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Do platinum group elements enhance the allergic immune response by acting on dendritic cells? | Atmospheric pollution may play a role in the immune response to allergens either directly or by entering the food chain. While particulate platinum group elements (PLGE) emitted by catalytic converters can be considered biologically inert, approximately 10% of these species accumulate in the environment as bioavailable soluble forms. We challenged in vitro human immature and mature monocyte-derived dendritic cells with subtoxic concentrations of soluble species of PLGE. Dendritic cells were studied both at baseline and following treatment with Na(2)PtCl(6), Na(2)PdCl(6) or Na(3)RhCl(6). (NH(4))(6)Mo(7)O(24) was included as control. The following end-points were considered: expression of differentiation markers, effectiveness of allergen presentation and Th2 cytokine production by cocultured T lymphocytes, expression of IgE-type I receptor and efficiency of IgE-dependent endocytosis. We found that treatment with PLGE (but not with the control metal) increased costimulatory molecule expression and antigen presentation, amplified IL-5 production by cocultured T lymphocytes, upregulated IgE-type I receptor membrane expression, and augmented IgE-type I receptor-mediated endocytosis. | To examine the relationship between statin use in Chinese patients with intracerebral hemorrhage (ICH) during their hospitalization and the outcomes. Data were collected from the China National Stroke Registry. Good functional outcome was defined by a modified Rankin Scale score between 0-2. Functional outcome and rate of mortality at 3 months and 1 year were compared between ICH patients on statin and those without it during their hospitalization. Odds ratios (ORs) with 95% confidence intervals (CI) were calculated using the multivariable logistic regression model adjusted for baseline risk factors. Among 3218 consecutive ICH patients from 2007 to 2008, 220 (6.8%) were on statin during their hospitalization. Compared with those without statin, patients on statin were younger, had more stroke risk factors but lower stroke severity. ICH patients on statin had better functional outcome at 3 months (OR 2.24, 95% CI 1.49-3.36) and at 1 year (OR 2.04, 95% CI 1.37-3.06). They also had lower rate of mortality at 3 months (OR 0.44, 95% CI 0.22-0.87) and 1 year (OR 0.49, 95% CI 0.27-0.86). |
Does identification of structural alert for liver and kidney toxicity using repeated dose toxicity data? | The potential for a compound to cause hepatotoxicity and nephrotoxicity is a matter of extreme interest for human health risk assessment. To assess liver and kidney toxicity, repeated-dose toxicity (RDT) studies are conducted mainly on rodents. However, these tests are expensive, time-consuming and require large numbers of animals. For early toxicity screening, in silico models can be applied, reducing the costs, time and animals used. Among in silico approaches, structure-activity relationship (SAR) methods, based on the identification of chemical substructures (structural alerts, SAs) related to a particular activity (toxicity), are widely employed. We identified and evaluated some SAs related to liver and kidney toxicity, using RDT data on rats taken from the hazard evaluation support system (HESS) database. We considered only SAs that gave the best percentages of true positives (TP). | Facial nerve regeneration is limited in some clinical situations: in long grafts, by aged patients, and when the delay between nerve lesion and repair is prolonged. This deficient regeneration is due to the limited number of regenerating nerve fibers, their immaturity and the unresponsiveness of Schwann cells after a long period of denervation. This study proposes to apply glial cell line-derived neurotrophic factor (GDNF) on facial nerve grafts via nerve guidance channels to improve the regeneration. Two situations were evaluated: immediate and delayed grafts (repair 7 months after the lesion). Each group contained three subgroups: a) graft without channel, b) graft with a channel without neurotrophic factor; and c) graft with a GDNF-releasing channel. A functional analysis was performed with clinical observation of facial nerve function, and nerve conduction study at 6 weeks. Histological analysis was performed with the count of number of myelinated fibers within the graft, and distally to the graft. Central evaluation was assessed with Fluoro-Ruby retrograde labeling and Nissl staining. This study showed that GDNF allowed an increase in the number and the maturation of nerve fibers, as well as the number of retrogradely labeled neurons in delayed anastomoses. On the contrary, after immediate repair, the regenerated nerves in the presence of GDNF showed inferior results compared to the other groups. |
Are the growth and tumor suppressors NORE1A and RASSF1A targets for calpain-mediated proteolysis? | NORE1A and RASSF1A are growth and tumour suppressors inactivated in a variety of cancers. Methylation of NORE1A and RASSF1A promoters is the predominant mechanism for downregulation of these proteins; however, other mechanisms are likely to exist. Here we describe a proteolysis of NORE1A and RASSF1A by calpains as alternative mechanism of their downregulation. Extracts of H358 cell line, a human bronchoalveolar carcinoma, and H460, a large cell carcinoma, were capable of proteolysis of NORE1A protein in the calpain-dependent manner. Likewise, RASSF1A tumor suppressor was proteolyzed by the H358 cell extract. Addition of calpain inhibitor to H358 and H460 cells growing in tissue culture resulted in re-expression of endogenous NORE1A. A survey of 10 human lung tumours revealed that three of them contain an activity capable of inducing NORE1A degradation. | To investigate the protective effects of magnolol on sepsis-induced inflammation and intestinal dysmotility. Sepsis was induced by a single intraperitoneal injection of lipopolysaccharide (LPS). Male Wistar rats were randomly assigned to one of three treatment groups: magnolol prior to LPS injection (LPS/Mag group); vehicle prior to LPS injection (LPS/Veh group); vehicle prior to injection of saline (Control/Veh). Intestinal transit and circular muscle mechanical activity were assessed 12 h after LPS injection. Tumor necrosis factor-alpha (TNF-alpha), interleukin-10 (IL-10), monocyte chemoattractant protein-1 (MCP-1) and inducible nitric oxide synthase (iNOS) mRNA in rat ileum were studied by RT-PCR 2 h after LPS injection. Nuclear factor-kappaB (NF-kappaB) activity in the intestine was also investigated at this time using electrophoretic mobility shift assay. In addition, antioxidant activity was determined by measuring malondialdehyde (MDA) concentration and superoxide dismutase (SOD) activity in the intestine 2 h after LPS injection. Magnolol significantly increased intestinal transit and circular muscle mechanical activity in LPS-treated animals. TNF-alpha, MCP-1 and iNOS mRNA expression in the small intestine were significantly reduced after magnolol treatment in LPS-induced septic animals, compared with untreated septic animals. Additionally, magnolol significantly increased IL-10 mRNA expression in septic rat ileum. Magnolol also significantly suppressed NF-kappaB activity in septic rat intestine. In addition, magnolol significantly decreased MDA concentration and increased SOD activity in rat ileum. |
Do brainstem infarcts predict REM sleep behavior disorder in acute ischemic stroke? | Rapid eye movement (REM) sleep behavior disorder (RBD) is a sleep disturbance in which patients enact their dreams while in REM sleep. The behavior is typically violent in association with violent dream content, so serious harm can be done to the patient or the bed partner. The prevalence of RBD is well-known in Parkinson's disease, Lewy body dementia, and multiple systems atrophy. However, its prevalence and causes in stroke remained unclear. The aim of this study was to determine factors influencing the appearance of RBD in a prospective cohort of patients with acute ischemic stroke. A total of 2,024 patients with first-ever or recurrent acute ischemic stroke were admitted to the Acute Stroke Unit at the Prince of Wales Hospital between January 2010 and November 2011; 775 of them received an MRI scan. Within 2 days of admission, a research nurse collected demographic and clinical data and assessed the severity of each stroke using the National Institute of Health Stroke Scale (NIHSS). One hundred and nineteen of the 775 patients meeting study entry criteria formed the study sample. All eligible participants were invited to attend a research clinic 3 months after the onset of the index stroke. In the attendance, a research assistant administered the MMSE and the 13-item RBD questionnaire (RBDQ). Among 119 stroke patients, 10.9% were exhibited RBD, defined as an REM sleep behavior disorder questionnaire score of 19 or above. The proportion of patients with acute brainstem infarct was significantly higher in RBD patients than those without RBD. Compared with patients without RBD, RBD patients were more likely to have brainstem infarcts and had smaller infarct volumes. In a multivariate analysis, in which stroke location and infarct volume were inserted, brainstem infarcts were an independent predictor of RBD (odds ratio = 3.686; P = 0.032). | The significance of bile duct injury and ductular reaction in biopsies from autoimmune hepatitis patients is not clear. We aim to establish the prevalence and clinical relevance of both phenomena in autoimmune hepatitis. Cases of newly diagnosed, untreated autoimmune hepatitis without overlap syndrome were selected. Pretreatment and follow up biopsies were scored for inflammation, fibrosis, bile ductal injury and ductular reaction. Thirty-five cases were studied of whom 14 cases had follow up biopsies. Bile duct injury was present in 29 cases (83%), mostly in a PBC-like pattern and was not correlated with demographical or laboratory findings. Ductular reaction, observed in 25 of 35 cases (71%) using conventional histology and in 30 of 32 cases (94%) using immunohistochemistry, was correlated with portal and lobular inflammation, interface hepatitis and centrilobular necrosis as well as bile duct injury and fibrosis. In 11 of 14 cases (79%) ductular reaction remained present on post-treatment biopsy whereas bile duct injury persisted in six of 14 (43%) of cases. |
Do glaucoma and associated visual acuity and field loss significantly affect glaucoma-specific psychosocial functioning? | To examine the impact of glaucoma and visual acuity (VA) and visual field (VF) losses on psychosocial functioning (PF). Cross-sectional study. We compared PF between 192 participants with bilateral glaucoma with VA or VF losses and 40 controls from a tertiary eye hospital clinic in Singapore. Glaucoma was defined using the Hodapp-Anderson-Parish criteria. Four psychosocial outcomes of the Glaucoma Quality of Life 36 questionnaire were psychometrically assessed using Rasch analysis. Multivariate regression was performed to determine the independent impact of glaucoma and VA and VF losses on PF. The impact of VA and VF on PF were evaluated by restricted cubic spline analysis. Anxiety, self-image, psychological well-being, and confidence in health care. The mean age of participants was 66.2±11.0 years, and 63% were male. In the better eye, VA and mean deviation were Snellen 20/25 and -8.89±6.52 dB, respectively. In multivariate models, glaucoma patients had 63.0% greater anxiety (95% confidence interval [CI], -66.0% to -61.2%; P<0.001), 71.0% lower self-image (95% CI, -74.1% to -68.5%; P<0.001), 38.3% less psychological well-being (95% CI, -37.4% to -39.0%; P<0.001), and 32.4% reduced confidence in health care than patients without glaucoma. The worst VA and VF categories had the most reduced PF (range, 26.0% to 81.5%; P<0.001 for all associations) compared with controls. With worsening VA, there was a linear increase in anxiety (P=0.009) and decrease in self-image (P=0.005). With worsening VF from 0 to -12.1 dB (P=0.003), anxiety increased before plateauing. Self-image decreased as VF worsened from 0 to -10 dB (P<0.001), and confidence in health care decreased when VF worsened from 0 to -9.3 dB (P=0.008). However, self-image and confidence in health care actually improved at greater levels of VF loss beyond these thresholds. | MRI of tissues with rapid transverse relaxation can be performed efficiently using the zero echo time (ZTE) technique. At high bandwidths leading to large relative initial radiofrequency (RF) dead times, the method becomes increasingly sensitive to artifacts related to signal stemming from outside the field of view, particularly from the RF coils. Therefore, in this work, a birdcage coil was designed that is virtually free of 1H signal. A transmit-receive birdcage RF coil for MRI of joints at 7T was designed by rigorously avoiding materials containing 1H nuclei, by using purely mechanical connections without glue, and by spoiling of unwanted signal by application of ferromagnetic materials. The coil was tested for residual 1H signal using ZTE phantom and in vivo joint imaging. In standard ZTE imaging, no 1H signal was detected above noise level. Only at extreme averaging, residual signal was observed close to conductors associated with 1H-containing molecules at adjacent glass surfaces. Phantom images with dead times up to 3.8 Nyquist dwells were obtained with only negligible background artifacts. Furthermore, high-quality ZTE images of human joints were acquired. |
Does glasgow Aneurysm Score predict survival after endovascular stenting of abdominal aortic aneurysm in patients from the EUROSTAR registry? | The aim of the present study was to evaluate the efficacy of the Glasgow Aneurysm Score (GAS) in predicting the survival of 5498 patients who underwent endovascular repair (EVAR) of an abdominal aortic aneurysm (AAA) and were enrolled in the EUROpean collaborators on Stent-graft Techniques for abdominal aortic Aneurysm Repair (EUROSTAR) Registry between October 1996 and March 2005. The GAS was calculated in patients who underwent EVAR and was correlated to outcome measurements. The median GAS was 78.8 (interquartile range 71.9-86.4, mean 79.2). Tertile 30-day mortality rates were 1.1 per cent for patients with a GAS less than 74.4, 2.1 per cent for those with a score between 74.4 and 83.6, and 5.3 per cent for patients with a score over 83.6 (P < 0.001). Multivariate analysis showed that GAS was an independent predictor of postoperative death (P < 0.001). The receiver-operator characteristic curve showed that the GAS had an area under the curve of 0.70 (95 per cent confidence interval 0.66 to 0.74; s.e. 0.02; P < 0.001) for predicting immediate postoperative death. At its best cut-off value of 86.6, it had a sensitivity of 56.1 per cent, specificity 76.2 per cent and accuracy 75.6 per cent. Multivariable analysis showed that overall survival was significantly different among the tertiles of the GAS (P < 0.001). | Vitamin D receptor (VDR)-knockout mice develop severe hypocalcemia and rickets, accompanied by disruption of active intestinal calcium absorption. To specifically study the effects of VDR in intestinal calcium absorption, we investigated whether restoration of intestinal VDR is sufficient to recover the phenotype of VDR-knockout mice. We generated mice with intestine-specific transgenic expression of human VDR and crossed them to VDR knockout mice. The intestine, kidney, and bone phenotypes of the VDR- knockout mice with intestine-specific expression of human VDR (knockout/transgenic [KO/TG]) were analyzed. Transgenic expression of VDR in the intestine of VDR-knockout mice normalized duodenal vitamin D-regulated calcium absorption as well as vitamin D-regulated calcium binding protein D9k and TRPV6 gene expression in the duodenum and proximal colon. As a result, animal growth and the serum levels of calcium and parathyroid hormone were normalized in KO/TG mice. Other phenotypes were revealed when calcium metabolism was normalized in KO/TG mice: serum 1,25 dihydroxyvitamin D levels were higher in KO/TG mice than normal mice owing to reduced renal expression of the vitamin D-degrading enzyme CYP24, urinary calcium excretion was higher and associated with lower renal calcium binding protein D9k and calcium binding protein D28k than normal mice, and bone density and volume increased in KO/TG compared with normal mice owing to increased mineral apposition rate and osteoblast number. |
Are cardiac repolarization and striatal dopamine transporter function interrelated? | In Parkinson's disease, striatal dopamine transporter (DAT) binding and cardiac sympathetic function are disturbed. In addition, heart rate (HR)-corrected cardiac repolarisation time (QTc interval), which is partly under autonomic control, is prolonged. Whether there is physiological coupling between striatal DAT binding and QTc time (QTc-DAT relation) is not known. The purpose of this study is to evaluate QTc-DAT relation in healthy young adults. Thirty-five participants (18 women, age 26.4+/-1.8 years; mean+/-SD) were studied with iodine-123 labelled 2beta-carbomethoxy-3beta-(4-iodophenyl) nortropane single photon emission tomography. Signal-averaged ECG was recorded at rest from each participant. QTc interval was computed with Bazett's correction and with the approach by Karjalainen, getting QTc and QTk intervals, respectively. Mean striatal DAT binding, as (striatum-cerebellum)/cerebellum, was 2.63+/-0.31. Mean HR, QT, QTc and QTk intervals were 66+/-9 bpm, 340+/-25 ms, 354+/-18 ms and 351+/-16 ms, respectively. HR-QT correlation was -0.63, P value of less than 0.001. HR was not related to striatal DAT binding. QTc-DAT and QTk-DAT relations were significant, r = -0.50, P = 0.004 and r = -0.59, P = 0.0002, respectively. In linear regression model, striatal DAT binding explained 35% of the variance of QTk interval (95% confidence interval: -46.9 to -13.0, P = 0.0002). | A severe and challenging complication in the treatment of hemophilia A is the development of inhibiting antibodies (inhibitors) directed towards factor VIII (FVIII). Inhibitors aggravate bleeding complications, disabilities and costs. The etiology of inhibitor development is incompletely understood. In a large cohort study in patients with mild/moderate hemophilia A we evaluated the role of genotype and intensive FVIII exposure in inhibitor development. Longitudinal clinical data from 138 mild/moderate hemophilia A patients were retrospectively collected from 1 January 1980 to 1 January 2008 and analyzed by multivariate analysis using Poisson regression. Genotyping demonstrated the Arg593Cys missense mutation in 52 (38%) patients; the remaining 86 patients had 26 other missense mutations. Sixty-three (46%) patients received intensive FVIII concentrate administration, 41 of them for surgery. Ten patients (7%) developed inhibitors, eight of them carrying the Arg593Cys mutation. Compared with the other patients, those with the Arg593Cys mutation had a 10-fold increased risk of developing inhibitors (RR 10; 95% CI, 0.9-119).The other two inhibitor patients had the newly detected mutations Pro1761Gln and Glu2228Asp. In both these patients and in five patients with genotype Arg593Cys, inhibitors developed after intensive peri-operative use of FVIII concentrate (RR 186; 95% CI, 25-1403). In five of the 10 inhibitor patients FVIII was administered by continuous infusion during surgery (RR 13; 95% CI, 1.9-86). |
Does bile acid binding resin improve hepatic insulin sensitivity by reducing cholesterol but not triglyceride levels in the liver? | Bile acid binding resin (BAR) improves glycaemic control in patients with type 2 diabetes. Although the mechanism is hypothesised to involve the clearance of excess hepatic triglyceride, this hypothesis has not been examined in appropriately designed studies. Therefore, we investigated whether reduced hepatic triglyceride deposition is involved in BAR-mediated improvements in glycaemic control in spontaneous fatty liver diabetic mice without dietary interventions. Male 6-week-old fatty liver Shionogi (FLS) mice were fed a standard diet without or with 1.5% BAR (colestilan) for 6 weeks. Glucose tolerance, insulin sensitivity, hepatic lipid content, and gene expression were assessed. A liver X receptor (LXR) agonist was also administered to activate the LXR pathway. We also retrospectively analysed the medical records of 21 outpatients with type 2 diabetes who were treated with colestilan for ≥6 months. BAR enhanced glucose tolerance and insulin sensitivity in FLS mice without altering fat mass. BAR improved hepatic insulin sensitivity, increased IRS2 expression, and decreased SREBP expression. BAR reduced hepatic cholesterol levels but not hepatic triglyceride levels. BAR also reduced the expression of LXR target genes, and LXR activation abolished the BAR-mediated improvements in glycaemic control. Colestilan significantly lowered serum cholesterol levels and improved glycaemic control in patients with type 2 diabetes. | We explored the clinical usefulness of serum carbonic anhydrase 9 as a potential biomarker for conventional renal cell cancer. This study included 91 patients with conventional renal cell cancer and 32 healthy individuals. Enzyme linked immunosorbent assay was used to measure the carbonic anhydrase 9 level. A followup (median 38 months) was performed to track early recurrence after surgery for patients with localized disease. Recurrence-free survival curves were calculated by the Kaplan-Meier method and compared using the log rank test. The mean serum carbonic anhydrase 9 level in patients with metastatic conventional renal cell cancer (216.68 +/- 67.02 pg/ml) or localized conventional renal cell cancer (91.65 +/- 13.29 pg/ml) was significantly higher than in healthy individuals (14.59 +/- 6.22 pg/ml, p <0.001 and p = 0.001, respectively). The mean serum carbonic anhydrase 9 level in patients with metastatic conventional renal cell cancer was significantly higher than in those with localized disease (p = 0.004). Of patients with localized disease those with recurrence had a significantly higher serum carbonic anhydrase 9 than those without recurrence (p = 0.001). On univariate analysis serum carbonic anhydrase 9, tumor stage, tumor grade and tumor size were associated with recurrence. The recurrence-free survival curve indicates that patients with a high serum carbonic anhydrase 9 level had a significantly higher recurrence rate than those with a low serum carbonic anhydrase 9 (p = 0.001). |
Does light Physical Activity be Associated with Quality of Life after Colorectal Cancer? | Emerging evidence suggests that light physical activity (LPA), besides moderate-to-vigorous physical activity (MVPA), may beneficially influence physical functioning of colorectal cancer survivors, but its relation with other health-related outcomes is unknown. We applied a biopsychosocial approach to investigate independent associations between self-reported LPA, MVPA, and multiple health-related quality of life (HRQoL) outcomes in 2- to 10-yr postdiagnosis colorectal cancer survivors. Stage I-III colorectal cancer survivors diagnosed between 2002 and 2010 at Maastricht University Medical Center+, the Netherlands, were included in a cross-sectional study (n = 151). Time spent in LPA and MVPA (h·wk⁻¹), and HRQoL outcome scores (0-100 points) were assessed by validated questionnaires. Median time spent in LPA and MVPA was 10.0 (interquartile range, 2.0-22.0) and 8.7 h·wk⁻¹ (4.5-15.0), respectively. In multivariable linear regression models, both LPA and MVPA were significantly and independently associated with higher physical functioning (mean difference [MD] between highest and lowest quartile, 10.2; 95% confidence interval [CI], 0.2-20.3; and 14.5; 5.1-23.9, respectively; both P-trend < 0.05). In addition, LPA was significantly associated with higher role functioning (MD, 19.5; 95% CI, 6.9-32.1; P-trend < 0.01) and lower disability (MD, -9.9; 95% CI, -17.8 to -1.9; P-trend = 0.02), independent from MVPA. Subgroup analyses showed that beneficial associations between LPA and HRQoL were mainly observed in women and participants with multiple comorbidities. | During myocardial ischemia, the increase in cytosolic Ca2+ promotes the activation of neutral proteases such as calpains. Since the troponin T subunit is a substrate for calpains, we investigated the effects of irreversible myocyte damage on troponin T immunoreactivity. Hearts from adult guinea pigs (n=32) were perfused under conditions of normoxia, ischemia, postischemic reperfusion, or Ca2+ paradox. Hearts were frozen and processed for immunohistochemistry and Western blot with three anti-troponin T monoclonal antibodies. Two of these antibodies are unreactive on cryosections of freshly isolated and normoxic hearts and of hearts exposed to 30 minutes of no-flow ischemia. In contrast, reactivity is detected in rare myocytes after 60 minutes of ischemia, in a large population of myocytes after 60 minutes of ischemia followed by 30 minutes of reperfusion, and in every myocyte exposed to Ca2+ paradox. In Western blots, samples from ischemia-reperfusion and Ca2+ overloaded hearts show reactive polypeptides of about 240 to 260 kD and 65 to 66 kD in addition to troponin T. A similar pattern of immunoreactivity is observed with an anti-troponin I antibody. Histochemical troponin T immunoreactivity and reactivity on high-molecular-weight polypeptides are detectable in normal heart samples after preincubation with 10 mmol/L Ca2+ or with transglutaminase, whereas they are not if either transglutaminase or calpain is inhibited. |
Does neutrophil gelatinase-associated lipocalin ( NGAL ) reflect iron status in haemodialysis patients? | An iron deficiency is often present in haemodialysis (HD) patients; however, although transferrin saturation (TSAT) of <20% and/or serum ferritin of <200 ng/mL should express iron scarcity, in HD patients high ferritin levels could be related to inflammation rather than reflecting optimal iron stores. The aim of the present study was to evaluate serum levels of neutrophil gelatinase-associated lipocalin (NGAL), a small siderophore-binding protein, in a cohort of 56 chronic HD patients in order to determine its possible relationships with iron status. NGAL levels were markedly higher in HD patients than in healthy controls; furthermore, HD patients with TSAT <20% had lower NGAL values than healthy controls, whereas the correction of iron deficiency by means of chronic i.v. iron administration significantly increased NGAL values from baseline. Findings from univariate and multivariate analyses demonstrated that NGAL was a significant predictor of hsCRP, spKT/V and TSAT. In ROC analysis, a NGAL cut-off level of <or=473 ng/mL had a greater sensitivity and specificity than a ferritin level of <200 ng/mL in identifying iron deficiency among HD patients. | Previous work has implicated noradrenergic beta-receptors in the consolidation and reconsolidation of conditioned fear. Less is known, however, about their role in fear expression and extinction. The beta-receptor blocker propranolol has been used clinically to reduce anxiety. With an auditory fear conditioning task in rats, we assessed the effects of systemic propranolol on the expression and extinction of two measures of conditioned fear: freezing and suppression of bar-pressing. One day after receiving auditory fear conditioning, rats were injected with saline, propranolol, or peripheral beta-receptor blocker sotalol (both 10 mg/kg, IP). Twenty minutes after injection, rats were given either 6 or 12 extinction trials and were tested for extinction retention the following day. The effect of propranolol on the firing rate of neurons in prelimbic (PL) prefrontal cortex was also assessed. Propranolol reduced freezing by more than 50%, an effect that was evident from the first extinction trial. Suppression was also significantly reduced. Despite this, propranolol had no effect on the acquisition or retention of extinction. Unlike propranolol, sotalol did not affect fear expression, although both drugs significantly reduced heart rate. This suggests that propranolol acts centrally to reduce fear. Consistent with this, propranolol reduced the firing rate of PL neurons. |
Does homocysteine-lowering treatment with folic acid , cobalamin , and pyridoxine reduce blood markers of inflammation , endothelial dysfunction , or hypercoagulability in patients with previous transient ischemic attack or stroke : a randomized substudy of the VITATOPS trial? | Epidemiological and laboratory studies suggest that increasing concentrations of plasma homocysteine (total homocysteine [tHcy]) accelerate cardiovascular disease by promoting vascular inflammation, endothelial dysfunction, and hypercoagulability. We conducted a randomized controlled trial in 285 patients with recent transient ischemic attack or stroke to examine the effect of lowering tHcy with folic acid 2 mg, vitamin B12 0.5 mg, and vitamin B6 25 mg compared with placebo on laboratory markers of vascular inflammation, endothelial dysfunction, and hypercoagulability. At 6 months after randomization, there was no significant difference in blood concentrations of markers of vascular inflammation (high-sensitivity C-reactive protein [P=0.32]; soluble CD40L [P=0.33]; IL-6 [P=0.77]), endothelial dysfunction (vascular cell adhesion molecule-1 [P=0.27]; intercellular adhesion molecule-1 [P=0.08]; von Willebrand factor [P=0.92]), and hypercoagulability (P-selectin [P=0.33]; prothrombin fragment 1 and 2 [P=0.81]; D-dimer [P=0.88]) among patients assigned vitamin therapy compared with placebo despite a 3.7-micromol/L (95% CI, 2.7 to 4.7) reduction in total homocysteine (tHcy). | Preoperative chemoradiotherapy (CRT) followed by esophagectomy is becoming one of the standard treatment strategies for esophageal cancer. Pathologic complete response (pCR) after CRT is the best predictor of survival in squamous cell carcinoma (SCC) of the esophagus. Although no adjuvant treatment is recommended for individuals who achieve pCR, approximately 30% of these patients develop recurrence. Herein we sought to retrospectively investigate the independent predictors of tumor recurrence in this patient group. Between 1995 and 2004, we investigated seventy patients (69 males and 1 female; mean age: 56.1 years) with esophageal SCC who achieved pCR following preoperative chemoradiotherapy. Study end points included tumor recurrence, disease-specific survival (DSS), and disease-free survival (DFS). Univariate and multivariate analyses were used to identify risk factors for the study end points. Mean follow-up time for patients who survived was 65.8 months. At the time of analysis, 18 patients (25.7%) died of the disease and 22 patients (31.4%) developed recurrence. Multivariate analysis showed that pretherapy T3-4 disease was the most important adverse factor for tumor recurrence (P = 0.007), DFS (P = 0.005), and DSS (P = 0.026). The 5-year DFS was 45% for patients with clinical T3-4 disease and 85% for those with clinical T1-2 disease (P = 0.02). |
Does plasmalogen modulation attenuate atherosclerosis in ApoE- and ApoE/GPx1-deficient mice? | We previously reported a negative association of circulating plasmalogens (phospholipids with proposed atheroprotective properties) with coronary artery disease. Plasmalogen modulation was previously demonstrated in animals but its effect on atherosclerosis was unknown. We assessed the effect of plasmalogen enrichment on atherosclerosis of murine models with differing levels of oxidative stress. Six-week old ApoE- and ApoE/glutathione peroxidase-1 (GPx1)-deficient mice were fed a high-fat diet with/without 2% batyl alcohol (precursor to plasmalogen synthesis) for 12 weeks. Mass spectrometry analysis of lipids showed that batyl alcohol supplementation to ApoE- and ApoE/GPx1-deficient mice increased the total plasmalogen levels in both plasma and heart. Oxidation of plasmalogen in the treated mice was evident from increased level of plasmalogen oxidative by-product, sn-2 lysophospholipids. Atherosclerotic plaque in the aorta was reduced by 70% (P = 5.69E-07) and 69% (P = 2.00E-04) in treated ApoE- and ApoE/GPx1-deficient mice, respectively. A 40% reduction in plaque (P = 7.74E-03) was also seen in the aortic sinus of only the treated ApoE/GPx1-deficient mice. Only the treated ApoE/GPx1-deficient mice showed a decrease in VCAM-1 staining (-28%, P = 2.43E-02) in the aortic sinus and nitrotyrosine staining (-78%, P = 5.11E-06) in the aorta. | The study assessed deformation of implant components submitted to torsion tests of 80 and 120 N · cm using an optical stereomicroscope. The following 3 types of Titaniumfix conical implant connections (n = 5) measuring Ø 4.0 × 11.5 mm were used: external, internal hexagon and Morse taper connections. The diagonal and lateral measurements of the hexagon implant platform were measured before and after the torsion test. The torsion test using torque of 80 and 120 N · cm altered the implant dental platforms. All groups presented deformation of implant component after torque of 80 N · cm with no statistical difference among them. During torque of 120 N · cm, a difference in the Morse taper connection in relation to the internal and external hexagon connection was observed. The Morse taper connection implant, followed by the internal hex implant, underwent less deformation. Greater deformation occurred in the external hex implants. |
