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Does the atypical zeta ( zeta ) isoform of protein kinase C regulate CD11b/CD18 activation in human neutrophils?
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The objective of this study was to examine the role of protein kinase C zeta (PKCzeta) in interleukin (IL)-8-mediated activation of Mac-1 (CD11b/CD18) in human neutrophils. Neutrophils were stimulated with IL-8 in the presence or absence of pharmacologic inhibitors of PKC or a myristoylated PKCzeta pseudosubstrate. The resulting changes in Mac-1 surface expression, affinity, and avidity, as measured by clustering, were determined by using a combination of flow cytometry and immunofluorescence (IF). Colocalization of Mac-1 with PKCzeta was also probed using IE Finally, neutrophil adhesion to matrix proteins was examined under static conditions and adhesion to tumor necrosis factor-alpha-stimulated human umbilical vein endothelial cells was examined under flow conditions, using a parallel-plate flow chamber PKCzeta and Mac-1 colocalized following stimulation with IL-8. Blocking PKCzeta prevented IL-8-induced Mac-1 clustering while simultaneously increasing Mac-1 affinity. To determine the relative contribution of affinity versus avidity in neutrophil adhesion, we examined adhesion under both static and flow conditions, and found that blocking PKCzeta prevented neutrophil adhesion, despite increased affinity of Mac-1.
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The high-density lipoprotein (HDL)-associated anti-oxidative and anti-inflammatory enzyme, paraoxonase-I, has been found previously to be lower in type 2 diabetes mellitus. We studied whether statin and fibrate treatment, alone and in combination, affect serum paraoxonase-I activity in conjunction with changes in HDL cholesterol in diabetic patients. A placebo-controlled crossover study was carried out in 14 type 2 diabetic patients to test the effect of 8 weeks of active treatment with simvastatin (40 mg daily), bezafibrate (400 mg daily), and their combination on serum paraoxonase-I activity, measured as its activity towards arylesterase and paraoxon. Serum paraoxonase-I activity was also compared between these diabetic patients and 49 non-diabetic control subjects. Serum arylesterase activity was lower in type 2 diabetic patients compared to control subjects (P < 0.001), but the difference in paraoxonase activity was not significant (P = 0.22). Neither arylesterase (P = 0.24) nor paraoxonase activity (P = 0.37) was increased in response to treatment, despite higher HDL cholesterol and apolipoprotein A-I during combination therapy (P < 0.05 for both).
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Does mMP13 regulate Aggressiveness of Pediatric Multiple Myeloma Through VEGF-C?
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Even though the blood and lymphatic vascular systems are both involved in the occurrence of cancer metastases, it is believed that lymphatic system is primarily responsible for the initial metastasis. Nevertheless, the molecular mechanisms underlying lymphangiogenesis of multiple myeloma (MM), especially in pediatric period, have not been clarified. Here we studied vascular endothelial growth factor C (VEGF-C) and matrix metalloproteinase 13 (MMP13) in pediatric MM patients. We overexpressed or inhibited VEGF-C in MM cells to study their effects on MMP13, and vice versa. A specific inhibitor for PI3k/Akt signaling pathway was used to examine the role of PI3k/Akt signaling in this regulatory axis. Both VEGF-C and MMP13 significantly upregulated in MM with lymph-node metastases. A strong correlation between VEGF-C and MMP13 were detected in MM specimen. Using a human MM line 8226, we found that VEGF-C was regulated by MMP13 in MM cells, but not vice versa. Moreover, a specific PI3k/Akt inhibitor significantly abolished the effect of MMP13 on VEGF-C activation.
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To study the pathophysiological importance of changes in insulin sensitivity and islet function over time for alterations in glucose tolerance in a randomly selected large group of non-diabetic women aged 57-59 years over a 3-year period. At baseline and at the 3-year follow-up, glucose tolerance (WHO 75 g oral glucose), insulin sensitivity (euglycaemic, hyperinsulinaemic clamp) and insulin and glucagon secretion (2 to 5-min responses to 5 g i.v. arginine at fasting, 14 and > 25 mmol/l glucose) were measured. At baseline, women with impaired glucose tolerance (IGT, n = 28) had lower insulin sensitivity (p = 0.048) than normal women (NGT, n = 58). The arginine-induced insulin responses (AIR) were inversely associated with insulin sensitivity (r > or = -0.55, p < 0.001). When related to the 3-year follow-up, the baseline product of AIR at 14 mmol/l glucose times insulin sensitivity, insulin effect index (IE) (r = -0.40, p < 0.001) and the arginine-induced glucagon response at 14 mmol/l glucose (AGR, r = 0.28, p = 0.009) both correlated with follow-up 2-h glucose. In a multiple regression model, baseline 2-h glucose, insulin effect index and arginine-induced glucagon response independently predicted 2-h glucose at follow-up (total r = 0.668, p < 0.001). Furthermore, delta insulin sensitivity (i. e. follow-up minus baseline) correlated with delta insulin secretion (r = -0.30, p = 0.006), whereas delta glucagon secretion correlated with delta2-h glucose (r = 0.30, p = 0.006) over the 3 years. In a multiple regression, alterations in 2-h glucose over the 3 years were independently determined by changes in fasting insulin and glucagon secretion (r = 0.424, p < 0.001).
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Does cT angiography spot sign in intracerebral hemorrhage predict active bleeding during surgery?
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To determine whether the CT angiography (CTA) spot sign marks bleeding complications during and after surgery for spontaneous intracerebral hemorrhage (ICH). In a 2-center study of consecutive spontaneous ICH patients who underwent CTA followed by surgical hematoma evacuation, 2 experienced readers (blinded to clinical and surgical data) reviewed CTAs for spot sign presence. Blinded raters assessed active intraoperative and postoperative bleeding. The association between spot sign and active intraoperative bleeding, postoperative rebleeding, and residual ICH volumes was evaluated using univariable and multivariable logistic regression. A total of 95 patients met inclusion criteria: 44 lobar, 17 deep, 33 cerebellar, and 1 brainstem ICH; ≥1 spot sign was identified in 32 patients (34%). The spot sign was the only independent marker of active bleeding during surgery (odds ratio [OR] 3.4; 95% confidence interval [CI] 1.3-9.0). Spot sign (OR 4.1; 95% CI 1.1-17), female sex (OR 6.9; 95% CI 1.7-37), and antiplatelet use (OR 4.6; 95% CI 1.2-21) were predictive of postoperative rebleeding. Larger residual hematomas and postoperative rebleeding were associated with higher discharge case fatality (OR 3.4; 95% CI 1.1-11) and a trend toward increased case fatality at 3 months (OR 2.9; 95% CI 0.9-8.8).
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In utero undernutrition is associated with obesity and insulin resistance, although its effects on skeletal muscle remain poorly defined. Therefore, in the current study we explored the effects of in utero food restriction on muscle energy metabolism in mice. We used an experimental mouse model system of maternal undernutrition during late pregnancy to examine offspring from undernourished dams (U) and control offspring from ad libitum-fed dams (C). Weight loss of 10-week-old offspring on a 4-week 40% calorie-restricted diet was also followed. Experimental approaches included bioenergetic analyses in isolated mitochondria, intact (permeabilized) muscle and at the whole body level. U have increased adiposity and decreased glucose tolerance compared to C. Strikingly, when U are put on a 40% calorie-restricted diet they lose half as much weight as calorie-restricted controls. Mitochondria from muscle overall from U had decreased coupled (state 3) and uncoupled (state 4) respiration and increased maximal respiration compared to C. Mitochondrial yield was lower in U than C. In permeabilized fiber preparations from mixed fiber-type muscle, U had decreased mitochondrial content and decreased adenylate-free leak respiration, fatty acid oxidative capacity and state 3 respiratory capacity through complex I. Fiber maximal oxidative phosphorylation capacity did not differ between U and C but was decreased with calorie restriction.
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Do akt/protein kinase B and endothelial nitric oxide synthase mediate muscular neovascularization induced by tissue kallikrein gene transfer?
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Angiogenesis gene therapy with human tissue kallikrein (hTK) has shown promise for ischemic disease. The present study was undertaken to (1) assess an optimal gene transfer modality, (2) clarify hTK angiogenic pathways, and (3) discount possible side effects. The hTK gene was transferred to murine adductors by increasing doses of an adenovirus (Ad.hTK). Heterologous protein production was evaluated by ELISA and immunohistochemistry. Structural and functional characteristics of hTK-induced neovascularization were assessed. Muscular endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF)-A mRNA and protein content were evaluated by real-time polymerase chain reaction and Western blotting. The ability of hTK to phosphorylate-activate Akt/protein kinase B (Akt-B) and VEGF receptor 2 (VEGF-R2) was also determined. Implication of the aforementioned mechanisms in Ad.hTK-induced neovascularization was challenged by blocking Akt-B with a dominant-negative Akt construct; NOS with N(G)-nitro-L-arginine methyl ester; and VEGF-A with neutralizing antibody, VEGF-R2 antagonist, or Ad carrying soluble VEGF-R1 gene. We found that 10(7) PFU Ad.hTK led to peak increases in capillary and arteriole density. Newly developed arterioles persisted for up to 8 weeks. Ad.hTK did not change microvascular permeability. Ad.hTK upregulated eNOS mRNA and protein and activated Akt-B through Ser-473 phosphorylation. Inhibitory studies documented that these biochemical events were instrumental to Ad.hTK-induced neovascularization. In contrast, Ad.hTK neither affected VEGF-A and VEGF-R2 levels nor increased VEGF-R2 phosphorylation. Consistently, Ad.hTK-induced neovascularization was not disturbed by any of the different approaches used to block VEGF-A.
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Nutritional status provides helpful information of disease severity and treatment effectiveness. Body mass index standard deviation scores (BMI-SDS) provide an approximation of body composition and thus are frequently used to classify nutritional status of sick children and adolescents. However, the accuracy of estimating body composition in this population using BMI-SDS has not been assessed. Thus, this study aims to evaluate the accuracy of nutritional status classification in sick infants and adolescents using BMI-SDS, upon comparison to classification using percentage body fat (%BF) reference charts. BMI-SDS was calculated from anthropometric measurements and %BF was measured using dual-energy x-ray absorptiometry (DXA) for 393 sick children and adolescents (5 months-18 years). Subjects were classified by nutritional status (underweight, normal weight, overweight, and obese), using 2 methods: (1) BMI-SDS, based on age- and gender-specific percentiles, and (2) %BF reference charts (standard). Linear regression and a correlation analysis were conducted to compare agreement between both methods of nutritional status classification. %BF reference value comparisons were also made between 3 independent sources based on German, Canadian, and American study populations. Correlation between nutritional status classification by BMI-SDS and %BF agreed moderately (r (2) = 0.75, 0.76 in boys and girls, respectively). The misclassification of nutritional status in sick children and adolescents using BMI-SDS was 27% when using German %BF references. Similar rates observed when using Canadian and American %BF references (24% and 23%, respectively).
