant cells and chromosomal aberrations like acentric fragments, chromatid and chromosome breaks, centric rings, dicentrics and total aberrations at all post-irradiation scoring times (p<0.01). The EAP showed a concentration dependent scavenging of hydroxyl, superoxide, 2,2'-diphenyl-1-picryl hydrazyl (DPPH) radicals and the 2,2-azino-bis-3-ethyl benzothiazoline-6-sulphonic acid (ABTS) cation radicals in vitro. EAP treatment also reduced lipid peroxidation in bone marrow cells in a concentration dependent manner. |
Is hydrogen sulphide pro-inflammatory in haemorrhagic shock? | H(2)S is pro-inflammatory in inflammatory models, thus we investigated whether H(2)S plays a role in haemorrhagic shock (HS)-associated inflammation. Male, Sprague-Dawley rats were given an inhibitor of H(2)S biosynthesis, DL-propargylglycine (PAG, 50 mg/kg, i. v.) or saline (1 ml/kg) 30 min before blood withdrawal and subjected to HS (mean arterial pressure (MAP) of 40 mM Hg for 90 min) followed by reinfusion of shed blood. Animals were killed at 5, 90, 270 and 630 min after reinfusion. Pre-treatment of animals with PAG 1) increased the HR recovery rate (n = 6 - 12, P < 0.05); 2) attenuated the increase in plasma levels of TNF-alpha and IL-6 and reduced lung iNOS expression levels (n =5 P, < 0.05); and 3) attenuated the increase in plasma levels of ALT and reduced HS-induced increase in liver and lung myeloperoxidase (MPO) activity (n = 5, P < 0.05). | This study evaluated the role for poly(ADP-ribose) polymerase (PARP) in diabetes-induced cataractogenesis and early retinal changes. Control and streptozotocin (STZ)-diabetic rats were treated with or without the PARP inhibitors 1,5-isoquinolinediol (ISO; 3 mg kg(-1) d(-1) intraperitoneally) and 10-(4-methyl-piperazin-1-ylmethyl)-2H-7-oxa-1,2-diaza-benzo[de]anthracen-3-1 (GPI-15427, 30 mg kg(-1) d(-1) orally) for 10 weeks after the first 2 weeks without treatment. Lens clarity was evaluated by indirect ophthalmoscopy and slit lamp examination, and retinal changes were evaluated by immunohistochemistry and Western blot analysis. In in vitro studies, cultured human lens epithelial cells and bovine retinal pericytes and endothelial cells were exposed to high glucose or palmitate. PARP is expressed in lens, and poly(ADP-ribosyl)ated proteins are primarily localized in the 38- to 87-kDa range of the protein spectrum, with several minor bands at 17 to 38 kDa. The 38- to 87-kDa and the 17- to 38-kDa poly(ADP-ribosyl)ated protein expression increased by 74% and 275%, respectively, after 4 weeks of diabetes and by approximately 65% early after exposure of lens epithelial cells to 30 mM glucose. Both PARP inhibitors delayed, but did not prevent, the formation of diabetic cataract. The number of TUNEL-positive nuclei in flatmounted retinas increased approximately 4-fold in STZ diabetic rats, and this increase was prevented by ISO and GPI-15427. Both PARP inhibitors reduced diabetes-induced retinal oxidative-nitrosative and endoplasmic reticulum stress and glial activation. GPI-15427 (20 microM) prevented oxidative-nitrosative stress and cell death in palmitate-exposed pericytes and endothelial cells. |
Is the homeostasis model assessment-insulin resistance index inversely associated with serum carotenoids in non-diabetic subjects? | Carotenoids may reduce the risk for diabetes mellitus, but little is known about the association of insulin resistance with serum carotenoids in non-diabetic subjects. This study aimed to investigate whether the homeostasis model assessment-insulin resistance (HOMA-IR) index would be lower in the presence of high serum carotenoid concentrations in non-diabetic subjects. A total of 812 subjects (256 males and 556 females) who had received health examinations in 2003 participated in the study. The associations of the serum-carotenoid concentrations and HOMA-IR were evaluated cross-sectionally. The multivariate-adjusted geometric means of HOMA-IR by the tertiles of the serum carotenoid concentration were calculated after adjusting for age, body mass index, systolic blood pressure, total cholesterol, triacylglycerols, current tobacco use, regular alcohol intake, exercise habits and total energy intake. Associations among high HOMA-IR (3.0+mUxmmol/L2) across tertiles of serum carotenoid concentration were assessed by tests for logistic regression analysis. In male subjects, the multivariate adjusted geometric mean of HOMA-IR was inversely associated with the serum beta-cryptoxanthin concentrations. In female subjects, an inverse association of the serum carotenoid concentration and HOMA-IR was observed in lycopene, beta-cryptoxanthin, and zeaxanthin. The confounding factor-adjusted odds ratios (OR) for high HOMA-IR on the highest tertiles of serum alpha-carotene, beta-carotene, beta-cryptoxanthin, and zeaxanthin were 0.18 [95% confidence interval (CI): 0.06-0.52], 0.22 (95% CI: 0.07-0.67), 0.34 (95% CI: 0.12-0.96), and 0.30 (95% CI: 0.11-0.79), respectively, in male subjects. On the other hand, in female subjects, the adjusted OR for high HOMA-IR on the highest tertiles of serum lycopene and beta-cryptoxanthin were 0.39 (95% CI: 0.21-0.73) and 0.51 (95% CI: 0.28-0.95), respectively. | Impairment of proteasomal function is pathogenic in several cardiac proteinopathies and can eventually lead to heart failure. Loss of proteasomal activity often results in the accumulation of large protein aggregates. The ubiquitin proteasome system (UPS) is primarily responsible for cellular protein degradation, and although the role of ubiquitination in this process is well studied, the function of an ancillary post-translational modification, SUMOylation, in protein quality control is not fully understood. To determine the role of ubiquitin-conjugating enzyme 9 (UBC9), a small ubiquitin-like modifier-conjugating enzyme, in cardiomyocyte protein quality control. Gain- and loss-of-function approaches were used to determine the importance of UBC9. Overexpression of UBC9 enhanced UPS function in cardiomyocytes, whereas knockdown of UBC9 by small interfering RNA caused significant accumulations of aggregated protein. UPS function and relative activity was analyzed using a UPS reporter protein consisting of a short degron, CL1, fused to the COOH-terminus of green fluorescent protein (GFPu). Subsequently, the effects of UBC9 on UPS function were tested in a proteotoxic model of desmin-related cardiomyopathy, caused by cardiomyocyte-specific expression of a mutated αB crystallin, CryAB(R120G). CryAB(R120G) expression leads to aggregate formation and decreased proteasomal function. Coinfection of UBC9-adenovirus with CryAB(R120G) virus reduced the proteotoxic sequelae, decreasing overall aggregate concentrations. Conversely, knockdown of UBC9 significantly decreased UPS function in the model and resulted in increased aggregate levels. |
Is exercise capacity in the heat greater in the morning than in the evening in man? | This study investigated the effect of time of day on endurance exercise capacity in a warm environment. Nine males cycled to exhaustion at 65% .VO2peak in an ambient temperature of 35 degrees C (60% relative humidity) at 0645 h (AM) and 1845 h (PM). Rectal temperature (Tc), skin temperature (Tsk), and heart rate (HR) were recorded and blood and expired air samples collected at rest every 5 min during exercise and during recovery. Time to exhaustion was longer in the AM trial (45.8 +/- 10.7 min) than in the PM trial (40.5 +/- 9.0 min; P = 0.009). Resting Tc was lower in the AM trial and remained lower for the first 25 min of exercise (P < 0.001). Tc was not different between trials at the point of exhaustion (AM = 38.7 +/- 0.9 degrees C, PM = 38.8 +/- 0.6 degrees C; P = 0.847). Tsk followed a similar pattern, being lower at rest (P = 0.003) and during the initial stages of exercise (P < 0.05) in the AM trial but not different at exhaustion (P = 0.896). The rate of rise of Tc tended to be greater in the AM trial (P = 0.052), and the rate of rise of Tsk (P = 0.032) and of body heat content (P = 0.009) was also greater in the AM trial. HR was initially higher in the PM trial, but