Does repeated maternal intramuscular or intraamniotic erythromycin incompletely resolve intrauterine Ureaplasma parvum infection in a sheep model of pregnancy? | Ureaplasma spp are the most commonly isolated microorganisms in association with preterm birth. Maternal erythromycin administration is a standard treatment for preterm prelabor rupture of membranes. There is little evidence of its effectiveness in eradicating Ureaplasma spp from the intrauterine cavity and fetus. We used a sheep model of intrauterine Ureaplasma spp infection to investigate the efficacy of repeated maternal intramuscular and intraamniotic erythromycin treatment to eradicate such an infection. Thirty ewes with singleton pregnancies received an intraamniotic injection of 10(7) color change units of erythromycin-sensitive Ureaplasma parvum serovar 3 at 55 days' gestation. At 116 days' gestation, 28 ewes with viable fetuses were randomized to receive (1) intraamniotic and maternal intramuscular saline solution treatment (n = 8), (2) single intraamniotic and repeated maternal intramuscular erythromycin treatment (n = 10), or (3) single maternal intramuscular and repeated intraamniotic erythromycin treatment (n = 10). Fetuses were surgically delivered at 125 days' gestation. Treatment efficacy was assessed by culture, quantitative polymerase chain reaction, and histopathologic evaluation. Animals treated with intraamniotic erythromycin had significantly less viable U parvum serovar 3 in the amniotic fluid at delivery. However, neither combination of maternal intramuscular and intraamniotic erythromycin treatment successfully cleared U parvum serovar 3 from the amniotic fluid or fetal tissues. Three de novo erythromycin-resistant U parvum isolates were identified in erythromycin-treated animals. | Adverse lifestyle factors have been associated with increased mortality, but data are lacking on their combined effect in developing populations, which we address in the present study. In a death registry-based, case-control study among Hong Kong Chinese aged 30+y, proxy-reported lifestyle factors 10 y ago were collected for 21,363 cases (81% of all deaths) and 12,048 living controls. Risks associated with poor diet, inactivity, heavy alcohol intake, and smoking for all-cause and cause-specific mortality, adjusting for potential confounders, were determined, and excess deaths for the Chinese population were calculated. Adjusted odds ratios for all-cause mortality were 1.15 (95% CI 1.09, 1.23), 1.34 (1.27, 1.43), 1.36 (1.21, 1.52), and 1.58 (1.46, 1.70) for poor diet, inactivity, heavy alcohol intake and smoking, respectively. Increasing numbers of adverse lifestyle factors were associated with a dose-dependent increase in adjusted odds ratios of 1.30 (1.20, 1.40), 1.67 (1.54, 1.81), 2.32 (2.08, 2.60), and 3.85 (3.12, 4.75) for 1, 2, 3, and 4 risk factors relative to those with none. The population attributable fraction for all-cause, all-CVD and all-cancer mortality were 26.6%, 15.0%, and 32.1%, resulting in an excess of 2,017,541; 489,884; and 607,517 deaths annually, respectively. Although smoking was associated with the greatest excess loss of life (867,530), heavy drinking (680,466), and physical inactivity (678,317) were similarly important. |
Is p2X1-regulated IL-22 secretion by innate lymphoid cells required for efficient liver regeneration? | Paracrine signalling mediated by cytokine secretion is essential for liver regeneration after hepatic resection, yet the mechanisms of cellular crosstalk between immune and parenchymal cells are still elusive. Interleukin-22 (IL-22) is released by immune cells and mediates strong hepatoprotective functions. However, it remains unclear whether IL-22 is critical for the crosstalk between liver lymphocytes and parenchymal cells during liver regeneration after partial hepatectomy (PH). Here, we found that plasma levels of IL-22 and its upstream cytokine, IL-23, are highly elevated in patients after major liver resection. In a mouse model of PH, deletion of IL-22 was associated with significantly delayed hepatocellular proliferation and an increase of hepatocellular injury and endoplasmic reticulum stress. Using Rag1(-/-) and Rag2(-/-) γc(-/) (-) mice, we show that the main producers of IL-22 post-PH are conventional natural killer cells and innate lymphoid cells type 1. Extracellular adenosine triphosphate (ATP), a potent danger molecule, is elevated in patients immediately after major liver resection. Antagonism of the P2-type nucleotide receptors, P2X1 and P2Y6, significantly decreased IL-22 secretion ex vivo. In vivo, specific inhibition of P2X1 was associated with decreased IL-22 secretion, elevated liver injury, and impaired liver regeneration. | Loss-of-function mutations in the SCN5A gene encoding the cardiac sodium channel are responsible for Brugada syndrome (BS) and also for progressive cardiac conduction disease (inherited Lenègre disease). In an attempt to clarify the frontier between these two entities, we have characterized cardiac conduction defect and its evolution with aging in a cohort of 78 patients carrying a SCN5A mutation linked to Brugada syndrome. Families were included in the study if a SCN5A mutation was identified in a BS proband and if at least two family members were mutation carriers. Sixteen families met the study criteria, representing 78 carriers. Resting ECG showed a spontaneous BS ECG pattern in 28 of 78 (36%) gene carriers. Intraventricular conduction anomalies were identified in 59 of 78 gene carriers including complete (17) or incomplete (24) right bundle branch block, right bundle branch block plus hemiblock (6), left bundle branch block (1), hemiblock (1), and parietal block (10). PR and QRS duration were longer in the gene carrier cohort in comparison with their relatives carrying no mutation. Finally, in the gene carrier cohort conduction defect progressively aggravated with aging leading in five occasions to pacemaker implantations. |
Is differential regulation of aortic growth in male and female rodents associated with AAA development? | The objective was to examine effects of gonadal hormone manipulation on aortic diameter and macrophage infiltration in rodents during abdominal aortic aneurysm (AAA) formation. Experiment 1: 17-beta estradiol and testosterone pellets were implanted in male (ME) and female (FT) rats. No pellet was implanted in shams (MES, FTS). Experiment 2: Testes and ovaries were removed from males (MO) and females (FO), respectively. No organs were removed from shams (MOS, FOS). Experiment 3: Male and female rats were orchiectomized and oophorectomized, respectively. Four weeks post-castration, testosterone (MOT) and 17-beta estradiol (FOE) pellets were implanted. Shams underwent castration, but no pellet was implanted (MOTS, FOES). All rats underwent infrarenal aortic infusion with elastase postimplantation/postcastration. Diameters were measured on postoperative d 14. Tissue was stained for macrophages by immunohistochemistry. Diameter (P = 0.046) and macrophage counts (P = 0.014) decreased in ME compared with shams, but not in females treated with testosterone (FT). Diameter (P = 0.019) and macrophage infiltration (P = 0.024) decreased in MO compared with shams, but not in FO. Diameter increased in MOT compared with MOTS (P = 0.033), but decreased in FOE compared with FOES (P = 0.002). Macrophages decreased in FOE compared with FOES (P = 0.002). | Cisplatin (CDDP) is one of the major chemotherapeutic drugs, but tumor cells' acquired resistance to CDDP limits its therapeutic potentials. One of the main reasons of resistance is reduced drug accumulation. The mechanism by which tumor cells accumulate reduced CDDP is not well elucidated yet. The aim of this study was to investigate what regulates intracellular CDDP accumulation. Six different types of oral squamous carcinoma cells were used in this study. Assessment of CDDP sensitivity was determined by measuring the ATP level of the cells. Intracellular CDDP and copper (Cu) accumulation were measured and CDDP efflux study was conducted. Assessment of Na(+),K(+)-ATPase alpha and beta subunits, ATP7A and ATP7B was done by western blotting. Specific activities of Na(+),K(+)-ATPase and copper-transporting P-type ATPase (Cu(2+)-ATPase) were detected and a role of Na(+),K(+)-ATPase inhibitor in intracellular CDDP accumulation was examined. Among the cells HSC-3 and BHY cells were found most CDDP-sensitive and CDDP-resistant, respectively. The most CDDP-sensitive HSC-3 cells exhibited an increased intracellular cisplatin accumulation, high Na(+),K(+)-ATPase activity and over-expressed Na(+),K(+)-ATPase alpha and beta subunits, ATP7A and ATP7B, compared to the most CDDP-resistant BHY cells, but there were no such differences between the two in the CDDP efflux level or Cu(2+)-ATPase activity. Moreover, pretreatment with Na(+),K(+)-ATPase inhibitor markedly reduced intracellular cisplatin accumulation. |
Is cigarette smoking associated with a reduction in the risk of incident gout : results from the Framingham Heart Study original cohort? | Cigarette smoking is correlated with other risk factors for gout such as adiposity and alcohol intake. The goal of this study was to study the direction and magnitude of association between cigarette smoking and risk for gout. We analysed 54-year follow-up data (1948-2002) for 2279 men and 2785 women who were gout-free at their first assessment as a part of the Framingham Heart Study. Using Cox proportional hazards models we estimated the association between cigarette smoking and incident gout among men and women separately after adjusting for age, BMI, alcohol intake, hypertension, kidney disease and diabetes. There were 399 incident cases (249 men and 150 women) of gout over 151 058 person-years of observation. Incidence rates of gout per 1000 person-years for smokers and non-smokers were 2.13 (95% CI 1.79, 2.53) and 3.04 (95% CI 2.70, 3.42), respectively. In multivariable Cox models, cigarette smoking was associated with gout with a hazard ratio of 0.76 (95% CI 0.59, 0.98) overall, 0.68 (95% CI 0.49, 0.93) among men and 0.92 (95% CI 0.60, 1.41) among women. Lower risk for smokers was evident among all obesity categories, but not among women. Sensitivity analysis suggested that the magnitude of the true odds ratio might be lower than our calculations. | One of the challenges faced by equine breeders is ensuring delivery of good quality semen doses for artificial insemination when the mare is due to ovulate. Single Layer Centrifugation (SLC) has been shown to select morphologically normal spermatozoa with intact chromatin and good progressive motility from the rest of the ejaculate, and to prolong the life of these selected spermatozoa in vitro. The objective of the present study was a proof of concept, to determine whether fertilizing ability was retained in SLC-selected spermatozoa during prolonged storage. Sixteen mares were inseminated with SLC-selected sperm doses that had been cooled and stored at 6°C for 48 h, 72 h or 96 h. Embryos were identified in 11 mares by ultrasound examination 16-18 days after presumed ovulation. |
Is serum vitamin D level associated with disease severity and response to ursodeoxycholic acid in primary biliary cirrhosis? | Serum vitamin D levels are associated with bone complications in patients with primary biliary cirrhosis (PBC). Increasing evidence suggests a nonskeletal role of vitamin D in various autoimmune and liver diseases. To investigate the clinical relevance of vitamin D levels in PBC, especially their association with the therapeutic effects of ursodeoxycholic acid (UDCA). Consecutive PBC patients were retrospectively reviewed. 25-hydroxyvitamin D [25(OH)D] levels were determined in frozen serum samples collected before initiation of UDCA treatment. Response to UDCA was evaluated by Paris-I and Barcelona criteria. Logistic regressions were performed to identify the treatment response-associated parameters. Among 98 patients, the mean serum 25(OH)D concentration was 17.9 ± 7.6 ng/mL. 25(OH)D levels decreased with increasing histological stage (P = 0.029) and were negatively correlated with bilirubin and alkaline phosphatase levels. After 1 year of UDCA therapy, 31 patients failed to achieve complete response according to Paris-I criteria. The baseline 25(OH)D level was significantly lower in nonresponders (14.8 ± 6.4 vs. 19.3 ± 7.6 ng/mL, P = 0.005). Vitamin D deficiency at baseline was associated with an increased risk of incomplete response independent of advanced stages (OR = 3.93, 95% CI = 1.02-15.19, P = 0.047). Similar results were obtained when biochemical response was evaluated by Barcelona criteria. Furthermore, 25(OH)D levels were lower in patients who subsequently suffered death or liver transplantation (12.1 ± 4.6 vs. 18.4 ± 7.6 ng/mL, P = 0.023). | MicroRNA-208a (miR-208a) exacerbated cardiomyocyte apoptosis via inhibiting nemo-like kinase (NLK). miR-208a is a crucial molecule in the regulation of heart diseases, however, the biological function and underlying mechanism of miR-208a in the progression of cardiomyocyte apoptosis is not clearly elucidated. We hypothesized that miR-208a might potentiate cardiomyocyte apoptosis through inhibiting NLK. Male Sprague-Dawley rats were underwent permanent coronary artery ligation to establish myocardial infarction (MI) model. The quantitative real-time RT-PCR (qRT-PCR) was used to evaluate the expression of miR-208a and NLK mRNA. Western blot was applied to detect NLK and Bcl-2 proteins expression. Luciferase reporter assay was performed to indentify NLK as a target of miR-208a. The apoptosis of H9C2 cells was assessed by flow cytometry (FCM). miR-208a was upregulated accompanying with a significant decrease of NLK in response to MI, and stronger miR-208a staining was detected by in situ hybridization in the cytoplasm of cardiomyocytes in MI group compared to the sham group. In vitro, overexpression of miR-208a greatly enhance Ang II-induced the apoptosis of H9C2 cells through downregulating of NLK and the anti-apoptosis protein Bcl-2 expression, whereas these effects were reversed when miR-208a was downregulated. Dual luciferase reporter assay and western blot results demonstrated that NLK was a direct target of miR-208a. Interestingly, upregulation of NLK obviously increased Bcl-2 expression and reduced the percentage of apoptotic cells, while attenuation of NLK reduced the level of Bcl-2 and cells apoptosis after treatment with Ang II. |
Does high-mobility group box 1 restore cardiac function after myocardial infarction in transgenic mice? | High-mobility group box 1 (HMGB1) is a nuclear DNA-binding protein and is released from necrotic cells, inducing inflammatory responses and promoting tissue repair and angiogenesis. To test the hypothesis that HMGB1 enhances angiogenesis and restores cardiac function after myocardial infarction (MI), we generated transgenic mice with cardiac-specific overexpression of HMGB1 (HMGB1-Tg) using alpha-myosin heavy chain promoter. The left anterior descending coronary artery was ligated in HMGB1-Tg and wild-type littermate (Wt) mice. After coronary artery ligation, HMGB1 was released into circulation from the necrotic cardiomyocytes of HMGB1-overexpressing hearts. The size of MI was smaller in HMGB1-Tg than in Wt mice. Echocardiography and cardiac catheterization demonstrated that cardiac remodelling and dysfunction after MI were prevented in HMGB1-Tg mice compared with Wt mice. Furthermore, the survival rate after MI of HMGB1-Tg mice was higher than that of Wt mice. Immunohistochemical staining revealed that capillary and arteriole formation after MI was enhanced in HMGB1-Tg mice. | After reviewing the negative effects of antiepileptic drugs (AEDs) on general health and quality of life, the Commission on Outcome Measurement from the International League Against Epilepsy (ILAE) recommended incorporating reliable and valid tools in clinical essays in order to achieve a more accurate assessment of the subjective adverse effects rate and disease severity when using AEDs. The aim of this study was to correlate the severity of adverse effects of AEDs, with the presence of anxiety and depression in patients with epilepsy. The Spanish version of the Liverpool Adverse Events Profile (LAEP) and the hospital anxiety and depression scale (HADS) were applied on 130 consecutive outpatients with epilepsy from the epilepsy clinic at the Mexico's National Institute of Neurology and Neurosurgery. A correlation analysis was carried out to determine if the presence of depression and anxiety was related to the adverse effects of AEDs. The relation between LAEP scores with other epidemiological variables was also assessed. Our study found a positive correlation between the LAEP and the HADS scores (p < or = 0.01). The most common adverse effects were drowsiness (81.5% [n=106]), difficulty in concentrating (76% [n=99]), and nervousness and/or agitation (75% [n=97]). Female gender, a history of febrile seizures, persistent seizures and polytherapy were associated with a higher toxicity on LAEP. In our study, age at epilepsy onset, duration of epilepsy, type of epilepsy and patients' age were not related to higher LAEP scores. |
Is bullying behavior related to suicide attempts but not to self-mutilation among psychiatric inpatient adolescents? | To investigate the association of bullying behavior with suicide attempts and self-mutilation among adolescents. The study sample consisted of 508 Finnish adolescents (age 12-17 years) admitted to psychiatric inpatient care between April 2001 and March 2006. DSM-IV psychiatric diagnoses and variables measuring suicidal behavior (i.e. suicide attempts and self-mutilation) and bullying behavior (i.e. a victim, a bully or a bully-victim) were obtained from the Schedule for Affective Disorder and Schizophrenia for School-Age Children Present and Lifetime (K-SADS-PL). Logistic regression analyses were conducted to examine the impact of being a victim, a bully or both a bully and a victim on suicide attempts and self-mutilation. After adjusting for age, school factors, family factors and psychiatric disorders, there was a higher risk of suicide attempts in girls who were victims of bullying (OR=2.07, CI=1.04-4.11, p=0.037) or who bullied others (OR=3.27, CI=1.08-9.95, p=0.037). Corresponding associations were not found for boys; nor was any association of bullying behavior with self-mutilation found among either sex. | We previously reported omega-3 polyunsaturated fatty acids (n-3PUFAs) supplementation does not reduce atrial fibrillation (AF) following coronary artery bypass graft (CABG) surgery. The aim of the present study is to evaluate the impact of n-3 PUFAs on electrocardiogram (ECG) atrial arrhythmic markers and compare with expression of gap-junction proteins, Connexins. Subset of clinical trial subjects with right atrial sampling during CABG surgery included. Twelve-lead ECG performed at recruitment and at surgery [after supplementation with n-3 PUFA (∼1.8 g/day) or matched placebo] for ∼14 days. Electrocardiograms analysed for maximum P-wave duration (P-max) and difference between P-max and minimum P-wave duration, P-wave dispersion (PWD). Right atrial specimens analysed for expression of Connexins 40 and 43 using real-time quantitative polymerase chain reaction (qPCR) and western blot. Serum levels of n-3 PUFA at baseline, at surgery, and atrial tissue levels at surgery collated from file. Postoperative AF was quantified by analysing data from stored continuous electrograms. A total of 61 patients (n-3 PUFA 34, Placebo 27) had ECG analysis and AF burden, of which 52 patients (26 in each group) had qPCR and 16 (8 in each group) had western blot analyses for Connexins 40 and 43. No difference between the two groups in ECG parameters or expression of Connexin 40 or 43. P-wave dispersion in the preoperative ECG independently predicted occurrence of AF following CABG surgery. |
Is snack intake reduced using an implicit , high-level construal cue? | Priming a high level construal has been shown to enhance self-control and reduce preference for indulgent food. Subtle visual cues have been shown to enhance the effects of a priming procedure. The current study therefore examined the combined impact of construal level and a visual cue reminder on the consumption of energy-dense snacks. A student and community-based adult sample with a wide age and body mass index (BMI) range (N = 176) were randomly assigned to a high or low construal condition in which a novel symbol was embedded. Afterward participants completed a taste test of ad libitum snack foods in the presence or absence of the symbol. The high (vs. the low) construal level prime successfully generated more abstract responses (p < .0001) and reduced intake when the cue-reminder was present (p = .02) but not when it was absent (p = .40). | The thrombocytopenia of the Paris-Trousseau (TCPT) type is a contiguous gene syndrome characterized by mild bleeding tendency, variable thrombocytopenia (THC), abnormal giant alpha-granules in platelets and dysmegakaryopoiesis: it derives from a constitutional deletion of chromosome 11 leading to the loss of FLI1, a transcription factor involved in megakaryocyte differentiation and maturation. A women with an acquired, isolated THC developing over 10 yr showed morphological features typical of TCPT in platelets and bone marrow (BM). Twenty years after the onset of THC, the other hematological parameters are still normal and the patient is well. Clonal hemopoiesis was shown and chromosome analyses performed on BM revealed a clone with 45 chromosomes and a complex unbalanced translocation involving chromosomes 2, 3, and 11. The anomaly was present in the majority of bone marrow cells but only in a few peripheral blood elements. A microarray-based comparative genomic hybridization defined the deleted region of chromosome 11 including the FLI1 locus that was missing. |
Does minocycline Effectively protect the Rabbit 's Spinal Cord From Aortic Occlusion-Related Ischemia? | To identify the minocycline anti-inflammatory and antiapoptotic mechanisms through which it is believed to exert spinal cord protection during aortic occlusion in the rabbit model. An animal model of aortic occlusion-related spinal cord ischemia. Randomized study with a control group and pre-ischemia and post-ischemia escalating doses of minocycline to high-dose minocycline in the presence of either hyperglycemia, a pro-apoptotic maneuver, or wortmannin, a specific phosphatidylinositol 3-kinase antagonist. Tertiary medical center and school of medicine laboratory. Laboratory animals-rabbits. Balloon obstruction of infrarenal aorta introduced via femoral artery incision. Severe hindlimb paralysis (mean Tarlov score 0.36±0.81 out of 3) was observed in all the control group animals (9 of 11 with paraplegia and 2 of 11 with paraparesis) compared with 11 of 12 neurologically intact animals (mean Tarlov score 2.58±0.90 [p = 0.001 compared with control]) in the high-dose minocycline group. This protective effect was observed partially during a state of hyperglycemia and was completely abrogated by wortmannin. Minocycline administration resulted in higher neurologic scores (p = 0.003) and a shift to viable neurons and more apoptotic-stained nuclei resulting from reduced necrosis (p = 0.001). | Bleach is widely used for household cleaning. Although it is recognized that occupational use of bleach may have adverse respiratory health effects, it is unknown whether common domestic use of bleach may be a risk factor for asthma. To assess whether the domestic use of bleach for home cleaning is associated with asthma and other respiratory outcomes. Questionnaire-based information on respiratory symptoms and cleaning habits and data from skin prick-tests, bronchial responsiveness challenge and white blood cells were analyzed in 607 women participating in the follow-up of the Epidemiological Study on the Genetics and Environment of Asthma (EGEA). Bleach use was evaluated in 3 categories (<1 day/week; 1-3 days/week; 4-7 days/week "frequent"). Overall, 37% of the women reported using bleach weekly. Women using bleach frequently (11%) were more likely to have current asthma as compared to non-users (adjusted Odds-Ratio (aOR) = 1.7; 95% Confidence Interval (95%CI) 1.0-3.0). Among women with asthma, frequent use of bleach was significantly associated with higher blood neutrophil cell counts. Bleach use was significantly associated with non-allergic asthma (aOR 3.3; 95%CI 1.5-7.1), and more particularly with non-allergic adult-onset asthma (aOR 4.9; 95%CI 2.0-11.6). Consistently, among women without allergic sensitization, significant positive associations were found between use of bleach and bronchial hyperresponsiveness, asthma like-symptoms and chronic cough. No association was observed for allergic asthma. |
Do rapid and accurate identification of Xanthomonas citri subspecies citri by fluorescence in situ hybridization? | Citrus canker is an economically important disease caused by the bacterial pathogen Xanthomonas citri subsp. citri (Xcc). This organism targets a wide range of citrus plants, including sweet orange, grapefruit, lemon and lime. As Xcc is spread by environmental factors such as wind and rain, it is difficult to control its movement once the disease has established. In order to facilitate monitoring of citrus canker we sought to design a novel diagnostic protocol based on fluorescence in situ hybridization (FISH) for identification of bacterial cells directly from canker pustules without cultivation or DNA extraction. This method was validated for specificity against a range of Xanthomonas species and strains. We show that our assay is extremely rapid (typically requiring between 2 and 3 h), and possesses a similar specificity to existing PCR diagnostic tools. The sensitivity of the assay is comparable to that of an existing PCR-based technique and sufficient for identifying Xcc in symptomatic plant material. The method is easily transferable to diagnosticians without prior experience using FISH. | Elderly patients are particularly susceptible to polypharmacy. The present study evaluated the renal effects of optimizing potentially nephrotoxic medications in an older population. Retrospective study of patients' ≥ 60 years treated between January of 2013 and February of 2015 in a Nephrology Clinic. The renal effect of avoiding polypharmacy was studied. Sixty-one patients were studied. Median age was 81 years (range 60-94). Twenty-five patients (41%) were male. NSAIDs alone were stopped in seven patients (11.4%), a dose reduction in antihypertensives was done in 11 patients (18%), one or more antihypertensives were discontinued in 20 patients (32.7%) and discontinuation and dose reduction of multiple medications was carried out in 23 patients (37.7%). The number of antihypertensives was reduced from a median of 3 (range of 0-8) at baseline to a median of 2 (range 0-7), p < 0.001 after intervention. After intervention, the glomerular filtration rate (GFR) improved significantly, from a baseline of 32 ± 15.5 cc/min/1.73 m(2) to 39.5 ± 17 cc/min/1.73 m(2) at t1 (p < 0.001) and 44.5 ± 18.7 cc/min/1.73 m(2) at t2 (p < 0.001 vs. baseline). In a multivariate model, after adjusting for ACEIs/ARBs discontinuation/dose reduction, NSAIDs use and change in DBP, an increase in SBP at time 1 remained significantly associated with increments in GFR on follow-up (estimate = 0.20, p = 0.01). |
Does pichia stipitis xylose reductase help detoxifying lignocellulosic hydrolysate by reducing 5-hydroxymethyl-furfural ( HMF )? | Pichia stipitis xylose reductase (Ps-XR) has been used to design Saccharomyces cerevisiae strains that are able to ferment xylose. One example is the industrial S. cerevisiae xylose-consuming strain TMB3400, which was constructed by expression of P. stipitis xylose reductase and xylitol dehydrogenase and overexpression of endogenous xylulose kinase in the industrial S. cerevisiae strain USM21. In this study, we demonstrate that strain TMB3400 not only converts xylose, but also displays higher tolerance to lignocellulosic hydrolysate during anaerobic batch fermentation as well as 3 times higher in vitro HMF and furfural reduction activity than the control strain USM21. Using laboratory strains producing various levels of Ps-XR, we confirm that Ps-XR is able to reduce HMF both in vitro and in vivo. Ps-XR overexpression increases the in vivo HMF conversion rate by approximately 20%, thereby improving yeast tolerance towards HMF. Further purification of Ps-XR shows that HMF is a substrate inhibitor of the enzyme. | This study investigates the relationship between current morphine use and the risk of pulmonary embolism (PE) development in deep vein thrombosis (DVT) patients. We conducted a population-based nested case-control retrospective analysis using the Longitudinal Health Insurance Database 2000 of Taiwan. A DVT cohort of 3668 patients with no history of PE from 1998 to 2010 and the other cohort of 174 patients who subsequently developed PE were evaluated. Morphine use was designated as 'current' if the prescription duration covered the index date or ended within 30 days before the index date. Logistic regression was used to estimate the odds ratios and 95% confidence intervals (CI), and the multivariable model was applied to control for age. Compared with non-morphine users, DVT patients who received morphine within 30 days of the index date had a 4.54-fold (95% CI = 2.30-8.97) chance of developing PE. The risk of PE development increased with an increase in cumulative dosage and in the average dosage of morphine. |
Does fluid shear stress regulate the expression of TGF-beta1 and its signaling molecules in mouse embryo mesenchymal progenitor cells? | Recently we reported that fluid shear stress promotes endothelial cell differentiation from a mouse embryo mesenchymal progenitor cell line C3H10T1/2. However, it is not clear whether the transforming growth factor-beta 1 (TGF-beta1) system is associated with shear-induced endothelial differentiation. The purpose of this study was to determine the effect of shear stress on the expression of TGF-beta1 and its signaling molecules in C3H10T1/2 cells. Murine C3H10T1/2 cells were incubated on collagen Type 1-coated dishes, and subjected to a steady fluid shear stress of 15 dyn/cm(2) for 6, 12, and 24 h. The mRNA levels for TGF-beta1, TGF-beta receptors (TGF-beta R), and Smad molecules were determined with real-time PCR analysis and normalized to glyceraldehyde-3-phosphate dehydrogenase mRNA levels. TGF-beta1 mRNA expression was down-regulated by 60% and 66% in shear stress-treated cells at 12 and 24 h, respectively, compared with static control group (P < 0.01). In addition, shear stress significantly decreased TGF-beta R1 mRNA levels by 30% and 50% in shear stress-treated cells at 12 and 24 h, respectively (P < 0.01). For TGF-beta R2, shear stress at 6, 12, and 24 h significantly reduced its expression by 93%, 95% and 97%, respectively, compared with static controls (P < 0.01). Furthermore, shear stress significant decreased mRNA levels of positive signaling molecules Smad2, Smad3, and Smad4 in a time-dependent manner (P < 0.01). However, shear stress significantly increased negative signaling molecule Smad7 mRNA levels by 100% at 24 h treatment compared with static control group (P < 0.01). | The mass drug administration (MDA) is one of the strategies to eliminate lymphatic filariasis in India. Eleven districts are endemic for the disease in Madhya Pradesh state of India, which conduct MDA activities annually. A mid-term evaluation was conducted with the objectives to review the progress of the single dose of di-ethyl-carbamazine (DEC) administration, and to understand the functioning of the programme to recommend mid-term amendments. A qualitative cross-sectional study was conducted in three endemic districts of Madhya Pradesh between July and October 2007. The teams of faculty members from medical college visited the study districts and collected data by desk review, indepth interviews, on site observations, and from the community. The filaria units in these districts were understaffed. There were no night clinics in two out of the three districts. The sufficient number of trainings for MDA were conducted without any mechanism for quality assurance. There was erratic and inadequate supply of DEC tablets, leading to the postponement of MDA activity, twice. The evaluated coverage with DEC tablets was much lower than that reported by the district officials. The tablet intake was not ensured by the distributors and the compliance rate was in the range of 60-70%. The IEC activities were conducted in limited areas, and there were prevailing myths and misconceptions, contributing to low compliance rate. There was no proper recording of the data on filariasis with gross mismatch at district headquarters and peripheral health facilities. A proportion of community members developed side effects following DEC tablet intake and had to visit private health facilities for treatment. |
Does stress-induced enhancement of mouse amygdalar synaptic plasticity depend on glucocorticoid and ß-adrenergic activity? | Glucocorticoid hormones, in interaction with noradrenaline, enable the consolidation of emotionally arousing and stressful experiences in rodents and humans. Such interaction is thought to occur at least partly in the basolateral nucleus of the amygdala (BLA) which is crucially involved in emotional memory formation. Extensive evidence points to long-term synaptic potentiation (LTP) as a mechanism contributing to memory formation. Here we determined in adolescent C57/Bl6 mice the effects of stress on LTP in the LA-BLA pathway and the specific roles of corticosteroid and β-adrenergic receptor activation in this process. Exposure to 20 min of restraint stress (compared to control treatment) prior to slice preparation enhanced subsequent LTP induction in vitro, without affecting baseline fEPSP responses. The role of glucocorticoid receptors, mineralocorticoid receptors and β2-adrenoceptors in the effects of stress was studied by treating mice with the antagonists mifepristone, spironolactone or propranolol respectively (or the corresponding vehicles) prior to stress or control treatment. In undisturbed controls, mifepristone and propranolol administration in vivo did not influence LTP induced in vitro. By contrast, spironolactone caused a gradually attenuating form of LTP, both in unstressed and stressed mice. Mifepristone treatment prior to stress strongly reduced the ability to induce LTP in vitro. Propranolol normalized the stress-induced enhancement of LTP to control levels during the first 10 min after high frequency stimulation, after which synaptic responses further declined. | Urotensin II (U-II), an 11-amino acid peptide, exerts a wide range of actions in cardiovascular systems. Interleukin-8 (IL-8) is secreted by endothelial cells, thereby enhancing endothelial cell survival, proliferation, and angiogenesis. However, the interrelationship between U-II and IL-8 as well as the detailed intracellular mechanism of U-II in vascular endothelial cells remain unclear. The aim of this study was to investigate the effect of U-II on IL-8 expression and to explore its intracellular mechanism in human umbilical vein endothelial cells. Primary human umbilical vein endothelial cells were used. Expression of IL-8 was determined by real-time quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, and luciferase reporter assay. Western blot analyses and experiments with specific inhibitors were performed to reveal the downstream signaling pathways as concerned. U-II increased the mRNA/protein levels of IL-8 in human umbilical vein endothelial cells. The U-II effects were significantly inhibited by its receptor antagonist [Orn(5)]-URP. Western blot analyses and experiments with specific inhibitors indicated the involvement of phosphorylation of p38 mitogen-activated protein kinase and extracellular signal-regulated kinase in U-II-induced IL-8 expression. Luciferase reporter assay further revealed that U-II induces the transcriptional activity of IL-8. The site-directed mutagenesis indicated that the mutation of AP-1 and NF-kB binding sites reduced U-II-increased IL-8 promoter activities. Proliferation of human umbilical vein endothelial cells induced by U-II could be inhibited significantly by IL-8 RNA interference. |