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Is pseudocholinesterase-mediated hydrolysis superior to neostigmine for reversal of mivacurium-induced paralysis in vitro?
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The metabolic hydrolysis of mivacurium (and succinylcholine) is markedly impaired in the presence of hereditary or acquired defects of pseudocholinesterase. Clinical reports are conflicting as to the utility of anticholinesterases, in the reversal of mivacurium paralysis. In the current study, the role of exogenous cholinesterases and/or of anticholinesterase, neostigmine, in the reversal of deep mivacurium-induced paralysis, was studied. The rat phrenic-diaphragm preparation, in a fixed volume of Krebs solution, was chosen to eliminate the confounding effects on the dissipation of neuromuscular effects caused by hydrolysis, elimination, and redistribution of the drug. In the phrenic-diaphragm preparation, mivacurium was administered to obtain >90% single twitch inhibition. Single twitch responses (0.1 Hz) were monitored for 60 min, after which the response to train-of-four stimulation was tested. The reversal of mivacurium by 0.5, 1.0, or 2.0 units/ml of (true) acetylcholinesterase, bovine pseudocholinesterase, or human plasma cholinesterase and by neostigmine, 0.1, 1.0, or 10.0 micrograms/ml tested. The efficacy of human plasma cholinesterase, 1 unit/ml in combination with each of the above neostigmine concentrations, also was examined. The reversal of succinylcholine-induced paralysis by the acetylcholinesterase, bovine pseudocholinesterase, or human plasma cholinesterase (1 unit/ml) alone and in the presence of neostigmine (10.0 micrograms/ml) was additionally tested as a positive control. A train-of-four ratio > 0.75 was considered adequate reversal. Acetylcholinesterase was a poor hydrolyzer of mivacurium, as bioassayed by reversal of paralysis. Bovine pseudocholinesterase in concentrations of 0.5 and 1.0 units/ml did not effectively reverse single twitch and train-of-four responses by 60 min, but bovine pseudocholinesterase (2 units/ml) and all concentrations of human plasma cholinesterase did. Neostigmine alone, tested at all concentrations, was an incomplete reversal drug. Clinical or therapeutic concentrations (0.1 and 1.0 micrograms/ml) of neostigmine did not, but pharmacologic concentrations (10 micrograms/ml) interfere with the efficacy of human plasma cholinesterase (1 unit/ml). Bovine pseudocholinesterase and human plasma cholinesterase equally reversed the effects of succinylcholine but acetylcholinesterase did not, whereas the addition of 10 micrograms/ml neostigmine to the enzymes inhibited the reversal of succinylcholine.
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Both obesity and type 2 diabetes are among the risk factors for breast cancer development. Combined effect of these metabolic abnormalities on breast cancer risk however, has not been examined in premenopausal women. We tested this association in type 2 diabetic women, categorized as obese, overweight and normal body weight groups based on BMI. A total of 101 subjects were included in this study. Serum levels of IL-6, TNF-alpha, C reactive protein, leptin, TGF-alpha, adiponectin and insulin were measured by ELISA. Data were logarithmically transformed for variables not normally distributed. Analysis of variance with post-hoc Bonferroni was applied to compare the data between the groups. Simple and partial correlation coefficients between the variables were determined and a stepwise multiple linear regression analysis was performed to determine the relationships between the variables of interest. Significantly increased levels of IL-6, C reactive protein, leptin and significantly decreased levels of adiponectin were found in obese group, while the levels of TNF-alpha and TGF-alpha were unaltered. A positive correlation between waist circumference and IL-6 was found in obese group. Similarly, C reactive protein, waist and hip circumferences were linearly correlated with BMI in obese group. Stepwise multiple linear regression analysis revealed several significant predictors for breast cancer risk.
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Are matrix metalloproteinase-9 ( MMP-9 ) , MMP-2 , and serum elastase activity associated with systolic hypertension and arterial stiffness?
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Arterial stiffness is an independent determinant of cardiovascular risk, and arterial stiffening is the predominant abnormality in systolic hypertension. Elastin is the main elastic component of the arterial wall and can be degraded by a number of enzymes, including matrix metalloproteinase-9 (MMP-9) and MMP-2. We hypothesized that elastase activity would be related to arterial stiffness and tested this using isolated systolic hypertension (ISH) as a model of stiffening and separately in a large cohort of healthy individuals. A total of 116 subjects with ISH and 114 matched controls, as well as 447 individuals free from cardiovascular disease were studied. Aortic and brachial pulse wave velocity (PWV) and augmentation index were determined. Blood pressure, lipids, C-reactive protein, MMP-9, MMP-2, serum elastase activity (SEA), and tissue-specific inhibitor 2 of metalloproteinases were measured. Aortic and brachial PWV, MMP-9, MMP-2, and SEA levels were increased in ISH subjects compared with controls (P=0.001). MMP-9 levels correlated linearly and significantly with aortic (r=0.45; P=0.001) and brachial PWV (r=0.22; P=0.002), even after adjustments for confounding variables. In the younger, healthy subjects, MMP-9 and SEA were also independently associated with aortic PWV.
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Pregnancy hormones were proposed to be crucially involved in fetal tolerance. Recently, we showed that human chorionic gonadotropin (hCG) not only increases the number and activity of regulatory T cells (Treg) but also retains tolerogenic dendritic cells (DCs). Here, we investigate whether the highly homologous luteinizing hormone (LH) modulates Treg number and DC phenotype and thereby supports pregnancy. Abortion-prone females were treated with LH or PBS on different gestation days. Pregnancy outcome and the number and phenotype of Treg and DCs were evaluated in the periphery and locally. We discovered that LH application completely prevented fetal rejection in abortion-prone females. This protective effect was associated with a Treg augmentation peripherally and locally. Moreover, LH reduced the number of total and mature DCs.
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Does [ Sanhuangyinchi decoction pretreatment ameliorate acute hepatic failure in rats by suppressing antioxidant stress and caspase-3 expression ]?
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To observe the effects of Sanhuangyinchi decoction (SHYCD) pretreatment on acute hepatic failure (AHF) induced by D-galactosamine and lipopolysaccharide (LPS) in rats and explore the possible mechanisms involving antioxidant stress and cell apoptosis-related protein expression. Forty-eight SD rats were randomized equally into control group, AHF model group, high-, medium- and low-dose SHYCD groups, and Bicyclol group. Five days after administration of the corresponding drugs, the rats were challenged with peritoneal D-galactosamine (700 mg/kg) plus LPS (10 ug/kg) injections to induce AHF acute hepatic failure except for those in the control group. At 48 h after the injections, blood samples were collected from the rats to detect the levels of ALT, AST, TBIL, PT, INR and FIB, and pathological changes and superoxide dismutase (SOD) and malondialdehyde (MDA) contents in the liver were examined; immunohistochemistry and western blotting were used to detect caspase-3 protein expression in the liver. The levels of ALT, AST, TBIL, TP and INR in the 3 SHYCD groups and Bicyclol group significantly decreased (P<0.05) while FIB significantly increased in comparison with those in the model group. SHYCD obviously ameliorated the pathological changes, enhanced SOD activity (P<0.05), and decreased MDA levels (P<0.05) and caspase-3 expression (P<0.05) in the liver tissue. SHYCD at the medium dose produced similar effects to Bicyclol (P>0.05) and showed better effects at the high dose than Bicyclol (P<0.05).
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Introduction of the new general medical services contract offered UK general practices the option to discontinue providing out-of-hours (OOH) care. This aimed to improve GP recruitment and retention by offering a better work-life balance, but put primary care organisations under pressure to ensure sustainable delivery of these services. Many organisations arranged this by re-purchasing provision from individual GPs. To analyse which factors influence an individual GP's decision to re-provide OOH care when their practice has opted out. Cross-sectional questionnaire survey. Rural and urban general practices in Scotland, UK. A postal survey was sent to all GPs working in Scotland in 2006, with analyses weighted for differential response rates. Analysis included logistic regression of individuals' decisions to re-provide OOH care based on personal characteristics, work and non-work time commitments, income from other sources, and contracting primary care organisation. Of the 1707 GPs in Scotland whose practice had opted out, 40.6% participated in OOH provision. Participation rates of GPs within primary care organisations varied from 16.7% to 74.7%. Males with young children were substantially more likely to participate than males without children (odds ratio [OR] 2.44, 95% confidence interval [CI] = 1.36 to 4.40). GPs with higher-earning spouses were less likely to participate. This effect was reinforced if GPs had spouses who were also GPs (OR 0.52, 95% CI = 0.37 to 0.74). GPs with training responsibilities (OR 1.36, 95% CI = 1.09 to 1.71) and other medical posts (OR 1.38, 95% CI = 1.09 to 1.75) were more likely to re-provide OOH services.
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Does histologic evidence that basic fibroblast growth factor enhance the angiogenic effects of transmyocardial laser revascularization?
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To determine whether addition of basic fibroblast growth factor (bFGF), an angiogenic growth factor, enhances the angiogenic effects of transmyocardial laser revascularization (TMR). TMR is an investigational therapy for treating patients with medically refractory angina not amenable to traditional therapies. Histologic and blood flow studies in animals have suggested that TMR enhances angiogenesis above that normally seen in ischemic myocardium. We tested the hypothesis that bFGF administered into TMR channels further enhance the angiogenic effects of TMR. Chronic ischemia was created in 3 groups of dogs using an ameroid constrictor on the proximal LAD. In the bFGF group (n = 5) non-transmyocardial channels were created in the LAD territory and bFGF, (100 ng/ml) dissolved in pluronic gel was injected into the each channel. In the TMR group (n = 7), transmyocardial channels were created without bFGF. A control group (n = 7) had ischemia without TMR of bFGF. 5-bromo-2'-deoxyuridine (BrdU) was administered to mark proliferating cells. After 8 weeks survival, colored microspheres were injected to assess the regional myocardial blood flow. TMR and TMR+bFGF increased total vascular density by approximately 40% over that observed in the control group. However, the number of large vessels (internal diameter > or = 50 microm) was doubled by the addition of bFGF, and this correlated with a 50% increase in the density of proliferating vascular cells and a tripling of the total estimated vascular cross sectional area. Blood flow to the LAD territory was increased by TMR compared to controls, with no further benefit observed in the bFGF group.