there was no difference at exhaustion. There were no differences between trials in blood glucose concentration or plasma volume change. | Inhibition of hepatoma cells by cyclooxygenase (COX)-2-dependent and -independent mechanisms has been shown previously. Here, we examine the effect of Celecoxib, a COX-2-inhibitor and R-Etodolac, an enantiomer of the nonsteroidal anti-inflammatory drug Etodolac, which lacks COX-inhibitory activity, on the Wnt/beta-catenin pathway and human hepatoma cells. Hep3B and HepG2 cell lines were treated with Celecoxib or R-Etodolac, and examined for viability, DNA synthesis, Wnt/beta-catenin pathway components, and downstream target gene expression. Celecoxib at high doses affected beta-catenin protein by inducing its degradation via GSK3beta and APC along with diminished tumor cell proliferation and survival. R-Etodolac at physiological doses caused decrease in total and activated beta-catenin protein secondary to decrease in its gene expression and post-translationally through GSK3beta activation. In addition, increased beta-catenin-E-cadherin was also observed at the membrane. An associated inhibition of beta-catenin-dependent Tcf reporter activity, decreased levels of downstream target gene products glutamine synthetase and cyclin-D1, and decreased proliferation and survival of hepatoma cells was evident. |
Do inhaled corticosteroids prevent the development of tolerance to the bronchoprotective effect of salmeterol? | Twice-daily inhaled salmeterol produces rapid reduction in its acute bronchoprotective effect against methacholine in patients with mild asthma. This investigation examined this effect in patients with moderate asthma who were using inhaled corticosteroids. Eight asthmatic volunteers who required inhaled corticosteroids for control of their symptoms and who were able to withhold treatment with beta 2-agonists for 4 weeks before and during the study participated in a double-blind, crossover, placebo-controlled study with two random-order treatment periods: inhaled salmeterol, 50 microg twice a day for seven doses, and placebo in similar fashion, with a 7-day or greater washout between these periods. Methacholine inhalation tests were done 1 h after doses 1, 3, 5, and 7, and then 24 h after the last dose of the study inhaler, 10 min post-200 microg salbutamol. Baseline FEV1 measurements before doses 3, 5, and 7 of salmeterol, ie, 12 h after salmeterol, were significantly higher than all other baseline values. Twenty-four hours after the last dose of salmeterol, the FEV1 was no different from that during the placebo period. The geometric mean methacholine concentration causing a 20% fall in FEV1 (PC20) following the third dose of salmeterol (6.8 mg/mL) was significantly lower than after the first dose of salmeterol (12.0 mg/mL; p=0.031), and this reduction of bronchoprotection persisted following doses 5 and 7. The methacholine PC20 10 min postsalbutamol measured after the salmeterol period was significantly lower than after placebo (5.6 vs 13.3 mg/mL; p<0.001). | CYR61 is an extracellular matrix-associated protein that promotes adhesion, migration, and proliferation of endothelial cells and fibroblasts. Prostate enlargement, which frequently causes the urethral compression, is often histologically observed as stromal and epithelial hyperplasia in an enlarged gland. To determine whether or not CYR61 has relevance to the progression of benign prostatic hyperplasia (BPH), we investigated the induction of CYR61, and also examined its function in both prostatic stromal and epithelial cells. Recombinant CYR61 protein was used for the examination of the activity of CYR61 as to cell adhesion and proliferation. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) was utilized to screen for inducers of the CYR61 gene in prostatic cells. Finally, the effects of an anti-sense oligonucleotide, which could reduce the production of CYR61, on the morphology and growth of prostatic cells were also examined. Recombinant CYR61 protein promotes prostatic cell adhesion and proliferation. The mRNA for CYR61, a growth factor-inducible immediate early gene, was markedly induced by fetal bovine serum (FBS) within 1 hr, and strongly induced by transforming growth factor-beta1 (TGF-beta) for at least 19 hr following stimulation. The suppression of CYR61 production with an anti-sense oligonucleotide causes obvious morphological changes of prostatic cells. Furthermore, we have shown that CYR61 is necessary, at least in part, for FBS-induced prostatic cell proliferation, because dramatic inhibition of cellular growth was caused by the suppression of CYR61 production with the addition of the anti-sense oligonucleotide before FBS stimulation. |
Are commensal isolates of methicillin-resistant Staphylococcus epidermidis also well equipped to produce biofilm on polystyrene surfaces? | To study biofilm production and to detect icaAD, atlE and aap genes in 137 isolates of methicillin-resistant Staphylococcus epidermidis (MRSE) obtained from healthy individuals from the community (35 isolates), from hospitalized patients at the Antônio Pedro University Hospital (25 isolates) and from individuals from a home-care system (HCS; 77 isolates). Biofilm production was determined in vitro using polystyrene inert surfaces. icaAD, atlE and aap genes were detected using PCR. Hybridization experiments were also carried out to confirm some PCR results. Antimicrobial susceptibility testing was carried out using the NCCLS methods. Although many of the commensal MRSE isolates produced biofilms, the percentage of biofilm producers was significantly higher (P = 0.0107) among hospital isolates (76%) than among isolates from the community (60%) and from the HCS (57%). An association was observed between multiresistance and biofilm production for isolates obtained from healthy individuals from the community and from household contacts from the HCS (P < 0.0001). The concomitant presence of the ica operon and atlE and aap genes was associated with the strong biofilm-producer phenotype (P < 0.0001). | Phosphatidylinositol 3-OH kinase (PI3K) has a long-recognized role in beta-cell mass regulation and gene transcription and is implicated in the modulation of insulin secretion. The role of nontyrosine kinase receptor-activated PI3K isoforms is largely unexplored. We therefore investigated the role of the G-protein-coupled PI3Kgamma and its catalytic subunit p110gamma in the regulation of insulin granule recruitment and exocytosis. The expression of p110gamma was knocked down by small-interfering RNA, and p110gamma activity was selectively inhibited with AS605240 (40 nmol/l). Exocytosis and granule recruitment was monitored by islet perifusion, whole-cell capacitance, total internal reflection fluorescence microscopy, and electron microscopy in INS-1 and human beta-cells. Cortical F-actin was examined in INS-1 cells and human islets and in mouse beta-cells lacking the phosphatase and tensin homolog (PTEN). Knockdown or inhibition of p110gamma markedly blunted depolarization-induced insulin secretion and exocytosis and ablated the exocytotic response to direct Ca(2+) infusion. This resulted from reduced granule localization to the plasma membrane and was associated with increased cortical F-actin. Inhibition of p110gamma had no effect on F-actin in beta-cells lacking PTEN. Finally, the effect of p110gamma inhibition on granule localization and exocytosis could be rapidly reversed by agents that promote actin depolymerization. |