Does a protein complex containing Inscuteable and the Galpha-binding protein Pins orient asymmetric cell divisions in Drosophila? | In the fruit fly Drosophila, the Inscuteable protein localises to the apical cell cortex in neuroblasts and directs both the apical-basal orientation of the mitotic spindle and the basal localisation of the protein determinants Numb and Prospero during mitosis. Asymmetric localisation of Inscuteable is initiated during neuroblast delamination by direct binding to Bazooka, an apically localised protein that contains protein-interaction motifs known as PDZ domains. How apically localised Inscuteable directs asymmetric cell divisions is unclear. A novel 70 kDa protein called Partner of Inscuteable (Pins) and a heterotrimeric G-protein alpha subunit were found to bind specifically to the functional domain of Inscuteable in vivo. The predicted sequence of Pins contained tetratrico-peptide repeats (TPRs) and motifs implicated in binding Galpha proteins. Pins colocalised with Inscuteable at the apical cell cortex in interphase and mitotic neuroblasts. Asymmetric localisation of Pins required both Inscuteable and Bazooka. In epithelial cells, which do not express inscuteable, Pins was not apically localised but could be recruited to the apical cortex by ectopic expression of Inscuteable. In pins mutants, these epithelial cells were not affected, but neuroblasts showed defects in the orientation of their mitotic spindle and the basal asymmetric localisation of Numb and Miranda during metaphase. Although localisation of Inscuteable in pins mutants was initiated correctly during neuroblast delamination, Inscuteable became homogeneously distributed in the cytoplasm during mitosis. | Vitamin C can be metabolized to oxalate. Case reports have suggested an association between IV vitamin C and urinary oxalate excretion. Recently, the US Food and Drug Administration required the dose of vitamin C in IV multivitamin preparations to be increased from 100 mg to 200 mg/d. We compared the urinary oxalate excretion level in stable home total parenteral nutrition (TPN) patients receiving both doses of vitamin C. Each participant provided a 24-hour urine sample for oxalate determination on the vitamin C dose (100 mg/d), and again after at least 1 month on the increased vitamin C dose (200 mg/d). A 2-day diet diary was completed covering the day before and the day of the urine collection and was analyzed for oxalate and vitamin C content. Comparisons were made using Student paired t test and Wilcoxon signed rank. Thirteen patients (7 males/6 females) aged 63.1 +/- 12.2 years who had no history of nephrolithiasis and had received TPN for 55.9 +/- 78.8 months were enrolled. The most common indication for TPN was short bowel syndrome (38.5%). Eight patients had an intact colon. Urinary oxalate excretion increased on the 200-mg vitamin C dose, from 0.34 +/- 0.13 to 0.44 +/- 0.17 mmol/d (mean increase = 0.10 mmol/d; p = .04; 95% confidence interval 0.004 to 0.19 mmol/d). Oral intake of vitamin C and oxalate did not differ between the 2 collection periods. |
Are somatic TP53 mutations relatively rare among adrenocortical cancers with the frequent 17p13 loss of heterozygosity? | Allelic losses [loss of heterozygosity (LOH)] at the 17p13 locus are frequent (85%) in adrenocortical cancers. The tumor suppressor gene TP53 is located at 17p13. The aim of the study was to determine the frequency of TP53 somatic inactivating mutations in adrenocortical tumors with 17p13 LOH and their clinico-biological correlations. TP53 somatic mutations, intragenic LOH (VNTR1 marker), and p53 overexpression were studied in 36 adrenocortical tumors with 17p13 LOH determined by Southern blot. TP53 mutations were detected in 33% of the tumors, and VNTR1 LOH was present in 44% of the cases and did not always correlate with the presence of a TP53 mutation. Only the TP53-mutant tumors exhibit a strong nuclear immunoreactivity. TP53-mutant tumors were significantly larger than wild-type TP53 tumors (median tumor weight: 640 versus 185 g; P=0.02), were associated with a more advanced stage of tumor progression (MacFarlane stage IV; P=0.01), and had a shorter disease-free survival (P=0.03). | To explore the roles of vacuum sealing drainage (VSD) in controlling infection and promoting healing on the experimental pigs with blast injury in the abdomen and exposed internal organs. All animals with full-thickness abdominal wall defect were randomly divided into experimental group (VSD group) and control group (saline gauze group). Debridement was performed 6 hours after wounding. VSD devices (-125 mmHg) were imbedded on animals in the experimental group, while in the control group gauzes with saline solution were used to cover the wound and conventional treatment of dressing change was done. Specimens of muscle tissue in the wound were collected respectively from the two groups to make bacteria quantification 6 hours before the treatment and on the 1st, 3rd, 5th, and 7th day of treatment. Specimens of abdominal drainage fluid were collected respectively on the 1st, 3rd, 5th, and 7th day of treatment to detect inflammatory cytokines (TNF-α, IL-1, IL-6) using ELISA kit. Specimens of the skin and muscle tissues were collected respectively from the two groups on the 7th day to detect target genes (VEGF, bFGF, EGF, and MMP-9) using qRT-PCR. The bacteria counts (CFU/g) in the VSD group on the 1st, 3rd, 5th, and 7th day of treatment were significantly less than those in the control group at the corresponding time points, and the differences between the two groups were statistically significant (P<0.01). There were no distinct differences between the two groups in the expressions of TNF-α, IL-1 and IL-6 in the abdominal drainage fluid of pig on the 1st day of treatment. The expressions of TNF-α, IL-1 and IL-6 on the 3rd, 5th, and 7th day of treatment in the VSD group were significantly lower than those in the control group at the corresponding time points (P<0.01). The expressions of VEGF, EGF and bFGF in the skin and soft tissues in the VSD group on the 7th day was higher than those in the control group (P<0.01), while the expression of MMP-9 showed no statistical significant difference between the two groups (P>0.05). |
Do serum miRNA biomarkers serve as a fingerprint for proliferative diabetic retinopathy? | Diabetic retinopathy (DR) is a retinopathy resulting from diabetes mellitus (DM) which was classified into non-proliferative DR (NPDR) and proliferative DR (PDR). Without an early screening and effective diagnosis, patients with PDR will develop serious complications. Therefore, we sought to identify special serum microRNAs (miRNAs) that can serve as a novel non-invasive screening signature of PDR and test its specificity and sensitivity in the early diagnosis of PDR. In total, we obtained serum samples from 90 PDR cases, 90 matched NPDR patients and 20 controls. An initial screening of miRNA expression was performed through TaqMan Low Density Array (TLDA). The candidate miRNAs were validated by individual reverse transcription quantitative real-time PCR (RT-qPCR) arranged in an initial and a two-stage validation sets. Moreover, additional double-blind testing was performed in 20 patients clinically suspected of having DR to evaluate the diagnostic value and accuracy of the serum miRNA profiling system in predicting PDR. Three miRNAs were significantly increased in patients with PDR compared with NPDR after the multiple stages. The areas under the receiver operating characteristic (ROC) curves of the validated three-serum miRNAs signature were 0.830, 0.803 and 0.873 in the initial and two validation sets, respectively. Combination of miR-21, miR-181c, and miR-1179 possessed a moderate ability to discrimination between PDR and NPDR with an area under ROC value of 0.89. The accuracy rate of the three-miRNA profile as PDR signature was 82.6%. | Exposure to androgens early in development, while activating adaptive aggressive behavior, may also exert long-lasting effects on non-target components of phenotype. Here we compare these organizational effects of perinatal androgens in closely related Nazca (Sula granti) and blue-footed (S. nebouxii) boobies that differ in neonatal social system. The older of two Nazca booby hatchlings unconditionally attacks and ejects the younger from the nest within days of hatching, while blue-footed booby neonates lack lethal aggression. Both Nazca booby chicks facultatively upregulate testosterone (T) during fights, motivating the prediction that baseline androgen levels differ between obligately siblicidal and other species. We show that obligately siblicidal Nazca boobies hatch with higher circulating androgen levels than do facultatively siblicidal blue-footed boobies, providing comparative evidence of the role of androgens in sociality. Although androgens confer a short-term benefit of increased aggression to Nazca booby neonates, exposure to elevated androgen levels during this sensitive period in development can also induce long-term organizational effects on behavior or morphology. Adult Nazca boobies show evidence of organizational effects of early androgen exposure in aberrant adult behavior: they visit unattended non-familial chicks in the colony and direct mixtures of aggression, affiliative, and sexual behavior toward them. In a longitudinal analysis, we found that the most active Non-parental Adult Visitors (NAVs) were those with a history of siblicidal behavior as a neonate, suggesting that the tendency to show social interest in chicks is programmed, in part, by the high perinatal androgens associated with obligate siblicide. Data from closely related blue-footed boobies provide comparative support for this interpretation. Lacking obligate siblicide, they hatch with a corresponding low androgen level, and blue-footed booby adults show a much lower frequency of NAV behavior and a lower probability of behaving aggressively during NAV interactions. This species difference in adult social behavior appears to have roots in both pleiotropic and experiential effects of nestling social system. |
Does metformin reduce circulating malondialdehyde-modified low-density lipoprotein in type 2 diabetes mellitus? | Type 2 diabetes is known to be associated with increasing cardiovascular mortality. Malondialdehyde-modified LDL (MDA-LDL) is an oxidized LDL and is increased in patients with diabetes or hypertriglyceridemia. Elevated MDA-LDL has been reported to be a risk factor of atherosclerosis or cardiovascular disease. Sitagliptin is a dipeptidyl peptidase-4 inhibitor and a new class of hypoglycemic agents. In this study, the effects of increasing the dose of metformin and add-on sitagliptin on MDA-LDL were examined in type 2 diabetes patients. Seventy patients with type 2 diabetes, inadequately controlled despite on-going treatment with metformin 500 mg/day, were enrolled in this randomized controlled trial. The patients received additional metformin (500 mg/day) or sitagliptin (50 mg/day) for 6 months, and changes in metabolic parameters including MDA-LDL were evaluated. After 6 months of treatment, add-on sitagliptin (n=35) improved fasting blood glucose (FBG) and hemoglobin A1c (HbA1c) to significantly greater extent than increasing the dose of metformin (n=35). There were no differences in total cholesterol and low-density lipoprotein cholesterol levels between two groups. MDA-LDL levels (mean ± S.E.) decreased significantly with increasing the dose of metformin (from 94.40 ± 6.35 to 77.83 ± 4.74 U/L, P < 0.005), but remained unchanged with add-on sitagliptin treatment (from 89.94 ± 5.59 to 98.46 ± 6.78 U/L, p > 0.05). Multiple linear regression analysis identified increasing the dose of metformin treatment as the only independent factor associated with decreased MDA-LDL (β coefficient 0.367, P < 0.0119), and no significant correlation between change in MDA-LDL and fasting blood glucose or HbA1c. | Childhood sexual abuse (CSA) has been associated with alterations in brain morphology using region of interest analyses that have focused on stress-sensitive target regions. This study was designed to ascertain the effects on gray matter volume (GMV) of exposure to CSA in healthy young adult college students selected based on exposure history regardless of psychiatric outcome. Voxel-based morphometry (VBM) provided unbiased delineation of the most significantly affected brain regions. High-resolution T1-weighted magnetic resonance imaging (MRI) datasets were obtained for 23 unmedicated female subjects with CSA and 14 healthy female control subjects of equivalent age and socioeconomic status with no history of trauma. Cortical surface-based analysis (FreeSurfer) was performed to verify VBM results. Gray matter volume was reduced by 12.6% and 18.1% in right and left primary visual (V1) and visual association cortices of abused subjects. This reduction was directly related to duration of CSA before age 12. Gray matter volume of left and right V1 correlated with measure of visual memory (r = .353, p = .032 and r = .448, p = .005). Cortical surface-based analysis indicated that GMV of abused subjects was reduced in the left fusiform (p = .004), left middle occipital (p = .04), and right lingual (p = .002) gyri. |
Is very early social support following mild stroke associated with emotional and behavioral outcomes three months later? | To investigate whether social contact and support received during hospitalization for acute ischemic stroke predict depression and daily life functioning three months later. Prospective observational study using Ecological Momentary Assessments to evaluate the number of social contacts as well as social support received from family, friends and medical staff within 24 hours following admission for stroke. Patients also monitored depression symptoms and behavior in real-time and in daily life contexts three months later. A university hospital acute stroke unit. Thirty-four mild ischemic stroke patients. None. One-day Ecological Momentary Assessments immediately following stroke collected information concerning perceived social support, number of social contacts and depression symptoms. Ecological Momentary Assessments was repeated three months later and addressed depression levels as well as activities of daily living, such as working, cooking, shopping and housework. The number of social interactions received at hospitalization did not predict three-month outcomes. However, a better quality of moral support from friends and family immediately after stroke was associated with decreases in later depression levels (p = 0.041) and increases in activities of daily living (p = 0.011). Material support from friends and family was associated with increases in activities of daily living (p = 0.012). No effect was observed for support received from medical staff. | Aberrant crypt foci (ACF) of the colon are possible precursors of adenoma and cancer. beta-catenin alterations are early events in human colorectal carcinogenesis. beta-catenin expression is altered in colorectal cancer, adenoma, and ACF with dysplasia. Here, we describe the expression of beta-catenin in ACF, especially nondysplastic ACF. Rectal chromoscopy with 4% indigo carmine was performed on 418 subjects and 146 biopsy specimens, including 10 dysplastic ACF, 106 nondysplastic ACF, and 30 normal colonic mucosal controls taken under endoscopy. The expression and subcellular distribution of beta-catenin were assessed by immunohistochemistry. beta-catenin expression was altered in 1 of 30 (3.3%) normal mucosa, 30 of 106 (28.3%) nondysplastic ACF, and 10 of 10 (100%) dysplastic ACF (P<0.001). Notably, most cells with altered beta-catenin expression in nondysplastic ACF were limited to the bottom of the crypt, where stem cells are located. |
Does human prostate support more efficient replication of HIV-1 R5 than X4 strains ex vivo? | In order to determine whether human prostate can be productively infected by HIV-1 strains with different tropism, and thus represent a potential source of HIV in semen, an organotypic culture of prostate from men undergoing prostatic adenomectomy for benign prostate hypertrophy (BPH) was developed. The presence of potential HIV target cells in prostate tissues was investigated using immunohistochemistry. The infection of prostate explants following exposures with HIV-1 R5, R5X4 and X4 strains was analyzed through the measure of RT activity in culture supernatants, the quantification of HIV DNA in the explants and the detection of HIV RNA+ cells in situ. The overall prostate characteristics were retained for 21/2 weeks in culture. Numerous potential HIV-1 target cells were detected in the prostate stroma. Whilst HIV-1 R5SF162 strain consistently productively infected prostatic T lymphocytes and macrophages, the prototypic X4IIIB strain and a primary R5X4 strain showed less efficient replication in this organ. | Angiotensin-converting enzyme (ACE) inhibitors improve prognosis in patients with post-myocardial infarction (MI) related cardiac dysfunction. Resveratrol is a polyphenol that has been reported to be beneficial in hypertension, ischemic heart disease, and cardiotoxicity in preclinical studies. Accordingly, we investigated the comparative and combinatorial efficacy of resveratrol and perindopril (ACE inhibitor) treatment on MI-related cardiac remodeling and contractile dysfunction. Left anterior descending artery-ligated and sham-operated male Sprague-Dawley rats were gavaged with vehicle, resveratrol, perindopril, and combination of resveratrol+perindopril (2.5 mg/kg bodyweight/day) for 8 weeks (starting immediately after acute MI). Echocardiography was performed to assess cardiac structure and function at baseline and 8 weeks. At 8 weeks, vehicle-MI rats had a significantly lower left ventricular ejection fraction (LVEF) and increased LV dilatation compared to vehicle-sham rats. MI rats treated with resveratrol, perindopril and a combination of both had significantly improved LVEF and reduced LV dilatation. Vehicle-treated MI rats also had increased level of lipid peroxidation product- malondialdehyde (MDA), proinflammatory protein- tumor necrosis factor-alpha (TNF-α) and cardiac fibrosis marker- collagen and decreased enzymatic activity of superoxide dismutase and catalase compared to vehicle-sham rats. Resveratrol, perindopril and combination of both significantly prevented the /ed to determine systolic functional parameter increase in MDA, TNF-α and collagen and improved the activity of superoxide dismutase and catalase in MI rats compared to vehicle-MI rats. |
Does leukodepletion of autologous whole blood have no impact on perioperative infection rate and length of hospital stay? | Several mechanisms have been proposed as possible causes of transfusion-related immunomodulation (TRIM) after allogeneic transfusion. If one of these mechanisms, the release of mediators of immunity and inflammation ("biologic response modifiers"[BRMs]) from disintegrating blood cells during storage of blood products, really causes TRIM, it should in principle also occur after autologous transfusion. As a consequence, prestorage leukoreduction of autologous blood should be able to prevent the clinical consequences of TRIM after autologous transfusion. This hypothesis was investigated in a multicenter, double-blind, randomized controlled trial. A total of 1089 patients scheduled for total hip arthroplasty and eligible for preoperative autologous blood donation were randomly assigned to receive autologous whole blood (AWB) either unmodified or leukoreduced when transfusion was indicated. Neither the primary study outcome, that is, the overall postoperative infection rate (17.3% vs. 17.6%, p = 0.59), nor several secondary outcomes like median length of hospital stay (14 days vs. 14 days, p = 0.17) were significantly different between groups, whether analyzed according to the intention-to-treat principle or "as treated." | Gliomas are the most common primary malignant brain tumors in adults with great heterogeneity in histopathology and clinical course. The intent was to evaluate the relevance of known glioblastoma (GBM) expression and methylation based subtypes to grade II and III gliomas (ie. lower grade gliomas). Gene expression array, single nucleotide polymorphism (SNP) array and clinical data were obtained for 228 GBMs and 176 grade II/II gliomas (GII/III) from the publically available Rembrandt dataset. Two additional datasets with IDH1 mutation status were utilized as validation datasets (one publicly available dataset and one newly generated dataset from MD Anderson). Unsupervised clustering was performed and compared to gene expression subtypes assigned using the Verhaak et al 840-gene classifier. The glioma-CpG Island Methylator Phenotype (G-CIMP) was assigned using prediction models by Fine et al. Unsupervised clustering by gene expression aligned with the Verhaak 840-gene subtype group assignments. GII/IIIs were preferentially assigned to the proneural subtype with IDH1 mutation and G-CIMP. GBMs were evenly distributed among the four subtypes. Proneural, IDH1 mutant, G-CIMP GII/III s had significantly better survival than other molecular subtypes. Only 6% of GBMs were proneural and had either IDH1 mutation or G-CIMP but these tumors had significantly better survival than other GBMs. Copy number changes in chromosomes 1p and 19q were associated with GII/IIIs, while these changes in CDKN2A, PTEN and EGFR were more commonly associated with GBMs. |
Does autocrine over expression of fibronectin by human transitional carcinoma cells impair bacillus Calmette-Guerin adherence and signaling? | Bacillus Calmette-Guerin (BCG) binds to the tumor cell as a result of mycobacterial receptors for fibronectin (FN). Cell surface bound FN serves as a bridge through which BCG attaches to the tumor cell. Despite the importance of FN studies have demonstrated an idiosyncratic decrease in BCG adherence in response to exogenous FN. We evaluated the effect of exogenous and autocrine FN on the ability of BCG to adhere to the tumor cell surface and initiate cellular signaling. BCG adherence to parental 253J and FN over expressing 253JTGFbeta1-8 cells as well as to the intrinsic FN expressing cell line 647V was quantified using green fluorescent protein-BCG. Experiments were performed to assess the effect of FN on BCG initiated signal transduction through nuclear factor kappaB and AP1. Finally, the integrity of the BCG activated signaling pathway in transforming growth factor-beta1/FN over expressors was assessed using antibody mediated cross-linking of the FN receptor. BCG adherence was decreased in cell lines with high autocrine expression of FN. Exogenous FN prevented BCG induced transactivation of nuclear factor kappaB and AP1 reporter constructs. No BCG stimulated signaling to these reporters could be detected in FN over expressing 253J cells. NonFN dependent alpha5beta1 cross-linking initiated signal transduction in FN over expressing cells. | Sympathetic nervous system hyperactivity promotes vascular disorders by its catabolic effects and by increasing arterial blood pressure. Levodopa-derived dopamine modulates sympathetic overactivity and is known to reduce blood pressure, but its effects on glucose and lipid metabolism have not been studied in large series of patients. We retrospectively examined 483 consecutive parkinsonian patients, admitted to a single institute between 1970 and 1987, before statins were available. We compared risk factors for vascular disease in the 305 who were on levodopa with the 178 who had never received the drug. On admission levodopa-treated patients had significantly lower plasma levels of triglycerides, total cholesterol and lipids, and lower frequency of diabetes and hypertension than untreated patients. Mean body mass index, resting blood pressure, fasting plasma glucose, and smoking did not differ between the groups. A year after enrollment 160 patients were re-hospitalized; of these 63 had started levodopa during first hospitalization. In these new levodopa users total cholesterol, triglycerides and lipids had reduced to levels comparable with those of longer-term levodopa users. |
Does mEF2D-BCL9 Fusion Gene be Associated With High-Risk Acute B-Cell Precursor Lymphoblastic Leukemia in Adolescents? | Acute lymphoblastic leukemia (ALL) makes up a significant proportion of all pediatric cancers, and relapsed ALL is a leading cause of cancer-associated deaths in children. Identification of risk factors and druggable molecular targets in ALL can lead to a better stratification of treatments and subsequent improvement in prognosis. We enrolled 59 children with relapsed or primary refractory ALL who were treated in our institutions. We primarily performed RNA sequencing (RNA-seq) using patients' leukemic cells to comprehensively detect gene fusions and analyze gene expression profiles. On the basis of results obtained by RNA-seq, we performed genetic validation, functional analysis, and in vitro drug sensitivity testing using patients' samples and an exogenous expression model. We identified a total of 26 gene fusions in 22 patients by RNA-seq. Among these, 19 were nonrandom gene fusions already described in ALL, and four of the remaining seven involved identical combination of MEF2D and BCL9. All MEF2D-BCL9-positive patients had B-cell precursor immunophenotype and were characterized as being older in age, being resistant to chemotherapy, having very early relapse, and having leukemic blasts that mimic morphologically mature B-cell leukemia with markedly high expression of HDAC9. Exogenous expression of MEF2D-BCL9 in a B-cell precursor ALL cell line promoted cell growth, increased HDAC9 expression, and induced resistance to dexamethasone. Using a primary culture of leukemic blasts from a patient, we identified several molecular targeted drugs that conferred inhibitory effects in vitro. | Slumped posture is a diagnostic feature of depression. While research shows upright posture improves self-esteem and mood in healthy samples, little research has investigated this in depressed samples. This study aimed to investigate whether changing posture could reduce negative affect and fatigue in people with mild to moderate depression undergoing a stressful task. Sixty-one community participants who screened positive for mild to moderate depression were recruited into a study purportedly on the effects of physiotherapy tape on cognitive function. They were randomized to sit with usual posture or upright posture and physiotherapy tape was applied. Participants completed the Trier Social Stress Test speech task. Changes in affect and fatigue were assessed. The words spoken by the participants during their speeches were analysed. At baseline, all participants had significantly more slumped posture than normative data. The postural manipulation significantly improved posture and increased high arousal positive affect and fatigue compared to usual posture. The upright group spoke significantly more words than the usual posture group, used fewer first person singular personal pronouns, but more sadness words. Upright shoulder angle was associated with lower negative affect and lower anxiety across both groups. |
Do factors for accessing a medical home vary among CSHCN from different levels of socioeconomic status? | The purpose of this research study was to identify factors that are associated with receiving care in a medical home for children with special health care needs (CSHCN) and to identify how these factors vary among different socioeconomic levels. Data were obtained from the National Survey of Children with Special Health Care Needs, 2000-2002. Access to a medical home was derived using an algorithm. This survey analysis also included demographic characteristics, geographical location of household, severity of condition, and social factors. Multiple logistic regression models were constructed for socioeconomic status (SES) levels defined by federal poverty level (FPL): <133%; 133-199%; 200-299%; > or =300%. Age group was significant in all but the 200-299% of FPL stratum. Severity of condition was significant in all strata. Race was significant in all but the > or =300% stratum. Maternal education was borderline significant in the lowest and highest strata. Insurance type/status was significant in all but the 133-199% of FPL stratum. Geographical location was significant in the lowest and highest strata. The language of the interview was only significant in the lowest stratum. The relationship of the respondent to the child was significant in the middle two strata. The total number of adults in the household was significant in the highest stratum, and the total number of children in the household was significant in the 200-299% of FPL stratum. | To provide optimal treatment of heterogeneous triple negative breast cancer (TNBC), we need biomarkers that can predict the chemotherapy response. We retrospectively investigated BRCAness in 73 patients with breast cancer who had been treated with taxane- and/or anthracycline-based neoadjuvant chemotherapy (NAC). Using multiplex, ligation-dependent probe amplification on formalin-fixed core needle biopsy (CNB) specimens before NAC and surgical specimens after NAC. BRCAness status was assessed with the assessor unaware of the clinical information. We obtained 45 CNB and 60 surgical specimens from the 73 patients. Of the 45 CNB specimens, 17 had BRCAness (38.6% of all subtypes). Of the 23 TNBC CNB specimens, 14 had BRCAness (61% of TNBC cases). The clinical response rates were significantly lower for BRCAness than for non-BRCAness tumors, both for all tumors (58.8% vs. 89.3%, P = .03) and for TNBC (50% vs. 100%, P = .02). All tumors that progressed with taxane therapy had BRCAness. Of the patients with TNBC, those with non-BRCAness cancer had pathologic complete responses significantly more often than did those with BRCAness tumors (77.8% vs. 14.3%, P = .007). After NAC, the clinical response rates were significant lower for BRCAness than for non-BRCAness tumors in all subtypes (P = .002) and in TNBC cases (P = .008). After a median follow-up of 26.4 months, 6 patients-all with BRCAness-had developed recurrence. Patients with BRCAness had shorter progression-free survival than did those with non- BRCAness (P = .049). |
Are prostatic fluid concentrations of isoflavonoids in soy consumers sufficient to inhibit growth of benign and malignant prostatic epithelial cells in vitro? | The differential intestinal metabolism of the soy isoflavones is likely to influence the ability of soy to prevent prostate cancer. While daidzein, genistein, and equol have direct antiproliferative effects on prostatic epithelial cells in vitro, there are no such data for the isoflavone glycitein, or seven metabolites: O-desmethylangolensin (ODMA), 6-hydroxyODMA (6H-ODMA), dihydrodaidzein (DHD), cis-4-hydroxyequol (C4HE), 3'-hydroxydaidzein (3HD), 6-hydroxydaidzein (6HD), and 8-hydroxydaidzein (8HD). In the current study, the in vitro activities of these compounds were elucidated, and the active ranges of concentrations were compared to that found in Caucasian prostatic fluid (PF) and plasma samples. The effects of isoflavonoids on cell growth, cell cycle distribution, and apoptosis (active Caspase 3) were examined on benign prostatic epithelial cells (PrEC), and the prostate cancer cell line LNCaP. PF concentrations of genistein, equol, and daidzein (but not ODMA or DHD) were often within the ranges that reduce PrEC growth in vitro. Profound differences in sensitivities were observed with LNCaP. The hydroxydaidzeins, C4HE, and 6H-ODMA had significant inhibitory effects at 10(-5)M on PrEC growth (but not LNCaP). Glycitein had significant effects on both. Reductions in cell growth were typically associated with both changes in cell cycle distribution and Caspase 3 activation. When five isoflavonoids were used in combination at concentrations present in PF samples, synergistic effects were observed. | We hypothesised that short-term application of bi-level nasal continuous positive airway pressure CPAP (SiPAP) compared with conventional nasal CPAP (nCPAP) at the same mean airway pressure in infants with persistent oxygen need recovering from respiratory distress syndrome would improve CO2 removal with no change in oxygen requirement. Non-blinded, randomised, observational four-period crossover study. Level III NICU; low-birthweight infants requiring CPAP and oxygen while recovering from respiratory distress syndrome. Infants requiring nasal CPAP for >24 h prior to study enrolment, and fraction of inspired oxygen requirement (FiO2) of 0.25-0.5, were randomised to either nCPAP or SiPAP. A crossover design with four 1 h treatment periods was used such that each infant received both treatments twice. Oxygen saturations (SaO2), transcutaneous CO2 (tcCO2) and vital signs were monitored continuously. Polysomnographic recordings were analysed for apnoea, bradycardia and oxygen desaturation. Twenty low-birthweight infants receiving 0.3±0.04% supplemental oxygen on CPAP of 6 cm H2O were studied at an average of 33 days of age (±23 days, SD). There were no differences in tcCO2 or other physiological parameters except mean blood pressure, which was lower during nCPAP (52.3±8.3 vs 54.4±9.1 mm Hg; ±SD; p<0.01). No differences in short or prolonged apnoea, bradycardia or significant desaturation events were observed. |