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This study examined the association between personality traits and work stress. The sample comprised 757 women and 613 men (aged 30 to 45 years in 2007) participating in the Young Finns study. Personality was assessed with the NEO-FFI questionnaire and work stress according to Siegrist's effort-reward imbalance (ERI) model. High neuroticism, low extraversion, and low agreeableness were associated with high ERI. Low conscientiousness was associated with high ERI in men. No association was found between openness and ERI. High neuroticism, high extraversion, and low agreeableness were associated with high effort and low neuroticism, high extraversion, and high agreeableness with high rewards. High conscientiousness was associated with high effort, and in women, with high rewards. High openness was associated with high effort.
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Is gABRA6 genetic polymorphism associated with the risk of functional heartburn in Chinese?
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Polymorphisms of GABA(A)alpha6 (GABRA6)-1521 and IL-1beta-511 have been linked with susceptibility to stress and gastric acid secretion. The aim of this study was to assess psychiatric profiles and GABRA6 and IL-1beta genotypes in functional heartburn, an important esophageal reflux condition. Psychological symptoms were assessed with a Brief Symptom Rating Scale and personality traits with a short-form Maudsley Personality Inventory. DNA from 452 healthy controls, 80 controls with neurosis, and 122 patients with functional heartburn was genotyped with PCR-RFLP technique. Symptom-scale parameters (except hostility) were significantly higher in patients with functional heartburn than in healthy controls; their neuroticism scores were also higher, but extroversion scores were lower. Distribution of GABRA6 genotypes in patients with functional heartburn showed more heterozygotes than among healthy controls and neurotic subjects, but distributions of IL-1beta genotypes were similar. Multiple logistic regression analysis showed GABRA6 heterozygosity was significantly associated with functional heartburn (odds ratio, 2.37; 95% confidence interval, 1.36-4.12; P < 0.01) even after adjustment for age, sex, Helicobacter pylori infection, General Symptom Index, and score of neuroticism.
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Bone loss is a common complication among renal transplant patients. Some studies have shown that alendronate may be effective to treat bone loss in these patients. In this study, we have reported our experience with administration of alendronate to treat bone loss in renal transplanted patients. The 46 kidney transplant recipients with bone loss were randomly divided into 2 groups: group I was treated with calcium and calcitriol, and group II with calcium, calcitriol, and alendronate. We examined bone mineral density (BMD) and biochemical indicators of both groups. All patients received cyclosporine and prednisone treatment. There was no significant difference in age, body mass index, gender, immunosuppression, time since transplantation, 25(OH)D(3), or intact parathyroid hormone levels at study commencement. The BMD of the femoral neck was significantly increased (P < .05), and the serum type I collagen-cross-linked N telopeptide (NTx) dramatically (P < .05) decreased in posttransplantation group II recipients treated with calcium, calcitriol, and alendronate. There were also significant differences in BMD and serum NTx between recipients treated with versus without alendronate (P < .05).
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Does mechanical fibrinogen-depletion support heparin-free mesenchymal stem cell propagation in human platelet lysate?
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Pooled human platelet lysate (pHPL) is an efficient alternative to xenogenic supplements for ex vivo expansion of mesenchymal stem cells (MSCs) in clinical studies. Currently, porcine heparin is used in pHPL-supplemented medium to prevent clotting due to plasmatic coagulation factors. We therefore searched for an efficient and reproducible medium preparation method that avoids clot formation while omitting animal-derived heparin. We established a protocol to deplete fibrinogen by clotting of pHPL in medium, subsequent mechanical hydrogel disruption and removal of the fibrin pellet. After primary culture, bone-marrow and umbilical cord derived MSCs were tested for surface markers by flow cytometry and for trilineage differentiation capacity. Proliferation and clonogenicity were analyzed for three passages. The proposed clotting procedure reduced fibrinogen more than 1000-fold, while a volume recovery of 99.5 % was obtained. All MSC types were propagated in standard and fibrinogen-depleted medium. Flow cytometric phenotype profiles and adipogenic, osteogenic and chondrogenic differentiation potential in vitro were independent of MSC-source or medium type. Enhanced proliferation of MSCs was observed in the absence of fibrinogen but presence of heparin compared to standard medium. Interestingly, this proliferative response to heparin was not detected after an initial contact with fibrinogen during the isolation procedure.
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Individuals with histories of smoking in first-degree relatives are significantly more likely to be persistent smokers themselves. The mechanisms underlying this relationship are unknown. Considerable research has demonstrated that smokers display heightened levels of cigarette craving after being exposed to stressful situations, and the magnitude of these craving responses is thought to be predictive of later cessation failure. Based on this research, we tested experimentally the hypothesis that smokers with two or more first-degree relatives who smoked (FH+) would exhibit stronger craving reactions following stressful stimuli than smokers without such family histories (FH-). We recruited 83 smokers by advertisement (mean age = 41.2 years, 57% female, 41% completed some college, 59% African American). The study was conducted in an interview room in an urban medical center. Participants were exposed to a neutral situation (changing a lightbulb) and a stressful situation (dental work) using script-guided imagery. Participants completed background measures of demographics, distress and smoking behavior. In addition, participants completed cigarette craving and anxiety questionnaires immediately before and after each condition. Supporting the study hypothesis, FH+ smokers (n = 39) selectively displayed stronger craving reactions to dental imagery (P < 0.03) than did FH- smokers (n = 44).
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Does perioperative Dexamethasone Administration Increase the Incidence of Postoperative Infection in Total Hip and Knee Arthroplasty : A Retrospective Analysis?
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Dexamethasone is frequently used for the treatment of postoperative nausea and vomiting and as an adjunct in multimodal postoperative analgesia after total joint arthroplasty; however, the incidence of periprosthetic joint infection (PJI) after the use of perioperative dexamethasone in total joint arthroplasty has yet to be fully elucidated. A retrospective chart review was conducted of all patients who underwent total hip or knee arthroplasty (N = 6294) between January 1, 2002 and January 31, 2014. The primary outcome was PJI requiring surgical intervention. Patients were subdivided into 2 cohorts; patients who received perioperative dexamethasone, a single 4- to 10-mg intravenous dose, as prophylaxis against postoperative nausea and vomiting (Dex group; N = 557) and those that did not receive perioperative dexamethasone (No Dex group; N = 5737). Secondary measures included timing of infection, culture data, and the type and number of subsequent procedures. Statistical analysis was performed using a chi-square or Fisher's exact test where appropriate. Seventy-four joints of the 6294 joints included in this analysis ultimately developed a PJI for an overall incidence of infection of 1.2%. Seven of the 557 joints (1.3%) in the Dex group developed a PJI; 67 of the 5737 joints (1.2%) in the No Dex group developed an infection. This difference was not significant (P = .8022). No significant difference in the timing of infection or the number of subsequent procedures was seen.
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Maternal smoking is a risk factor for low birth weight and other adverse developmental outcomes. We sought to determine the impact of standard tobacco cigarettes and e-cigarettes on heart development in vitro and in vivo. Zebrafish (Danio rerio) were used to assess developmental effects in vivo and cardiac differentiation of human embryonic stem cells (hESCs) was used as a model for in vitro cardiac development. In zebrafish, exposure to both types of cigarettes results in broad, dose-dependent developmental defects coupled with severe heart malformation, pericardial edema and reduced heart function. Tobacco cigarettes are more toxic than e-cigarettes at comparable nicotine concentrations. During cardiac differentiation of hESCs, tobacco smoke exposure results in a delayed transition through mesoderm. Both types of cigarettes decrease expression of cardiac transcription factors in cardiac progenitor cells, suggesting a persistent delay in differentiation. In definitive human cardiomyocytes, both e-cigarette- and tobacco cigarette-treated samples showed reduced expression of sarcomeric genes such as MLC2v and MYL6. Furthermore, tobacco cigarette-treated samples had delayed onset of beating and showed low levels and aberrant localization of N-cadherin, reduced myofilament content with significantly reduced sarcomere length, and increased expression of the immature cardiac marker smooth muscle alpha-actin.
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Does dental caries and their treatment need in 3-5 year old preschool children in a rural district of India?
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Dental problems in the preschool children are neglected by their parents as the deciduous teeth are going to shed off, and hence considered to be of no importance and more of economic burden if attended to them. This study was to determine the caries prevalence in preschool children (3-5-year-old) of rural Moradabad district, to analyze the specific pattern of dental caries experience in this population and to assess the treatment needs among them. Children within the age group of 3-5 years attending Anganwadi centers of rural Moradabad district were included in the study. Caries diagnosis was based on decayed, extracted, filled surface (defs) and the treatment needs were recorded using World Health Organization (WHO) oral health assessment form 1997. Out of 1,500 children examined, 48.7% males and 52.6% females did not require any treatment. The mean decayed, extracted, filled teeth (deft) value was found to be significantly high in 5-year-old participants when compared to 3-year-old participants (P < 0.01). Majority of the children required one surface filling followed by two surface fillings, caries arresting sealant care, extraction, crown bridge element, pulp care, and space maintainer.
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To determine whether angiotensin-converting enzyme (ACE) inhibition would affect ovarian steroid synthesis in the oocyte donors undergoing controlled ovarian hyperstimulation (COH). The IVF program of the University of Southern California. Prospective matched clinical trial. Twelve oocyte donors were studied in 28 hyperstimulation cycles. Donors underwent a standard COH protocol. Follicle aspiration was performed 34 hours after administration of hCG. After the procedure, seven donors were administered the ACE inhibitor, captopril, 6.25 mg orally twice daily for 4 days. The remaining patients served as controls. Serum E2, P, plasma prorenin, active renin, and angiotensin II (Ang II). Angiotensin II increased after aspiration in both groups but was significantly lower in those receiving captopril. Peak P in the captopril group was significantly lower than controls (81.8 +/- 27.8 versus 208.5 +/- 23.9 ng/mL [conversion factor to SI unit, 3.180]). Peak E2 was significantly higher (2,222.4 +/- 875.3 versus 425.6 +/- 490.4 pg/mL [conversion factor to SI unit, 3.671]). Active renin and Ang II correlated with P.
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Does movement demands of elite rugby league players during Australian National Rugby League and European Super League match?