Does effective treatment with intravenous immunoglobulins reduce autoreactive T-cell response in patients with CIDP? | To investigate changes in autoreactive T-cell responses against PMP-22 and P2 antigen as well as a T-cell memory repertoire in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) induced by repeated intravenous immunoglobulin (IVIg) treatment. In an observational trial, we prepared cryopreserved human peripheral blood monocytes from blood from 34 patients with CIDP (18 treatment naïve and 16 maintenance IVIg treatment) and from 14 healthy controls (non-immune neuropathy and healthy control). Treatment response was defined by clinical evaluation. The autoantigen-specific T-cell response was analysed by enzyme linked immunosorbent spot (ELISPOT) assay before IVIg start (baseline) and at follow-up. The T-cell memory subsets were analysed by using flow cytometric analysis. Myelin-derived P2-specific and PMP-22-specific IFN-γ producers were increased in IVIg responders compared with non-responders before treatment, which decreased by repeated IVIg infusion cycles. Treatment responders but not non-responders showed higher frequencies of CD4 T effector memory (TEM) and T central memory frequencies at baseline compared with maintenance IVIg treatment patients and controls. In addition, IVIg treatment was associated with a significant reduction in CD8 TEM at follow-up. | Salt tolerance in plants is rare, yet it is found across a diverse set of taxonomic groups. This suggests that, although salt tolerance often involves a set of complex traits, it has evolved many times independently in different angiosperm lineages. However, the pattern of evolution of salt tolerance can vary dramatically between families. A recent phylogenetic study of the Chenopodiaceae (goosefoot family) concluded that salt tolerance has a conserved evolutionary pattern, being gained early in the evolution of the lineage then retained by most species in the family. Conversely, a phylogenetic study of the Poaceae (grass family) suggested over 70 independent gains of salt tolerance, most giving rise to only one or a few salt tolerant species. Here, we use a phylogenetic approach to explore the macroevolutionary patterns of salt tolerance in a sample of angiosperm families, in order to ask whether either of these two patterns - deep and conserved or shallow and labile - represents a common mode of salt tolerance evolution. We analyze the distribution of halophyte species across the angiosperms and identify families with more or less halophytes than expected under a random model. Then, we explore the phylogenetic distribution of halophytes in 22 families using phylogenetic comparative methods. We find that salt tolerance species have been reported from over one-third of angiosperm families, but that salt tolerant species are not distributed evenly across angiosperm families. We find that salt tolerance has been gained hundreds of times over the history of the angiosperms. In a few families, we find deep and conserved gains of salt tolerance, but in the majority of families analyzed, we find that the pattern of salt tolerant species is best explained by multiple independent gains that occur near the tips of the phylogeny and often give rise to only one or a few halophytes. |
Is hURP part of a Ran-dependent complex involved in spindle formation? | GTP-loaded Ran induces the assembly of microtubules into aster-like and spindle-like structures in Xenopus egg extract. The microtubule-associated protein (MAP), TPX2, can mediate Ran's role in aster formation, but factors responsible for the transition from aster-like to spindle-like structures have not been described. Here we identify a complex that is required for the conversion of aster-like to spindle-like structures. The complex consists of two characterized MAPs (TPX2, XMAP215), a plus end-directed motor (Eg5), a mitotic kinase (Aurora A), and HURP, a protein associated with hepatocellular carcinoma. Formation and function of the complex is dependent on Aurora A activity. HURP protein was further characterized and shown to bind microtubules and affect their organization both in vitro and in vivo. In egg extract, anti-HURP antibodies disrupt the formation of both Ran-dependent and chromatin and centrosome-induced spindles. HURP is also required for the proper formation and function of mitotic spindles in HeLa cells. | Tissue factor (TF) contributes to thrombosis following plaque disruption in acute coronary syndromes (ACS). Aim of the study was to investigate the impact of plasma TF activity on prognosis in patients with ACS. One-hundred seventy-four patients with unstable Angina pectoris (uAP) and 112 patients with acute myocardial infarction (AMI) were included with a mean follow up time of 3.26 years. On admission, plasma TF activity was assessed. Patients were categorized into 2 groups: a high-TF activity group with TF >24 pmol/L and low TF activity group with TF ≤ 24 pmol/L. Fifteen cardiovascular deaths occurred in the uAP group and 16 in the AMI group. In AMI TF activity was 24,9 ± 2,78 pmol/l (mean ± SEM) in survivors and 40,9 ± 7,96 pmol/l in nonsurvivors (P = 0.024). In uAP no differences were observed (25.0 ± 8.04 pmol/L nonsurvivors vs. 25.7 ± 2.14 pmol/L survivors; P = 0.586). Kaplan-Meier estimates of survival at 3.26 years regarding TF activity in AMI were 81.3% and 92.2% with an hazard ratio of 3.02 (95% CI [1.05-8.79], P = 0.03). The Cox proportional hazards model adjusting for correlates of age and risk factors showed that plasma TF activity was an independent correlate of survival (hazard ratio 9.27, 95% CI [1.24-69.12], P = 0.03). In an additional group of patients with uAP and AMI, we identified circulating microparticles as the prevailing reservoir of plasma TF activity in acute coronary syndromes. |
Is stromal cell-derived factor-1-3 ' A polymorphism associated with decreased risk of myocardial infarction and early endothelial disturbance? | Genome-wide association studies have identified single-nucleotide polymorphisms at the 10q11 locus as risk factors for myocardial infarction (MI). This locus lies upstream (∼80 kb) of the stromal cell-derived factor-1 (SDF1) gene that codify for a chemokine with protective atherogenetic effects and with a major role in the mobilization, homing, and differentiation of endothelial progenitor cells (EPCs). The purpose of this study was to investigate the possible association of SDF1-3'A polymorphism, that upregulates SDF1 protein expression, with MI and early endothelial dysfunction and atherosclerosis in young healthy subjects. 200 patients (181 men age 57.3 ± 7.7 years) and 230 healthy controls (96 men, age 52 ± 11.9 years) were recruited to investigate the association between MI and SDF1-3'A polymorphism. The relationship between SDF1-3'A polymorphism and brachial artery flow-mediated dilation and the number of circulating EPCs was examined in 50 healthy young adults. A significant difference in SDF1-3'A genotype distribution was observed between patients and controls (P = 0.006). Patients carrying the A allele had a significantly reduced MI risk compared with subjects with GG genotype (odds ratio = 0.5, 95% CI = 0.3-0.9, P = 0.001). SDF1-3'A polymorphism presented a significant interaction with other cardiovascular risk factors (Pinteraction < 0. 0001). Controls carrying the A allele showed significantly higher flow-mediated dilation (13.9 ± 4.9 vs 10.8 ± 4.3, P = 0.03) and significantly higher values of EPCs (0.029 ± 0.009 vs 0.022 ± 0.008, P = 0.02) compared with GG homozygotes. | Flat and depressed lesions are becoming increasingly recognized in the esophagus, stomach, and colon. Various techniques have been described for endoscopic mucosal resection (EMR) of these lesions. To evaluate the efficacy of lift-grasp-cut EMR using a prototype dual-channel forward-viewing endoscope with an instrument elevator in one accessory channel (dual-channel elevator scope) as compared to standard dual-channel endoscopes. EMR was performed using a lift-grasp-cut technique on normal flat rectosigmoid or gastric mucosa in live porcine models after submucosal injection of 4 mL of saline using a dual-channel elevator scope or a standard dual-channel endoscope. With the dual-channel elevator scope, the elevator was used to attain further lifting of the mucosa. The primary endpoint was size of the EMR specimen and the secondary endpoint was number of complications. Twelve experiments were performed (six gastric and six colonic). Mean specimen diameter was 2.27 cm with the dual-channel elevator scope and 1.34 cm with the dual-channel endoscope (P = 0.018). Two colonic perforations occurred with the dual-channel endoscope, vs no complications with the dual-channel elevator scope. |