Is kCNT1 gain of function in 2 epilepsy phenotypes reversed by quinidine? | Mutations in KCNT1 have been implicated in autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) and epilepsy of infancy with migrating focal seizures (EIMFS). More recently, a whole exome sequencing study of epileptic encephalopathies identified an additional de novo mutation in 1 proband with EIMFS. We aim to investigate the electrophysiological and pharmacological characteristics of hKCNT1 mutations and examine developmental expression levels. Here we use a Xenopus laevis oocyte-based automated 2-electrode voltage clamp assay. The effects of quinidine (100 and 300 μM) are also tested. Using quantitative reverse transcriptase polymerase chain reaction, the relative levels of mouse brain mKcnt1 mRNA expression are determined. We demonstrate that KCNT1 mutations implicated in epilepsy cause a marked increase in function. Importantly, there is a significant group difference in gain of function between mutations associated with ADNFLE and EIMFS. Finally, exposure to quinidine significantly reduces this gain of function for all mutations studied. | Systemic inflammation, insulin resistance, and endothelial dysfunction have been implicated in the development of cardiovascular disease in rheumatoid arthritis (RA). Since insulin resistance can promote endothelial dysfunction and anti-TNF-alpha blockade yield a rapid improvement of endothelial function, we have sought to assess whether TNF-alpha blockade may also result in a reduction of insulin serum levels and improvement of insulin resistance in RA patients who require this therapy because of severe and refractory disease. We recruited patients with RA seen over a period of 1 month at Hospital Xeral-Calde, Lugo, Spain, that were on treatment with anti-TNF-alpha monoclonal antibody-infliximab. Patients with diabetes mellitus or plasma glucose > 110 mg/dl were excluded. Fasting blood samples were taken for determination of plasma glucose and serum insulin levels immediately prior to and after infliximab infusion. Twenty-seven RA patients (21 women; mean age: 57.1 years; mean DAS28: 4.43) fulfilled the inclusion criteria. Dramatic reduction in the serum insulin levels and insulin/glucose index was observed following infliximab infusion. Also, a significant improvement of insulin resistance and insulin sensitivity was found. |
Does celecoxib induce epithelial-mesenchymal transition in epithelial ovarian cancer cells via regulating ZEB1 expression? | The purpose of our study was to investigate the therapeutic potential of Celecoxib for epithelial ovarian cancer, especially on cellular morphological changes, proliferation invasion and epithelial-mesenchymal transition (EMT). The MTT and transwell assays were performed to evaluate the effect of Celecoxib on proliferation and invasion ability of ovarian cancer cell lines, respectively. Western blot was carried out to detect the expression of epithelial phenotypes, E-cadherin and Keratin, and mesenchymal phenotypes, N-cadherin and Vimentin, as well as p-AKT, p-ERK and ZEB1. ZEB1 small-interfering RNA (siRNA) was used to downregulate the expression of ZEB1 to further inquiring into the downstream of Celecoxib-induced EMT. Cellular morphological assessment revealed that both A2780 and SKOV3 cells gradually appeared in the morphology of mesenchymal cells after Celecoxib treatment. The MTT assay demonstrated that celecoxib had no effect on cell proliferation. Transwell assay showed that Celecoxib significantly increased the cell invasion ability. Western blot data proved that the expression of E-cadherin and keratin was elevated, whereas the expression of N-cadherin and Vimentin was decreased in a dose-dependent manner compared with the untreated cells, the expression of p-AKT, p-ERK and ZEB1 was also obviously elevated. However, ZEB1 siRNA reversed Celecoxib-induced E-cadherin expression and N-cadherin expression, as well as cellular invasiveness. | While many recent publications have examined the ability of amputees to return to active duty, it remains largely unknown why few amputees deploy after amputation and many amputees do not. The purpose of this study is to examine what predictor(s) exist for whether or not an amputee will deploy after sustaining a combat-related amputation. All U.S. Service members who sustained major extremity amputations from September 2001 through July 2011 were analysed. Amputation level(s), mechanism of injury, time interval to amputation, age, rank, Physical Evaluation Board (PEB) disposition and ability to deploy after amputation were determined. Deployment information after amputation was obtained for 953 amputees. There were 47 (5%) amputees who deployed. There were no significant differences amongst service branches for the deployment of amputees (p > 0.2). Amputees who underwent their amputation on the same day of their injury were significantly less likely to deploy after amputation than those who had their amputation on the day of injury (p = .01). Deployed amputees had significantly lower Injury Severity Scores than amputees who did not deploy (15.98 vs 20.87, p < 0.01) and officers were significantly (p < .01) more likely to deploy and the average age of amputees who deployed was significantly higher than those who did not (27.5 vs 25.1, p < .01). Lastly, those amputees who sustained a transtibial amputation were significantly more likely to deploy than all other amputation levels (p < .01). Nine out of 19 (47%) Special Forces amputees were able to deploy. |
Do [ Effects of continuous positive airway pressure treatment of inflammatory factors in patients with overlap syndrome ]? | To explore the effects of continuous positive airway pressure (CPAP) treatment on the serum levels of associated inflammatory factors in patients with overlap syndrome (OS). Seventy-four patients with obstructive sleep apnea syndrome (OSAS) or chronic obstructive pulmonary disease (COPD) or overlap syndrome (OS) were recruited from Department of Respirology and Affiliated Sleep Center of our hospital from March 2012 to September 2013. They were divided into OSAS (n = 25), COPD (n = 26) and OS (n = 23) groups according to the results of polysomnography (PSG) and spirometry. By enzyme linked immunosorbent assay (ELISA), the serum levels of C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α) and asymmetric dimethylarginine (ADMA) were measured and compared before and at Day 30 post-CPAP in OSAS and OS groups. At pre-CPAP, there was no statistical difference in serum levels of CRP ((7.2 ± 6.6),(8.4 ± 6.8),(8.5 ± 7.9) mg/L) and TNF-α ((33 ± 13),(52 ± 34),(41 ± 33) ng/L) among OSAS, COPD and OS groups (all P > 0.05).However, serum ADMA level in OSAS group were significantly lower than those in COPD group ((0.50 ± 0.08) vs (0.71 ± 0.31) µmol/L, P = 0.002). Compared with before and at Day 30 post-CPAP, although no significant difference existed in serum levels of ADMA (all P > 0.05), at Day 30 post-CPAP there were significantly lower serum levels of CRP ((4.5 ± 4.2) and (5.5 ± 4.1) mg/L) and TNF-α levels ((31 ± 9) and (35 ± 24) ng/L) than those pre-CPAP in OSAS and OS groups respectively (all P < 0.05).No significant difference existed between OSAS and OS groups (all P > 0.05). | Our purpose was to evaluate whether prolonged or irregular bleeding during Norplant implant use could be alleviated with the use of oral hormonal medication. One hundred fifty users of the Norplant levonorgestrel contraceptive implant with prolonged or frequent bleeding were enrolled in this prospective, randomized, comparative study and assigned to one of three treatment groups for 20 days: ethinyl estradiol 50 microg, an oral contraceptive (50 microg ethinyl estradiol and 250 microg levonogestrel), and placebo. Total days of bleeding during treatment and length of the bleeding-free interval were analyzed. Women treated with the levonorgestrel-ethinyl estradiol pill bled an average of 2.6 days during treatment compared with 5.4 and 12.3 days in the ethinyl estradiol and placebo groups, respectively. Differences between both hormonal groups and placebo were significant (p <0.00001); moreover, the combined pill was more effective than ethinyl estradiol along (p <0.0001). |
Is neurodegeneration in frontotemporal lobar degeneration and motor neurone disease associated with expansions in C9orf72 linked to TDP-43 pathology and not associated with aggregated forms of dipeptide repeat proteins? | A hexanucleotide expansion in C9orf72 is the major genetic cause of inherited behavioural variant Frontotemporal dementia (bvFTD) and motor neurone disease (MND), although the pathological mechanism(s) underlying disease remains uncertain. Using antibodies to poly-GA, poly-GP, poly-GR, poly-AP and poly-PR proteins, we examined sections of cerebral cortex, hippocampus, thalamus, cerebellum and spinal cord, from 20 patients with bvFTD and/or MND bearing an expansion in C9orf72 for aggregated deposits of dipeptide repeat proteins (DPR). Antibodies to poly-GA, poly-GP and poly-GR detected numerous rounded cytoplasmic inclusions (NCI) within granule cells of hippocampal dentate gyrus and those of the cerebellum, as well as 'star-burst' shaped NCI in pyramidal neurones of CA3/4 region of hippocampus. NCI were uncommon in Purkinje cells, and only very rarely seen in anterior horn cells. Poly-PA antibody detected occasional NCI within CA3/4 neurones alone, whereas poly-PR antibody did not identify any NCI but immunostained the nucleus of anterior horn cells, CA3/4 neurones and Purkinje cells, in patients with or without expansion in C9orf72, as well as in normal controls. Poly-GA antibody generally detected more DPR than poly-GP, which in turn was greater than poly-GR. All patients with bvFTD + MND or MND showed plentiful p62/TDP-43 positive inclusions in remaining anterior horn cells. | To estimate the frequency of ambulatory care-sensitive hospitalizations (ACSHs) and to compare the risk of ACSH in breast cancer survivors living in high-poverty with that of those in low-poverty areas. Prospective, multilevel study. National, population-based 1991 to 1999 National Cancer Institute Surveillance, Epidemiology, and End Results Program data linked with Medicare claims data throughout the United States. Breast cancer survivors aged 66 and older. ACSH was classified according to diagnosis at hospitalization. The percentage of the population living below the U.S. federal poverty line was calculated at the census-tract level. Potential confounders included demographic characteristics, comorbidity, tumor and treatment factors, and availability of medical care. Of 47,643 women, 13.3% had at least one ACSH. Women who lived in high-poverty census tracts (>or=30% poverty rate) were 1.5 times (95% confidence interval (CI)=1.34-1.72) as likely to have at least one ACSH after diagnosis as women who lived in low-poverty census tracts (<10% poverty rate). After adjusting for most confounders, results remained unchanged. After adjustment for comorbidity, the hazard ratio (HR) was reduced to 1.34 (95% CI=1.18-1.52), but adjusting for all variables did not further reduce the risk of ACSH associated with poverty rate beyond adjustment for comorbidity (HR=1.37, 95% CI=1.19-1.58). |
Does joint instability lead to long-term alterations to knee synovium and osteoarthritis in a rabbit model? | Joint instability is believed to promote early osteoarthritic changes in the knee. Inflammatory reactions are associated with cartilage degradation in osteoarthritis (OA) but their possible synergistic or additive effects remain largely unexplored. The goal of the present study was to investigate the in vivo effects of Botulinum Toxin A (BTX-A) induced joint instability on intraarticular alterations in an otherwise intact rabbit knee joint model. Ten 1-year-old female New Zealand White rabbits (average 5.7 kg, range 4.8-6.6 kg) were randomly assigned to receive three monthly unilateral intramuscular injections of BTX-A (experimental group), or no treatment (control group). After 90 days, all knees were analyzed for specific mRNA levels using RT-qPCR. The synovium and cartilage tissue was assessed for histological alterations using the OARSI scoring system. Cartilage and synovial histology showed significant higher OARSI scores in the BTX-A group animals compared to the untreated controls and contralateral limbs. There were no differences between the untreated control and the contralateral experimental limbs. Gene expression showed significant elevations for collagen I, collagen III, nitric oxide, TGF-β, IL-1 and IL-6 compared to the healthy controls. | The NewHealth Foundation, a Spanish non-for-profit organisation, is leading the project Compassionate Cities. "We are all one". The project aims to involve citizens in creating communities of care to help people at the end of life phase. To design and develop a practical model to engage communities in the process of improving the quality of public palliative care. To empower key advocates of end-of-life care. To evaluate communities' interventions, their feasibility and impact in terms of shared benefit for stakeholders. Identification and recruitment of key advocates of care. Design of an innovative model of compassionate cities. Define community of care activities through a triple-dimension methodology: [To Want - To Know - To Do]. An innovative model has been developed: The Collaborating Centre (schools, colleges, cultural centres, professional's associations, patient's associations, NGOs, brotherhoods, churches, etc.) organises the agenda of training events and promotes networking. Citizens set up "care clusters", becoming available to provide care. The Beneficiaries Centres (hospices, nursing homes, residential centres, patient organisations, hospitals, health and social care centres, etc.) contact the clusters when care needs of patients are identified. The palliative care specialist supports Compassionate Communities training and refer patients to clusters. Local Government (also a collaborating centre) encourages awareness campaigns and provides institutional support. Companies collaborate in promoting and funding the project. Six cities in Spain and 3 in Colombia have already been selected and local initiatives are already being promoted (more results to be provided at the Congress). |
Does maternal high-fat hypercaloric diet during pregnancy result in persistent metabolic and respiratory abnormalities in offspring? | We have shown in a previous population-based study significant correlation between childhood asthma and early abnormalities of lipid and glucose metabolism. This study's specific aim was to determine whether maternal nutrition in pregnancy affects postnatal metabolic and respiratory outcomes in the offspring. On gestation day 1, dams were switched from standard chow to either high-fat hypercaloric diet or control diet. Terminal experiments were performed on newborn and weanling offspring of dams fed the study diet during gestation and lactation, and on adult offspring maintained on the same diet as their mother. Pups born from high-fat hypercaloric diet (HFD) dams developed metabolic abnormalities persistent throughout development. Cytokine expression analysis of lung tissues from newborns born to HFD dams revealed a strong proinflammatory pattern. Gene expression of neurotrophic factors and receptors was upregulated in lungs of weanlings born to HFD dams, and this was associated to higher respiratory system resistance and lower compliance at baseline, as well as hyperreactivity to aerosolized methacholine. Furthermore, HFD dams delivered pups prone to develop more severe disease after respiratory syncytial virus (RSV) infection. | The aim of this study was to review the impact of salvage external beam radiotherapy (EBRT) of postprostatectomy patients with long-term follow-up on biochemical-free recurrence (BFR) and metastatic-free survival, and to describe pathological and clinical predictors of outcome. In the period 1987-2010, 76 postprostatectomy patients with biochemical and clinical recurrence received salvage EBRT. Patients were treated with conformal EBRT and 68 (90%) received a dose of 70 Gy; eight patients (10%) received a dose of 60-64 Gy. No patients received adjuvant or neoadjuvant androgen deprivation therapy in conjunction with salvage EBRT. The median follow-up time after salvage EBRT was 82 months (range 5-192 months). Seventeen patients (22%) developed biochemical recurrence subsequent to postprostatectomy salvage EBRT during the observation time, and the overall 50 and 75 month actuarial BFR rates after salvage EBRT were 84% and 79%, respectively. Seven patients (9%) developed metastatic disease and two patients died of prostate cancer. Independent predictors of biochemical recurrence were seminal vesicle invasion (SVI) in the prostatectomy specimen (p < 0.05) and prostate-specific antigen doubling time (PSADT) of 6 months or less (p = 0.041) before salvage EBRT. |
Is high-sensitivity C-reactive protein only weakly related to cardiovascular damage after adjustment for traditional cardiovascular risk factors? | The independent prognostic value of high-sensitivity C-reactive protein (hsCRP) has been questioned, and consequently we decided to investigate whether hsCRP was associated with subclinical cardiovascular (CV) damage independently of traditional CV risk factors. In a population-based sample of 2028 apparently healthy individuals without prior stroke or myocardial infarction not receiving any CV, anti-diabetic or lipid-lowering treatment, aged 41, 51, 61 or 71 years, we measured in 1993 serum hsCRP, traditional CV risk factors (lifestyle, metabolic and hemodynamic) and assessed subclinical CV damage [atherosclerotic plaques in the carotid arteries, pulse wave velocity (PWV), urine albumin/creatinine ratio (UACR), left ventricular (LV) mass and ejection fraction]. Adjusting for age and gender in multiple regression analyses, higher log(hsCRP) was associated with higher logPWV (beta = 0.15) and log(left ventricular mass index) (LVMI) (beta = 0.09, both P < 0.001), LV relative wall thickness (beta = 0.07, P < 0.01), logUACR (beta = 0.04, P = 0.06) and more atherosclerotic plaques (beta = 0.06, P < 0.05). However, higher log(hsCRP) was only weakly associated with higher logPWV(beta = 0.06, P < 0.05) and more atherosclerotic plaques (beta = 0.04, P = 0.06) when adjusting for other significant CV risk factors, such as daily smoking (beta = 0.18), female gender (beta = -0.17), older age (beta = 0.11), lower log(high density lipoprotein cholesterol) (beta = -0.11, all P < 0.001); wider waist (beta = 0.17), higher body mass index (beta = 0.14), higher heart rate (beta = 0.06, all P < 0.01); and higher log(plasma glucose) (beta = 0.05, P < 0.05) (adj. R2 = 0.19, P < 0.001). | Intrathecal adenosine is antinociceptive under conditions of central sensitization, but not in response to acute stimuli in normals. The reasons for this selective circumstance of action remain unclear, but some evidence links adenosine's antinociceptive effects to release of norepinephrine by terminals in the spinal cord. The purpose of this study was to test whether spinal adenosine induces norepinephrine release selectively in settings of hypersensitivity. Rats randomly assigned to spinal nerve ligation, sham operation, or no operation were anesthetized. A microdialysis fiber was implanted in the spinal cord dorsal horn at the L5-L6 level and perfused with artificial cerebrospinal fluid. After washout and a baseline sample period, adenosine at various concentrations was infused through the fiber for 150 min, and samples were collected every 15 min. In ligated, but not in sham or normal animals, adenosine perfusion increased norepinephrine in spinal cord microdialysates in a concentration-dependent manner. The effects of adenosine plateaued after 75 min and remained stable until the end of the experiment. Intravenous injection of selective adenosine A1 and A2 receptor antagonists revealed that adenosine's effect on spinal norepinephrine release was A1 receptor mediated. |
Does lipid emulsion infusion rescue dogs from bupivacaine-induced cardiac toxicity? | We previously demonstrated in rats that intravenous infusion of a lipid emulsion increases survival in resuscitation from severe bupivacaine cardiac toxicity. The present studies were undertaken to determine if this method is similarly effective in a non-rodent model using a larger animal. Bupivacaine, 10 mg/kg, was administered intravenously over 10 seconds to fasted dogs under isoflurane general anesthesia. Resuscitation included 10 minutes of internal cardiac massage followed with either saline or 20% lipid infusion, administered as a 4-mL/kg bolus followed by continuous infusion at 0.5 mL/kg/min for 10 minutes. Electrocardiogram (EKG), arterial blood pressure (BP), and myocardial pH (pHm) and pO2 (pmO2) were continuously measured. Survival after 10 minutes of unsuccessful cardiac massage was successful for all lipid-treated dogs (n = 6), but with no survivors in the saline controls (n = 6) (P <.01). Hemodynamics, PmO2, and pHm were improved during resuscitation with lipid compared with saline treatment in which dogs did not recover. | One of the recognized candidate genes of osteoarthritis (OA) is the ADAM metallopeptidase domain 12 (meltrin alpha) gene. We investigated the potential role of two single nucleotide polymorphisms (SNP) of the ADAM12 gene in susceptibility to radiographic knee OA and its progression in an Estonian cohort. The rs3740199 and rs1871054 polymorphisms were genotyped according to restriction fragment polymorphism in a population-based cohort consisting of 189 subjects selected from the age group 32-55 years. The radiological features of OA were measured in the tibio- and patellofemoral joints (PFJ). The X-ray investigation was repeated 3 years later for estimation of OA progression. We found statistically significant association between rs3740199 polymorphism and patellofemoral OA in male patients (P=0.014), genetic risk was mostly related to CC homozygosity. The same SNP also affected the presence of advanced grade (II+III) osteophytes in the whole group (P=0.042) and the occurrence of osteophytes on the patellar margins in the PFJ (P=0.046). In OA progression the most significant association was found between joint space narrowing of the tibiofemoral joint and rs3740199 SNP in women (P=0.018). The rs1871054 polymorphism was not related to OA susceptibility or to progression traits. In our study the haplotype GC (rs3740199/rs1871054) was associated with reduced risk for development of osteophytes in the PFJ (P=0.041). |
Does the CC chemokine eotaxin/CCL11 have a selective profibrogenic effect on human lung fibroblasts? | Eotaxin/CCL11 plays an important role in asthma. It acts through the chemokine receptor CCR3 expressed on hematopoietic and nonhematopoietic cells in the lung. To determine whether eotaxin/CCL11 modulates lung and bronchial fibroblast properties and thereby might contribute to airway remodeling. CCR3 expression was characterized on a lung fibroblast line (MRC-5; flow cytometry, fluorescent microscopy, RT-PCR, and Northern blotting), on primary bronchial fibroblasts (flow cytometry), and on fibroblasts in human lung tissue (confocal laser microscopy). The effects of eotaxin/CCL11 on lung fibroblast migration (Boyden chamber), proliferation (tritiated thymidine incorporation), alpha-smooth muscle actin expression (ELISA), 3-dimensional collagen gel contraction (floating gel), pro-alpha1(I) collagen mRNA (Northern blotting), total collagen synthesis (tritiated proline incorporation), matrix metalloproteinase activity (gelatin zymography), and TGF-beta(1) release (ELISA) were evaluated. The contribution of eotaxin/CCL11/CCR3 binding on lung fibroblasts was also investigated by neutralizing experiments. CCR3 is constitutively expressed in cultured lung and primary bronchial fibroblasts and colocalizes with specific surface markers for human fibroblasts in lung tissue. Eotaxin/CCL11 selectively modulates fibroblast activities by increasing their proliferation, matrix metalloproteinase 2 activity, and collagen synthesis but not their differentiation into myofibroblasts, contractility in collagen gel, or TGF-beta(1) release. Eotaxin/CCL11 enhances migration of lung fibroblasts in response to nonspecific chemoattractants, and this effect is completely inhibited by anti-CCR3-neutralizing antibodies. | Post-prandial glucose may be a risk factor for cardiovascular disease and chronic diabetic complications. We tested the hypothesis that post-prandial hyperglycaemia is common in type 2 diabetes, even among patients in apparently good glycaemic control, and that simple clinical characteristics identify subsets of diabetic patients with frequent post-prandial hyperglycaemia. Three self-assessed daily blood glucose profiles over a 1-week period, including 18 glucose readings before and 2 h after meals, were obtained from 3,284 unselected outpatients (men 51%; age 63+/-10 years) with non-insulin-treated type 2 diabetes mellitus attending 500 different diabetes clinics operating throughout Italy. A post-prandial blood glucose value >8.89 mmol/l (160 mg/dl) was recorded at least once in 84% of patients, and 81% of patients had at least one Delta glucose > or =2.22 mmol/l (40 mg/dl). Among patients with apparently good metabolic control, 38% had >40% of post-prandial blood glucose readings >8.89 mmol/l (> or =4 of 9 meals in total), and 36% had >40% Delta glucose > or =2.22 mmol/l. In multivariate analysis adjusted for pre-prandial glucose levels, older age, longer duration of diabetes, absence of obesity, hyperlipidaemia and hypertension, as well as treatment with sulfonylureas, were significantly associated with greater glucose excursions after meals. |
Is contralateral duplex scanning for deep venous thrombosis unnecessary in patients with symptoms? | Bilateral lower extremity venous duplex scanning for acute deep venous thrombosis (DVT) has been advocated because of the high incidence of occult contralateral leg involvement. We investigated the clinical necessity of such a policy. The results from 2996 venous duplex studies performed during the past 2 years were retrospectively reviewed. A total of 1694 of these scans were performed on patients with symptoms, of whom 248 (15%) were found to have an acute DVT. Symptoms were limited to one side in 198 patients, whereas bilateral complaints were noted in 50 patients. Among the patients with symptoms of acute DVT, 72 (29%) had bilateral involvement. Bilaterality was more likely in patients with bilateral symptoms than in those with only unilateral symptoms (56% vs 22%; p < 0.005). Of the patients with unilateral symptoms and bilateral DVT, all of them had either acute (80%) or acute and chronic (20%) thrombosis in the symptomatic leg. The contralateral asymptomatic limb had fewer acute and more chronic DVT (41% and 55%, respectively). No patient from the entire group admitted with symptoms had an acute DVT in the asymptomatic limb without a concomitant acute DVT in the symptomatic leg. Unilateral scanning would decrease the examination time by 21% and potentially increase total reimbursement for symptomatic venous scans by 9% compared with routine bilateral duplex scanning. | We have shown in a previous population-based study significant correlation between childhood asthma and early abnormalities of lipid and glucose metabolism. This study's specific aim was to determine whether maternal nutrition in pregnancy affects postnatal metabolic and respiratory outcomes in the offspring. On gestation day 1, dams were switched from standard chow to either high-fat hypercaloric diet or control diet. Terminal experiments were performed on newborn and weanling offspring of dams fed the study diet during gestation and lactation, and on adult offspring maintained on the same diet as their mother. Pups born from high-fat hypercaloric diet (HFD) dams developed metabolic abnormalities persistent throughout development. Cytokine expression analysis of lung tissues from newborns born to HFD dams revealed a strong proinflammatory pattern. Gene expression of neurotrophic factors and receptors was upregulated in lungs of weanlings born to HFD dams, and this was associated to higher respiratory system resistance and lower compliance at baseline, as well as hyperreactivity to aerosolized methacholine. Furthermore, HFD dams delivered pups prone to develop more severe disease after respiratory syncytial virus (RSV) infection. |
Is limited range of motion a significant factor in venous ulceration? | Calf muscle pump dysfunction is a recognized factor in chronic venous insufficiency (CVI). We investigated the hypothesis that limbs with CVI have a reduced ankle range of motion (ROM) that may be responsible for the poor calf pump function associated with venous ulceration. Ankle ROM and calf pump function were assessed in 32 limbs of 26 adult men. Limbs were selected on the basis of clinical presentation: normal (n = 6 limbs), class 1 or 2 CVI with no history of ulceration (n = 9 limbs), class 3 CVI with healed ulceration (n = 9 limbs), and class 3 CVI with active ulceration (n = 8 limbs). ROM was determined by goniometry during maximal plantar flexion and dorsiflexion of the ankle. Calf pump function was determined by air plethysmographic measurement of ejection fraction (EF) and residual volume fraction (RVF). Ankle ROM was significantly (p < 0.05) reduced in each CVI group compared with age-matched control subjects, because of decreases in both plantar flexion and dorsiflexion. Calf pump function was significantly impaired (decreased EF and increased RVF) in ulcerated limbs. ROM was significantly correlated to EF and RVF. Impairment of ROM and calf pump function was associated with deterioration in the clinical classification of venous disease. | Recent studies have demonstrated that the neural precursor cell expressed, developmentally downregulated 4-like (Nedd4L) gene plays a role in the progression of various cancers. However, reports describing Nedd4L expression in ovarian cancer tissues are limited. A cohort (n = 117) of archival formalin-fixed, paraffin embedded resected normal ovarian epithelial tissues (n = 10), benign ovarian epithelial tumor tissues (n = 10), serous borderline ovarian epithelial tumor tissues (n = 14), mucous borderline ovarian epithelial tumor tissues (n = 11), and invasive ovarian epithelial cancer tissues (n = 72) were assessed for Nedd4L protein expression using immunohistochemistry. Nedd4L protein expression was significantly decreased in invasive ovarian epithelial cancer tissues compared to non-cancer tissues (P < 0.05). Decreased Nedd4L protein expression correlated with clinical stage, pathological grade, lymph node metastasis and survival (P < 0.05). |
Is intraflagellar transport protein 27 a small G protein involved in cell-cycle control? | Intraflagellar transport (IFT) is a motility process operating between the ciliary/flagellar (interchangeable terms) membrane and the microtubular axoneme of motile and sensory cilia. Multipolypeptide IFT particles, composed of complexes A and B, carry flagellar precursors to their assembly site at the flagellar tip (anterograde) powered by kinesin, and turnover products from the tip back to the cytoplasm (retrograde) driven by cytoplasmic dynein. IFT is essential for the assembly and maintenance of almost all eukaryotic cilia and flagella, and mutations affecting either the IFT motors or the IFT particle polypeptides result in the inability to assemble normal flagella or in defects in the sensory functions of cilia. We found that the IFT complex B polypeptide, IFT27, is a Rab-like small G protein. Reduction of the level of IFT27 by RNA interference reduces the levels of other complex A and B proteins, suggesting that this protein is instrumental in maintaining the stability of both IFT complexes. Furthermore, in addition to its role in flagellar assembly, IFT27 is unique among IFT polypeptides in that its partial knockdown results in defects in cytokinesis and elongation of the cell cycle and a more complete knockdown is lethal. | The purpose of the present study was to investigate the relationships between blood pressure (BP), insulin resistance as determined by a homeostasis model (HOMA-IR), and body fat distribution. Anthropometric indices of adiposity, metabolic variables (fasting serum insulin and a homeostasis model assessment [HOMA] index of insulin sensitivity), BP and several cardiovascular risk factors were measured during a cross sectional survey of 53477 apparently healthy Korean subjects who requested a health status check. Hypertension was defined as a systolic BP > or = 140 mmHg or a diastolic BP > or = 90 mmHg and we excluded the subjects taking BP-lowering medication. Systolic and diastolic blood pressure (SBP, DBP) were positively and significantly associated with age, body mass index, waist circumference, and waist/hip ratio. In addition, SBP and DBP were positively associated with fasting serum insulin levels and the HOMA index. By multiple regression analysis age, waist circumference, body mass index, HOMA index and female sex were independently associated with either increased SBP or DBP. When the population is divided into quintiles according to insulin resistance (measured by HOMA analysis) prevalence of hypertension in the second, third, fourth and fifth quintiles compared to subjects in the first quintile are 1.004(95% CI 0.875-1.152, p = 0.957), 1.200(95% CI 1.052-1.369, p = 0.007), 1.312(95% CI 1.151-1.494 p < 0.001 ), and 1.603(95% CI 1.408-1.825 p < 0.001). In addition age, sex, body mass index and waist circumference were found to be significantly associated with hypertension. |