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This study compared the movement demands of players competing in matches from the elite Australian and European rugby league competitions. Global positioning system devices were used to measure 192 performances of forwards, adjustables, and outside backs during National Rugby League (NRL; n = 88) and European Super League (SL; n = 104) matches. Total and relative distances covered overall and at low (0-3.5 m/s), moderate (3.6-5 m/s), and high (>5 m/s) speeds were measured alongside changes in movement variables across the early, middle, and late phases of the season. The relative distance covered in SL matches (95.8 ± 18.6 m/min) was significantly greater (P < .05) than in NRL matches (90.2 ± 8.3 m/min). Relative low-speed activity (70.3 ± 4.9 m/min vs 75.5 ± 18.9 m/min) and moderate-speed running (12.5 ± 3.3 m m/min vs 14.2 ± 3.8 m/min) were highest (P < .05) in the SL matches, and relative high-speed distance was greater (P < .05) during NRL matches (7.8 ± 2.1 m/min vs 6.1 ± 1.7 m/min).
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The role of BRCA1 in chronic ischemic episodes seems to be pivotal for adverse remodeling and development of ischemic cardiomyopathy, because of its role in DNA repair and apoptosis. The aim of this study was to investigate the role of BRCA-1 in idiopathic dilated cardiomyopathy (IDCM). The study group (IDCM) comprised myocardial samples from hearts explanted before transplantation owing to IDCM in 10 males (age 44 ± 5.3 years) without clinical symptoms of ischemic heart disease. The control group consisted myocardial fragments taken from 10 male heart valve and pulmonary artery donors with diagnosed cerebral death (age 40 ± 2.3 years). BRCA1 was detected immunohistochemically with rabbit anti-BRCA1 polyclonal antibody. The intensity of BRCA1 expression was semiquantitatively assessed for cardiocytes, small vessels including capillaries, and interstitial cells. The significances between groups were estimated using the Mann-Whitney U test. All IDCM cases were positive and presented nonuniform BRCA1 expression: hypertrophied cardiocytes showed very intense staining and typical cardiomyopathic cardiocytes were stained weakly forming mosaic. Control cases showed weak-to-moderate uniform staining. Intensity of staining was significantly higher in IDCM cardiocytes, whereas small vessels and interstitial were stained similarly in both groups.
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Does tLR4 activation induce IL-1β release via an IPAF dependent but caspase 1/11/8 independent pathway in the lung?
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The IL-1 family of cytokines is known to play an important role in inflammation therefore understanding the mechanism by which they are produced is paramount. Despite the recent plethora of publications dedicated to the study of these cytokines, the mechanism by which they are produced in the airway following endotoxin, Lipopolysaccharide (LPS), exposure is currently unclear. The aim was to determine the mechanism by which the IL-1 cytokines are produced after LPS inhaled challenge. Mice were challenged with aerosolised LPS, and lung tissue and bronchiolar lavage fluid (BALF) collected. Targets were measured at the mRNA and protein level; caspase activity was determined using specific assays. BALF IL-1b/IL-18, but not IL-1a, was dependent on Ice Protease-Activating Factor (IPAF), and to a lesser extent Apoptosis-associated Speck-like protein containing a CARD (ASC). Interestingly, although we measured an increase in mRNA expression for caspase 1 and 11, we could not detect an increase in lung enzyme activity or a role for them in IL-1a/b production. Further investigations showed that whilst we could detect an increase in caspase 8 activity at later points in the time course (during resolution of inflammation), it appeared to play no role in the production of IL-1 cytokines in this model system.
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High-resolution ultrasound and sestamibi scanning are regarded as the first-line methods for preoperative localization of parathyroid adenomas. The utility of ultrasound in reoperative cases has been questioned because of concern that scarring will obscure normal tissue planes and vascularity that are critical to identification of an adenoma using this imaging modality. The purposes of the study were to evaluate the ability of high-resolution ultrasound to accurately localize parathyroid adenomas in the reoperative exploration and to identify any factors that influence its accuracy Retrospective chart review at a tertiary care academic medical center. All patients seen in referral for parathyroid surgery between May 1994 and September 2002 underwent high-resolution ultrasound as their initial diagnostic test. Patients who subsequently underwent exploration were included in the study. Intraoperative and ultrasound findings were compared. One hundred forty-two patients were included, 116 without and 26 with prior exploration. The sensitivity and positive predictive value of ultrasound were 86.9% and 89.1%, respectively. These data were not significantly different in patients without (88.2% and 90%) and in patients with (80% and 84.2%) prior thyroid or parathyroid surgery. The overall accuracy was 79% with a false-negative rate of 11.3%. Thyroid nodularity was significantly more common (81.8%) in patients who had a false-positive or false-negative finding on ultrasound than in the total population (61.3%).
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Does ischemic preconditioning protect against paraplegia after transient aortic occlusion in the rat?
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Paraplegia can result from operations requiring transient occlusion of the thoracic aorta. A rat model of paraplegia with the characteristics of delayed paraplegia and transient ischemic dysfunction was developed to determine whether ischemic preconditioning (IPC) improved neurologic outcome. Rats underwent balloon occlusion of the upper descending thoracic aorta. One group (2 minute IPC, n = 19) underwent 2 minutes of IPC and a second group (5 minute IPC, n = 19) had 5 minutes of IPC 48 hours before 10 minutes of occlusion. The control group (n = 31) had no IPC prior to 10 minutes of occlusion. Paraplegia occurred in 68% of the control animals (21 of 31 paraplegic: 6 delayed and 15 immediate paraplegia). Both the 2-minute IPC and 5-minute IPC groups had a decreased incidence of paraplegia when compared to controls (32%, p = 0.011 and 26%, p = 0.009, respectively).
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It is largely unknown how frequently low-abundance HIV drug-resistant variants at levels under limit of detection of conventional genotyping (<20% of quasi-species) are present in antiretroviral-experienced persons experiencing virologic failure. Further, the clinical implications of low-abundance drug-resistant variants at time of virologic failure are unknown. Plasma samples from 22 antiretroviral-experienced subjects collected at time of virologic failure (viral load 1380 to 304,000 copies/mL) were obtained from a specimen bank (from 2004-2007). The prevalence and profile of drug-resistant mutations were determined using Sanger sequencing and ultra-deep pyrosequencing. Genotypes were interpreted using Stanford HIV database algorithm. Antiretroviral treatment histories were obtained by chart review and correlated with drug-resistant mutations. Low-abundance drug-resistant mutations were detected in all 22 subjects by deep sequencing and only in 3 subjects by Sanger sequencing. In total they accounted for 90 of 247 mutations (36%) detected by deep sequencing; the majority of these (95%) were not detected by standard genotyping. A mean of 4 additional mutations per subject were detected by deep sequencing (p<0.0001, 95%CI: 2.85-5.53). The additional low-abundance drug-resistant mutations increased a subject's genotypic resistance to one or more antiretrovirals in 17 of 22 subjects (77%). When correlated with subjects' antiretroviral treatment histories, the additional low-abundance drug-resistant mutations correlated with the failing antiretroviral drugs in 21% subjects and correlated with historical antiretroviral use in 79% subjects (OR, 13.73; 95% CI, 2.5-74.3, p = 0.0016).
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Is self-rated health associated with the length of stay at the intensive care unit and hospital following cardiac surgery?
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Recently, a considerable amount of evidence suggested that anxiety, depression and other psychosocial variables might influence the outcomes of cardiac surgery. This study investigated the relationship between length of stay at the intensive care unit (ICU) and hospital after surgery and different psychosocial variables (e.g. depression, anxiety, self rated health, happiness, satisfaction). We enrolled prospective patients who were waiting for elective cardiac surgery (N = 267) and consented to take part in the study. We collected data of sociodemographic, medical and perioperative factors as well as psychosocial questionnaires completed 1.56 days (standard deviation [SD] = 0.7) before surgery. The primary clinical endpoint was an ICU stay of at least 3 days and the secondary was hospital stay of at least 10 days. Two hundred sixty-seven patients participated in this study. Four patients (1.5%) died in the hospital and 38 patients (14.5%) spent more than 3 days in the ICU and 62 patients (23.2%) spent more than 10 days in the hospital. After controlling for medical and sociodemographic factors, lower self rated health (Adjusted Odds Ratio [AOR]: 0.51, 95% confidence interval [CI]: 0.28-0.95; p = 0.03), lower rate of happiness (AOR: 0.76, 95% CI: 0.59-0.97, p = 0.03), postoperative cardiac failure (AOR: 7.09, 95% CI:1.21-41.54; p = 0.03) and postoperative complications (AOR: 9.52, 95% CI: 3.76-24.11; p < 0.001) were associated with longer ICU stay. More than 10 days of hospital stay was associated with higher occurrence of COPD (AOR 4.56, CI: 1.95-10.67, p < 0.001), NYHA stage (AOR 6.76, CI: 2.57-17.79, p < 0.001), operation time (AOR 1.45, CI: 1.19-1.76, p < 0.001), female gender (AOR 2.16, CI: 1.06-4.40, p = 0.034) and lower self-rated health (AOR 0.63, CI: 0.41-0.99, p = 0.044).
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Vitamin B6 synthesis requires a functional Pdx1 assembly that is dodecameric in vivo. We have previously shown that mutation of a catalytic lysine in the plasmodial Pdx1 protein results in a protein that is both inactive and hexameric in vitro. Static and dynamic light scattering, circular dichroism, co-purification and enzyme assays are used to investigate the role of a glycine conserved in all Pdx1 family members. Static light scattering indicates that a glycine to alanine mutant is present as a hexamer in vitro. Subsequent circular dichroism experiments demonstrate that a significant change in secondary structure content is induced by this mutation. However, this mutant is still competent to bind and support Pdx2 activity.
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Does oestrogen modulate cardiac ischaemic remodelling through oestrogen receptor-specific mechanisms?
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Observational and clinical studies suggest different responses upon sex hormone replacement therapy in ischaemic heart disease. Few studies, however, have examined the impact of oestrogen receptor-dependent mechanisms on the extent of injury after myocardial infarction (MI). Therefore, we set out to evaluate the effect of oestrogen (E2) replacement on infarct size and remodelling, and the respective role of the oestrogen receptors (ER)alpha and -beta in this process, using ERalpha- and ERbeta-deficient mice. Wild type (WT) (ERalpha(+/+) and ERbeta(+/+)), ERalpha-deficient (ERalpha(-/-)) and ERbeta-deficient (ERbeta(-/-)) mice were ovariectomized and subsequently supplemented with E2 or placebo using subcutaneous 60-day release pellets. MI was induced by left coronary artery ligation. Two weeks following MI, haemodynamic function was assessed and infarct size was determined. There was no significant difference in infarct size between E2- or placebo-treated WT (ERalpha(+/+) and ERbeta(+/+)) mice. Surprisingly, E2 treatment did result in smaller infarct sizes in ERalpha(-/-) mice, but increased the infarct size in ERbeta(-/-) mice. Increase of the left ventricular mass post-MI was significantly larger in the E2-treated ERalpha(-/-) animals compared with placebo-treated animals. E2 treatment also significantly increased post-MI mortality in ERalpha(+/+), ERbeta(+/+) and ERalpha(-/-) animals, but not in ERbeta(-/-) mice.