Does stigma predict residential treatment length for substance use disorder? | Stigma has been suggested as a possible contributor to the high rates of treatment attrition in substance-dependent individuals, but no published empirical studies have examined this association. The present paper assessed the relationship between baseline stigma variables and length of treatment stay in a sample of patients in a residential addictions treatment unit. The relationship between baseline stigma variables (self-stigma, enacted stigma, and shame) and length of stay for participants (n=103) in a residential addictions treatment unit was examined. Higher self-stigma predicted longer stay in residential addictions treatment, even after controlling for age, marital status, race, overall mental health, social support, enacted stigma, and internalized shame. However, other stigma variables (i.e. internalized shame, stigma-related rejection) did not reliably predict length of treatment stay. | To observe the effect of Nur77 on lipid loading in macrophages exposed to 40 microg/ml oxidized low density lipoprotein (ox-LDL). Stable RAW264.7 strain expressing green fluorescent protein (GFP) or GFP-Nur77 was established by G418 screening after transfection with corresponding plasmids and identified by Western blot. After 24 h stimulation with ox-LDL, intracellular lipid loading of each strain was observed by Oil Red O dyeing, and the intracellular cholesterol level was measured by liquid chromatographic-mass spectrometry (LC-MS). The transcriptional changes of CD36 and ABCA1 were monitored by Real Time Quantitative-PCR, while the expressions of these two proteins were assayed by flow cytometry and Western blot, respectively. After 24 h stimulation with ox-LDL, intracellular total cholesterol and esterified cholesterol concentration in GFP-Nur77-RAW264.7 were significantly dropped by 26.15% and 30.93% respectively (P < 0.05 vs. GFP-RAW264.7). The transcription and expression of ABCA1 in GFP-Nur77-RAW264.7 were significantly increased while the transcription and expression of CD36 were significantly reduced (all P < 0.05 vs. GFP-RAW264.7). |
Are clinical Neonatal Seizures Independently Associated with Outcome in Infants at Risk for Hypoxic-Ischemic Brain Injury? | To examine whether neonatal seizures are associated with neurodevelopmental outcomes in infants with hypoxia-ischemia independent of the presence and severity of brain injury seen on magnetic resonance imaging (MRI). We used multivariate regression to examine the independent effect of clinical neonatal seizures and their treatment on neurodevelopment in 77 term newborns at risk for hypoxic-ischemic brain injury. Clinical seizures were recorded prospectively, and high-resolution newborn MRI measured the severity of brain injury. The outcome measure was the Full-Scale Intelligence Quotient (FSIQ) of the Wechsler Preschool and Primary Scale of Intelligence-Revised and neuromotor score at age 4 years. After controlling for severity of injury on MRI, the children with neonatal seizures had worse motor and cognitive outcomes compared with those without seizures. The magnitude of effect varied with seizure severity; children with severe seizures had a lower FSIQ than those with mild/moderate seizures (P < .0001). | The deposition of the complement split fragment C4d and its association with acute antibody-mediated rejection (AMR) in pancreas transplant (PTx) is not well defined. To characterize the deposition of C4d in PTx, we analyzed 27 PTx biopsies from 18 patients transplanted between 2004 and 2007 at the University of Wisconsin. The presence of C4d was graded in interacinar capillaries (IAC), islets, interstitium, and small- and medium-size vessels. Sera obtained at the time or within 5 days of the biopsy were tested for antidonor-specific antibodies (DSA). 16 biopsies (59.26%) showed at least 5% C4d+ IAC (range 5%-90%). Of those, five biopsies (18.5%) revealed diffuse labeling (>50% C4d+ IAC) and 11 (40.74%) showed focal staining (5%-50% C4d+ IAC). C4d+ IAC (>5%) was significantly associated with the presence of strong DSA for class I or class II (P<0.018). C4d staining of the media or endothelium of small and medium-size vessels was a common finding in all biopsies without any association with DSA. Similarly, staining of islets and parenchymal interstitium was not statistically associated with AMR. The majority of patients received intravenous corticosteroid bolus and taper, with specific cases requiring thymoglobulin, IVIg, rituximab, or plasmapheresis. Forty-six percent of patients who demonstrated AMR returned to insulin therapy because of chronic graft damage and loss of C-peptide. |
Does isoflurane reduce hypoxia/reoxygenation-induced apoptosis and mitochondrial permeability transition in rat primary cultured cardiocytes? | The volatile anesthetic isoflurane protects the heart from hypoxia/reperfusion (H/R) injury. However, it is still incompletely understood whether isoflurane exerts its protective role through preventing mitochondrial permeability transition pore (MPTP) opening. Primary cultured cardiocytes were exposed to H/R in the absence or presence of isoflurane. Cell cytotoxicity and apoptosis were detected by MTT assay and TUNEL staining, respectively. MPTP function was monitored by confocal imaging after reoxygenation. ROS production and activation of caspase-3 were determined by fluorescent reader and western blot, respectively. As compared to the control group, H/R led to significant cell cytotoxicity and apoptosis, while application of isoflurane markedly reversed the effects. Furthermore, isoflurane significantly inhibits the formation of H/R-induced excess ROS production. Finally, isoflurane attenuated the onset of mitochondrial permeability transition pore (MPTP) occurred during hypoxia/reoxygenation, and in turn inhibited activation of caspase-3. | Mineral bone disorder (MBD) is prevalent among chronic dialysis patients. However, relationship between different forms of vitamin D and fibroblast growth factor 23 (FGF-23) remains unclear in this population. A multicenter hemodialysis cohort was assembled. We evaluated 25-OH-D and 1,25-(OH)2-D, vitamin D-binding protein, and FGF-23, in this cohort. Multiple regression analyses were performed to investigate the relationship and stewardship between different vitamin D forms and FGF-23 concentrations. Chronic dialysis patients presented significantly higher FGF-23 concentrations. 25-OH-D concentrations of <20 ng/ml (deficiency), 20-30 ng/ml (insufficiency), and ≥30 ng/ml (sufficiency) were associated with progressively lower FGF-23 concentrations (p<0.01). Serum FGF-23 concentrations were significantly correlated with total (p=0.02), free (p<0.01) and bioavailable (p<0.01) 25-OH-D and total (p=0.04), free (p=0.02), and bioavailable (p=0.03) 1,25-(OH)2-D concentrations. With all 25-OH-D and 1,25-(OH)2-D forms in the regression model, we found that free 1,25-(OH)2-D outweighed all other vitamin D forms regarding its association with FGF-23 (p=0.03). |