Does tryptase inhibit motility of human spermatozoa mainly by activation of the mitogen-activated protein kinase pathway? | We previously localized protease-activated receptor 2 (PAR-2) on human spermatozoa and demonstrated that activation of PAR-2 by the mast cell (MC) product tryptase inhibits sperm motility. Importantly, tryptase-secreting MCs are encountered in the male and female genital tract, implying that MC-spermatozoa interactions may be as yet unrecognized factors affecting sperm fertilizing ability. In order to elucidate how tryptase via activation of PAR-2 acts in human spermatozoa, we studied intracellular signal transduction events. Impairment of sperm motility by tryptase was not dependent on the presence of extracellular Ca2+ and tryptase did not alter intracellular Ca2+ levels. Pre-incubation with pertussis toxin (PTX) failed to prevent tryptase effects on sperm motility. Western blot analyses revealed that tryptase increased phosphorylation of the mitogen-activated protein kinases (MAPK) ERK1/2, an effect which was blocked by the MAPK pathway inhibitor PD98059. Pre-treatment of spermatozoa with this inhibitor also blocked the inhibtion of sperm motility evoked by tryptase. | Treating hyperglycaemia in hospitalized patients has proven to be beneficial, particularly in those with obstructive vascular disease. In a cohort of patients undergoing resection for oesophageal carcinoma (a group of patients with severe surgical stress but a low prevalence of vascular disease), we investigated whether early postoperative hyperglycaemia is associated with increased incidence of infectious complications and prolonged in-hospital stay. Postoperative glucose values up to 48 hours after surgery were retrieved for 151 patients with American Society of Anesthesiologists class I or II who had been previously included in a randomized trial conducted in a tertiary referral hospital. Multivariate regression analysis was used to define the independent contribution of possible risk factors selected by univariate analysis. In univariate regression analysis, postoperative glucose levels were associated with increased length of in-hospital stay (P < 0.001) but not with infectious complications (P = 0.21). However, postoperative glucose concentration was not found to be an independent risk factor for prolonged in-hospital stay in multivariate analysis (P = 0.20). |
Do birth order and hospitalization for alcohol and narcotics use in Sweden? | Previous studies have shown that birth order is an important predictor of later life health as well as socioeconomic attainment. In this study, we examine the relationship between birth order and hospitalization for alcohol and narcotics use in Sweden. We study the relationship between birth order and hospitalization related to alcohol and narcotics use before and after the age of 20 using Swedish register data for cohorts born 1987-1994. We apply Cox proportional hazard models and use sibling fixed effects, eliminating confounding by factors shared by the siblings. Before age 20 we find that later born siblings are hospitalized for alcohol use at a higher rate than first-borns, and there is a monotonic increase in the hazard of hospitalization with increasing birth order. Second-borns are hospitalized at a rate 47% higher than first-borns, and third-borns at a rate 65% higher. Similar patterns are observed for hospitalization for narcotics use. After age 20 the pattern is similar, but the association is weaker. These patterns are consistent across various sibling group sizes. | Human ZR75-1 cells were among the first few characterized estrogen-dependent mammary gland carcinoma cell lines and had been utilized in various studies for the pro- or antitumor effect of xenoestrogens and antiestrogens. The objective of this study was to establish a breast tumor model in ZR75-1 cells bearing multimodal reporter genes to allow noninvasive imaging of tumor growth using fluorescence and nuclear imaging platforms. Enhanced green fluorescent protein (eGFP) cDNA was fused at the C-terminus with herpes simplex virus type 1 thymidine kinase (HSV1-tk) to form the fusion reporter gene (eGFP-tk). In vitro proliferation, migration, and invasion assays revealed that eGFP-tk-transfected ZR75-1 cells exhibited decreased proliferation rate, migratory activity, and invasion ability compared to the wild-type cells. The functional HSV1-tk enzymatic activity in stably transfected cells were confirmed by in vitro ganciclovir (GCV) sensitivity and [123I]2-fluoro-2-deoxy-1-beta-D-arabinofuranosyl-5-iodouracil (FIAU) accumulation assays. In vivo fluorescence and nuclear imaging were performed on nude mice bearing multiple subcutaneous xenografts established from ZR75-1-eGFP-tk and wild-type cells. Optical imaging was able to detect the green fluorescence of eGFP-tk tumor. The eGFP-tk reporter gene-specific imaging was achieved by single photon emission computed tomography (SPECT) using [123I]FIAU as a radiotracer and demonstrated decreased FIAU uptake in eGFP-tk tumor by GCV treatment. Probably due to a flare reaction after GCV treatment, micro-positron emission tomography (micro-PET) imaging using 2-deoxy-2-[18F]fluoro-D-glucose (FDG) could not demonstrate decreases in FDG uptake. However, in vitro metabolic assay also revealed that eGFP-tk cells transiently increased [3H]-deoxyglucose uptake in response to GCV treatment. |
Do calyx and dimorphic neurons of mouse Scarpa 's ganglion express histamine H3 receptors? | Histamine-related drugs are commonly used in the treatment of vertigo and related vestibular disorders. The site of action of these drugs however has not been elucidated yet. Recent works on amphibians showed that histamine H3 receptor antagonists, e.g. betahistine, inhibit the afferent discharge recorded from the vestibular nerve. To assess the expression of H3 histamine receptors in vestibular neurons, we performed mRNA RT-PCR and immunofluorescence experiments in mouse Scarpa's ganglia. RT-PCR analysis showed the presence of H3 receptor mRNA in mouse ganglia tissue. H3 protein expression was found in vestibular neurons characterized by large and roundish soma, which labeled for calretinin and calbindin. | To determine whether there is a direct relationship between diet quality and quality of life in breast cancer survivors. Subjects (n = 714) were members of the Health, Eating, Activity, and Lifestyle study, a study of breast cancer prognosis conducted in three areas of the western United States. Approximately 2 years after entry to this study, diet data were collecting using food frequency questionnaires. These data were used to classify diet quality using the Diet Quality Index. Approximately 10 months later, data on quality of life were gathered using the Medical Outcomes Study 36-Item short form health survey. After controlling for age, education, race/ethnicity, body mass index, stage of disease, and time from diagnosis to quality of life measurement, women with excellent diet quality had significantly better scores than women with poor diet quality for overall mental health functioning and for 3 of 4 mental health subscale scores and 2 of 4 physical health subscale scores. |
Does variation in axillary node dissection influence the degree of nodal involvement in breast cancer patients? | The number of positive axillary lymph nodes predicts prognosis and is often important in determining adjuvant chemotherapy in breast cancer patients. This study was undertaken to determine if differences in the extent of axillary node dissection would alter the number of reported positive nodes. The study population consisted of 302 patients with invasive breast cancer who underwent complete (level I/II/III) axillary lymph node dissection. Assuming that all patients had undergone a level I/II dissection, it was determined how frequently a patient's nodal category (0, 1-3, 4-9, >10 positive nodes) would have been altered if a level I or level I/II/III dissection were performed. Assuming that all 302 patients had undergone a level I/II dissection, performing only level I dissection would have resulted in a change in nodal category in 15.9% of all patients and 36.1% of patients with positive nodes. The corresponding changes for a level I/II/III dissection would have been 4.3% and 9.5%, respectively. | The dietary determinants of adolescent blood pressure (BP) are not well understood. We determined the association between major dietary patterns and BP in a sample of Iranian adolescents. This cross-sectional study was conducted among a representative sample (n = 557) of Shirazi adolescents aged 12-19 years. Participants' systolic and diastolic BP was measured using a validated oscillometric BP monitor. Usual dietary intakes during the past 12 months were assessed using a valid and reproducible 168-item semiquantitative food frequency questionnaire through face-to-face interviews. Principal component factor analysis was used to identify major dietary patterns based on a set of 25 predefined food groups. Overall, three major dietary patterns were identified, among which only the Western pattern (abundant in soft drinks, sweets and desserts, salt, mayonnaise, tea and coffee, salty snacks, high-fat dairy products, French fries, and red or processed meats) had a significant association with BP. After adjusting for potential confounders in the analysis of covariance models, multivariable adjusted means of the systolic and mean BP of subjects in the highest tertile of the Western pattern score were significantly higher than those in the lowest tertile (for systolic BP: mean difference 6.9 mmHg, P = 0.001; and for mean BP: mean difference 4.2 mmHg, P = 0.003). A similar but statistically insignificant difference was observed in terms of diastolic BP. |
Do treatment of Renal Stones ≥20 mm with Extracorporeal Shock Wave Lithotripsy? | To identify subgroups of patients with renal stones ≥20 mm that are more suitable for extracorporeal shock wave lithotripsy (ESWL) monotherapy. A total of 376 patients with renal stones ≥20 mm underwent monotherapy with ESWL. The treatment outcome was evaluated after 3 months of follow-up. A stone-free status or fragmentation of stones to 4 mm or smaller was considered efficacious. At 3 months after treatment, the overall stone-free rate was 64.4%, and the efficacy rate was 70.7%. The efficacy rate was 89.4% for patients with a residual stone surface area ≤50% of baseline after the first ESWL, while the efficacy rate was 32.4% for other patients. The efficacy was 92.2% for stones ≤400 mm2 and those with lower radiodensity, as determined by a plain (KUB) film. | Allergic bronchopulmonary aspergillosis (ABPA) is characterized by a Th2 immune response. Mouse models suggest a critical role for the Th2 chemokines thymus- and activation-regulated chemokine (TARC) and macrophage-derived chemokine (MDC) in ABPA. To determine whether serum levels of TARC and MDC characterize ABPA in patients with cystic fibrosis (CF) and to examine longitudinally if levels of TARC and MDC indicate ABPA exacerbations in patients with CF. Levels of TARC and MDC and levels of Th1 (IL-12 and IFN-gamma) and Th2 (IL-4, IL-5, and IL-13) cytokines were analyzed in serum of 16 patients with CF with ABPA, six non-CF patients with asthma with ABPA, 13 patients with CF colonized with Aspergillus fumigatus, six patients with CF sensitized to A. fumigatus, 12 atopic patients with CF, and 13 non-CF atopic control subjects by ELISA. The longitudinal course of TARC, MDC, and IgE levels was assessed during ABPA episodes. Patients with ABPA had significantly higher serum levels of TARC compared with the other patient groups. Cytokine levels did not differ among the patient groups. Longitudinally, levels of TARC indicated ABPA exacerbations in patients with CF more clearly than IgE levels. In patients with CF and ABPA, levels of TARC correlated positively with specific IgE to A. fumigatus and rAsp f4. |
Is pKCε a negative regulator of PVAT-derived vessel formation? | Vessel formation is a crucial event in tissue repair after injury. Thus, one assumption of innovative therapeutic approaches is the understanding of its molecular mechanisms. Notwithstanding our knowledge of the role of Protein Kinase C epsilon (PKCε) in cardio-protection and vascular restenosis, its role in vessel progenitor differentiation remains elusive. Given the availability of PKCε pharmacological modulators already tested in clinical trials, the specific aim of this study is to unravel the role of PKCε in vessel progenitor differentiation, with implications in vascular pathology and vasculogenesis. Mouse Peri-Vascular Adipose Tissue (PVAT) was used as source of mesenchymal vessel progenitors. VEGF-induced differentiation of PVAT cells down-regulates both PKCε and p-PAK1 protein expression levels. PKCε overexpression and activation: i) reduced the expression levels of SMA and PECAM in endothelial differentiation of PVAT cells; ii) completely abrogated tubules formation in collagen gel assays; iii) increased the expression of p-PAK1. | Fusarium onychomycoses are weakly responsive or unresponsive to standard onychomycosis treatments with oral terbinafine and itraconazole. To examine whether the use of terbinafine and itraconazole, which are highly effective in fighting Trichophyton onychomycoses, could be a cause of the high incidence of Fusarium nail infections. Polymerase chain reaction methods were used to detect both Fusarium spp. and Trichophyton spp. in nails of patients who had either received treatment previously or not. No significant microbiological differences were found between treated and untreated patients. In 24 of 79 cases (30%), Fusarium spp. was detected in samples of patients having had no previous antifungal therapy and when Trichophyton spp. grew in culture. |
Are n-palmitoylethanolamine and N-acetylethanolamine effective in asteatotic eczema : results of a randomized , double-blind , controlled study in 60 patients? | Asteatotic eczema (AE) is characterized by itchy, dry, rough, and scaling skin. The treatments for AE are mainly emollients, usually containing urea, lactic acid, or a lactate salt. N-palmitoylethanolamine (PEA) and N-acetylethanolamine (AEA) are both endogenous lipids used as novel therapeutic tools in the treatment of many skin diseases. The purpose of this study was to compare a PEA/AEA emollient with a traditional emollient in the treatment of AE. A monocentric, randomized, double-blind, comparative trial was conducted in 60 AE patients to evaluate and compare the efficacy of the two emollients. The level of skin dryness among the subjects ranged from mild to moderate. The subjects' skin barrier function and the current perception threshold were tested for 28 days by clinical scoring and bioengineering technology. The results showed that, although some aspects were improved in both groups, the group using the emollient containing PEA/AEA presented a better skin surface change in capacitance. However, the most impressive finding was the ability of the PEA/AEA emollient to increase the 5 Hz current perception threshold to a normal level after 7 days, with a significant difference between values at baseline and after 14 days. A current perception threshold of 5 Hz was positively and significantly correlated with skin surface hydration and negatively correlated with transepidermal water loss in the PEA/AEA emollient group. | The intertidal copepod Tigriopus californicus is a model for studying the process of genetic divergence in allopatry and for probing the nature of genetic changes that lead to reproductive isolation. Although previous studies have revealed a pattern of remarkably high levels of genetic divergence between the populations of this species at several spatial scales, it is not clear what types of historical processes are responsible. Particularly lacking are data that can yield insights into population history from the finest scales of geographic resolution. Sequence variation in both cytochrome b (CYTB, mtDNA) and the rieske iron-sulfur protein (RISP, nuclear) are examined at a fine scale within four different regions for populations of T. californicus. High levels of genetic divergence are seen for both genes at the broader scale, and genetic subdivision is apparent at nearly all scales in these populations for these two genes. Patterns of polymorphism and divergence in both CYTB and RISP suggest that selection may be leading to non-neutral evolution of these genes in several cases but a pervasive pattern of neither selection nor coadaptation is seen for these markers. |
Is core imprint cytology of screen-detected breast lesions predictive of the histologic results? | In multidisciplinary assessment clinics for screen-detected breast lesions, onsite cytopathologists provide immediate results of fine-needle aspiration biopsies (FNABs) and this information is used for patient counseling and treatment planning. Such consultation is not possible for the increasing proportion of lesions that are being assessed by core biopsy. If core imprint cytology (CIC) of breast cores can be shown to be reliable in a significant proportion of screen-detected lesions, this technique may be of clinical value in such clinics. In the setting of a large, accredited, population-based breast cancer screening program, prospective results of CIC were gathered on 567 lesions and correlated with the results of core biopsy to determine the performance indicators for CIC. The positive predictive value of a diagnosis of malignancy on CIC was 98.2% and the negative predictive value was 77.8%. The absolute sensitivity was 42.2%, complete sensitivity (inclusive of suspicious and atypical results) was 86.4%, absolute specificity was 56.3%, and total specificity (inclusive of acellular imprints) was 83.7%. The 2 false-positive imprints had atypical ductal hyperplasia on core histology but were found to be ductal carcinoma in situ (DCIS) on excision. False-negative imprints are a greater challenge, with 13.6% of malignant lesions producing benign-appearing or acellular imprints. Low-grade DCIS, lobular, and special type cancers account for most such lesions. The results of the current study also demonstrated significant variations in the accuracy of CIC in microcalcifications versus parenchymal lesions. In particular, the results of acellular imprints are analogous to benign CIC findings for microcalcifications but not in parenchymal lesions. | Ischemia/reperfusion (I/R) injury, which is commonly seen in the field of renal surgery or transplantation, is a major cause of acute renal failure (ARF). The ischemic ARF in diabetic rats is much more severe than that in the normal rats exposed to as same ischemic time. Ischemic post-conditioning (IPO) is a phenomenon by which intermittent interruptions of blood flow in the early phase of reperfusion can protect organs from I/R injury. To determine whether the renal protection effect of IPO mediates by toll-like receptor 4 (TLR4) signaling pathway in diabetic rats. Streptozotocin-induced diabetic rats were randomly divided into three groups: sham operation group, I/R group, and IPO group. Except sham operation group, rats were subjected to 30 min of renal ischemia, both with and without treatment with IPO, then reperfusion 24 h. Light microscope and transmission electronic microscope were used to observe structural changes of renal tubule. RT-PCR was used to measure TLR4 and tumor necrosis factor-alpha (TNF-α) mRNA expression level, renal TLR4 and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) protein expression was detected by Western blot. The results demonstrated that IPO markedly decreased renal ischemic injury caused by I/R and inhibited the proinflammatory expression levels of TLR4, TNF-α, and NF-κB, all of which up-regulated by I/R in diabetic rats. |
Does vitamin C attenuate Chronic Chlorpyrifos-induced Alteration of Neurobehavioral Parameters in Wistar Rats? | Oxidative stress is one of the molecular mechanisms in chlorpyrifos toxicity. The present study was designed to evaluate the attenuating effect of vitamin C on chlorpyrifos-induced alteration of neurobehavioral performance and the role of muscle acetylchloinesterase (AChE), glycogen and lipoperoxidation in the accomplishment of this task. Male rats were randomly assigned into 4 groups with the following regimens: soya oil (S/oil), vitamin C (VC), chlorpyrifos (CPF) and vitamin C+CPF (VC+CPF). The regimens were administered by gavage once daily for a period of 17 weeks. Neurobehavioral parameters measuring efficiency of locomotion, motor strength, righting reflex and excitability were evaluated at day 0 (pretreatment value), weeks 8 and 16. The rats were sacrificed at week 17 and evaluated for muscle glycogen and malonaldehyde (MDA) concentrations and AChE activity. The result showed that deficits in locomotion efficiency, motor strength, righting reflex and excitability score induced by chronic CPF were mitigated but not completely abolished by vitamin C. The reduced muscle AChE activity and concentrations of glycogen and MDA evoked by chronic CPF were ameliorated by vitamin C. | HAGE protein is a known immunogenic cancer-specific antigen. The biological, prognostic and predictive values of HAGE expression was studied using immunohistochemistry in three cohorts of patients with BC (n=2147): early primary (EP-BC; n=1676); primary oestrogen receptor-negative (PER-BC; n=275) treated with adjuvant anthracycline-combination therapies (Adjuvant-ACT); and primary locally advanced disease (PLA-BC) who received neo-adjuvant anthracycline-combination therapies (Neo-adjuvant-ACT; n=196). The relationship between HAGE expression and the tumour-infiltrating lymphocytes (TILs) in matched prechemotherapy and postchemotherapy samples were investigated. Eight percent of patients with EP-BC exhibited high HAGE expression (HAGE+) and was associated with aggressive clinico-pathological features (Ps<0.01). Furthermore, HAGE+expression was associated with poor prognosis in both univariate and multivariate analysis (Ps<0.001). Patients with HAGE+did not benefit from hormonal therapy in high-risk ER-positive disease. HAGE+and TILs were found to be independent predictors for pathological complete response to neoadjuvant-ACT; P<0.001. A statistically significant loss of HAGE expression following neoadjuvant-ACT was found (P=0.000001), and progression-free survival was worse in those patients who had HAGE+residual disease (P=0.0003). |
Do therapeutic potential of Polyalthia cerasoides stem bark extracts against oxidative stress and nociception? | Polyalthia cerasoides is a medicinal plant known for its ethnopharmacological importance. Despite this, investigation related to its therapeutic benefit is still unexplored. To evaluate the stem bark extracts of Polyalthia cerasoides for pharmacological activities relating to inflammation, nociception and oxidative stress using in vivo and in vitro models. Pet ether, ethyl acetate and chloroform fractions of the stem bark were evaluated for anti-inflammatory activity by carrageenan-induced hind paw edema in rats. Anti-nociceptive activity in mice was assessed using thermally and chemically induced analgesic models. The free radical quenching potential of the extracts was initially analyzed using the in vitro DPPH photometric assay, Hydroxyl radical scavenging and Lipid Peroxidation assays. Then modulatory effect of the extracts on in vivo antioxidant system was evaluated by carbon tetrachloride induced hepatotoxicity and subsequent measurements of antioxidant enzymes such as Superoxide dismutase, Catalase and Peroxidase from the liver homogenate. Among the tested fractions, ethyl acetate extract had substantially inhibited the inflammation by 68.5% that was induced by subcutaneous carrageenan injection whereas pet ether and chloroform extract showed only minimal inhibitory effect. Investigation of the anti-nociceptive activity revealed that the ethyl acetate fractions had significantly repressed the algesia in both the analgesic experimental models. In vitro and in vivo individual antioxidant assays demonstrated that the ethyl acetate fraction has strong free radical quenching potential which also restores the endogenous hepatic enzymes. | Although serum thyroglobulin (Tg) is an excellent marker for detecting recurrent or persistent differentiated thyroid cancer (DTC), it is unreliable in patients who have positive anti-Tg antibodies. Furthermore, a growing number of patients with DTC have elevated Tg levels but no detectable disease on radioiodine scanning or other imaging studies. The objective of this study was to determine whether a gradient in Tg protein level exists in patients with DTC. Fifteen patients who underwent thyroidectomy and/or lymph node dissection for primary DTC (n = 10 patients) and recurrent or persistent DTC (n = 5 patients). A venipuncture was performed simultaneously from the internal jugular vein adjacent to the tumor and the ipsilateral antecubital vein. Venous Tg protein levels were measured by using a chemiluminescence assay. RESULTS.: The average internal jugular-to-antecubital vein Tg protein ratio was 3.4:1.0 (median Tg ratio, 2.9:1; range, 0.8-62.2). Four patients had positive anti-Tg antibodies but still had a Tg gradient. Tg levels were significantly higher in the adjacent internal jugular vein than in the antecubital vein (P = .0019). The Tg ratio between the internal jugular and antecubital veins was significantly higher in patients with recurrent or persistent DTC than in patients with primary tumors (P = .0196). |
Are [ Withdrawal symptoms of ethanol ameliorated by thymopentin in mice ]? | To explore the effect of thymopentin (TP5) on the choice of ethanol and ameliorating withdrawal symptoms (anxiety) of ethanol in mice. Mice were administered ethanol (v/v) in schedular fashion: 5% (1 week), 10% (1 week) and 15% (4 weeks), followed with the free choice between ethanol and water. Ethanol/(ethanol+water)x100% [E/(E+W)x100%] was measured as an index of ethanol selection. Light-dark box test and elevated plus maze test were chosen for the assessment of anxiety pre-drug and post-drug. After TP5 [0.2 mg/(kgxd), 0.4 mg/(kgxd)], i.p. or saline (vehicle control), i.p. for 14 days, the procedure was repeated. (1) E/(E+W)x100%: the post-drug values of TP5 (0.2 mg/kg, 0.4 mg/kg) were lower significantly than the pre-drug values. (2) Light-dark box test: the post-drug values of number of entries and time spent in the light chamber of TP5 (0.2 mg/kg, 0.4 mg/kg) were more than the pre-drug values themselves and the post-drug value of saline. (3) Elevated plus maze test: the post-drug values of time spent on open arms of TP5 (0.2 mg/kg, 0.4 mg/kg) were more than the pre-drug values themselves and the post-drug value of salineìand the post-drug values of time spent on close arms of TP5 were less than the pre-drug values. | Limited data exist on the risk of developing cardiac sarcoidosis (CS) and/or adverse events in sarcoidosis patients. Using LV global longitudinal strain (GLS), an emerging sensitive parameter of LV function, we evaluated the prevalence of subclinical cardiac dysfunction in sarcoidosis and investigated whether LVGLS predicts adverse outcomes in this population. A total of 130 patients with proven sarcoidosis undergoing echocardiography at our referral centre were identified. Following exclusion of those with evidence of CS (n = 14) or other pre-existing structural heart disease (n = 16), 100 patients (55 ± 13 years, 48% male, 90% pulmonary involvement) and 100 age- and gender-matched controls were included. LVGLS was measured by speckle-tracking analysis. The primary endpoint was a composite of all-cause mortality, heart failure hospitalization, device implantation, new arrhythmias, or future development of CS on advanced cardiac imaging modalities. LVGLS was significantly impaired in sarcoidosis patients compared with controls (-17.3 ± 2.5 vs. -20.0 ± 1.6%, P < 0.001). Overall, 27 patients (27%) reached the endpoint during a median follow-up of 35 months. On Cox proportional hazards model analysis, abnormal 24-h Holter, larger LV end-diastolic diameters, and more impaired LVGLS were significantly associated with the endpoint; however, only LVGLS remained independently associated on multivariate analysis [hazard ratio (HR) 1.4, 95% confidence interval (CI) 1.1-1.7, P = 0.006]. Patients with LVGLS less than -17.3% were significantly more likely to be free of the primary endpoint (log-rank P = 0.01). |
Does continuing education need assessment of acute care and long-term-care nurses in a Veterans Affairs Medical Center? | This study was done to identify nurses' priorities for continued learning and to examine the priorities in relation to age, educational level, location in the organization, experience, position in the organization, and shift worked. A random sample of nurses at a Veterans Affairs Medical Center completed surveys consisting of 58 educational topics and demographic information. The results were analyzed using descriptive statistics, analysis of variance, and Tukey's HSD method to identify differences within the various subgroups of nurses. Of the 58 educational topics, 21 were determined to be high priority educational needs and were significantly correlated with one or more of the independent variables. | It has been suggested that anti-citrullinated protein antibodies (ACPAs) play an important role in the pathogenesis of rheumatoid arthritis (RA). To exert their pathologic effects, ACPAs must recruit immune effector mechanisms such as activation of the complement system. Mouse models of RA have shown that, surprisingly, arthritogenic antibodies activate the alternative pathway of complement rather than the expected classical pathway. This study was undertaken to investigate whether human anti-cyclic citrullinated peptide (anti-CCP) antibodies activate the complement system in vitro and, if so, which pathways of complement activation are used. We set up novel assays to analyze complement activation by anti-CCP antibodies, using cyclic citrullinated peptide-coated plates, specific buffers, and normal and complement-deficient sera as a source of complement. Anti-CCP antibodies activated complement in a dose-dependent manner via the classical pathway of complement, and, surprisingly, via the alternative pathway of complement. The lectin pathway was not activated by anti-CCP antibodies. Complement activation proceeded in vitro up to the formation of the membrane attack complex, indicating that all activation steps, including the release of C5a, took place. |
Is hyperinsulinemia and insulin resistance associated with low T₃/T₄ ratio in pre diabetic euthyroid Pakistani subjects? | To investigate the relationship of thyroid hormones in glucose homeostasis in impaired glucose-tolerant subjects with normal thyroid functions. Cross-sectional analysis was carried out in (n=260) impaired glucose-tolerant (IGT) and normal glucose-tolerant (NGT) subjects. Thyrotropin (TSH), total triiodothyronine (TT₃), total thyroxin (TT₄) free T₃ (fT₃), free T₄ (fT₄), and insulin were assessed by enzyme-linked immunoassays (ELISA). Fasting plasma glucose (FPG) and HbA1c were measured by glucose oxidase and low-pressure cation exchange chromatography. Homeostasis model of assessment (HOMA-IR) was employed to assess the level of insulin resistance; fT₃/fT₄ ratio was calculated. Anthropometric measurement and habits were recorded. Marked hyperinsulinemia and insulin resistance were observed in IGT subjects. Serum TT₃ and fT₃ levels were significantly low in the IGT as compared to normal glucose-tolerant (NGT) controls. TT₄ and TSH were higher in IGT subjects as compared to control subjects. There was a significant positive correlation of TSH with BMI only in the control group (r=0.351; P<0.05). Correlation of insulin with TT₃, fT₃,and TSH was significant (P<0.05) in IGT subjects. A significant low fT₃/fT₄ ratio was observed in IGT subjects as compared to NGT subjects (P<0.01). In multiple regression analysis, TSH, TT₄ and fT₃ contributed significantly to the variance of fasting insulin and insulin resistance in IGT subjects. | Endothelial cell migration is essential for tumor angiogenesis, and interleukin-8 (IL-8) has been shown to play an important role in tumor growth, angiogenesis, and metastasis. The objective of this study was to investigate the molecular mechanism of IL-8 induced endothelial cell migration in vitro. Fluorescence microscope was used to study the distribution of cytoskeleton. The expression of Rac1 and RhoA protein was detected by western blotting. After endothelial cells were transfected by lipofectamine 2000 reagent, the Transwell chamber motility assay was applied to observe the migration of endothelial cells induced by IL-8. The active p38MAPK (mitogen-activated protein kinase) was evaluated by the p38MAPK activation assay. We demonstrated that IL-8 activated cell migration can be impaired by p38MAPK inhibitor, suggesting the participation of p38MAPK in the cell migration. Our results indicated that p38MAPK signaling is required for membrane ruffles, lamellipodia extensions, and actin stress fibers formation induced by IL-8. Furthermore, p38MAPK inhibitor led to increased Rac1 and RhoA expression in IL-8 treated EA.hy926 cells. In addition, IL-8 induced p38MAPK activation was suppressed by dominant-negative mutant for Rac1 and RhoA. |