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Epidemiological evidence shows that people with thicker, or higher stage, melanomas have lower vitamin D status compared to those with thinner tumours. Evidence from experimental studies is inconsistent, but some suggest that administration of vitamin D metabolites can decrease tumour aggressiveness. Determine the relationship between vitamin D status at diagnosis and melanoma thickness (as an indicator of prognosis), in a subtropical setting with high melanoma incidence. We recruited 100 melanoma patients in Brisbane, Australia within days of their diagnosis. Data on factors previously associated with melanoma risk or prognosis were collected by questionnaire and physical examination. Serum for 25-hydroxyvitamin D3 [25(OH)D] levels was collected prior to wider excision biopsy; histological indicators of prognosis were obtained from pathology reports. We used multivariable logistic regression models to analyse the association between Breslow thickness (≥0.75 mm compared to <0.75 mm), Clark level (2-5 compared to 1) and presence of mitoses, and vitamin D status. Serum 25(OH)D <50 nmol/L (versus ≥50 nmol/L) was associated with a nearly four-fold increase in risk of having a thicker tumour (Adjusted OR = 3.82, 95% CI: 1.03, 14.14; p = 0.04, adjusted for age, sex, skin phototype, body mass index and season at diagnosis). There was no significant association with Clark level or presence of mitosis. Serum 25(OH)D levels in the highest quartile (≥69.8 nmol/L) were not associated with a more favourable prognosis.
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Do stricter criteria increase the validity of a quick intraoperative parathyroid hormone assay in primary hyperparathyroidism?
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A "quick" intraoperative parathyroid hormone (PTH) (QPTH) assay evaluates parathyroid hypersecretion during parathyroidectomy. We investigated the likelihood of increasing surgical success rates by introducing stricter parameters in intraoperative PTH monitoring. One hundred one patients with sporadic primary hyperparathyroidism were studied. Intraoperative plasma intact PTH (iPTH) levels were measured with a modified 2-site antibody immunochemiluminometric assay. iPTH values were determined before the manipulation of parathyroid tissue (t-10') and then 3 (t+3') and 10 (t+10') minutes after resection of the suspected pathologic parathyroid gland(s). The median (interquartile range) baseline iPTH level was 259.6 (536) ng/L at t-10' and 64.1 (139.5) ng/L at t+10'. At t+3' and t+10', the median percentage decrease of iPTH from baseline was 56.1% and 77.3%, respectively. In 7 patients, the iPTH level decreased very slowly, and in patients with a double adenoma, an initial increase in the iPTH level occurred because of considerable manipulation during surgery. Despite a decrease of about 50% in iPTH level, persistent hyperparathyroidism was identified after a few months in 2 patients with a multiglandular pathologic condition in which a relatively larger parathyroid "masked" the hyperactivity of other parathyroid glands.
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Myosin light chain kinase (MLCK) plays a central role in the mechanisms of barrier dysfunction, and intestinal epithelial MLCK protein expression is upregulated in active ulcerative colitis (UC). ML-7, a MLCK inhibitor, has been used in many MLCK studies. However, the effect of ML-7 has never been estimated in colitis models. The aim of this study was to determine whether ML-7 can treat UC. Experimental colitis was induced and ML-7 was administered by intraperitoneal injection. The disease activity index (DAI) scores were evaluated and colon tissue was collected for the assessment of histological changes, myeloperoxidase (MPO) activity, and tumor necrosis factor (TNF)-α, interferon (IFN)-γ, interleukin (IL)-13 and interleukin (IL)-17 levels. The small intestinal mucosa was ultrastructurally examined, epithelial MLCK protein expression and enzymatic activity were determined, and intestinal permeability was assayed using FITC-dextran 4000 (FD-4) and Evans blue (EB). ML-7 was found to be significantly effective in reducing the DAI scores and histological index scores, and decreasing MPO activity and TNF-α, IFN-γ, IL-13 and IL-17 levels. The small intestinal epithelial MLCK protein expression and enzymatic activity were downregulated by ML-7. The epithelial cells and intercellular tight junctions were ameliorated, and the amount of FD-4 in blood and EB permeating into the intestine were decreased by ML-7 in colitis mice.
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Does naringin ameliorate memory deficits in experimental paradigm of Alzheimer 's disease by attenuating mitochondrial dysfunction?
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Mitochondrial dysfunction has been well documented in age related disorders like Alzheimer's disease. Alterations in mitochondrial membrane potential lead to neuronal death by excessive generation of free radicals, inflammatory cytokines, and excitotoxins. Intracerebroventricular (ICV) streptozotocin (STZ) induced-cognitive impairment has been widely used as an experimental model of Alzheimer's disease. Naringin is a potent antioxidant, which can cross the blood brain barrier protecting brain tissue and modulating brain chemistry. The present study was designed to evaluate the effect of naringin, in ICV STZ-induced mitochondrial dysfunction and memory loss in rats. Streptozotocin (3mg/kg, ICV) was injected bilaterally in two divided doses on first and third day followed by treatment with different doses of naringin (50, 100 and 200mg/kg; p.o.) for twenty one days. Behavioral alterations were monitored using Morris water maze paradigm and elevated plus maze test. Animals were sacrificed to evaluate various biochemical and mitochondrial parameters in brain. Rivastigmine was used as a standard drug. ICV-STZ administration produced significant cognitive deficits as assessed by both Morris water maze and elevated plus maze task which is accompanied by significantly enhanced oxidative-nitrosative stress, altered acetylcholinesterase and mitochondrial enzyme activities in cerebral cortex and hippocampus of rats brain along with significantly increased brain TNF-α and IL-1β levels. Chronic treatment with naringin dose dependently restored cognitive deficits in ICV-STZ rat along with mitigation of mitochondrial dysfunction mediated oxido-nitrosative stress and cytokine release.
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Chondrosarcoma of the chest wall is the most frequent primary malignant chest wall tumor. Surgery remains the only effective treatment. Sarcoma treatment in Sweden is centralized to sarcoma centers; however, sarcomas of the chest wall have also been handled by thoracic and general surgeons. One hundred six consecutive reports of chondrosarcomas of the rib and sternum over a 22-year period (1980 to 2002) were studied, with a median of 9 (4 to 23) years of follow-up for survivors. Clinical files were gathered and pathologic specimens reviewed and graded 1 to 4 by the Scandinavian sarcoma pathology group. Surgical margins were defined as wide, marginal, or intralesional. Ninety-seven patients were treated with a curative intent. Patients operated with wide surgical margins had a 10-year survival of 92% compared with 47% for those with intralesional resections. The 10-year survival was 75% for patients treated at sarcoma centers and 59% for those treated by thoracic or general surgeons. Local recurrence rate was highly dependent of the surgical margins-4% after wide resections and 73% after intralesional resections. The proportion of intralesional resections was higher outside sarcoma centers. Prognostic factors (multivariate analysis) for local recurrence included surgical margin and histological grade; for metastases, prognostic factors included histologic grade, tumor size, and local recurrence. Metastases occurred in 21 of the patients and only 2 were cured.
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Are fresh blood and aged stored blood equally efficacious in immediately reversing anemia-induced brain oxygenation deficits in humans?
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Erythrocytes are transfused to treat or prevent imminent inadequate tissue oxygenation. 2,3-diphosphoglycerate concentration decreases and oxygen affinity of hemoglobin increases (P50 decreases) with blood storage, leading some to propose that erythrocytes stored for 14 or more days do not release sufficient oxygen to make their transfusion efficacious. The authors tested the hypothesis that erythrocytes stored for 3 weeks are as effective in supplying oxygen to human tissues as are erythrocytes stored for less than 5 h. Nine healthy volunteers donated 2 units of blood more than 3 weeks before they were tested with a standard, computerized neuropsychological test (digit-symbol substitution test [DSST]) on 2 days, 1 week apart, before and after acute isovolemic reduction of their hemoglobin concentration to 7.4 and 5.5 g/dl. Volunteers randomly received autologous erythrocytes stored for either less than 5 h ("fresh") or 3 weeks ("stored") to return their hemoglobin concentration to 7.5 g/dl (double blinded). Erythrocytes of the alternate storage duration were transfused on the second experimental day. The DSST was repeated after transfusion. Acute anemia slowed DSST performance equivalently in both groups. Transfusion of stored erythrocytes with decreased P50 reversed the altered DSST (P < 0.001) to a time that did not differ from that at 7.4 g/dl hemoglobin during production of acute anemia (P = 0.88). The erythrocyte transfusion-induced DSST improvement did not differ between groups (P = 0.96).
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Although animal studies demonstrated that Smad7 induction ameliorates TGF-β/SMAD-mediated fibrogenesis, its role in human hepatic diseases is rather obscure. Our study explored the activation status of TGF-β/activin pathway in patients with chronic liver diseases, and how it is affected by successful antiviral treatment in chronic HBV hepatitis (CHB). Thirty-seven CHB patients (19 with active disease, 14 completely remitted on long-term antiviral treatment and 4 with relapse after treatment withdrawal), 18 patients with chronic HCV hepatitis, 12 with non-alcoholic fatty liver disease (NAFLD), and 3 controls were enrolled in the study. Liver mRNA levels of CTGF, all TGF-β/activin isoforms, their receptors and intracellular mediators (SMADs) were evaluated using qRT-PCR and were correlated with the grade of liver inflammation and fibrosis staging. The expression and localization of pSMAD2 and pSMAD3 were assessed by immunohistochemistry. TGF-β signalling is activated in CHB patients with active disease, while SMAD7 is up-regulated during the resolution of inflammation after successful treatment. SMAD7 overexpression was also observed in NAFLD patients exhibiting no or minimal fibrosis, despite the activation of TGF-β/activin signaling.
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Is late follicular progesterone to estradiol ratio influenced by protocols or gonadotropins used?