Does caregiver Quality of Life be Related to Severity of Otitis Media in Children? | Otitis media (OM) in children is the most frequent reason for physician visits in developed countries and burdens caregivers, society, and the child. Our objective was to describe the impact of OM severity on parent/caregiver quality of life (QoL). Multi-institutional prospective cross-sectional study. Otolaryngology, family, and pediatric practices. Children 6 to 24 months old with and without a primary diagnosis of recurrent OM and their caregivers. Physicians provided patient history, and parents/caregivers completed a Family Information Form, the PedsQL Family Impact survey, the Patient Reported Outcomes Measurement Information System (PROMIS) survey, and the OM 6-item severity survey (OM-6). A total of 2413 subjects were enrolled and data from 1208 patients and physician were analyzed. The average child age was 16 months, and 54% were male. The mean OM-6 score was 3.2. The mean PedsQL Family Impact score for parents was 66.9 from otolaryngology sites and 78.8 from pediatrics/family practice sites (P < .001). Higher (worse) OM-6 scores correlated significantly with worse PedsQL Family Impact scores (Pearson r = -0.512, P < .01). Similarly, increasing OM-6 scores strongly correlated with increased parental anxiety, depression, and fatigue, as well as decreased satisfaction (all P < .01). | Exercise (RUN) prevents declines in insulin-mediated vasodilation, an important component of insulin-mediated glucose disposal, in rats prone to obesity and insulin resistance. Determine whether RUN (1) improves insulin-stimulated vasodilation after insulin resistance has been established, and (2) differentially affects arterioles from red and white muscle. Insulin signaling and vasoreactivity to insulin (1-1000 μIU/mL) were assessed in 2A from the Gw and Gr of SED OLETF rats at 12 and 20 weeks of age (SED12, SED20) and those undergoing RUN (RUN20) or caloric restriction (CR20; to match body weight of RUN) from 12 to 20 weeks. Glucose and insulin responses to i.p. glucose were reduced in RUN20, elevated in SED20 (p < 0.05 vs. SED12), and maintained in CR20. Insulin-stimulated vasodilation was greater in Gw but not Gr, 2As of RUN20 (p < 0.01 vs. all groups), and was improved by ET-1 receptor inhibition in Gw 2As from SED20 and CR20 (p < 0.05). There were no differences in microvascular insulin signaling among groups or muscle beds. |
Is serum lactate predicted by anion gap or base excess after trauma resuscitation? | The inability to normalize lactate predicts death after trauma, but lactate may not be immediately available in every center. We postulated that, in a normal acid-base environment, lactate would correlate with the anion gap and the base excess of an arterial blood gas. We studied 52 consecutive, invasively monitored patients with trauma admitted directly to the intensive care unit (ICU) from the emergency department or operating room in our level I center to determine whether base excess and anion gap could predict lactate. Lactate, base excess, and anion gap were recorded upon admission to the ICU and 8, 16, 24, 36, and 48 hours after admission. Correlation coefficients (r2) were calculated for the total patients, the 43 survivors, and the nine non-survivors. Serum lactate was significantly higher in nonsurvivors at 16 hours after post ICU admission (4.0 +/- 1.69 vs. 2.84 +/- 1.49, p < 0.05), and this trend persisted; the greatest difference was seen at 48 hours after admission (2.92 +/- 1.47 vs. 1.76 +/- 0.57, p < 0.001). There were no differences in base excess or anion gap between survivors and nonsurvivors. We found no consistent correlation between lactate versus anion gap, lactate versus base excess, or anion gap versus base excess. | To assess the suppression effect on WWOX gene in SKOV3/SB cell line by small interference RNA (siRNA). Transfection of siRNA using lipofectamine 2000 was conducted to silence WWOX gene expression, the expression levels of WWOX mRNA and protein were evaluated, and the effects on the cell cycles at 48 hours of transfection were assessed by RT-PCR, western blot and flow cytometry (FCM) respectively. The cisplatin resistance index was assayed after transfection of SKOV3/SB with siRNA by methyl thiazolyl tetrazolium (MTT) and the cisplatin concentration of SKOV3/SB cells transfected with siRNA of WWOX was measured by high performance liquid chromatography. (1) In SKOV3/SB cells transfected with WWOX interference fragment, whether at the mRNA or protein level, the expression of both of WWOX decreased. There was a significant difference (P < 0.05) compared with SKOV3 cells and non-transfected cells. (2) After transfection of the WWOX interference fragment, the index of platinum resistance of SKOV3/SB decreased from 5.04 to 3.89. (3) The number of cell transfected with the WWOX interference fragment in G(1) phase was increased, while that in S-phase was decreased. (4) The cisplatin concentration of SKOV3/SB cells transfected with the WWOX interference fragment was increased from 9.43 ng/L to 23.45 ng/L compared with SKOV3/SB cells non-transfected with a significant difference (P < 0.05). |
Are sAH gene variants associated with obesity-related hypertension in Caucasians : the PEGASE Study? | 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. | Cyclosporine is a molecule used in ophthalmology for the prevention of corneal graft rejection. The systemic use of this product can lead to serious adverse side effects that can be avoided using the topical formulation of cyclosporine. However, cyclosporine application can induce ocular irritation. The aim of this study is to evaluate the cytotoxicity of four formulations of 2% cyclosporine eye drops: Sandimmum intravenous solution diluted with NaCl 0.9%, Sandimmun oral solution diluted in castor oil or corn oil after ethanol evaporation, and Sandimmun oral solution diluted in castor oil without previous ethanol evaporation. Two tests--the Draize test and the evaluation of cytotoxicity of adherent alive cells with cold light cytofluorimetry on microplates--were used in this study. These tests demonstrated that the aqueous solution shows more toxicity than the other formulations, and the type of oil and ethanol concentration influence cell viability. |
Is ethanol-associated hypoglycemia uncommon? | To determine the association of ethanol intoxication with hypoglycemia in ED patients. Retrospective, laboratory log review of 953 consecutive patients who were evaluated for ethanol intoxication in an urban university hospital ED over a three-month period. Simultaneous serum glucose determination was carried out for each patient and associations between ethanol level and glucose were sought. Glucose concentrations were unavailable for 16 patients (1.7%). Of the remaining patients, 584 patients had detectable ethanol concentrations (ethanol-positive), and 353 had no detectable ethanol (ethanol-negative). Ethanol concentrations (mean +/- SD) in the ethanol-positive group were 50.11 +/- 24.08 mmol/L (231 +/- 111 mg/dL), and glucose concentrations were 5.83 +/- 1.94 mmol/L (105 +/- 35 mg/dL). Hypoglycemia [glucose < 3.72 mmol/L (67 mg/dL)] was observed for five (0.9%) ethanol-positive patients. It was classified as mild-moderate [2.78-3.66 mmol/L (50-66 mg/dL)] for four patients (0.7%) and severe [< 2.78 mmol/L (50 mg/dL)] for one (0.2%). Ethanol concentrations ranged from 25.60 to 68.33 mmol/L (118 to 315 mg/dL). There was no correlation between ethanol and glucose concentrations in any subset of the ethanol-positive patients population. In the ethanol-positive group, patients who had several ethanol-positive visits (56 patients, mean 3.6 visits/patient) accounted for four of the five episodes of hypoglycemia, including the one episode of severe hypoglycemia. The frequency of hypoglycemia in repeat visitors (2.0%) was higher than that in the group of patients without repeat visits (0.2%). In the ethanol-negative group, there were four (1.1%) episodes of mild-moderate hypoglycemia and no severely hypoglycemic patients. Hypoglycemia was not more likely to occur among ethanol-positive patients than it was among ethanol-negative patients. | Aortic dissection or rupture resulting from aneurysm causes 1% to 2% of deaths in developed countries. These disorders are associated with mutations in genes that affect vascular smooth muscle cell differentiation and contractility or extracellular matrix composition and assembly. However, as many as 75% of patients with a family history of aortic aneurysms do not have an identified genetic syndrome. To determine the role of the protease MMP17/MT4-MMP in the arterial wall and its possible relevance in human aortic pathology. Screening of patients with inherited thoracic aortic aneurysms and dissections identified a missense mutation (R373H) in the MMP17 gene that prevented the expression of the protease in human transfected cells. Using a loss-of-function genetic mouse model, we demonstrated that the lack of Mmp17 resulted in the presence of dysfunctional vascular smooth muscle cells and altered extracellular matrix in the vessel wall; and it led to increased susceptibility to angiotensin-II-induced thoracic aortic aneurysm. We also showed that Mmp17-mediated osteopontin cleavage regulated vascular smooth muscle cell maturation via c-Jun N-terminal kinase signaling during aorta wall development. Some features of the arterial phenotype were prevented by re-expression of catalytically active Mmp17 or the N-terminal osteopontin fragment in Mmp17-null neonates. |