Does catecholamine and volume therapy for cardiac surgery in Germany -- result from a postal survey? | Management of cardiac surgery patients is a very standardized procedure in respective local institutions. Yet only very limited evidence exists concerning optimal indication, safety and efficacy of hemodynamic monitoring catecholamine and fluid therapy. Between April and May 2013, all 81 German anaesthesia departments involved in cardiac surgery care were asked to participate in a questionnaire addressing the institutional specific current practice in hemodynamic monitoring, catecholamine and volume therapy. 51 (63%) questionnaires were completed and returned. All participating centers used basic hemodynamic monitoring (i.e. invasive arterial blood pressure and central venous pressure), supplemented by transesophageal echocardiography. Pulmonary arterial catheter and calibrated trend monitoring devices were also routinely available. In contrast, non-calibrated trend monitoring and esophageal doppler ultrasound devices were not commonly in use. Cerebral oximetry is increasingly emerging, but lacks clear indications. The majority of patients undergoing cardiac surgery, especially in university hospitals, required catecholamines during perioperative care, In case of low cardiac output syndrome, dobutamine (32%), epinephrine (30%) or phosphodiesterase inhibitors (8%) were first choice. In case of hypotension following vasoplegia, norepinephrine (96%) represented the most common catecholamine. 88% of the participating centers reported regular use of colloid fluids, with hydroxyethyl starches (HES) being first choice (64%). | Subtypes of juvenile idiopathic arthritis (JIA) share phenotypic features with other autoimmune disorders. We investigated several genetic variants associated with rheumatoid arthritis (RA) and other autoimmune disorders for association with JIA to test the hypothesis that clinically distinct phenotypes share common genetic susceptibility factors. Cases were 445 children with JIA, and controls were 643 healthy adults. Using the TaqMan assay, subjects were genotyped for 8 single-nucleotide polymorphisms in 7 loci including rs10499194 and rs6920220 in the TNFAIP3 locus, rs6679677 in the RSBN1 locus, rs17696736 in the C12orf30 locus, rs3761847 in the TRAF1/C5 locus, rs2104286 in the IL2RA locus, rs7574865 in the STAT4 locus, and rs2542151 in the PTPN2 locus. Alleles and genotypes were analyzed for association with JIA and JIA subtypes. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. The strongest associations with JIA risk or protection were observed for TNFAIP3 variants rs10499194 (OR 0.74 [95% CI 0.61-0.91], P < 0.004) and rs6920220 (OR 1.30 [95% CI 1.05-1.61], P = 0.015). We also observed associations between JIA and both STAT4 (OR 1.24 [95% CI 1.02-1.51], P = 0.029) and C12orf30 (OR 1.20 [95% CI 1.01-1.43], P = 0.041) variants. The PTPN2 variant rs2542151 deviated from Hardy-Weinberg equilibrium and was excluded from analyses. Variants in IL2RA, TRAF1/C5, and RSBN1 were not associated with JIA. After stratification by JIA subtype, the TNFAIP3 and C12orf30 variants were associated with oligoarticular JIA, while the STAT4 variant was associated primarily with polyarticular JIA. |
Does morphine attenuate testosterone response to central injection of kisspeptin in male rats? | Kisspeptin and naloxone stimulate the reproductive axis while morphine inhibits its function. We have investigated the effect of central injection of kisspeptin-10 on mean plasma testosterone concentration in morphine or naloxone pretreated rats. In this experimental study, 60 male Wistar rats that were divid- ed into 12 groups (n=5 per group) received saline, kisspeptin (1 nmol, ICV), naloxone (2 mg/kg, subcutaneously), morphine (5 or 10 mg/kg, sc) or co-administrations of kisspeptin, morphine and naloxone at 09:00 - 09:30. In the co-administrated groups, kisspeptin was injected 15 minutes following morphine or naloxone injections. Blood samples were collected 60 minutes following injections via the tail vein. Plasma testosterone concentration was measured by a rat testosterone ELISA kit. Central injection of kisspeptin or subcutaneous injection of naloxone significantly increased the mean plasma testosterone concentration compared to saline while subcutaneous injections of different doses of morphine (5 or 10 mg/kg) significantly decreased testosterone compared to saline. The results revealed that morphine significantly attenuated the testosterone increase after kisspeptin injection compared to kisspeptin while a stimulatory additive effect was observed in the kisspeptin/naloxone group compared to either naloxone or kisspeptin. | The aim of this study was to investigate the influence of low iron availability on biofilm formation and adherence to HEp-2 cells of enteroaggregative Escherichia coli (EAEC) strains isolated from diarrhoea cases. The ability of EAEC to form biofilm on a plastic surface was evaluated quantitatively and qualitatively after 3 and 18 h of incubation of strains with or without the iron chelator 2,2-dipyridyl. When submitted to low iron conditions, prototype EAEC 042 strain showed a decrease in biofilm formation. Conversely, an increase in biofilm formation was observed for the clinical EAEC strains cultured in restricted iron condition. Moreover, the reduction of iron concentration inhibited the aggregative adherence to HEp-2 cells of all EAEC strains tested. However, all effects promoted by iron chelation were suppressed by thiourea. |
Is both increased and decreased platelet adhesion to thermally injured subendothelium caused by denaturation of von Willebrand factor? | Thermal angioplasty methods heat the arterial wall. We related platelet adhesion to the temperature to which subendothelium and purified adhesive proteins had been exposed. Cultured subendothelium, purified von Willebrand factor, collagen types I and III, or fibronectin was applied to glass coverslips. Coverslips were mounted on a heating device that applied a temperature gradient from 30 to 100 degrees C. De-endothelialized umbilical arteries were heated by immersion in phosphate-buffered saline. After cooling to room temperature, the surfaces were perfused with blood at 37 degrees C (shear rate, 1600 sec-1). Compared with 37 degrees C, platelet adhesion to endothelial cell matrix was significantly reduced by 25%, 50% or 75% after heating to 69 +/- 1 degree C (mean +/- SEM, P < .05), 72 +/- 1 degree C, or 75 +/- 1 degree C, respectively. Platelet coverage to umbilical artery subendothelium was in the same way significantly reduced after heating to 71 +/- 1 degree C, or 77 +/- 1 degree C, respectively. In contrast to endothelial cell matrix, however, heating to about 55 degrees C increased platelet coverage from 30 +/- 5% to 54 +/- 6% (P < .05). Both platelet adhesion to von Willebrand factor and monoclonal antibody binding against the GpIb binding site of von Willebrand factor showed a comparable temperature dependence as platelet adhesion to subendothelium, provided the proper von Willebrand factor concentration was used. Platelet adhesion to heated collagen types I and III was increased and maximal at 57 +/- 2 degrees C and 62 +/- 2 degrees C, respectively. Preincubation of collagen III with proteins resulted in decreased platelet adhesion with increasing temperatures. Heating did not affect the reactivity of fibronectin. | Efavirenz frequently causes central nervous system (CNS) symptoms. We evaluated genetic associations with efavirenz discontinuation for CNS symptoms within 12 months of treatment initiation. Patients had initiated efavirenz-containing regimens at an HIV primary care clinic in the Southeastern United States and had at least 12 months of follow-up data. Polymorphisms in CYP2B6 and CYP2A6 defined efavirenz metabolizer categories. Genome-wide genotyping enabled adjustment for population stratification. Among 563 evaluable patients, 99 (17.5%) discontinued efavirenz within 12 months, 29 (5.1%) for CNS symptoms. The hazard ratio (HR) for efavirenz discontinuation for CNS symptoms in slow versus extensive metabolizers was 4.9 [95% confidence interval (CI): 1.9-12.4; P=0.001]. This HR in Whites was 6.5 (95% CI: 2.3-18.8; P=0.001) and 2.6 in Blacks (95% CI: 0.5-14.1; P=0.27). Considering only slow metabolizers, the HR in Whites versus Blacks was 3.1 (95% CI: 0.9-11.0; P=0.081). The positive predictive value of slow metabolizer genotypes for efavirenz discontinuation was 27% in Whites and 11% in Blacks. |
Does kaempferol be an Anti-Inflammatory Compound with Activity towards NF-κB Pathway Proteins? | The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway is critical in inflammation, proliferation and carcinogenesis. There exist three main players in this pathway. The inhibitor of NF-κB (IκB), IκB kinase (IκK)- NF-κB essential modulator (NEMO) complex and NF-κB. The IkK-NEMO complex activates NF-κB via phosphorylation of Iκβ and, eventually, leads to its proteasomal degradation. This leads to nuclear translocation of NF-κB and activation of target genes, such as cyclooxygenases and interleukins. The identification of anti-inflammatory compounds might be an effective strategy to target inflammatory disorders and cancer. In the present investigation, kaempferol was investigated in terms of its effect on NF-κB activity with a SEAP-driven reporter cell line, NF-κB DNA binding with electromobility shift assay (EMSA) and translocation of NF-κB-p65 from cytosol to the nucleus with western blot in Jurkat cells. Kaempferol revealed anti-inflammatory activity, as shown in vitro and in silico. Molecular docking studies of kaempferol revealed comparable binding energies and similar docking poses on target proteins such as MG-132, a known NF-κB inhibitor. | Insulin is a major post-prandial muscle-anabolic hormone. A substantial loss of skeletal muscle mass occurs in insulin-deprived diabetes and is reversed by insulin treatment. Myostatin is a negative regulator of muscle mass upregulated in several chronic catabolic conditions. Whether myostatin expression is altered in insulin-deprived diabetes is unknown. In spite of opposite effects on muscle mass the potential role of basal circulating insulin in the regulation of myostatin expression is also undetermined. We measured (Northern Blot) myostatin transcript levels in muscle groups with different fiber composition in streptozotocin-diabetic male rats receiving one of the following treatments for eight weeks: (1) control (C); (2) diabetes without treatment (DM); (3) diabetes with once-daily slow-acting insulin treatment (INS). INS normalized plasma insulin and prevented weight reduction observed in DM. In fast-twitch gastrocnemius muscle myostatin transcript levels were unchanged (P>0.4) in both DM and INS compared to C. Myostatin transcripts were not measurable in any group in slow-twitch soleus muscle. |
Does intracanal delivery of Resolvin E1 control inflammation in necrotic immature rat teeth? | Pulp necrosis in immature teeth and the resulting periodontal apical inflammation negatively affect root formation. Resolvin E1 (RvE1) is a lipid-derived endogenous pro-resolution molecule that controls inflammation. The aim of this investigation was to evaluate the impact of RvE1 applied as an intracanal medication on root formation in nonvital immature teeth. To arrest root development, pulpectomy was performed in the lower first molars of 4-week-old Wistar rats. After 3 weeks, irrigation with 2.5% sodium hypochlorite and 0.9% sterile saline was performed, and either a triple antibiotic paste (TAP) or RvE1 in saline was applied into the root canals. In the control group, access openings drilled into molars were left exposed to the oral environment. Root development and periapical repair were evaluated radiographically and histologically at 3 and 6 weeks after treatment. RvE1 reduced periapical lesion size compared with the control at 3 weeks, which was similar to TAP. Inflammatory response in the RvE1-treated group was markedly reduced compared with both TAP and control specimens. At 6 weeks, root development was observed in both groups, but RvE1 treatment produced less cellularity with more regular calcified tissue deposition. | Injuries to runners are common. However, there are many potential contributing factors to injury. While lack of flexibility alone is commonly related to injury, there are clear differences in hamstring flexibility between males and females. To compare the effect of static hamstring length on sagittal plane mechanics between male and female runners. Forty subjects (30.0±6.4 years) participated and were placed in one of 4 groups: flexible males (n=10), inflexible males (n=10), flexible females (n=10), and inflexible females (n=10). All subjects were free of injury at the time of data collection. Three-dimensional kinematics and kinetics were collected while subjects ran over ground across 2 force platforms. Sagittal plane joint angles and moments were calculated at the knee and hip and compared with a 2-way (sex X flexibility) ANOVA (α=0.05). Males exhibited greater peak knee extension moment than females (M=2.80±0.47, F=2.48±0.52 Nm/kg*m, p=0.05) and inflexible runners exhibited greater peak knee extension moment than flexible runners (In=2.83±0.56, Fl=2.44±0.51 Nm/kg*m, p=0.01). For hip flexion at initial contact, a significant interaction existed (p<0.05). Flexible females (36.7±7.4º) exhibited more hip flexion than inflexible females (27.9±4.6º, p<0.01) and flexible males (30.1±9.5º, p<0.05). No differences existed for knee angle at initial contact, peak knee angle, peak hip angle, or peak hip moment. |
Is extent of microinvasion in ductal carcinoma in situ associated with sentinel lymph node metastases? | Ductal carcinoma in situ with microinvasion (DCISM) is a rare diagnosis with a good prognosis. Although nodal metastases are uncommon, sentinel lymph node biopsy (SLNB) remains standard care. Volume of disease in invasive breast cancer is associated with SLNB positivity, and, thus we hypothesized that in a large cohort of patients with DCISM, multiple foci of microinvasion might be associated with a higher risk of positive SLNB. Records from a prospective institutional database were reviewed to identify patients with DCISM who underwent SLNB between June 1997 and December 2010. Pathology reports were reviewed for number of microinvasive foci and categorized as 1 focus or ≥2 foci. Demographic, pathologic, treatment, and outcome data were obtained and analyzed. Of 414 patients, 235 (57 %) had 1 focus of microinvasion and 179 (43 %) had ≥2 foci. SLNB macrometastases were found in 1.4 %, and micrometastases were found in 6.3 %; neither were significantly different between patients with 1 focus versus ≥2 foci (p = 1.0). Patients with positive SLNB or ≥2 foci of microinvasion were more likely to receive chemotherapy. At median 4.9 years (range 0-16.2 years) follow-up, 18 patients, all in the SLNB negative group, had recurred for an overall 5-year recurrence-free proportion of 95.9 %. | Subjects with a psychotic disorder show mild to moderate cognitive impairment, which is an important determinant of functional outcome. The underlying biological process of cognitive impairment in psychosis is unclear. We aimed to explore whether hypothalamic-pituitary-thyroid axis hormones or thyroid autoimmunity modulate cognitive functioning in subjects with early psychosis. We studied 70 patients with a psychotic disorder (<3years of illness) and a control group of 37 healthy subjects (HS). Plasma levels of thyroid-stimulating hormone (TSH), free thyroxine (FT4) and thyroid-peroxidase (TPO-Abs) and thyroglobulin antibodies (TG-Abs) were determined. Cognitive assessment was performed with the MATRICS Cognitive Consensus Cognitive Battery. We also explored the relationship between thyroid variables and cognition in three subgroups of psychotic patients: psychosis not otherwise specified, affective psychosis (bipolar disorder or schizoaffective disorder) and non-affective psychosis (schizophrenia or schizophreniphorm disorder). In patients with early psychosis, higher FT4 levels (but not TSH or thyroid antibodies) were associated with better cognitive performance in attention/vigilance and overall cognition. The relationship between FT4 levels and the attention/vigilance domain remained significant in a multivariate analysis after adjusting for education level, age, gender, substance use, and benzodiazepine and antipsychotic treatments. We did not find a significant association between FT4 and cognitive performance in HS. In the exploratory analysis by psychotic subtypes, subjects with affective psychosis had increased FT4 levels and better cognitive profile than those with non-affective psychosis. |
Is only female age , and not blood type , associated with ovarian reserve? | The association between blood types and ovarian reserve is investigated in this study. As an index of ovarian reserve, women with a follicle stimulat- ing hormone (FSH) level of ≥10 mIU/ml in the early follicular phase were designated as having diminished ovarian reserve. In this prospective study, early follicular phase serum FSH and estradiol levels and blood types were evaluated in 500 patients who were admitted to the Infertility Department of Ministry of Health Etlik Zübeyde Hanım Women's Health Training and Research Hospital between January 2012 and June 2012. Women with serum FSH level <10 mIU/ml formed group I, and women with serum FSH ≥10 mIU/ml formed group II. The prevalence of blood types in each group and their associa- tion with ovarian reserve were analyzed. Out of 500 patients, 438 women were in group I, while 62 women were in group II. There was no statistically significant difference among the two groups in terms of blood group proportions (p=0.69), this did not change after age adjustment (p=0.77). The presence of A antigen (in A and AB blood type) (p=0.91), the blood type O (p=0.70), and the blood type B (p=0.51) were not statistically related to ovarian reserve after age adjustment. There was also no statistically significant correlation between rhesus factor and ovarian reserve after age adjustment (p=0.83). The only factor that affected ovarian reserve was age of patients (p=0.006). | In respiratory self-navigated coronary MRA, the selection of a reference position may have a direct effect on image quality. While end-expiration is commonly used as reference, it may be ill defined in cases of irregular breathing. Here, an iterative self-navigation approach that operates without a reference position was implemented and tested in healthy volunteers and patients. Data were acquired in 15 healthy volunteers and in 23 patients. Images obtained with end-expiratory self-navigation were compared with those obtained with the iterative approach that incorporates cross-correlation to iteratively minimize a global measure of respiratory displacement. Vessel sharpness, length, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) were evaluated while differences in breathing patterns between the two sub-groups were assessed, too. Vessel sharpness and length were similar for both methods in healthy volunteers. In patients, a significant improvement in vessel sharpness and length was obtained using the iterative approach. SNR and CNR remained constant. While end-expiration was the most frequent respiratory phase in healthy volunteers (57.6 ± 16.2%), intermediate respiratory phases (43.4 ± 30.1%) were predominantly found in patients. |
Is the activity of camptothecin analogues enhanced in histocultures of human tumors and human tumor xenografts by modulation of extracellular pH? | Most solid human tumors exist in an acidic microenvironment, due in part to inefficient vasculature and a higher intrinsic rate of glycolysis. This leads to a tumor-selective pH gradient, which can be exploited therapeutically with antitumor agents such as the camptothecins (CPTs). Previous work in this laboratory has shown that camptothecin activity is enhanced 40- to 60-fold in monolayer cell culture by reducing the extracellular pH to 6.8. Three-dimensional histoculture has been shown to be a technique that allows human tumor tissue to grow in an in vivo-like way with maintenance of tissue histology and function and drug sensitivity for long periods of time. In the current study, we utilized these features of histoculture to study new analogues of camptothecin that have superior pharmacological properties. We evaluated six CPT analogues in histocultures of human brain, neuroblastoma, breast, colon, and prostate tumors. Fragments were exposed to 10,11-methylenedioxy-CPT (MDC), 7-chloromethyl-MDC, SN-38, topotecan (TPT), 9-amino-CPT, 10-amino-CPT, paclitaxel, 5-fluorouracil, 4-hydroperoxycyclophosphamide and doxorubicin, and antitumor activity was assessed. For in vivo tumor outgrowth studies, fragments were treated in parallel, implanted into nude mice, and monitored for development of tumors. RESULTS. Against 15 of 16 tumor xenografts and all primary tumor samples tested, all compounds were cytotoxic at pH 7.4 (IC(50) range 13-921 microM). MDC, SN-38, TPT, and 9-amino-CPT achieved an average 5-fold increase in activity (range 3-14) at pH 6.8, while 7-chloromethyl-MDC was enhanced 8-fold (range 6-14). The most potentiated analogue was 10-amino-CPT at 27-fold (range 17-49). In contrast, the other agents were active against one or more tumor types but were not enhanced by acidic pH. Importantly, the toxicity of MDC in histoculture of D54 glioma xenografts strongly correlated with the outgrowth of treated fragments subsequently implanted in vivo. | To describe and critically appraise available methods for handling missing variance data in meta-analysis (MA). Systematic review. MEDLINE, EMBASE, Web of Science, MathSciNet, Current Index to Statistics, BMJ SearchAll, The Cochrane Library and Cochrance Colloquium proceedings, MA texts and references were searched. Any form of text was included: MA, method chapter, or otherwise. Descriptions of how to implement each method, the theoretic basis and/or ad hoc motivation(s), and the input and output variable(s) were extracted and assessed. Methods may be: true imputations, methods that obviate the need for a standard deviation (SD), or methods that recalculate the SD. Eight classes of methods were identified: algebraic recalculations, approximate algebraic recalculations, imputed study-level SDs, imputed study-level SDs from nonparametric summaries, imputed study-level correlations (e.g., for change-from-baseline SD), imputed MA-level effect sizes, MA-level tests, and no-impute methods. |
Does sUV on dual-phase FDG PET/CT correlate with the Ki-67 proliferation index in patients with newly diagnosed non-Hodgkin lymphoma? | PET using 18F-FDG integrated with CT is beneficial for staging patients with non-Hodgkin lymphoma (NHL). The Ki-67 index is used to assess the proliferation potential of tumor cells. The aim of this study was to evaluate the correlation of the Ki-67 index in tissue samples with the SUV at different sites on dual-phase FDG PET/CT of patients with newly diagnosed NHL. From September 2009 to March 2011, patients with newly diagnosed NHL who had received dual-phase FDG PET/CT for staging and biopsy samples that were evaluated for the Ki-67 expression were enrolled. The SUVmax of the biopsy site, the tumorous lesion sites, and 3 different bone marrow sites (right iliac crest, sternum, and L1) were measured. The SUVmean of the liver and spleen were also measured. There were a total of 27 patients in this study. Significant correlations were observed between the Ki-67 index and the SUVmax of the right iliac crest in patients with early-stage disease (stage I and II) patients, the SUVmax of the biopsy and whole-body lesion sites in patients with late-stage disease (stage III and IV), and the retention index of SUVmax of the right iliac crest in patients whose bone marrow were involved by lymphoma cells. | Cardioprotective effects of Mediterranean-style diet have been shown. Instead of excluding foods, replacement or addition may facilitate compliance with impact on glucose metabolism of individuals at cardiometabolic risk. This study investigated the effect of changing selected nutrients intake on glucose metabolism during a lifestyle intervention tailored to living conditions of prediabetic Brazilians. 183 prediabetic adults treated under the Brazilian public health system underwent an 18-month intervention on diet and physical activity. Dietary counseling focused on reducing saturated fat replaced by unsaturated fatty acids. Data were collected at baseline and after follow-up. ANOVA and multiple linear regression were used to test association of changes in nutrients intake with changes in plasma glucose. Changes in fasting and 2-h plasma glucose but not in weight, HOMA-IR or C-reactive protein decreased after intervention across tertiles of MUFA changes (p-trend 0.017 and 0.024, respectively). Regression models showed that increase in MUFA intake was independently associated with reduction in fasting (β -1.475, p = 0.008) and 2-h plasma glucose (β -3.321, p = 0.007). Moreover, increase in soluble fibers intake was associated with decrease in fasting plasma glucose (β -1.579, p = 0.038). Adjustment for anthropometric measurements did not change the results but did after including change in insulin in the models. |
Do serum thioredoxin reductase levels increase in response to chemically induced acute liver injury? | Mammalian thioredoxin reductases (TrxR) are selenoproteins with important roles in antioxidant defense and redox regulation, principally linked to functions of their main substrates thioredoxins (Trx). All major forms of TrxR are intracellular while levels in serum are typically very low. Serum TrxR levels were determined with immunoblotting using antibodies against mouse TrxR1 and total enzyme activity measurements were performed, with serum and tissue samples from mouse models of liver injury, as triggered by either thioacetamide (TAA) or carbon tetrachloride (CCl4). TrxR levels in serum increased upon treatment and correlated closely with those of alanine aminotransferase (ALT), an often used serum biomarker for liver damage. In contrast, Trx1, glutathione reductase, superoxide dismutase or selenium-containing glutathione peroxidase levels in serum displayed much lower increases than TrxR or ALT. | Low-intensity pulsed ultrasound (US) can accelerate fracture healing and osteogenic differentiation. The aim of this study was to investigate the osteogenic effect of low-intensity pulsed US on human periodontal ligament cells and to determine whether bone morphogenetic protein (BMP)-Smad signaling was involved. Human periodontal ligament cells were exposed to low-intensity pulsed US at a frequency of 1.5 MHz and intensity of 90 mW/cm(2) for 20 min/d. Osteogenic differentiation was determined by assaying alkaline phosphatase (ALP) and calcium deposition. Expression of BMP-2, BMP-6, and BMP-9 was detected by real-time polymerase chain reaction analysis. Phosphorylated Smad was detected by western blotting; Smad in the cells was labeled by an immunofluorescent antibody and observed by laser-scanning confocal microscopy. The optical density of ALP stimulated by US at 1.5 MHz and 90 mW/cm(2) for 20 min/d was significantly higher than in other groups (P < .01); therefore, this dosage was considered optimal for promoting osteogenic differentiation. After 13 days of US exposure, ALP increased gradually after 5 days, peaked at 11 days, and decreased at 13 days, with a significant difference compared with the control group (P < .05). Osteocalcin production increased from 9 to 13 days and peaked at 15 days, with a significant difference compared with the control group (P < .05). BMP-2 and BMP-6 increased dynamically after exposure for 13 days. BMP-2 increased 6.07-fold at 3 days, 6.39-fold at 11 days, and 5.97-fold at 13 days. BMP-6 expression increased 6.82-fold at 1 day and 51.5-fold at 3 days and decreased thereafter. BMP-9 was not expressed. Phospho-Smad1/5/8 expression was significantly increased after exposure (P< .05) and transferred from the cytoplasm into the nuclei. |
Is low-dose aprotinin ineffective to treat excessive bleeding after cardiopulmonary bypass? | Uncontrolled clinical experience at our institution suggested that low-dose aprotinin could control excessive bleeding after cardiopulmonary bypass (CPB). A randomized clinical trial was conducted to determine the efficacy of low-dose aprotinin in the treatment of hemorrhage after cardiac surgery. One hundred seventy-one patients undergoing cardiac surgery with CPB were included. Forty-four patients (26%) bled significantly in the intensive care unit (>100 mL/h) and received either aprotinin (200,000 KIU bolus + 100,000 KIU/h for 8 hours) or placebo in addition to our standard management of excessive bleeding. Median bleeding before study drug administration was not different between aprotinin (200 mL) and placebo (212.5 mL) groups. Bleeding decreased significantly with time and similarly in both groups. Ninety-five percent of patients required transfusions in both groups. Median blood products transfused were 13 and 8 units per patient in the aprotinin and placebo groups respectively (p = NS). | It has been shown that maternal mental health is associated with poorer skills development in the offspring. However, the evidence evaluating the association between social anxiety disorder (SAD) and cognitive or language development, is scarce. To evaluate the association between maternal SAD and performance in cognitive and language tests in 30-month old children. This was a cohort study involving young women evaluated since pregnancy. We evaluated 520 mother-child dyads who received prenatal medical assistance through the National Public Health System in a southern Brazilian city, from October 2009 to March 2011. We used the Mini Neuropsychiatric Interview Plus (MINI Plus) to assess SAD among young mothers. Cognitive and language performance in their offspring was analyzed using the Bayley Scales of Infant and Toddler Development - 3rd Edition. We found an association between maternal SAD and performance in cognitive and language tests. Children of mothers with SAD had in average 4.5 less points in the Bayley scale, when compared to those with mothers without SAD: in the cognitive (β=-4.53 [95% CI -7.8; -1.1] p=0.008) and language subscales (β=-4.54 [95% CI -9.0; -0.5] p=0.047). |
Are subnormal levels of vitamin D associated with acute wheeze in young children? | This study evaluated risk factors for acute wheeze in preschool children and investigated whether subnormal levels of vitamin D were associated with increased risk for acute wheeze, atopy or viral/bacterial respiratory infections. We recruited 130 children with acute wheeze, aged 6 months to 4 years, from paediatric emergency departments in Stockholm, Sweden, and 101 age-matched controls with no history of wheeze or sensitisation to airborne allergens. Parents answered standardised questionnaires, and blood samples were analysed for specific IgE to airborne and food allergens and levels of 25 hydroxyvitamin D (25(OH)D). Nasopharyngeal virus samples were collected during the emergency department visit in the group of children with wheeze, and a subset were also tested for bacteria. Vitamin D insufficiency (25(OH)D < 75 nmol/L (30 ng/mL)) was associated with an odds ratio of 2.7 (95% confidence interval 1.1-6.2) for acute wheeze. However, no association was found between vitamin D insufficiency and atopy, presence of virus or bacteria or recurrent infections. Children older than 24 months were particularly at risk of subnormal vitamin D levels, irrespective of wheezing history. | To determine whether the hemodynamic response to functional stimulation is sensitive to proximal arterial occlusion, we measured the activation flow coupling response in a rat model of acute reversible vascular occlusion. In alpha-chloralose-anesthetized rats (n=18), laser Doppler measurements were made through a thinned skull over the somatosensory cortex in response to electrical forepaw stimulation. Signal-averaged responses to 4 and 8 seconds of electrical forepaw stimulation were obtained before, during, and shortly after acute unilateral or bilateral carotid occlusion produced with the use of a surgically placed snare. Baseline cerebral blood flow was significantly decreased over the forepaw region of the somatosensory cortex after both occlusion of the carotid contralateral to the stimulated forepaw and bilateral occlusion compared with preocclusion (P<0.05). Postocclusion and ipsilateral occlusion led to a nonsignificant increase in baseline cerebral blood flow compared with preocclusion. Contralateral carotid occlusion and bilateral occlusion significantly prolonged the temporal characteristics of the flow response, especially the delay to peak (P<0.05), compared with preocclusion, whereas ipsilateral carotid occlusion significantly shortened the delay to peak (P<0.05). Only contralateral carotid occlusion produced a significant reduction in the peak amplitude of the flow response compared with preocclusion (P<0.05). |
Does change in health-related quality of life in patients with coronary artery disease predict 4-year mortality? | Self-reported health-related quality of life (HRQL) and changes in HRQL have been shown to predict mortality and/or adverse events in patients with coronary artery disease. MacNew Heart Disease HRQL questionnaire scores were examined as predictors of 4-year all-cause mortality. Following referral for angioplasty in 385 patients with coronary artery disease, data were analyzed for differences in all-cause mortality by MacNew Global and subscale baseline and 1- and 3-month change scores (deteriorated ≥0.50; unchanged (-0.49 to +0.49); and improved ≥0.50 points). Mean baseline, 1-month, and 3-month MacNew Global and subscale scores were similar in survivors and non-survivors. Mean 1- and 3-month Global and emotional subscale and mean 1-month social subscale change scores decreased more in non-survivors than survivors. Compared with patients whose Global MacNew HRQL scores improved at one month, 4-year all-cause mortality hazard ratio (HR) was higher in patients whose HRQL deteriorated (HR, 1.70, 95% CI, 1.09, 2.65; p=0.021). Compared with patients whose Global MacNew HRQL improved at three months, 4-year all-cause mortality was higher in both patients whose HRQL had deteriorated (HR, 2.07, 95% CI, 1.29, 3.32; p=0.003) and patients with unchanged HRQL (HR, 2.62, 95% CI, 1.11, 6.17; p=0.028). | Is the proteolytic activity of pregnancy-associated plasma protein-A (PAPP-A) regulated by the stanniocalcins (STC1 and STC2) during human follicle maturation? |