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Increased progesterone level during follicular phase seemed to be associated with decreased pregnancy rate. A prospective cohort study, 1.1.2012 - 31.8.13. The Progesterone (P) and Progesterone/Estrogen (P/E2) level on ovulation induction day were compared between the protocols and the different gonadotropins used. Roc analysis was calculated to determine the cutoff of P/E2 to predict delivery rates. P/E2 ratio was calculated as PX1000/e2 level. One hundred thirty-nine patients were enrolled to the study. No difference in the P level at hCG stimulation day between different protocols, however, E2 and P/E2 ratio were significantly lower in the long protocol compare with antagonist protocol 1757.7 ± 923.2 vs. 1342.9 ± 1223; P = 0.003 and 0.48 ± 0.31 vs. 0.83 ± 0.87; P = 0.038). The endometrium was significantly thicker in the long group compare with short and antagonist. Significantly more top-quality embryos (TOP) were achieved in the antagonist group. Comparable results between the types of gonadotropins used in regards with cycle characteristics and pregnancy and delivery rates. The P/E2 ratio which can predict live birth rate was found to be 0.45, AUC = 0.632, p = 0.02 and 95 % CI 0.525-0.738 and a significantly higher pregnancy and delivery rates at a P/E2 bellow 0.45.
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CTCs provide prognostic information and their application is under investigation in multiple tumor types. Of the multiple variables inherent in any such process, none is more important to outcome than the appropriateness of the sample source. To address this question, we investigated CTCs in paired peripheral venous and arterial blood specimens obtained from stage IV uveal melanoma patients. Blood specimens were obtained from both common femoral arteries and antecubital veins in 17 uveal melanoma patients with multiple hepatic metastases for CTC measurements. CTCs were detectable with greater frequency (100%) and in larger numbers (median 5, range 1 to 168) in all arterial blood specimens than in venous samples (52.9%; median 1, range 0 to 8). Patients with hepatic as well as extra-hepatic metastasis showed higher number of arterial CTCs, compared to patients with liver-only metastasis (p = 0.003). There was no significant association between the number of arterial CTCs and the tumor burden within the liver in patients who had liver-only metastases.
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Does virus-mediated EpoR76E gene therapy preserve vision in a glaucoma model by modulating neuroinflammation and decreasing oxidative stress?
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Glaucoma is a complex neurodegeneration and a leading cause of blindness worldwide. Current therapeutic strategies, which are all directed towards lowering the intraocular pressure (IOP), do not stop progression of the disease. We have demonstrated that recombinant adeno-associated virus (rAAV) gene delivery of a form of erythropoietin with attenuated erythropoietic activity (EpoR76E) can preserve retinal ganglion cells, their axons, and vision without decreasing IOP. The goal of this study was to determine if modulation of neuroinflammation or oxidative stress played a role in the neuroprotective activity of EPO.R76E. Five-month-old DBA/2J mice were treated with either rAAV.EpoR76E or a control vector and collected at 8 months of age. Neuroprotection was assessed by quantification of axon transport and visual evoked potentials. Microglia number and morphology and cytokine and chemokine levels were quantified. Message levels of oxidative stress-related proteins were assessed. Axon transport and visual evoked potentials were preserved in rAAV.EpoR76E-treated mice. The number of microglia was decreased in retinas from 8-month-old rAAV.EpoR76E-treated mice, but proliferation was unaffected. The blood-retina barrier was also unaffected by treatment. Levels of some pro-inflammatory cytokines were decreased in retinas from rAAV.EpoR76E-treated mice including IL-1, IL-12, IL-13, IL-17, CCL4, and CCL5. TNFα messenger RNA (mRNA) was increased in retinas from 8-month-old mice compared to 3-month-old controls regardless of treatment. Expression of several antioxidant proteins was increased in retinas of rAAV.EpoR76E-treated 8-month-old mice.
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Obesity is associated with altered atrial electrophysiology and a prominent risk factor for atrial fibrillation. Body mass index, the most widely used adiposity measure, has been related to atrial electrical remodeling. We tested the hypothesis that pericardial fat is independently associated with electrocardiographic measures of atrial conduction. We performed a cross-sectional analysis of 1946 Framingham Heart Study participants (45% women) to determine the relation between pericardial fat and atrial conduction as measured by P wave indices (PWI): PR interval, P wave duration (P-duration), P wave amplitude (P-amplitude), P wave area (P-area), and P wave terminal force (P-terminal). We performed sex-stratified linear regression analyses adjusted for relevant clinical variables and ectopic fat depots. Each 1-SD increase in pericardial fat was significantly associated with PR interval (β=1.7 ms, P=0.049), P-duration (β=2.3 ms, P<0.001), and P-terminal (β=297 μV·ms, P<0.001) among women; and P-duration (β=1.2 ms, P=0.002), P-amplitude (β=-2.5 μV, P<0. 001), and P-terminal (β=160 μV·ms, P=0.002) among men. Among both sexes, pericardial fat was significantly associated with P-duration in analyses additionally adjusting for visceral fat or intrathoracic fat; a similar but non-significant trend existed with P-terminal. Among women, pericardial fat was significantly associated with P wave area after adjustment for visceral and intrathoracic fat.
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Does a Single Protein Kinase A or Calmodulin Kinase II Site Control the Cardiac Pacemaker Ca2+ Clock?
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Fight or flight heart rate (HR) increases depend on protein kinase A (PKA)- and calmodulin kinase II (CaMKII)-mediated enhancement of Ca(2+) uptake and release from sarcoplasmic reticulum (SR) in sinoatrial nodal cells (SANC). However, the impact of specific PKA and CaMKII phosphorylation sites on HR is unknown. We systematically evaluated validated PKA and CaMKII target sites on phospholamban and the ryanodine receptor using genetically modified mice. We found that knockin alanine replacement of ryanodine receptor PKA (S2808) or CaMKII (S2814) target sites failed to affect HR responses to isoproterenol or spontaneous activity in vivo or in SANC. Similarly, selective mutation of phospholamban amino acids critical for enhancing SR Ca(2+) uptake by PKA (S16) or CaMKII (T17) to alanines did not affect HR in vivo or in SANC. In contrast, CaMKII inhibition by expression of AC3-I has been shown to slow SANC rate responses to isoproterenol and decrease SR Ca(2+) content. Phospholamban deficiency rescued SR Ca(2+) content and SANC rate responses to isoproterenol in mice with AC3-I expression, suggesting that CaMKII affects HR by modulation of SR Ca(2+) content. Consistent with this, mice expressing a superinhibitory phospholamban mutant had low SR Ca(2+) content and slow HR in vivo and in SANC.
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The aim of this study was to evaluate the effects of tri-antibiotic paste (TAP) on microtensile bond strengths (MTBS) of dental adhesives to dentin. Sixty extracted molars had their occlusal surfaces flattened to expose dentin. They were divided into two groups, i.e., control group with no dentin treatment and experimental group with dentin treatment with TAP. After 10 days, specimens were bonded using self-etch (Filtek P90 adhesive) or etch-and-rinse (Adper Single Bond Plus) adhesives and restored with composite resin. Teeth were sectioned into beams, and the specimens were subjected to MTBS test. Data were analyzed using two-way ANOVA and post hoc Tukey tests. There was a statistically significant interaction between dentin treatment and adhesive on MTBS to coronal dentin (p = 0.003). Despite a trend towards worse MTBS being noticed in the experimental groups, TAP application showed no significant effect on MTBS (p = 0.064).
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Is anxiety associated with increased risk of dementia in older Swedish twins?
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We asked whether anxiety is associated with prospective risk of dementia, and the extent to which genetic influences mediate this association. Nondemented twins (n = 1082) from the Swedish Adoption Twin Study of Aging completed an assessment of anxiety symptoms in 1984 and were followed for 28 years. Baseline anxiety score, independent of depressive symptoms, was significantly associated with incident dementia over follow-up (hazard ratio [HR] = 1.04; 95% confidence interval [CI] = 1.01-1.06). There was 48% increased risk of becoming demented for those who had experienced high anxiety at any time compared with those who had not. In co-twin analyses, the association between anxiety symptoms and dementia was greater for dizygotic (HR = 1.11; 95% CI = 1.02-1.20) compared with monozygotic twins (HR = 1.06; 95% CI = 0.95-1.20), indicating genetic mediation.
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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.
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Does cardiomyocyte-specific overexpression of NO synthase-3 protect against myocardial ischemia-reperfusion injury?
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The protective effect of NO synthase-3 (eNOS)-derived NO in limiting myocardial ischemia-reperfusion (MI-R) injury is well established. We reported previously that systemic genetic overexpression of eNOS attenuates MI-R injury. The purpose of the current study was to investigate tissue-specific genetic overexpression of the human eNOS gene. To accomplish this, we used 2 distinct murine models of transgenic overexpression, a cardiomyocyte-specific eNOS overexpresser (CS eNOS-Tg) under the control of the alpha-myosin heavy chain promoter, and a systemic eNOS transgenic mouse (SYS eNOS-Tg) under control of the native eNOS promoter with an upstream endothelial enhancer element. Mice were subjected to 30 or 45 minutes of left coronary artery ischemia and 24 or 72 hours of reperfusion. CS eNOS-Tg mice displayed significantly decreased infarct size beyond that of mice with systemic overexpression. Additionally, CS eNOS-Tg mice exhibited better preservation of cardiac function compared with SYS eNOS-Tg mice after myocardial infarction.
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Autoantibody responses reactive with the E2 and E3BP components of pyruvate dehydrogenase complex (PDC), which characterise primary biliary cirrhosis (PBC) crossreact, precluding the identification, from serological studies, of the antigen to which the principal breakdown of tolerance occurs. Although autoreactive T-cell responses to PDC-E2 have been well characterised it is, at present, unclear whether T-cell tolerance breakdown also occurs to PDC-E3BP. The aims of this study were to characterise autoreactive T-cell responses to PDC-E3BP in PBC and potential factors regulating their expression. Peripheral blood T-cell proliferative responses to purified recombinant human PDC-E2 and PDC-E3BP at a range of concentrations were characterised in PBC patients and control subjects. T-cell proliferative responses to both E2 and E3BP were absent from control subjects (median peak stimulation index (SI) to PDC-E2 1.2 [range 0.3-1.9], 0/10 positive (SI>2.32), median peak SI to PDC-E3BP 1.1 [0.7-2.1]], 0/10 positive). Significant responses to PDC-E2 were seen in the majority of patients (median peak SI 11.4 [0.4-24.4], 17/20 (85%) positive) but to PDC-E3BP in only a minority (median peak SI 1-9 [0.6-9.95], 8/20 (40%) positive). Where responses to PDC-E3BP were seen they were universally secondary to responses to PDC-E2.
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Are markers of endothelial and platelet activation associated with high on-aspirin platelet reactivity in patients with stable coronary artery disease?