Is pleocytosis associated with disruption of HIV compartmentalization between blood and cerebral spinal fluid viral populations? | We hypothesized that pleocytosis, which is a marker of central nervous system (CNS) inflammation, would result in viral genetic equilibration or de-compartmentalization between HIV populations in the blood and cerebrospinal fluid (CSF), suggesting viral trafficking. Study subjects, who started or interrupted their antiretroviral treatment, had viral loads measured and clonal viral env sequences generated from HIV RNA extracted from paired blood and CSF samples. White blood counts in CSF were also measured at each timepoint. Degree of inter-compartment segregation was calculated by posterior probability using linear discriminant analysis and multidimensional scaling. Co-receptor usage was determined using a trained support vector machine. Pleocytosis was strongly associated with disruption of viral compartmentalization. | Free radicals are reported to be associated with fibrosis in the pancreas. It is generally accepted that pancreatic stellate cells (PSC) play an important role in pancreatic fibrosis. However, the exact role of free radicals in activation of PSC has not been fully elucidated. In the present study, using a superoxide dismutase (SOD) inhibitor, diethyldithiocarbamate (DDC) with cultured PSC, we investigated how free radicals act on the activation of PSC. PSC were isolated from male Wister rats. Cultured rat PSC were incubated with DDC for 48 h. Intracellular SOD activity and lipid peroxidation were examined in DDC-treated PSC. Activation of PSC was examined by determining the expression of alpha-smooth muscle actin (alpha-SMA) by immunocytochemistry. The number of PSC using a hemocytometer, type I collagen secretion with ELISA and matrix metalloproteinases (MMP) activities with gelatin zymography were also examined. Secretion of transforming growth factor-beta1 (TGF-beta1) was evaluated by ELISA. The effects of the allopurinol, a xanthine oxidase (XOD) inhibitor, on PSC were also examined. DDC decreased SOD activity and increased lipid peroxidation products in PSC. DDC activated PSC, increasing the number of alpha-SMA positive cells, enhancing secretion of type I collagen and MMP, inhibiting PSC proliferation. Secretion of TGF-beta1, which is known to activate PSC, was increased by DDC treatment. These alterations were prevented by allopurinol. |
Does up-regulation of FOXM1 by E6 oncoprotein through the MZF1/NKX2-1 axis is require for human papillomavirus-associated tumorigenesis? | Foxhead box M1 (FOXM1) expression has been shown to be linked with human papillomavirus (HPV) 16/18-infected cervical cancer. However, the mechanism underlying the induction of FOXM1 in HPV 16/18-infected cancers remains elusive. The mechanistic actions of FOXM1 induced by the E6/NKX2-1 axis in tumor aggressiveness were elucidated in cellular and animal models. The prognostic value of FOXM1 for overall survival (OS) and relapse-free survival (RFS) in HPV-positive oral and lung cancers was assessed using Kaplan-Meier and Cox regression models. Herein, FOXM1 expression is upregulated by E6-mediated NKX2-1 in HPV-positive cervical, oral, and lung cancer cells. Induction of FOXM1 by E6 through the MZF1/NKX2-1 axis is responsible for HPV-mediated soft agar growth, invasiveness, and stemness through activating Wnt/β-catenin signaling pathway. In a nude mice model, metastatic lung tumor nodules in HPV 18 E6-positive GNM or HPV 16 E6-positive TL-1-injected nude mice were markedly decreased in both cell types with E6 knockdown, FOXM1 knockdown, or treatment with FOXM1 inhibitor (thiostrepton). Among the four subgroup patients, the worst FOXM1 prognostic value for OS and RFS was observed in HPV 16/18-positive patients with tumors with high-expressing FOXM1. | Mental fatigue can negatively impact on submaximal endurance exercise and has been attributed to changes in perceived exertion rather than changes in physiological variables. The impact of mental fatigue on maximal anaerobic performance is, however, unclear. Therefore, the aim of the present study was to induce a state of mental fatigue to examine the effects on performance, physiological and perceptual variables from subsequent tests of power, strength and anaerobic capacity. Twelve participants took part in the single-blind, randomised, crossover design study. Mental fatigue was induced by 90 min of the computer-based Continuous Performance Task AX version. Control treatment consisted of 90 min of watching emotionally neutral documentaries. Participants consequently completed countermovement jump, isometric leg extension and a 3-min all-out cycling tests. Results of repeated measures analysis of variance and paired t tests revealed no difference in any performance or physiological variable. Rating of perceived exertion tended to be greater when mentally fatigued (mental fatigue = 19 ± 1 vs control = 18 ± 1, p = 0.096, [Formula: see text] = .232) and intrinsic motivation reduced (mental fatigue = 11 ± 4 vs control = 13 ± 6, p = 0.063, d = 0.597) in the mental fatigue condition. |
Does mammalian prion protein ( PrP ) form conformationally different amyloid intracellular aggregates in bacteria? | An increasing number of proteins are being shown to assemble into amyloid structures that lead to pathological states. Among them, mammalian prions outstand due to their ability to transmit the pathogenic conformation, becoming thus infectious. The structural conversion of the cellular prion protein (PrP(C)), into its misfolded pathogenic form (PrP(Sc)) is the central event of prion-driven pathologies. The study of the structural properties of intracellular amyloid aggregates in general and of prion-like ones in particular is a challenging task. In this context, the evidence that the inclusion bodies formed by amyloid proteins in bacteria display amyloid-like structural and functional properties make them a privileged system to model intracellular amyloid aggregation. Here we provide the first demonstration that recombinant murine PrP and its C-terminal domain (90-231) attain amyloid conformations inside bacteria. Moreover, the inclusions formed by these two PrP proteins display conformational diversity, since they differ in fibril morphology, binding affinity to amyloid dyes, stability, resistance to proteinase K digestion and neurotoxicity. | Native Andean ancestry gives partial protection from reduced birthweight at high altitude in the Andes compared with European ancestry. Whether Andean ancestry is also associated with body proportions and greater postnatal body size at altitude is unknown. Therefore, we tested whether a greater proportion of Andean ancestry is associated with stature and body proportions among Peruvian children at high and low altitude. Height, head circumference, head-trunk height, upper and lower limb lengths, and tibia, ulna, hand and foot lengths, were measured in 133 highland and 169 lowland children aged 6 months to 8.5 years. For highland and lowland groups separately, age-sex-adjusted anthropometry z scores were regressed on the number of indigenous parental surnames as a proxy for Andean ancestry, adjusting for potential confounders (maternal age and education, parity, altitude [highlands only]). Among highland children, greater Andean ancestry was negatively associated with stature and tibia, ulna, and lower limb lengths, independent of negative associations with greater altitude for these measurements. Relationships were strongest for tibia length: each additional Andean surname or 1,000 m increase at altitude among highland children was associated with 0.18 and 0.65 z score decreases in tibia length, respectively. Anthropometry was not significantly associated with ancestry among lowland children. |