Are biologic factors associated with tumor oxygenation prognostic in patients with stage III esophageal cancer : long-term results? | Long-term results of a study investigating potential prognostic factors for treatment outcomes in patients with stage III esophageal cancer are presented. In 64 patients, the impact of tumor cell expression of erythropoietin (EPO) and erythropoietin-receptor (EPO-R) and ten additional factors (age, gender, performance status, tumor length, tumor stage (T-stage), nodes (N-stage), histology/grading, hemoglobin levels during radiotherapy, surgery) on survival and loco-regional control was evaluated up to 10 years following radio-chemotherapy. On multivariate analysis, improved survival was associated with low EPO-R expression (p=0.034) and hemoglobin levels during radiotherapy ≥ 12 g/dl (p=0.026). Low EPO expression was associated with survival on univariate (p=0.010) but not on multivariate analysis (p=0.42). On multivariate analysis, improved loco-regional control was significantly associated with hemoglobin levels during radiotherapy ≥ 12 g/dl (p<0.001). | There is an emerging consensus that increased posterior-inferior directed slope of the subchondral bone portion of the tibial plateau is associated with increased risk of suffering an anterior cruciate ligament (ACL) injury; however, most of what is known about this relationship has come from unmatched case-control studies. These observations need to be confirmed in more rigorously designed investigations. Increased posterior-inferior directed slope of the medial and lateral tibial plateaus are associated with increased risk of suffering a noncontact ACL injury. Case-control study; Level of evidence, 3. In sum, 176 athletes competing in organized sports at the college and high school levels participated in the study: 88 suffering their first noncontact ACL injury and 88 matched controls. Magnetic resonance images were acquired, and geometry of the subchondral bone portion of the tibial plateau was characterized on each athlete bilaterally by measuring the medial and lateral tibial plateau slopes, coronal tibial slope, and the depth of the medial tibial plateau. Comparisons between knees of the same person were made with paired t tests, and associations with injury risk were assessed by conditional logistic regression analysis of ACL-injured and control participants. Controls exhibited side-to-side symmetry of subchondral bone geometry, while the ACL-injured athletes did not, suggesting that the ACL injury may have changed the subchondral bone geometry. Therefore, the uninjured knees of the ACL-injured athletes and the corresponding limbs of their matched controls were used to assess associations with injury risk. Analyses of males and females as a combined group and females as a separate group showed a significant association between ACL injury risk and increased posterior-inferior directed slope of the lateral tibial plateau slope. This relationship was not apparent when males were analyzed as a group. Multivariate analyses indicated that these results were independent of the medial tibial plateau slope, coronal tibial slope, and depth of the medial tibial plateau, which were not associated with ACL injury. |
Is high seizure frequency prior to antiepileptic treatment a predictor of pharmacoresistant epilepsy in a rat model of temporal lobe epilepsy? | Progress in the management of patients with medically intractable epilepsy is impeded because we do not fully understand why pharmacoresistance happens and how it can be predicted. The presence of multiple seizures prior to medical treatment has been suggested as a potential predictor of poor outcome. In the present study, we used an animal model of temporal lobe epilepsy to investigate whether pharmacoresistant rats differ in seizure frequency from pharmacoresponsive animals. Epilepsy with spontaneous recurrent seizures (SRS) was induced by status epilepticus. Frequency of SRS was determined by video/EEG (electroencephalography) monitoring in a total of 33 epileptic rats before onset of treatment with phenobarbital (PB). Thirteen (39%) rats did not respond to treatment with PB. Before treatment with PB, average seizure frequency in PB nonresponders was significantly higher than seizure frequency in responders, which, however, was due to six nonresponders that exhibited > 3 seizures per day. Such high seizure frequency was not observed in responders, demonstrating that high seizure frequency predicts pharmacoresistance in this model, but does not occur in all nonresponders. | Bone cutting error can be one of the causes of malalignment in unicompartmental knee arthroplasty (UKA). The amount of cutting error in total knee arthroplasty has been reported. However, none have investigated cutting error in UKA. The purpose of this study was to reveal the amount of cutting error in UKA when open cutting guide was used and clarify whether cutting the tibia horizontally twice using the same cutting guide reduced the cutting errors in UKA. We measured the alignment of the tibial cutting guides, the first-cut cutting surfaces and the second cut cutting surfaces using the navigation system in 50 UKAs. Cutting error was defined as the angular difference between the cutting guide and cutting surface. The mean absolute first-cut cutting error was 1.9° (1.1° varus) in the coronal plane and 1.1° (0.6° anterior slope) in the sagittal plane, whereas the mean absolute second-cut cutting error was 1.1° (0.6° varus) in the coronal plane and 1.1° (0.4° anterior slope) in the sagittal plane. Cutting the tibia horizontally twice reduced the cutting errors in the coronal plane significantly (P<0.05). |
Is increased CSF tau level correlated with decreased lamina cribrosa thickness? | This study was to investigate whether the previously proposed link between Alzheimer's disease (AD) and decreased retinal nerve fiber layer thickness could be explained by the relationship between abnormal CSF profiles and optic nerve head characteristics, focusing on the influence of CSF tau protein on the lamina cribrosa (LC) thickness (LCT). A total of 44 eyes from 18 patients with AD and 26 healthy subjects were subjected to enhanced-depth-imaging volume scanning of the optic nerve using spectral-domain optical coherence tomography. The B-scan images were constructed three-dimensionally using maximum intensity projection (MIP), and the LCT was measured at three locations (superior midperipheral, midhorizontal, and inferior midperipheral) using the thin-slab MIP images. CSF levels of amyloid β 1-42 peptide, (Aβ1-42), total tau (T-tau) and tau phosphorylated at threonine 181 (P-tau181P) were measured from CSF samples of each subject. The relationship between the level of CSF proteins and the LCT was determined using linear regression and fractional polynomial analyses. Univariate regression analysis revealed that higher CSF levels of T-tau (P = 0.004) and P-tau181P (P = 0.027), as well as a smaller central corneal thickness (P = 0.032), were significantly associated with a smaller LCT. Multivariate analysis indicated that only CSF T-tau (P = 0.041) was significantly associated with the LCT. The relationship was well explained by both linear regression (R(2) = 0.179, P = 0.004) and fractional polynomial analysis (R(2) = 0.275, P = 0.001). When we performed an assessment by linear regression with an indicator, the relationship was significant both in the healthy and AD groups, with a stronger correlation found in the healthy group (regression coefficients = -1.098 vs. -0.280, P = 0.018). | Post kala-azar dermal leishmaniasis (PKDL) is a neglected parasitic disease that occurs after apparent cure from visceral leishmaniasis (VL) and poses a challenge for elimination of VL, being its proposed reservoir. Several epidemiological studies have proposed that sex hormones may account for the increased susceptibility of males towards infectious diseases, including leishmaniasis; however, the role of testosterone and sex bias, if any, in PKDL has not been evaluated. The study population included 87 patients with PKDL and 39 with VL; levels of testosterone were measured by competitive enzyme-linked immunosorbent assay along with their levels of antileishmanial immunoglobulin and IgG. The association of testosterone, if any, was then correlated with age, gender, humoral response, lesional profile, disease duration, and lag period. A male predominance was evident in PKDL, not in VL; importantly, this male bias was predominant postpubertal, strongly indicative of an association between sex hormone and disease progression. Male patients with PKDL had significantly higher levels of testosterone, which regressed significantly with miltefosine, not with sodium antimony gluconate. Additionally, a significant correlation was found between plasma testosterone and antileishmanial IgG. |
Does cardiac imaging improve risk stratification in high-risk patients undergoing surgical revascularization? | In patients with ischaemic left ventricular dysfunction, multivessel disease and dominance of necrotic myocardium, perioperative mortality due to coronary artery bypass grafting is still a rather unclear issue. The aim of this study was to analyse the impact of different imaging variables in predicting perioperative mortality. We selected a group of 259 patients who had preoperatively been defined as 'high-risk patients' and who showed a mostly necrotic myocardium as detected by thallium-201 myocardial scintigraphy. Mean ejection fraction was 0.26 +/- 0.07. In a 16-segment model, the mean number of scintigraphic necrotic myocardial segments was 5.07 +/- 1.09, echocardiographic end-diastolic diameter was 29.41 +/- 2.38 mm/m2 and wall motion score index was 2.29 +/- 0.19. Perioperative mortality increased along with the increase in the number of necrotic segments: 5/105 (5%), 4/63 (6%), 8/52 (15%) and 8/39 (20%) patients with four, five, six and seven necrotic segments, respectively. The analysis of additional variables in survived vs. deceased patients demonstrated a significant difference in echocardiographic end-diastolic diameter (27 +/- 8 vs. 31.9 +/- 1.9 mm/m2, P < 0.001) and in wall motion score index (2.2 +/- 0.1 vs. 2.4 +/- 0.2, P < 0.001). | To investigate the role of proteinase-activated receptor 4 (PAR-4) in mediating joint inflammation and pain in mice. Knee joint blood flow, edema, and pain sensitivity (as induced by thermal and mechanical stimuli) were assessed in C57BL/6 mice following intraarticular injection of either the selective PAR-4 agonist AYPGKF-NH(2) or the inactive control peptide YAPGKF-NH(2). The mechanism of action of AYPGKF-NH(2) was examined by pretreatment of each mouse with either the PAR-4 antagonist pepducin P4pal-10 or the bradykinin antagonist HOE 140. Finally, the role of PAR-4 in mediating joint inflammation was tested by pretreating mice with acutely inflamed knees with pepducin P4pal-10. PAR-4 activation caused a long-lasting increase in joint blood flow and edema formation, which was not seen following injection of the control peptide. The PAR-4-activating peptide was also found to be pronociceptive in the joint, where it enhanced sensitivity to a noxious thermal stimulus and caused mechanical allodynia and hyperalgesia. The proinflammatory and pronociceptive effects of AYPGKF-NH(2) could be inhibited by pepducin P4pal-10 and HOE 140. Finally, pepducin P4pal-10 ameliorated the clinical and physiologic signs of acute joint inflammation. |
Are beneficial effects of soy supplementation on postmenopausal atherosclerosis dependent on pretreatment stage of plaque progression? | The objective of this study was to use a well-established monkey model of atherosclerosis to determine how life stage and preexisting atherosclerosis influence the effectiveness of high-isoflavone soy diet in inhibiting progression of atherosclerosis. For 34 months, premenopausal monkeys were fed an atherogenic diet, with protein derived primarily from either animal sources (casein-lactalbumin [CL], n = 37) or high-isoflavone soy beans (Soy, n = 34). Animals were ovariectomized and randomized to groups fed the same diet (CL-CL, n = 20; Soy-Soy, n = 17) or an alternate diet (CL-Soy, n = 17; Soy-CL, n = 17) for an additional 34 months. At ovariectomy, the left common iliac artery was removed to determine the amount of premenopausal atherosclerosis. At necropsy, the right common iliac artery and coronary arteries were collected, and atherosclerosis extent was quantified. CL-CL condition was considered "control." Modeling Asian women who remain in Asia, monkeys fed soy protein both premenopausally and postmenopausally had a markedly reduced extent of coronary artery atherosclerosis relative to CL controls (P = 0.008). The subset of animals that modeled Asian women who migrate to a Western country (consuming soy premenopausally and CL postmenopausally) had increased progression of postmenopausal iliac artery atherosclerosis (P = 0.003) and was not protected against the development of coronary artery atherosclerosis relative to controls. Relevant to the administration of soy diets to postmenopausal Western women, monkeys fed CL premenopausally and switched to soy postmenopausally derived atheroprotective benefits only if they began the postmenopausal treatment period with relatively small (below the median) plaques. Relative to controls, this group (with small plaques at ovariectomy) had reduced progression of iliac atherosclerosis (P = 0.038) and smaller coronary artery plaques (P = 0.0001) that were less complicated (P = 0.05) relative to controls. | To test device integrity and objective auditory reaction for cochlear implant patients intraoperatively. Our protocol for intraoperative testing of the implant device includes device electrode impedance test and neural response telemetry (NRT), which measures the electrically evoked auditory nerve compound action potentials (ECAP). We completed electrode integrity tests and NRT intraoperatively on 40 patients with the Nucleus CI24M cochlear implant. We have measured normal implant function on all 40 patients and obtained ECAP results from 39 patients. Out of 33 patients with normal inner ear, typical ECAPs were recorded in 195 electrodes in all 198 testing electrodes(98.5%). In 7 patients with inner ear Mondini dysphasia, affirmative ECAP waveforms were recorded in 26 electrodes in all 42 testing electrodes. The basal electrode ECAP threshold was higher than that of the epical one. |
Is prophylactic Gentamicin Associated with Acute Kidney Injury in Patients with Open Fractures? | Data on antimicrobial prophylaxis for open fractures is limited, with many protocols based on expert recommendations. These protocols include aminoglycosides (AGs) for fractures with significant soft tissue injury, but these drugs are associated with acute kidney injury (AKI) in other settings; this risk has not been defined for open fracture prophylaxis. We performed a retrospective study from May 2012 to October 2014 at our Level 1 trauma center. Patients with open fractures were evaluated for demographics, location/type of fracture, injury severity, and receipt of an AG. Outcomes included rates of AKI, infection, and mortality. There were 167 patients with open fractures during the study period (119 males, mean age 42 ± 17 [standard deviation] years), with 80 (48%) receiving prophylactic gentamicin (AG+ group). The AG+ and AG- patients had similar fracture sites and Injury Severity Scores (ISSs) (12.6 ± 9.9 AG+ vs. 15.9 ± 13.2 AG-) but were more likely to have sustained blunt trauma (96% AG+ vs. 77%; p < 0.001) or received intravenous contrast medium ≤48 h from admission (75% AG+ vs. 56% AG-; p = 0.01). Gentamicin was not associated with AKI (odds ratio [OR] 0.22; 95% confidence interval [CI] 0.020-2.44; p = 0.22), whereas hypotension on admission (OR 10.7; 95% CI 1.42-80.93; p = 0.02) and ISS (OR 1.1; 95% CI 1.01-1.20; p = 0.02) were both associated with AKI. Only four fracture site infections were identified, three in the AG+ group and one in the AG- group (3.8% vs. 1.1%; p = 0.27). The mortality rate was greater in the AG- group (3.8% vs. 12.6%; p = 0.04). | To investigate the cross-sectional association between smoking and happiness in Chinese adults in Hong Kong. Telephone surveys were conducted between 2009 and 2012, with 4553 randomly sampled Chinese adults (male 54%, mean age 58.3 years) in Hong Kong. Happiness was measured using the four-item Subjective Happiness Scale (SHS) and single-item Global Happiness Item (GHI). Smoking status was categorized as current smokers (7.7%%), ex-smokers (6.5%, 93% quit for >6 months) and never smokers (85.8%). Linear and ordinal logistic regressions were used to calculate adjusted β-coefficients for SHS and proportional adjusted odds ratios (aOR) for GHI in relation to smoking. Compared with current smokers, ex-smokers enjoyed greater happiness according to both SHS (adjusted β = 0.16, P < 0.05) and GHI (aOR = 1.52, P < 0.05) measurements, but current and never smokers were similar. Among current smokers, the number of cigarettes smoked was not associated with happiness, but the lack of any attempt to quit was associated significantly with greater happiness (adjusted β = 0.31 for SHS, aOR = 1.82 for GHI) compared with smokers who had tried to quit but not succeeded. Smokers not intending to quit in the next 6 months had higher odds of happiness (GHI) than those wanting to quit within 6 months (aOR = 1.86, P < 0.05). |
Does sildenafil enhance the peripheral antinociceptive effect of ellagic acid in the rat formalin test? | Ellagic acid (EA), a major polyphenolic compound of pomegranate juice, produces antinociceptive effects, which are mediated through opioidergic and nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathways. The present study was conducted to elucidate the peripheral antinociceptive effect of EA alone and in combination with sildenafil in the rat formalin test. Pain was produced by intraplantar injection of formalin (2.5%) in rats and nociceptive behavior was measured as the number of flinches every 5 min in 60 min after injection. Local administration of EA and sildenafil dose-dependently increased the nociception threshold in both phases of the test. Moreover, sub-effective doses of sildenafil (25 or 50 mcg/paw, i.p.) significantly and dose-dependently enhanced the antinociception induced by a sub-effective dose of EA (60 mcg/paw, i.pl.) in both phases of the test. The antinociception produced by these drugs alone, or in combination, was due to a peripheral site of action, since the administration in the contralateral paw was ineffective. | As a result of improved diagnostic methods, medical treatment, surgical correction, and palliation in childhood, there is a growing number of adult patients with congenital heart disease (CHD) who may experience heart failure and subsequently require heart transplantation (HT). Because of complex anatomy, previous operations, and frequently increased pulmonary vascular resistance (PVR), these patients represent a group with a higher risk of early mortality after transplantation. From May 1999 to December 2014, our institution performed 25 HTs in adult patients with end-stage CHD. We present our data and outcomes of transplantation in this group. The median age at transplantation was 38 years (range, 18.4-53.7 years). Survival was 88% at 30 days, 88% at 1 year, and 77% at 5 years. We identified long donor heart ischemic time (>4 hours) as an important risk factor for early mortality. There was no significant difference in the survival of patients undergoing transplantation for CHD and patients undergoing transplantation for other diagnoses. |
Is the Brugada type 1 electrocardiographic pattern common among Filipinos? | To measure the prevalence of the Brugada type 1 ECG pattern in the general population in the Philippines. STUDY SETTING AND DESIGN: Sudden unexplained death syndrome is rare in the West but is common among Southeast Asians. Ventricular fibrillation is the terminal event. The Brugada type 1 electrocardiographic (ECG) pattern with J point and coved ST elevation in right precordial leads, is a marker for sudden unexplained death syndrome. Its prevalence in the general population is unknown. A cross-sectional nationwide survey was performed in the Philippines in 2003 using a stratified multistage sampling design covering all the regions and provinces in the country. ECGs were performed in all adults surveyed. The prevalences of the Brugada type 1 ECG pattern (coved type) and any type Brugada ECG pattern were determined. The Brugada type 1 (coved) ECG pattern in the general population in the Philippines was found in 0.2% (95% Confidence Interval [CI] 0.03%-0.36%) of the population. Among males the prevalence was 0.3% (+/-0.1). The prevalence of any type Brugada ECG was 2% (95% CI 1.5%-2.6%). | The cross talk between the stroma and cancer cells plays a major role in phenotypic modulation. During peritoneal carcinomatosis ovarian cancer cells interact with mesenchymal stem cells (MSC) resulting in increased metastatic ability. Understanding the transcriptomic changes underlying the phenotypic modulation will allow identification of key genes to target. However in the context of personalized medicine we must consider inter and intra tumoral heterogeneity. In this study we used a pathway-based approach to illustrate the role of cell line background in transcriptomic modification during a cross talk with MSC. We used two ovarian cancer cell lines as a surrogate for different ovarian cancer subtypes: OVCAR3 for an epithelial and SKOV3 for a mesenchymal subtype. We co-cultured them with MSCs. Genome wide gene expression was determined after cell sorting. Ingenuity pathway analysis was used to decipher the cell specific transcriptomic changes related to different pro-metastatic traits (Adherence, migration, invasion, proliferation and chemoresistance). We demonstrate that co-culture of ovarian cancer cells in direct cellular contact with MSCs induces broad transcriptomic changes related to enhance metastatic ability. Genes related to cellular adhesion, invasion, migration, proliferation and chemoresistance were enriched under these experimental conditions. Network analysis of differentially expressed genes clearly shows a cell type specific pattern. |
Do pyrethroid insecticides influence the signal transduction in T helper lymphocytes from atopic and nonatopic subjects? | Pyrethroids are claimed to have a low human toxicity with some neuro- and immunotoxicity. The objective of this study was to investigate the immunotoxicological properties of six commercially used pyrethroids, including natural pyrethrum and synergist piperonyl-butoxide (PBO). PHA-stimulated cultures of T-helper lymphocytes and blood basophil incubates from nonatopic and atopic patients (IgE > 1000 IU) provided cytokine and histamine determination. Western blot analysis was used for the measurement of Th2-specific signal transducer and activator of transcription-6 (STAT6). Pyrethroids and xenobiotics were added 4 h post-plating. We demonstrated that interferon-gamma (IFN-gamma) production and expression was correlated with lymphocyte proliferation, however, interleukin-4 (IL-4) was down-regulated at the end of the 3 day culture. Atopics showed significantly higher IL-4 activity than nonatopics. Pyrethroids inhibited IFN-gamma and IL-4 in both groups at around 10(-5) M. Only fenvalerate and S-bioallethrin combined with 10-fold PBO in the atopic-enriched blood basophil incubates caused a weak but significant increase in histamine release. Histamine acted bidirectionally on STAT6, but pyrethroids inhibited the intracellular Th2-specific STAT6 more effectively in atopics than in nonatopics. | This was a prospective cohort observational study. To determine the effect of dehydration and rehydration on spinal cord cross-sectional area (CSA) measurement on magnetic resonance imaging (MRI). MRI Research Centre, University of British Columbia, Canada. Ten healthy subjects (aged 21-32 years) were scanned on a 3T MRI scanner at four time points: (1) baseline, (2) rescan after 1 h, (3) the next day after fasting for a minimum of 14 h and (4) after rehydration with 1.5 l of water over the course of 1 h. Two independent, established semi-automatic CSA measurement techniques (one based on two-dimensional (2D) edge detection, the other on three-dimensional (3D) surface fitting) were applied to a 3D T1-weighted scan of each subject at each time point, with the operator blinded to scan order. The percentage change in CSA from baseline to each subsequent time point was calculated. One-tailed paired t-tests were used to assess the significance of the changes from baseline. A decrease in CSA following dehydration was detected by both measurement methods, with a mean change of -0.654% (s.d.=0.778, P<0.05) and -0.650% (s.d.=1.071, P<0.05) for the first and second methods, respectively. |
Does monascus pilosus-fermented black soybean inhibit lipid accumulation in adipocytes and in high-fat diet-induced obese mice? | To explore the anti-obesity effects and the mechanism of action of Monascus pilosus(M. pilosus)-fermented black soybean (MFBS) extracts (MFBSE) and MFBS powders (MFBSP) in adipocytes and high-fat diet (HFD)-induced obese mice, respectively. Black soybean was fermented with M. pilosus, and the main constituents in MFBS were analyzed by HPLC analysis. In vitro, MFBSE were examined for anti-adipogenic effects using Oil-Red O staining. In vivo, mice were fed a normal-fat diet (NFD) control, HFD control or HFD containing 1 g/kg MFBSP for 12 weeks, and then body weight gain and tissues weight measured. Real-time PCR and western blot assay were used to determine the mechanism of anti-adipogenic effects. MFBSE inhibited lipid accumulation in 3T3-L1 adipocytes without exerting cell cytotoxicity. MFBSP treatment in HFD-fed mice significantly decreased the body weight gain compared with the HFD control mice. MFBSE and MFBSP treatment resulted in significantly lower mRNA levels of adipogenesis-related genes, such as peroxisome proliferator-activated receptor γ(PPAR γ), fatty acid-binding protein 4 (FABP4), and fatty acid synthase (FAS), in adipocytes and in white adipose tissue (WAT) of HFD-induced obese mice. | Pulmonary aspiration of gastric acid is a serious complication during anaesthesia and may cause aspiration pneumonitis and adult respiratory distress syndrome. The development of pulmonary hypertension may aggravate the initial course of the aspiration pneumonitis. The authors hypothesized that acid aspiration induces an acute increase in right ventricular pressure in the rat heart. Additionally, it was hypothesized as a secondary study that endothelin levels would be increased in this rat model. Male Sprague Dawley rats, anaesthetized with sevoflurane, underwent tracheostomy, and catheters were inserted into the carotid and right ventricle. Lung injury was induced by instillation of 0.4 ml kg(-1) 0.1 mol l(-1) HCl; a control group received the same volume of 0.9% NaCl. Rats were then ventilated for 6 hours. p(a)O2, mean arterial blood pressures and right ventricular systolic pressures were documented every 30 minutes, and arterial blood gases were measured at baseline, 30, 90, 180, 270 and 360 min. Wet/dry ratio was performed and additionally endothelin-1 levels were examined before and 180 and 360 min after aspiration. p(a)O2 values were lower, whereas right ventricular systolic pressures were significantly higher in the HCl group. Mortality rate was 50% after HCl aspiration, whereas 100% of the rats survived NaCl aspiration. Wet/dry ratio and endothelin-1 levels showed a significant increase after 180 and 360 min of HCl aspiration. |
Does a novel anti-microtubule agent with carbazole and benzohydrazide structures suppress tumor cell growth in vivo? | The mitotic spindles are among the most successful targets of anti-cancer chemotherapy, and they still hold promise as targets for novel drugs. The anti-mitotic drugs in current clinical use, including taxanes, epothilones, vinca alkaloids, and halichondrins, are all microtubule-targeting agents. Although these drugs are effective for cancer chemotherapy, they have some critical problems; e.g., neurotoxicity caused by damage to neuronal microtubules, as well as innate or acquired drug resistance. To overcome these problems, a great deal of effort has been expended on development of novel anti-mitotics. We identified novel microtubule-targeting agents with carbazole and benzohydrazide structures: N'-[(9-ethyl-9H-carbazol-3-yl)methylene]-2-methylbenzohydrazide (code number HND-007) and its related compounds. We investigated their activities against cancer cells using various methods including cell growth assay, immunofluorescence analysis, cell cycle analysis, tubulin polymerization assay, and tumor inhibition assay in nude mice. HND-007 inhibits tubulin polymerization in vitro and blocks microtubule formation and centrosome separation in cancer cells. Consequently, it suppresses the growth of various cancer cell lines, with IC50 values in the range 1.3-4.6μM. In addition, HND-007 can inhibit the growth of taxane-resistant cancer cells that overexpress P-glycoprotein. Finally, HND-007 can inhibit HeLa cell tumor growth in nude mice. | C-reactive protein (CRP) levels predict incident and recurrent cardiovascular disease (CVD) events; however, associations between CRP and pre-clinical atherosclerosis is less certain. Since high concentrations of high-density lipoprotein cholesterol (HDL-C) are inversely associated with CVD risk, we investigated whether HDL-C modified the association between CRP concentration and measures of preclinical atherosclerosis. Data were analyzed from a Korean occupational cohort of 12,030 male subjects who underwent a cardiac computed tomography (CT) estimation of coronary artery calcification (CAC) score and an assessment of CVD risk factors. Logistic regression was used to describe associations between CRP and measures of pre-clinical atherosclerosis, such as CAC scores >0. As many as 1351 (11.2%) participants had a CAC score>0. CRP was stratified into 3 groups based on clinical category: <1 mg/L, 1 to <2 mg/L, and ≥ 2 mg/dL. In the bottom CRP group, 907/8697 (10.4%) of subjects had a CAC score >0, compared with 242/1943 (12.5%) in the middle group and 202/1396 (14.5%) in the top CRP group (p < 0.0001). After adjustment for multiple CVD risk factors, there was a positive association between CRP and CAC score>0 (OR between top and bottom CRP groups, 1.41 [1.04, 1.90], p = 0.027) in the lowest HDL-C quartile but not in the highest HDL-C (OR between top and bottom CRP group, 0.80 [0.46, 1.39], p = 0.425). |
Does high-resolution intravital NADH fluorescence microscopy allow measurements of tissue bioenergetics in rat ileal mucosa? | NADH fluorescence microscopy has been used as an index of the metabolic state of tissue but is associated with various obstacles such as low spatial resolution and quenching effects of blood pigments that prevent reliable monitoring of tissue bioenergetics. The objective of this study was to develop a system to monitor tissue bioenergetics in vivo using NADH fluorescence microscopy in the rat ileal mucosa. Using an inverted microscope with an epifluorescence unit and an intensified charge-coupled device camera, NADH fluorescence images were visualized. Fluorescence intensity was measured of beta-NADH solutions at varying concentration (n = 6) and pH (n = 3) and in ex vivo (n = 6) and in vivo (n = 6) preparations of ileal mucosa of Sprague-Dawley rats anesthetized with isoflurane. Intravital fluorescence microscopy reveals a map of the microcirculation that permits visualization of NADH fluorescence and intercapillary areas. The system was adjusted so a linear relationship between physiological concentrations of beta-NADH and fluorescence was achieved (r(2) = 0.98, p < .0001). Decreasing the pH of the solution had no effect on fluorescence intensity and fluorescence intensity in an anoxic ex vivo ileal segment was similar to that of the in vivo ileum after ischemia. Ischemia also resulted in spatial heterogeneity that was abolished by the addition of a 550-nm LP filter. | To assess prospectively the impact of psychiatric disorders on risk for exacerbations. The course of chronic obstructive pulmonary disease (COPD) is punctuated by acute exacerbations. Although anxiety and mood disorders are common in patients with COPD, no studies have assessed prospectively the association between these disorders and exacerbations. Psychiatric disorders were evaluated by a structured psychiatric interview in 110 patients (51% women, age (mean +/- standard deviation) = 66 +/- 8 years) with stable COPD and previous admission for exacerbations recruited from two outpatient clinics. Patients were followed for a mean of 2 years and both inpatient-treated (i.e., treated in the emergency department or hospital) and outpatient-treated (i.e., treated with medication in the patient's own environment) exacerbations were recorded. Independent of covariates, patients with psychiatric disorders exhibited a significantly higher weighted annual rate of exacerbations treated in an outpatient setting after adjustment for covariates (3 versus 2, p = .003) than patients without psychiatric disorders, but no difference in exacerbations treated in the inpatient setting. They were also at a higher risk for any (relative risk (RR) = 1.56, 95% Confidence Interval (CI) = 1.02-2.37) and outpatient (RR = 1.68, 95% CI = 1.08-2.59) exacerbations, but not inpatient exacerbations (RR = 1.36, 95% CI = 0.82-2.25). |
Does endometriosis also affect the decidua in contact with the fetal membranes during pregnancy? | Are the fetal membranes of women affected with endometriosis similar to those from disease-free women? | The present study was designed to examine the influence of suicidality on relapse in alcohol-dependent patients. Specifically, a lifetime suicide attempt at baseline was used to predict relapse in the year after treatment. Also, the unique contribution of impulsive suicide attempts was examined. A total of 154 patients with alcohol dependence, consecutively admitted to four addiction treatment facilities in Warsaw, Poland participated in the study. Of the 154 eligible patients, 118 (76.6%) completed a standardized follow-up assessment at 12 months. Previous suicide attempts were common in adults treated for alcohol dependence with 43% patients in the present sample reporting an attempt at some point during their lifetime. Additionally, more than 62% of those with a lifetime suicide attempt reported making an impulsive attempt. Lifetime suicide attempts were not associated with post-treatment relapse (chi-square=2.37, d.f.=1, p=0.124). However, impulsive suicide attempts strongly predicted relapse (OR=2.81, 95% CI=1.13-6.95, p=0.026) and time to relapse (OR=2.10, 95% CI=1.18-3.74, p=0.012) even after adjusting for other measures of baseline psychopathology, depression, impulsivity, hopelessness and alcohol use severity. |