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Aspirin inhibits the cyclooxygenase-1 (COX-1) mediated thromboxane A2 synthesis. Despite COX-1 inhibition, in patients with coronary artery disease (CAD), platelets can be activated through other mechanisms, like activation by thrombin. At baseline in this cross-sectional substudy of the ASCET trial, 1001 stable CAD patients, all on single aspirin treatment, were classified by the PFA100® method, as having high on-aspirin residual platelet reactivity (RPR) or not. Markers of hypercoagulability, endothelial and platelet activation as related to RPR, were evaluated to explore the potential mechanisms behind high on-aspirin RPR. Altogether, 25.9% (n=259) of the patients were found to have high on-aspirin RPR. S-thromboxane B(2) levels were very low and did not differ between patients having high on-aspirin RPR or not. Patients with high on-aspirin RPR had significantly higher levels of von Willebrand Factor (vWF) (124 vs 100%, p<0.001, platelet count (236 vs 224 × 10(9)/l, p=0.008), total TFPI (68.4 vs 65.5 ng/ml, p=0.005) and ß-thromboglobulin (ß-TG) (33.3 vs 31.3 IU/ml, p=0.041) compared to patients with low on-aspirin RPR. No significant differences between the groups were observed in levels of endogenous thrombin generation (ETP), pro-thrombin fragment 1+2 (F1+2), D-dimer, soluble TF (sTF) or P-selectin (all p>0.05).
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We previously showed that the level of enteral nutrient intake determines the rate of intestinal growth in piglets. Our objective was to determine whether providing enteral nutrition in the form of elemental nutrients (glucose, amino acids, lipid [ED]) rather than cow's milk formula (lactose, protein, lipid [FORM]) reduces small intestinal growth and lactase activity. Three-week-old piglets were fed either ED (n = 7) intragastrically or FORM (n = 6) orally for 6 days. Intestinal protein and DNA masses, villus height, and crypt depth were not different in ED and FORM pigs. Crypt cell proliferation, measured by in vivo bromodeoxyuridine labeling, was significantly (p < .05) higher (+37%) in ED than in FORM pigs. Rates of mucosal protein synthesis (%/d), measured by in vivo 2H-leucine incorporation, were higher (p < .05) in ED than FORM (147 vs 89) pigs. Circulating concentrations (pmol/L) of the intestinotrophic peptide, glucagon-like peptide-2 (GLP-2), were also higher (p < .05) in ED than in FORM (148 vs 87) pigs. The mean lactase-specific activity (micromol/min/g) in proximal and distal segments was higher (p < .05) in FORM than in ED (124 vs 58) pigs.
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Does prevalence and correlate of post-prandial hyperglycaemia in a large sample of patients with type 2 diabetes mellitus?
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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.
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Neonatal respiratory distress syndrome is a restrictive lung disease characterized by surfactant deficiency. Decreased vascular endothelial growth factor (VEGF), which demonstrates important roles in angiogenesis and vasculogenesis, has been implicated in the pathogenesis of restrictive lung diseases. Current animal models investigating VEGF in the etiology and outcomes of RDS require premature delivery, hypoxia, anatomically or temporally limited inhibition, or other supplemental interventions. Consequently, little is known about the isolated effects of chronic VEGF inhibition, started at birth, on subsequent developing lung structure and function. To determine whether inducible, mesenchyme-specific VEGF inhibition in the neonatal mouse lung results in long-term modulation of AECII and whole lung function. Triple transgenic mice expressing the soluble VEGF receptor sFlt-1 specifically in the mesenchyme (Dermo-1/rtTA/sFlt-1) were generated and compared to littermate controls at 3 months to determine the impact of neonatal downregulation of mesenchymal VEGF expression on lung structure, cell composition and function. Reduced tissue VEGF bioavailability has previously been demonstrated with this model. Triple transgenic mice demonstrated restrictive lung pathology. No differences in gross vascular development or protein levels of vascular endothelial markers was noted, but there was a significant decrease in perivascular smooth muscle and type I collagen. Mutants had decreased expression levels of surfactant protein C and hypoxia inducible factor 1-alpha without a difference in number of type II pneumocytes.
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Is congenital penile pathology associated with abnormal development of the dartos muscle : a prospective study of primary penile surgery at a tertiary referral center?
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Pathophysiological mechanisms leading to chordee in patients with hypospadias and to the hidden state of buried penis in the prepubic fat remain unclear. Resection of dartos tissue usually makes the penis straight in patients with hypospadias and corrects it in those with buried penis, suggesting a common pathophysiology related to dartos tissue. Tissue samples from 113 children undergoing primary penile surgery for hypospadias (94 patients), epispadias (1) or buried penis (18) were collected between November 2011 and September 2013. Tissue samples from 79 children undergoing circumcision for nonmedical reasons served as controls. All samples were stained with smooth muscle actin and analyzed by the same pathologist, who was blinded to indication for surgery. Chi-square and Fisher exact tests were applied. Three different dartos tissue patterns were observed. Pattern I (normal) consisted of smooth muscle fibers of dartos tissue organized in a parallel configuration in the subcutaneous tissue. Pattern II was characterized by poorly developed and hypotrophic smooth muscle fibers. Pattern III was determined by randomly distributed smooth muscle fibers in the subcutaneous tissue, without parallel configuration. Pattern I was observed in 45 circumcision specimens (64%). Of buried penis cases 78% were considered abnormal (pattern II in 4 cases and III in 10, p = 0.001). Of hypospadias cases 70% were considered abnormal (pattern II in 31 cases, III in 32, and mixed II and III in 3, p < 0.001). The only epispadias case was designated pattern II.
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In a collaborative effort between the Missouri Department of Health, Area Agencies on Aging (AAA), Alzheimer Association, and academic researchers, we tested whether early dementia detection and comprehensive care consultations would improve health outcomes in care receivers (CRs) and their family caregivers (FCGs), therefore addressing an important public health concern. A total of 244 community-dwelling older adults screened for early-stage dementia by the AAA field staff were referred to the Alzheimer Association and participated in Project Learn MORE (Missouri Outreach and Referral Expanded) (PLM) - a 2-year, nonrandomized multisite intervention consisting of comprehensive care consultations to improve coping skills. PLM participants were compared against 96 controls receiving the Alzheimer Association's "usual services" between January 2011 and December 2012. We examined CR and FCG outcomes, including burden, care confidence, and mood, as effects of PLM, on delaying transitions in level of care. CRs showed improved knowledge (P=0.002) and reduced depression (P=0.007), while FCGs demonstrated improved knowledge (P=0.003) and ability to identify sources of support for the CR (P=0.032) and for themselves (P=0.043). However, FCGs were more burdened after PLM (P=0.02), due to increased awareness of Alzheimer's disease. PLM delayed transitions in care (odds ratio [OR] 3.32, 95% confidence level [CI]: 1.25-8.83) with the number needed to treat =6.82.
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Does dexamethasone increase pigment epithelium-derived factor in perfused human eyes?
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To investigate the effects of dexamethasone (DEX) on pigment epithelium-derived factor (PEDF) cDNA and secreted protein in human trabecular meshwork (TM). Anterior segment organ cultures were perfused with 0.1 microM DEX (OD) and vehicle (OS). Primary human TM cells (HTM) were treated with DEX under similar conditions. PEDF mRNA and secreted PEDF protein were quantitated by RT-PCR and Western blot. PEDF mRNA and secreted PEDF protein levels were significantly higher in DEX over vehicle-treated cultures. In contrast, DEX decreased the activity of a 92-kDa gelatinolytic zymogen in organ culture effluents.
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We investigated and compared diets and physical activity levels of renal transplant recipients (RTRs) with normal glucose tolerance (NGT) and abnormal glucose tolerance (AGT), and we identified clinical risk factors for AGT. This study was cross-sectional and observational. This study took place in a hospital's renal outpatient department. Patients included adult RTRs with NGT and AGT. All patients were assessed regarding age, body mass index (BMI), waist circumference (WC), waist/hip ratio (WHR), percent body fat (measured using dual-energy x-ray absorptiometry), dietary intake (3-day diet diary), and physical activity (PA) levels (total minutes/week, using the Physical Activity Statewide Questionnaire). The RTRs with AGT (n = 47) were significantly more obese (P = .04) and more centrally obese (P = .05) than RTRs with NGT (n = 35). The mean self-reported dietary macronutrient and energy intake was not significantly different between groups. However, the total amount of PA (median) was significantly lower in RTRs with AGT versus RTRs with NGT (255 [median, range 0 to 1940] versus 580 [median, 75 to 1095] minutes/week, respectively, P = .03), particularly in female RTRs (P = .007). After logistic regression analysis, total PA was identified as an independent predictor of AGT in all RTRs (beta = 0.940, R(2) = 0.090, P = .04). Percent body fat according to dual-energy x-ray absorptiometry was inversely associated with a high level of PA (>300 minutes/week) (beta = 0.906, R(2) = 0.211, P = .003).
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Is metformin-induced thyrotropin suppression associated with cardiac effects?
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Metformin treatment may induce a decrease/suppression in serum TSH levels, mimicking sub-clinical hyperthyroidism (SHT). The aim of the present study was to retrospectively evaluate changes in several electrocardiographic indices in euthyroid subjects with diabetes who, after starting metformin treatment, developed a low serum TSH as compared to patients with SHT resulting from an underlying thyroid disease or TSH suppressive treatment with L-thyroxine. Heart rate, P wave duration, P wave dispersion, QTmax, QTmin and QT-dispersion were assessed in 23 patients with diabetes treated with metformin before and after 6 months of TSH-suppression and in 31 control patients with SHT. No significant changes in electrocardiographic parameters were observed from baseline to the TSH-suppression measurement. A significant difference in P wave duration (102.9 ± 7.4 vs. 92.1 ± 5.8 ms, p<0.001), P wave dispersion (13.1 ± 3.4 vs. 7.1 ± 3.5 ms, p<0.001), QTmax (399 ± 18 vs. 388 ± 16 ms, p=0.024), QTmin (341 ± 14 vs. 350 ± 17 ms, p=0.038) and QT dispersion (49.9 ± 9.6 vs. 30.9 ± 9.2 ms, p<0.001) were observed between the control group with SHT and the group of diabetic patients with low serum levels of TSH.