Is overcrowding in Psychiatric Wards Associated With Increased Risk of Adverse Incidents? | 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. | 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). |
Does co-Transplantation of Skin-Derived Precursors and Collagen Sponge facilitate Diabetic Wound Healing by Promoting Local Vascular Regeneration? | Impaired diabetes wound healing can often lead to serious complications and remains a major health concern due to the lack of effective therapeutic approaches. Compromised angiogenesis, disrupted growth factor and cytokine activity are all attributable to diabetic wound healing impairment. The skin-derived precursors (SKPs) have been shown to differentiate into vascular and nerve cells, both of which are crucial components for wound repair. Given their easy accessibility and multipotency, the SKPs were proposed as an ideal therapeutic candidate for diabetic wound healing. Since the efficacy of cell therapy is limited by poor cell survival, collagen sponge was employed for better SKPs delivery. SKPs were isolated and transplanted directly to the wound areas of diabetic mice in the absence and presence of collagen sponge. The effects of SKPs and/or collagen sponge on diabetic wound healing were examined histologically as well as immunostaining of isolectin and α-SMA. Mechanisms via which the SKPs facilitate wound healing were then investigated by transplanting SKPs that have been pre-labelled with a fluorescence dye, Dil. Expression patterns of Dil and an SKP marker, nestin, was also examined. | The Mine Safety and Health Administration (MSHA) proposes to issue citations for non-compliance with the exposure limit for respirable coal mine dust when measured exposure exceeds the exposure limit with a "high degree of confidence." This criterion threshold value (CTV) is derived from the sampling and analytical error of the measurement method. This policy is based on a combination of statistical and legal reasoning: the one-tailed 95% confidence limit of the sampling method, the apparent principle of due process and a standard of proof analogous to "beyond a reasonable doubt." This policy raises the effective exposure limit, it is contrary to the precautionary principle, it is not a fair sharing of the burden of uncertainty, and it employs an inappropriate standard of proof. Its own advisory committee and NIOSH have advised against this policy. For longwall mining sections, it results in a failure to issue citations for approximately 36% of the measured values that exceed the statutory exposure limit. |
Is narrow band CE-Chirp auditory steady-state response more reliable than the conventional ASSR in predicting the behavioral hearing threshold? | We evaluated conventional ASSR (Bio-logic MASTER II) and NB CE-Chirp ASSR thresholds as objective hearing measures in both normal and hearing loss subjects. Patients with sensorineural hearing loss and volunteer normal hearing subjects were enrolled. Pure tone thresholds at 0.5, 1, 2 and 4 kHz were compared with the corresponding thresholds measured using Bio-logic MASTER II and the Eclipse ASSR systems. The threshold differences and correlation with pure tone were measured and reliability was evaluated with Cronbach's α. In part I of the study, all subjects were included, in part II of the study, only mild hearing loss and normal hearing subjects were included. In part I, NB CE-Chirp ASSR revealed a significantly smaller difference in threshold than conventional ASSR, a better correlation and better reliability. However, lower frequencies of NB CE-Chirp tended to be less reliable than higher frequencies. In part II, NB CE-Chirp revealed smaller threshold differences than conventional ASSR. Both correlation scores and reliability values were generally lower in the part II results. | Hepatocellular carcinoma and cholangiocarcinoma form the majority of primary hepatic tumours and are the third most common cause of cancer-related deaths. These liver tumours rapidly outgrow their vascular supply and become hypoxic, resulting in the production of hypoxia inducible factors and triggering the angiogenic switch. Therefore, inhibiting angiogenesis has proven to be a valuable therapeutic strategy in hepatocellular carcinoma, yet less is known about its use in cholangiocarcinoma. In this study, we assess whether inhibiting the placental growth factor (PlGF) could offer a therapeutic option in mice with hepatocellular carcinoma and cholangiocarcinoma. PlGF is a homologue of the vascular endothelial growth factor, which is only involved in pathological angiogenesis, therefore, its inhibition does not induce adverse effects. We have used a chemically induced transgenic mouse model in which both hepatocellular carcinoma and cholangiocarcinoma develop after 25 weeks and are treated with murine monoclonal antibodies targeting PlGF. This study has shown for the first time that inhibiting PlGF decreases the burden of cholangiocarcinoma, by affecting both angiogenesis and inflammation. |
Do late childhood interpersonal callousness and conduct problem trajectories interact to predict adult psychopathy? | Studies have demonstrated a robust association between interpersonal callousness (IC) and the development of severe and chronic conduct problems (CP) in youth. Although children exhibiting IC are also believed to be at particularly high risk for developing psychopathic personality features in adulthood, there is little longitudinal evidence supporting this assumption, particularly after controlling for co-occuring CP severity. This study used data collected on a longitudinal cohort of boys (n = 508), with an oversampling of youth exhibiting elevated conduct problems. Analyses examined the unique and interactive association between latent growth curve trajectories of IC and CP assessed bi-annually from late childhood to early adolescence (~ages 10-13) and features of psychopathy in early adulthood (age ~ 24) assessed using the Psychopathy Checklist - Short Version (PCL:SV; Hart, Cox, & Hare, 1995). Growth curve analysis indicated that initial levels of IC and CP in childhood (~age 10 intercept) both uniquely predicted the development of the interpersonal/affective features of adult psychopathy, and boys with a combination of high initial levels of IC and CP were at particularly high risk for developing the impulsive/antisocial features of the disorder. Boys who exhibited systematic increases in CP from late childhood to early adolescence also demonstrated higher adult psychopathy scores, but changes in IC across this developmental period did not significantly add to the prediction of adult psychopathy. | Tamoxifen is the standard endocrine therapy for ER+ breast cancer; however, many women still relapse after long-term therapy. 3-Bromopyruvate, a glycolytic inhibitor, has shown high selective anti-tumor activity in vitro, and in vivo. The aim of this study was to evaluate the possible augmentation of the effect of tamoxifen via reprograming cancer cell metabolism using 3-bromopyruvate. An in vitro screening of antitumor activity as well as the apoptotic, anti-metastatic, and anti-angiogenic potentials of the combination therapy were carried out using different techniques on breast cancer cell lines MCF7and T47D. In addition the antitumor effect of the combined therapy was done on mice bearing tumor. Our results showed modulation in apoptosis, angiogenesis and metastatic potential by either drug alone; however, their combination has surpassed that of the individual one. Combination regimen enhanced activated caspases-3, 7 and 9, as well as oxidative stress, signified by increased malondialdehyde and decreased glutathione level. Additionally, the angiogenesis and metastasis markers, including hypoxia inducing factor-1α, vascular endothelia growth factor, and metaloproteinases-2 and 9 were decreased after using the combination regimen. These results were further confirmed by the in vivo study, which depicted a decrease in the tumor volume and angiogenesis and an increase in oxidative stress as well. |