Is altered synaptic transmission in the hippocampus of the castrated male mouse reversed by testosterone replacement? | To determine the effect of castration on hippocampal function, we have investigated synaptic transmission in the castrated male mouse in vivo. We also examined whether administering testosterone can reverse the changes. Male 12 weeks-old C57BL/6J mice were divided into three experimental groups; sham-castration (Control), the castration group (Cast), and the castration plus testosterone propionate group (Cast+TP). Field excitatory postsynaptic potentials (fEPSP) were evoked in the CA1 area of the hippocampus by stimulating the commissural fibers of the contralateral hippocampus. Field EPSPs were evoked in the granular cells of the dentate gyrus (DG) by stimulating the ipsilateral perforant path fibers. Laminar analysis of the fEPSPs in the hippocampal CA1 pyramidal cell layer did not differ significantly between the three experimental groups. However, paired pulse facilitation (PPF) of the fEPSP with short inter-stimulus intervals (30 to 100 msec) was significantly suppressed in Cast group. This suppression was reversed by testosterone injection (Cast+TP). Longterm potentiation (LTP) in the CA1 pyramidal neurons by high frequency stimulation (HFS) did not differ significantly between the three experimental groups, whereas potentiation evoked by primed burst stimulation (PBS) was much weaker in the Cast group compared with the Control group. Testosterone injection restored the PBS-induced potentiation to the control level. Synaptic transmission between perforant pathway and the granule cells in the dentate gyrus (DG) did not differ significantly among the three experimental groups. | Several biomarkers indicating poor prognosis have been reassessed in patients receiving rituximab combination chemotherapy for diffuse large B-cell lymphoma (DLBCL). However, few studies have investigated outcome in relation to a combination of these biomarkers. In addition, no large-scale studies have reassessed the outcome of patients with CD5-positive DLBCL treated with rituximab. We conducted a retrospective study and investigated the predictive value of three biomarkers -- BCL2, germinal center (GC) phenotype and CD5 -- in 121 DLBCL patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone. CD5-positive patients showed significantly poorer event-free survival (EFS) and overall survival (OS) than CD5-negative patients (2-year EFS, 18% versus 73%, P < 0.001; 2-year OS, 45% versus 91%, P = 0.001). However, no significant difference in outcome according to BCL2 or GC phenotype was observed. Multivariate analysis revealed that CD5 expression was a significant prognostic factor for EFS [hazard ratio 14.2, 95% confidence interval (CI) 4.7-43.2] and OS (hazard ratio 20.3, 95% CI 3.6-114.4). |
Is the nonsynonymous Thr105Ile polymorphism of the histamine N-methyltransferase associated to the risk of developing essential tremor? | We analyzed in patients with essential tremor (ET) the Thr105Ile polymorphism of the Histamine N-methyltransferase (HNMT) enzyme that is associated to Parkinson's disease (PD) risk. Leukocytary DNA from 204 ET patients and a control group of 295 unrelated healthy individuals was studied for the nonsynonymous HNMT Thr105Ile polymorphism by using amplification-restriction analyses. Patients with ET showed a higher frequency of homozygous HNMT 105Thr genotypes leading to high metabolic activity (p < 0.015) with a statistically significant gene-dose effect, as compared to healthy subjects. These findings were independent of gender, and of tremor localization, but the association of the HNMT polymorphism is more prominent among patients with late-onset ET (p < 0.007). | To compare histologically the size and appearance of capsule disks after femtosecond laser-assisted cataract surgery and conventional cataract surgery. In 100 eyes of 100 patients with visually significant cataracts, a femtosecond laser capsulotomy or a capsulorhexis with an aimed diameter of 5.0 mm was performed by one experienced surgeon. The diameter, area, circularity, and cut quality was histologically examined with light microscopy and scanning electron microscopy. The mean diameter of the manual and the femtosecond laser capsule disk group were not statistically significantly different (manual 4.91 ± 0.34; femtosecond: 4.93 ± 0.03; p = 0.58). The mean area of the capsule disks was 18.85 ± 2.69 mm2 in the manual and 19.03 ± 0.26 mm2 in the femtosecond group (p = 0.64). The capsules of the femtosecond group (0.95 ± 0.02) were significantly more circular than the ones of the manual group (0.81 ± 0.07; p<0.0001). The femtosecond laser capsule disks displayed a more saw blade-like structure created through the single laser spots. The histologic examination combined with prospective video analysis revealed respiratory movement of the eye during the capsulotomy as a potential risk factor for redial tears. |
Does feG-COOH blunt eosinophilic airway inflammation in a feline model of allergic asthma? | This study investigated if feG-COOH would decrease allergen-induced airway inflammation. Seven adult cats sensitised to Bermuda grass allergen (BGA) to induce an asthmatic phenotype. Cats were randomized to receive either feG-COOH (1 mg/kg, PO) or placebo (saline 1 ml, PO) immediately prior to BGA aerosol challenge in a cross-over design. Bronchoalveolar lavage fluid (BALF) was collected and airway inflammatory response assessed via inflammatory cell number and type; IL-4, IFN-gamma and nitric oxide metabolite concentrations. A paired t test was used to compare parameters with a P < 0.05 considered significant. The BALF eosinophil percentage was significantly lower in asthmatic cats treated with feG compared with placebo (placebo, 35.3 +/- 12.2%; feG, 22.4 +/- 8.6%; P = 0.002). Treatment with feG did not result in a significant change in any other parameter measured. | MicroRNAs (miR, miRNAs) play pivotal roles in numerous physiological and pathophysiological contexts. We investigated whether miR-362-5p act as an oncogene in chronic myeloid leukaemia (CML) and aimed to understand its potential underlying mechanisms. We compared the miR-362-5p expression levels between CML and non-CML cell lines, and between fresh blood samples from CML patients and normal healthy controls using quantitative real-time PCR (qPCR). Cell counting kit-8 (CCK-8) and Annexin V-FITC/PI analyses were used to measure the effects of miR-362-5p on proliferation and apoptosis, and Transwell assays were used to evaluate migration and invasion. A xenograft model was used to examine in vivo tumourigenicity. The potential target of miR-362-5p was confirmed by a luciferase reporter assay, qPCR and western blotting. Involvement of the JNK1/2 and P38 pathways was investigated by western blotting. miR-362-5p was up-regulated in CML cell lines and fresh blood samples from CML patients, and was associated with Growth arrest and DNA damage-inducible (GADD)45α down-regulation. Inhibition of miR-362-5p simultaneously repressed tumour growth and up-regulated GADD45α expression in a xenograft model. Consistently, the knockdown of GADD45α expression partially neutralized the effects of miR-362-5p inhibition. Furthermore study suggested that GADD45α mediated downstream the effects of miR-362-5p, which might indirectly regulates the activation of the JNK1/2 and P38 signalling pathways. |
Does dimethyl sulfoxide provide neuroprotection in a traumatic brain injury model? | The objective of this study was to evaluate the neuroprotective potential of the antioxidant, curcumin compared to alpha-tocopherol in a rat model of traumatic brain injury (TBI). Male Sprague-Dawley rats were administered curcumin (3, 30, 300 mg/kg), alpha-tocopherol (100 mg/kg), DMSO vehicle, or saline, 30 min prior to and 30 and 90 min after moderate lateral fluid percussion TBI. Rats were euthanized at 24 hours after injury and coronal brain sections were stained with Fluoro-Jade to identify degenerating neurons. Degenerating neurons in the CA2-3 sector of the dorsal hippocampus were quantified in 10 sections spaced 300 microm apart in each rat. One way ANOVA revealed a significant difference (p = 0.01) between groups. The curcumin, alpha-tocopherol, and DMSO groups had significantly reduced numbers of degenerating neurons compared to the saline-treated group. No significant differences were observed between any of the drug treatment groups or the DMSO group. | Reduced levels of free and total insulin-like growth factor 1 (IGF-I) have been observed in type-1 diabetes (T1D) patients. The bioavailability of IGF-I from the circulation to the target cells is controlled by multifunctional IGF-binding proteins (IGFBPs). The aim of this study was to profile serum IGFBPs in T1D and its complications. We measured the IGFBP levels in 3662 patient serum samples from our ongoing Phenome and Genome of Diabetes Autoimmunity (PAGODA) study. IGFBP levels of four different groups of T1D patients (with 0, 1, 2, and ≥3 complications) were compared with healthy controls. Three serum IGFBPs (IGFBP-1, -2, and -6) are significantly higher in T1D patients, and these alterations are greater in the presence of diabetic complications. IGFBP-3 is lower in patients with diabetic complications. Analyses using quintiles revealed that risk of T1D complications increases with increasing concentrations of IGFBP-2 (fifth quintile ORs: 18-60, p < 10(-26)), IGFBP-1 (fifth quintile ORs: 8-20, p < 10(-15)), and IGFBP-6 (fifth quintile ORs: 3-148, p < 10(-3)). IGFBP-3 has a negative association with T1D complications (fifth quintile ORs: 0.12-0.25, p < 10(-5)). |
Do increase of MMP-13 expression in multi-stage oral carcinogenesis and epigallocatechin-3-gallate suppress MMP-13 expression? | Matrix metalloproteinases (MMPs) play pivotal roles in tumor progression. MMP-13 (collagenase-3) digests collagen and other extracellular components. Reverse transcriptase-polymerase chain reaction (RT-PCR), immunohistochemistry and zymograph were used to study the roles of MMP-13 during the neoplastic process of oral squamous cell carcinoma (OSCC). Increase of MMP-13 mRNA and protein expression in OSCC cell lines relative to cultivated normal oral keratinocytes was found. MMP-13 mRNA expression in OSCC was significantly higher than in non-cancerous match tissue (NCMT) in 36 tissue pairs. Esophageal squamous cell carcinoma also exhibited high MMP-13 mRNA expression. The percentage of OSCC exhibiting strong MMP-13 immunoreactivity was significantly higher than pre-invasive lesion and NCMT. Treatment with >5 microm epigallocatechin-3-gallate (EGCG) to OEC-M1 cells suppressed the expression and activity of MMP-13. | To investigate the effects of ventilatory mode, injectate temperature, and clinical situation on the precision of cardiac output measurements. Randomized, prospective observational study. Single university hospital. Forty patients undergoing planned cardiac surgery, receiving a pulmonary artery catheter according to institutional routine. Cardiac output was measured at 4 predefined time points during the perioperative patient course, twice during controlled and twice during spontaneous ventilation, using 2 blocks of 8 measurement replications with cold and tepid injectate in random order. The data were analyzed using a hierarchical linear mixed model. Clinical precision was determined as half the width of the 95% confidence interval for the underlying true value. The single-measurement precision measured in 2 different clinical situations for each temperature/ventilation combination was 8% to 10%, 11% to 13%, 13% to 15%, and 23% to 24% in controlled ventilation with cold injectate, controlled ventilation with tepid injectate, spontaneous breathing with cold injectate, and spontaneous breathing with tepid injectate, respectively. Tables are provided for the number of replications needed to achieve a certain precision and for how to identify significant changes in cardiac output. |
Is urinary creatinine concentration inversely related to glycaemic control and the presence of some diabetic complications in patients with newly diagnosed Type 2 diabetes? | The ratio between urinary albumin concentration (UAC) and urinary creatinine concentration (UCC) is widely used to estimate renal involvement. We examined how UAC and UCC associate with each other, with other risk factors, and with diabetic complications in a population-based sample of Type 2 diabetic patients. A freshly voided morning urine specimen was provided by 1,284 consecutive, newly diagnosed diabetic patients aged 40 years or over in general practice. Albumin was measured by a polyethyleneglycol radioimmunoassay and creatinine by a modified Jaffe method. In a multivariate model including UAC, UCC, age, sex, HbA1c, and urinary glucose concentration, UAC increased with both age (P=.042) and HbA1c (P=.014), while UCC decreased (P<.001 and P<.001, respectively). In two regression models, the prevalence of diabetic retinopathy (P<.001) and relatively high resting heart rate (P<.001) increased with increasing UAC but decreased with increasing UCC (P=.002 and P=.005, respectively). | Mast cells have been associated with obliterative bronchiolitis (OB) in human pulmonary allografts, although their role in the development of OB remains unknown. In this study, we evaluated the role of mast cells in pulmonary allograft rejection using an orthotopic rat pulmonary allograft model that utilizes chronic aspiration of gastric fluid to reliably obtain OB. Pulmonary allograft recipients (n = 35) received chronic aspiration of gastric fluid with (n = 10) and without (n = 16) treatment with a mast cell membrane stabilizer, cromolyn sodium, or chronic aspiration with normal saline (n = 9) as a control. The acute graft injury associated with long ischemic time in the model (6 hours total ischemic time; typical acute graft injury rate ~30%) was apparently blocked by cromolyn, because peri-operative mortality associated with the acute graft injury was not observed in any of the animals receiving cromolyn (p = 0.045). Further, the rats receiving cromolyn developed significantly fewer OB lesions than those treated with gastric fluid alone (p < 0.001), with a mean reduction of 46% of the airways affected. |
Does patatin-Like Phospholipase Domain-Containing 3 I148M Variant be Associated with Liver Steatosis and Fat Distribution in Chronic Hepatitis B? | The patatin-like phospholipase domain-containing 3 gene (PNPLA3) has been associated with liver steatosis and disease progression in nonalcoholic steatohepatitis and chronic hepatitis C. The aim of the present study was to evaluate the influence of the PNPLA3 I148M polymorphisms on the clinical, histological, viral, and host parameters in Italian patients with chronic hepatitis B (CHB). Ninety-nine patients with CHB entered the study and underwent a clinical, histological, virological, and biochemical evaluation. PNPLA3 (p.I148M) variants were genotyped. PNPLA3 rare variant (148M) was significantly associated with liver steatosis (p = 0.0019) and cholesterol (p = 0.04) levels, but not with fibrosis or histological activity index. The 13 patients with severe liver steatosis (score > 3) (38%) were more frequently homozygous for PNPLA3 148M variant than the 86 without (6%, p = 0.003). At logistic regression analysis, severe steatosis was independently associated with the rare allele (p = 0.001) and waist circumference, but not with body mass index (BMI). | To assess whether the free radical scavenger, edaravone, could provide protection from oxidative stress and hearing loss induced by noise exposure. Forty-eight guinea pigs were divided into six groups and exposure to a stationary noise at 125 dB SPL for 2 h only once. Group A: measured hearing and reactive oxygen species (ROS) level without noise exposure. Group B: intratympanic saline injection. Group C: intratympanic edaravone injection. Group D: exposed to noise for 2 h. Group E: intravenous edaravone injection after noise exposure. Group F: intratympanic edaravone injection after noise exposure. All animals of group D, E and F were measured hearing with ABR before noise exposure, immediately after noise exposure and at 2, 6, 12, 24, 48, 72 h after noise exposure, and then were decapitated for ROS measurement with electron spin resonance technology. After noise exposure, the ABR threshold of group D increased immediately after acute acoustic trauma and did not get right finally, while group F came back about 10 dB SPL. The normal level of ROS in the cochlea of guinea pigs was about 21.68 (cm/g) and significantly increased after acute acoustic trauma, reaching its peak in 2h, and didn't return to normal after 72 h. Group E did not inhibit free radicals, while group F showed significant effect on inhibiting production of free radicals. |
Is [ Ischemia an independent predictive factor of chronic renal failure after partial nephrectomy in a solitary kidney in patients without pre-operative renal insufficiency ]? | To assess the influence of vascular clamping and ischemia time on long-term post-operative renal function following partial nephrectomy (PN) for cancer in a solitary kidney. This is a retrospective study including 259 patients managed by PN between 1979 and 2010 in 13 centers. Clamping use, technique choice (pedicular or parenchymal clamping), ischemia time, and peri-operative data were collected. Pre-operative and last follow-up glomerular filtration rates were compared. A multivariate analysis using a Cox model was performed to assess the impact of ischemia on post-operative chronic renal failure risk. Mean tumor size was 4.0±2.3cm and mean pre-operative glomerular filtration rate was 60.8±18.9mL/min. One hundred and six patients were managed with warm ischemia (40.9%) and 53 patients with cold ischemia (20.5%). Thirty patients (11.6%) have had a chronic kidney disease. In multivariate analysis, neither vascular clamping (P=0.44) nor warm ischemia time (P=0.1) were associated with a pejorative evolution of renal function. Pre-operative glomerular filtration rate (P<0.0001) and blood loss volume (P=0.02) were significant independent predictive factors of long-term renal failure. | TAR DNA binding protein, encoded by TARDBP, was shown to be a central component of ubiquitin-positive, tau-negative inclusions in frontotemporal lobar degeneration (FTLD-U) and amyotrophic lateral sclerosis (ALS). Recently, mutations in TARDBP have been linked to familial and sporadic ALS. To further examine the frequency of mutations in TARDBP in sporadic ALS, 279 ALS cases and 806 neurologically normal control individuals of European descent were screened for sequence variants, copy number variants, genetic and haplotype association with disease. An additional 173 African samples from the Human Gene Diversity Panel were sequenced as this population had the highest likelihood of finding changes. No mutations were found in the ALS cases. Several genetic variants were identified in controls, which were considered as non-pathogenic changes. Furthermore, pathogenic structural variants were not observed in the cases and there was no genetic or haplotype association with disease status across the TARDBP locus. |
Does a novel aspirin prodrug inhibit NFκB activity and breast cancer stem cell properties? | Activation of cyclooxygenase (COX)/prostaglandin and nuclear factor κB (NFκB) pathways can promote breast tumor initiation, growth, and progression to drug resistance and metastasis. Thus, anti-inflammatory drugs have been widely explored as chemopreventive and antineoplastic agents. Aspirin (ASA), in particular, is associated with reduced breast cancer incidence but gastrointestinal toxicity has limited its usefulness. To improve potency and minimize toxicity, ASA ester prodrugs have been developed, in which the carboxylic acid of ASA is masked and ancillary pharmacophores can be incorporated. To date, the effects of ASA and ASA prodrugs have been largely attributed to COX inhibition and reduced prostaglandin production. However, ASA has also been reported to inhibit the NFκB pathway at very high doses. Whether ASA prodrugs can inhibit NFκB signaling remains relatively unexplored. A library of ASA prodrugs was synthesized and screened for inhibition of NFκB activity and cancer stem-like cell (CSC) properties, an important PGE2-and NFκB-dependent phenotype of aggressive breast cancers. Inhibition of NFκB activity was determined by dual luciferase assay, RT-QPCR, p65 DNA binding activity and Western blots. Inhibition of CSC properties was determined by mammosphere growth, CD44(+)CD24(-)immunophenotype and tumorigenicity at limiting dilution. While we identified multiple ASA prodrugs that are capable of inhibiting the NFκB pathway, several were associated with cytotoxicity. Of particular interest was GTCpFE, an ASA prodrug with fumarate as the ancillary pharmacophore. This prodrug potently inhibits NFκB activity without innate cytotoxicity. In addition, GTCpFE exhibited selective anti-CSC activity by reducing mammosphere growth and the CD44(+)CD24(-)immunophenotype. Moreover, GTCpFE pre-treated cells were less tumorigenic and, when tumors did form, latency was increased and growth rate was reduced. Structure-activity relationships for GTCpFE indicate that fumarate, within the context of an ASA prodrug, is essential for anti-NFκB activity, whereas both the ASA and fumarate moieties contributed to attenuated mammosphere growth. | Adolescent depression is more common in lower socio-economic groups. Whether this pattern has changed over time, is not known.We examined the prevalence of self-reported depression and its changes in socio-economic groups from 2000 to 2011 among Finnish adolescents. Data were based on classroom surveys every second year from 2000-2001 to 2010-2011 using nationwide samples of 14-16-year old Finns (n = 618,084). Data were collected using self-administered questionnaires including questions on health, health behaviours, and school experiences. Depression was measured with a Finnish modification of the 13-item Beck Depression Inventory, and divided into no, mild, moderate and severe depression. The association between depression and the social background (parents' education and employment) over time was studied using a multinomial regression analysis. The prevalence of self-reported severe depression slightly increased from 2000-2001 to 2010-2011 in girls. In boys a slight increase was observed when adjusting for background variables. The differences in the prevalence of depression between the social background groups persisted over the entire study period. In both sexes, severe depression nearly doubled among those adolescents whose parents were unemployed and had a low education level; among boys, the prevalence was 6.5% in 2000-2001 and 12.8% in 2010-2011, and among girls 6.4% and 11.4% respectively. |
Do interleukin-1beta and tumor necrosis factor alpha inhibit chondrogenesis by human mesenchymal stem cells through NF-kappaB-dependent pathways? | The differentiation of mesenchymal stem cells (MSCs) into chondrocytes provides an attractive basis for the repair and regeneration of articular cartilage. Under clinical conditions, chondrogenesis will often need to occur in the presence of mediators of inflammation produced in response to injury or disease. The purpose of this study was to examine the effects of 2 important inflammatory cytokines, interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNFalpha), on the chondrogenic behavior of human MSCs. Aggregate cultures of MSCs recovered from the femoral intermedullary canal were used. Chondrogenesis was assessed by the expression of relevant transcripts by quantitative reverse transcription-polymerase chain reaction analysis and examination of aggregates by histologic and immunohistochemical analyses. The possible involvement of NF-kappaB in mediating the effects of IL-1beta was examined by delivering a luciferase reporter construct and a dominant-negative inhibitor of NF-kappaB (suppressor-repressor form of IkappaB [srIkappaB]) with adenovirus vectors. Both IL-1beta and TNFalpha inhibited chondrogenesis in a dose-dependent manner. This was associated with a marked activation of NF-kappaB. Delivery of srIkappaB abrogated the activation of NF-kappaB and rescued the chondrogenic response. Although expression of type X collagen followed this pattern, other markers of hypertrophic differentiation responded differently. Matrix metalloproteinase 13 was induced by IL-1beta in a NF-kappaB-dependent manner. Alkaline phosphatase activity, in contrast, was inhibited by IL-1beta regardless of srIkappaB delivery. | Microalbuminuria is associated with cardiovascular mortality, particularly among individuals with type 2 diabetes, but the mechanisms underlying this association are not completely understood. Microalbuminuria is known to be associated with cardiovascular autonomic dysfunction (C-AD), and C-AD in turn is associated with cardiovascular mortality. The purpose of this study, therefore, was to investigate whether C-AD can explain the relationship between microalbuminuria and cardiovascular mortality. We studied 490 individuals from a population-based cohort of individuals aged 50-75 years who were followed for a median period of 13.6 years. Microalbuminuria was defined as an albumin-to-creatinine ratio > or =2.0 mg/mmol in an early-morning spot-urine sample. Ten parameters reflecting different aspects of cardiovascular autonomic function were measured and compiled into a total score of C-AD (mean of separate z scores). The association between C-AD and microalbuminuria was estimated by multiple linear regression, and relative risks (RRs) for cardiovascular mortality were estimated by Cox proportional hazards analyses. After adjustments for age, sex, glucose tolerance status, and other risk factors, C-AD was associated with microalbuminuria (beta = 0.16 [95% CI 0.01-0.33]), and both microalbuminuria (RR 2.09 [1.07-4.08]) and C-AD (1.74 [1.04-2.89]) were associated with cardiovascular mortality. These associations did not change after further mutual adjustment for C-AD (2.13 [1.09-4.17]) or microalbuminuria (1.76 [1.05-2.94]), respectively. |
Does inhibition of notch signaling in combination with Paclitaxel reduce platinum-resistant ovarian tumor growth? | Ovarian cancer (OvCa) is the most lethal gynecologic malignancy in the United States because of chemoresistant recurrent disease. Our objective was to investigate the efficacy of inhibiting the Notch pathway with a γ-secretase inhibitor (GSI) in an OvCa patient-derived xenograft model as a single agent therapy and in combination with standard chemotherapy. Immunocompromised mice bearing xenografts derived from clinically platinum-sensitive human ovarian serous carcinomas were treated with vehicle, GSI (MRK-003) alone, paclitaxel and carboplatin (P/C) alone, or the combination of GSI and P/C. Mice bearing platinum-resistant xenografts were given GSI with or without paclitaxel. Gene transcript levels of the Notch pathway target Hes1 were analyzed using RT-PCR. Notch1 and Notch3 protein levels were evaluated. The Wilcoxon rank-sum test was used to assess significance between the different treatment groups. Expression of Notch1 and 3 was variable. GSI alone decreased tumor growth in two of three platinum-sensitive ovarian tumors (p < 0.05), as well as in one of three platinum-sensitive tumors (p = 0.04). The combination of GSI and paclitaxel was significantly more effective than GSI alone and paclitaxel alone in all platinum-resistant ovarian tumors (all p < 0.05). The addition of GSI did not alter the effect of P/C in platinum-sensitive tumors. Interestingly, although the response of each tumor to chronic GSI exposure did not correlate with its endogenous level of Notch expression, GSI did negatively affect Notch signaling in an acute setting. | Mild cognitive impairment (MCI) is recognized as a predementia state, but its definition is inconsistent and only 20%-30% develop dementia after 2 years. Biomarkers may help identify individuals at greatest risk of progressive decline. The authors examine a novel neuroimaging technique, diffusion tensor imaging (DTI) as a potential biomarker of MCI. Cross-sectional prospective study. Subjects were recruited randomly using the electoral roll from two electorates in East Sydney, Australia. A community-dwelling sample (N = 249) and age 70-90 years. Screening to exclude dementia, comprehensive neuropsychiatric assessment, cognitive test battery, structural magnetic resonance imaging and DTI to obtain measures of fractional anisotropy (FA) and mean diffusivity (MD). MCI was diagnosed by standard criteria. After controlling for age, sex, and years of education, the amnestic MCI (aMCI) group demonstrated microstructural pathology in the parahippocampal white matter, frontal white matter, splenium of corpus callosum, and posterior cingulate region. The nonamnestic MCI (naMCI) group demonstrated microstructural pathology in the frontal white matter, internal capsule, occipital white matter, and the posterior cingulate region. A binary logistic regression model showed that DTI of the left posterior cingulate was significant in identifying persons with aMCI to an accuracy of 85.1%. Receiver operating characteristics curve analysis yielded a sensitivity of 80% and specificity of 60.3% in distinguishing aMCI from naMCI and the normal comparison group. |
Does drought degree constrain the beneficial effects of a fungal endophyte on Atractylodes lancea? | Plants, fungal endophytes (FEs) and the changing environment interact with each other forming an interlaced network. This study evaluates nonadditive and interactive effects of the FE Acremonium strictum and drought treatment on Atractylodes lancea plantlets. By applying FEs (meristem cultures of At. lancea, fungal inoculation of Ac. strictum and plantlet acclimatization) and drought treatment (regular watering, mild drought, severe drought), a research system of At. lancea ramets under different treatments was established. During 12 days of drought treatment, the plantlets' physiological responses and basic growth traits were measured and analysed. Although drought and FE presence affected plantlet traits to differing degrees, the interactive effects of the two were more pronounced. In particular under mild drought treatment, the FE conferred drought tolerance to plantlets by enhancing leaf soluble sugars, proteins, proline and antioxidant enzyme activity; decreasing the degree of plasmalemma oxidation; and increasing the host's abscisic acid level and root:shoot ratio. When exposed to regular watering or severe drought, these effects were not significant. | Multi-atlas fusion is a promising approach for computer-assisted segmentation of anatomic structures. The purpose of this study was to evaluate the accuracy and time efficiency of multi-atlas segmentation for estimating spleen volumes on clinically acquired computed tomography (CT) scans. Under an institutional review board approval, we obtained 294 de-identified (Health Insurance Portability and Accountability Act-compliant) abdominal CT scans on 78 subjects from a recent clinical trial. We compared five pipelines for obtaining splenic volumes: Pipeline 1 - manual segmentation of all scans, Pipeline 2 - automated segmentation of all scans, Pipeline 3 - automated segmentation of all scans with manual segmentation for outliers on a rudimentary visual quality check, and Pipelines 4 and 5 - volumes derived from a unidimensional measurement of craniocaudal spleen length and three-dimensional splenic index measurements, respectively. Using Pipeline 1 results as ground truth, the accuracies of Pipelines 2-5 (Dice similarity coefficient, Pearson correlation, R-squared, and percent and absolute deviation of volume from ground truth) were compared for point estimates of splenic volume and for change in splenic volume over time. Time cost was also compared for Pipelines 1-5. Pipeline 3 was dominant in terms of both accuracy and time cost. With a Pearson correlation coefficient of 0.99, average absolute volume deviation of 23.7 cm(3), and time cost of 1 minute per scan, Pipeline 3 yielded the best results. The second-best approach was Pipeline 5, with a Pearson correlation coefficient of 0.98, absolute deviation of 46.92 cm(3), and time cost of 1 minute 30 seconds per scan. Manual segmentation (Pipeline 1) required 11 minutes per scan. |
Does perfusion scanning using 99mTc-HMPAO detect early cerebrovascular changes in the diabetic rat? | 99mTc-HMPAO is a well-established isotope useful in the detection of regional cerebral blood flow. Diabetes gives rise to arterial atherosclerotic changes that can lead to significant end organ dysfunction, prominently affecting perfusion to the heart, kidneys, eyes and brain. In the current study, we investigated the role of 99mTc-HMPAO cerebral perfusion scans in detecting early vascular changes in the diabetic brain. Cerebral perfusion studies were performed on both control and streptozotocin-(STZ) induced diabetic male Wistar rats. Rat brain imaging using a gamma camera was performed for each group 0.5, 2, 4, and 24 hours post 99mTc-HMPAO injection. Data processing for each cerebral perfusion scan was performed by drawing a region of interest (ROI) circumferentially around the brain (B). Background (BKG) due to signal from the soft tissue of each rat was subtracted. Brain 99mTc-HMPAO uptake minus background counts (net brain counts; NBC) were then compared between the two groups. The NBC (mean +/- SD) for the STZ group were statistically significantly higher (p = 0.0004) than those of the control group at each of the time points studied. | Allergic rhinitis is a morbid condition that is frequently overlooked by patients and physicians. This type of atopy has not been adequately investigated in the United Arab Emirates. This cross-sectional, population-based observational study was conducted in the seven Emirates (Abu Dhabi, Dubai, Sharjah, Ajman, Umm Al-Quwain, Ras Al-Khaimah, and Fujairah). It used the European Community Respiratory Health Survey (ECRHS II) to screen for allergic rhinitis in people living in this region. Symptoms of allergic rhinitis were present in 85 (7%) of the 1,229 study population. Only 33 (39%) patients received treatment. Seventy-six (89%) patients had asthma. Thirty-seven (44%) patients were poly-sensitized. Symptoms were aggravated by dust (59%), grass/pollens (44%) and proximity to animals (21%). Winter was the peak season (37%), followed by spring (30%), autumn (18%) and summer (15%). Grass/pollen allergies were clustered in the winter, spring and summer (p ≤ 0.001). Dust was non-seasonal (p ≥ 0.121) and animal allergy was worse in the winter (p = 0.024) and spring (p = 0.044). Spring symptoms were less common in people living in the inner city (p = 0.003). |
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