Do alcohol-preferring rats show decreased corticotropin-releasing hormone-2 receptor expression and differences in HPA activation compared to alcohol-nonpreferring rats? | Corticotropin-releasing hormone (CRH) and urocortins (UCNs) bind to corticotropin-releasing hormone type 2 receptor (CRF2 receptor ), a Gs protein-coupled receptor that plays an important role in modulation of anxiety and stress responses. The Crhr2 gene maps to a quantitative trait locus (QTL) for alcohol preference on chromosome 4 previously identified in inbred alcohol-preferring (iP) and-nonpreferring (iNP) F2 rats. Real-time polymerase chain reaction was utilized to screen for differences in Crhr2 mRNA expression in the central nervous system (CNS) of male iP and iNP rats. DNA sequence analysis was then performed to screen for polymorphism in Crhr2 in order to identify genetic variation, and luciferase reporter assays were then applied to test their functional significance. Next, binding assays were used to determine whether this polymorphism affected CRF2 receptor binding affinity as well as CRF2 receptor density in the CNS. Finally, social interaction and corticosterone levels were measured in the P and NP rats before and after 30-minute restraint stress. Crhr2 mRNA expression studies found lower levels of Crhr2 mRNA in iP rats compared to iNP rats. In addition, DNA sequencing identified polymorphisms in the promoter region, coding region, and 3'-untranslated region between the iP and iNP rats. A 7 bp insertion in the Crhr2 promoter of iP rats altered expression in vitro as measured by reporter assays, and we found that CRF2 receptor density was lower in the amygdala of iP as compared to iNP rats. Male P rats displayed decreased social interaction and significantly higher corticosterone levels directly following 30-minute restraint when compared to male NP rats. | The purpose of this study was to determine the prevalence of vitamin D deficiency in CTCL patients and whether supplementation corrects vitamin D deficiency or treatment outcome. Three hundred eleven CTCL patients including 27/311 (8.7%) with Sézary syndrome (SS), 169 cancer controls, and 69 normal controls from the M.D. Anderson clinics had 25(OH)D3 levels determined and categorized as deficient (< 20 ng/mL),insufficient (20-29 ng/mL), or sufficient (≥ 30 ng/mL). Clinical response was determined according to a change in percent body surface area involvement. Low 25(OH)D3 (< 30 ng/mL) levels were present in 76.9% of mycosis fungoides/SS patients, 75.2% of cancer controls, and 66.7% of healthy controls (P ¼ .05, .07) and in 30% to 39% of historical normal controls. Correction of deficiency was successful in 35% or 55 of 156 patients who were given dealer's choice of either vitamin D2 at 50,000 IU orally (p.o.) biweekly or D3 1000 IU p.o. daily. Correction of vitamin D levels was noted in 27 of 100 (27%) patients given D3 and 28 of 56 (50%) given D2. Responses to standard CTCL therapy was similar among patients with corrected and persistently low levels (P ¼ .51). |
Does minimizing tacrolimus decrease the risk of new-onset diabetes mellitus after liver transplantation? | To investigate the impact of minimum tacrolimus (TAC) on new-onset diabetes mellitus (NODM) after liver transplantation (LT). We retrospectively analyzed the data of 973 liver transplant recipients between March 1999 and September 2014 in West China Hospital Liver Transplantation Center. Following the exclusion of ineligible recipients, 528 recipients with a TAC-dominant regimen were included in our study. We calculated and determined the mean trough concentration of TAC (cTAC) in the year of diabetes diagnosis in NODM recipients or in the last year of the follow-up in non-NODM recipients. A cutoff of mean cTAC value for predicting NODM 6 mo after LT was identified using a receptor operating characteristic curve. TAC-related complications after LT was evaluated by χ(2) test, and the overall and allograft survival was evaluated using the Kaplan-Meier method. Risk factors for NODM after LT were examined by univariate and multivariate Cox regression. Of the 528 transplant recipients, 131 (24.8%) developed NODM after 6 mo after LT, and the cumulative incidence of NODM progressively increased. The mean cTAC of NODM group recipients was significantly higher than that of recipients in the non-NODM group (7.66 ± 3.41 ng/mL vs 4.47 ± 2.22 ng/mL, P < 0.05). Furthermore, NODM group recipients had lower 1-, 5-, 10-year overall survival rates (86.7%, 71.3%, and 61.1% vs 94.7%, 86.1%, and 83.7%, P < 0.05) and allograft survival rates (92.8%, 84.6%, and 75.7% vs 96.1%, 91%, and 86.1%, P < 0.05) than the others. The best cutoff of mean cTAC for predicting NODM was 5.89 ng/mL after 6 mo after LT. Multivariate analysis showed that old age at the time of LT (> 50 years), hypertension pre-LT, and high mean cTAC (≥ 5.89 ng/mL) after 6 mo after LT were independent risk factors for developing NODM. Concurrently, recipients with a low cTAC (< 5.89 ng/mL) were less likely to become obese (21.3% vs 30.2%, P < 0.05) or to develop dyslipidemia (27.5% vs 44.8%, P <0.05), chronic kidney dysfunction (14.6% vs 22.7%, P < 0.05), and moderate to severe infection (24.7% vs 33.1%, P < 0.05) after LT than recipients in the high mean cTAC group. However, the two groups showed no significant difference in the incidence of acute and chronic rejection, hypertension, cardiovascular events and new-onset malignancy. | 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. |
Does adenosine-activated myocardial ischemia induce delayed preconditioning? | Our objective was to determine whether adenosine-induced ischemia exerts a delayed cardiac protective effect in patients with stable effort angina ischemic heart disease. The study group was comprised of 32 patients (men) with symptoms of stable effort angina, aged 38-65 years (Group 1), and 18 clinically healthy subjects (3 women, 15 men), aged 35-55 years (Control group). The study protocol included baseline ECG and treadmill echocardiogram (ET1); ECG and adenosine echocardiogram performed 7 days after ET1; repeated exercise test exactly 24 h after adenosine infusion (ET2). Increases in heart rate (HR), systolic (SBP) and diastolic (DBP) blood pressure, maximum ST-segment depression (max IST) and total ST-segment depression (SIST) on ECG were compared, as well as left ventricular end-diastolic volume (LVEDV), end-systolic (LVESV) volume, ejection fraction (EF), and wall motion synergy index (WMSI). No statistically significant differences were found in the increased values of the investigated electrocardiographic and echocardiographic parameters in either group on either exercise test. The only positive trend was observed in LVEDV. In Group 1 LVEDV increased significantly from rest values during ET1, whereas during ET2 LVEDV did not change. | The fetal inflammatory response (FIR) in placental membranes to an intrauterine infection often precedes premature birth raising neonatal mortality and morbidity. However, the precise molecular events behind FIR still remain largely unknown, and little has been investigated at gene expression level. We collected publicly available microarray expression data profiling umbilical cord (UC) tissue derived from the cohort of extremely low gestational age newborns (ELGANs) and interrogate them for differentially expressed (DE) genes between FIR and non-FIR-affected ELGANs. We found a broad and complex FIR UC gene expression signature, changing up to 19% (3,896/20,155) of all human genes at 1% false discovery rate. Significant changes of a minimum 50% magnitude (1,097/3,896) affect the upregulation of many inflammatory pathways and molecules, such as cytokines, toll-like receptors, and calgranulins. Remarkably, they also include the downregulation of neurodevelopmental pathways and genes, such as Fragile-X mental retardation 1 (FMR1), contactin 1 (CNTN1), and adenomatous polyposis coli (APC). |
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