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The optimal type of mesh for complex abdominal wall reconstruction has not been elucidated. We hypothesized that AWRs using acellular dermal matrix (ADM) experience low rates of surgical site occurrence (SSO) and surgical site infection, despite increasing degrees of wound contamination. We retrospectively reviewed prospectively collected data from consecutive abdominal wall reconstructions with ADM over a 9-year period. Outcomes of abdominal wall reconstructions were compared between patients with different CDC wound classifications. Univariate and multivariate logistic regression and Cox proportional hazard regression analyses identified potential associations and predictive/protective factors. The 359 patients had a mean follow-up of 28.3 ± 19.0 months. Reconstruction of clean wounds (n = 171) required fewer reoperations than that of combined contaminated (n = 188) wounds (2.3% vs 11.2%; p = 0.001) and trended toward experiencing fewer SSOs (19.9% vs 28.7%, p = 0.052). There were no significant differences between clean and combined contaminated cases in 30-day SSI (8.8% vs 8.0%), hernia recurrence (9.9% vs 10.1%), and mesh removal (1.2% vs 1.1%) rates. Independent predictors of SSO included body mass index ≥30 kg/m(2) (odds ratio [OR] 3.6; p < 0.001), 1 or more comorbidities (OR 2.5; p = 0.008), and defect width ≥15 cm (OR 1.8; p = 0.02).
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Does reconstruction of the Posterolateral Corner After Sequential Sectioning restore Knee Kinematics?
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Various surgical techniques to treat posterolateral knee instability have been described. To date, the recommended treatment is an anatomic form of reconstruction in which the 3 key structures of the posterolateral corner (PLC) are addressed: the popliteofibular ligament, the popliteus tendon, and the lateral collateral ligament. The purpose of this study was to identify the role of each key structure of the PLC in kinematics of the knee and to biomechanically analyze a single-graft, fibular-based reconstruction that replicates the femoral insertions of the lateral collateral ligament and popliteus to repair the PLC. The hypothesis was that knee kinematics can be reasonably restored using a single graft with a 2-strand "modified Larson" technique. Descriptive laboratory study. Eight fresh-frozen cadaveric knees were used in this study. We conducted sequential sectioning of the popliteofibular ligament (PFL) and then subsequently the popliteal tendon (PT), the lateral collateral ligament (LCL), and the anterior cruciate ligament (ACL). We then reconstructed the ACL first and then the posterolateral corner using the modified Larson technique. A surgical navigation system was used to measure varus laxity and external rotation at 0°, 30°, 60°, and 90° with a 9.8-N·m varus stress and 5-N·m external rotation force applied to the tibia. In extension, varus laxity increased only after the sectioning of the lateral collateral ligament. At 30° of flexion, external rotation in varus and translation of the lateral tibial plateau increased after the isolated popliteofibular ligament section. From 60° to 90° of flexion, translation and mobility of the lateral plateau section increased after sectioning of the PFL. After reconstruction, we observed a restoration of external varus rotation in extension and translation of the lateral tibial plateau at 90° of flexion. This technique provided kinematics similar to the normal knee.
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P53 is a key protein which controls cell cycle arrest and apoptosis in response to DNA damage. Auto-antibodies against p53 have been detected in some cancer patients and also in patients with autoimmune diseases. In these patients, the main cause of anti-p53 antibody occurrence was considered to be increased intracellular p53 protein in cancer cells and autoreactive lymphocytes, respectively. Intracellular p53 also increases with cardiomyocyte apoptosis during heart failure and autoreactive lymphocytes play a role in the course of idiopathic dilated cardiomyopathy (IDC) and ischemic cardiomyopathy (ICM). Based on these observations, we hypothesized that anti-p53 antibody response may also occur in patients with heart failure due to ICM and IDC. The aim of this study was to evaluate anti-p53 antibodies in the serum of patients with heart failure due to IDC and ICM. 70 eligible patients with heart failure and severe left ventricular systolic dysfunction (mean fractional shortening 12.03 +/- 3.93%) were included in the study. The aetiology of heart failure was IDC in 26 patients and ICM in 44 patients, according to the angiographic and echocardiographic findings. Anti-p53 antibodies were not detected in any of the patients.
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Is plasma microRNA-21 a potential diagnostic biomarker of acute myocardial infarction?
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Previous studies have demonstrated that microRNA-21 (miR-21) is involved in the pathogenesis of myocardium infarction and cardiac fibrosis; the present study aimed to investigate its potential role in the diagnosis of acute myocardium infarction (AMI). A cohort of patients with AMI and angina pectoris (AP) were studied, plasma miR-21 level was determined by Realtime-PCR. We found that the plasma miR-21 level was significantly elevated in patients with AMI compared with those with AP or healthy people. Further studies demonstrated the correlation of miR-21 and several traditional markers such as creatine kinase (CK), creatine kinase-MB (CK-MB) and troponin I (cTnI) in study subjects. Finally, receiver-operator characteristic curve (ROC) analysis showed that miR-21 has similar diagnostic ability compared with CK, CK-MB and cTnI.
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Jejunal pouch reconstruction is used to provide reservoir function after total gastrectomy, but controversy remains regarding pouch functions and quality of life (QOL). In this study, pouch motility was studied in conjunction with postoperative QOL. Pouch motility of 23 patients with jejunal pouch interposition after total gastrectomy was examined by manometry under fasting conditions and by an emptying test using dual-scintigraphy under postprandial conditions. Residual food was graded by endoscopic examinations. QOL was evaluated using the Gastrointestinal Quality of Life Index, and a stasis- or dumping-related symptom score. The pouch showed interdigestive contractile activity. Bursts of contractile activity occurred frequently and were long-lasting compared with the migrating motor complex phase III of the control jejunum. The percentage of time of contractile bursts correlated with postprandial pouch emptying (liquid: R(2) = 0.229, P < .03; solid: R(2) = 0.243, P < .02). Patients with little or no residual food had more percentage of time of contractile bursts than those with moderate residual food (P < .01). The percentage of time of contractile bursts was correlated with the Gastrointestinal Quality of Life Index score (R(2) = 0.262, P < .02), stasis-related symptoms (R(2) = 0.279, P < .01), and dumping-related symptoms (R(2) = 0.218, P < .03).
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Does insulin-like growth factor 1 myocardial expression decrease in chronic alcohol consumption?
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Alcoholic cardiomyopathy (CMP) is one of the major complications of chronic excessive alcohol consumption. The pathogenic mechanisms implicated are diverse, inducing functional and structural changes in the myocardium. Insulin-like Growth Factor 1 (IGF-1) plays an important role in modulating the cell cycle, and helps the differentiation and proliferation of cardiac tissue inhibiting apoptosis. Experimental studies have suggested the role of IGF-1 in alcohol-induced cardiac damage. The aim of the present study was to determine the effect of chronic alcohol consumption on IGF-1 myocardial expression and to compare this expression in cases of hypertension and other cardiac diseases. We studied heart samples from human organ donors: 10 healthy donors, 16 with hypertension, 23 with chronic alcohol consumption and 7 with other causes of cardiac disease. IGF-1 myocardial expression was evaluated with a specific immunohistochemistry assay using a semi-quantitative method. A significant decrease in IGF-1 myocardial expression was observed comparing all the cases included with control donors. This decrease in IGF-1 myocardial expression was significantly lower in the group of donors with chronic alcohol consumption compared to controls. On group evaluation according to the presence of CMP, donors with chronic alcohol consumption without CMP presented significantly lower IGF-1 expression than controls, whereas donors with chronic alcohol consumption with CMP showed a downward trend without achieving significance.
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To further explore the mechanism of etanercept (ENT, rhTNFR:Fc) and methotrexate (MTX) in the combined treatment of rheumatoid arthritis (RA), we investigated whether thymic and splenic T-cell subsets and their related cytokines imbalance could be restored by ETN/MTX treatment. The effect of ETN/MTX on collagen-induced arthritis (CIA) was evaluated by arthritis scores, joint and spleen histopathology, as well as indices of thymus and spleen. T lymphocytes proliferation was determined by [(3)H]-TdR incorporation. Levels of TNF-α, LT-α, IL-1β, RANKL, IL-10, IL-17, IFN-γ and IL-6 were detected by enzyme linked immunosorbent assay. The subsets of T lymphocytes including CD4(+), CD8(+), CD3(+)CD4(+), CD4(+)CD25(+), CD4(+)CD62L(+) and CD4(+)CD25(+)Foxp3(+) cells were quantified using flow cytometry. Combined administration of ETN/MTX significantly inhibited the proliferation of T lymphocytes, decreased serum IL-6, TNF-α, IL-1β, RANKL and macrophage supernatant IL-17, LT-α, increased serum IFN-γ and macrophage supernatant IL-10. Moreover, the combined administration could restore CD4(+)/CD8(+) ratio and Treg cells of CIA thymus and spleen.
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Is yttrium-90 radioembolization a safe and effective treatment for unresectable hepatocellular carcinoma : a single centre experience of 45 consecutive patients?
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There is controversy regarding the role of yttrium-90 (90Y) radioembolization in the management of advanced, unresectable hepatocellular carcinoma (HCC). Forty-five consecutive patients underwent resin-based 90Y radioembolization for unresectable, HCC between 2006 and 2013 in Sydney, Australia. All patients were followed up with imaging studies at regular intervals until death. Radiologic response was evaluated with the Response Criteria in Solid Tumors (RECIST) criteria. Clinical toxicities were prospectively recorded. Survival was calculated by the Kaplan-Meier method and potential prognostic variables were identified on univariate and multivariate analysis. Follow-up in the complete cohort was 7.8 (range, 0.1-41.8) months. The median survival after 90Y radioembolization was 27.7 months with a 36-month survival of 26%. By RECIST criteria of the 40 patients followed-up beyond 2 months, a complete response (CR) to treatment was observed in 1 patients (3%), partial response (PR) in 18 (45%), stable disease (SD) in 11 (22%) and progressive disease (PD) in 10 (25%). On multivariate analysis only radiological response to treatment was independently associated with improved survival: CR/PR to treatment vs. SD vs. PD; p < 0.001. Thirteen patients (29%) developed clinical toxicity after treatment; all complications were minor (grade I/II) and resolved without active intervention.
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Acne inversa is a chronic inflammatory disorder of apocrine gland-bearing skin. The role of the innate immune system in the pathogenesis of the disease is controversial. We investigated the expression of antimicrobial peptide/proteins in acne inversa. Tissue samples were obtained from patients with acne inversa and compared with normal-appearing skin. The expression of psoriasin and human beta-defensin (hBD)-2 on messenger RNA and protein level was analyzed. Both messenger RNA and protein levels of psoriasin and hBD-2 were significantly increased in acne inversa. Macrophages expressing hBD-2 were found in the dermis.
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Do the interleukin-6 gene -174G > C and -572G > C promoter polymorphisms are related to cerebral aneurysms?
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An important part is played by inflammation in intracranial aneurysm formation. The hypothesis that there is an association of the proinflammatory cytokine interleukin-6 (IL-6) genotypes (-572G>C and -174G>C) with intracranial aneurysms was tested. IL-6 genotypes were determined in 91 Caucasian patients with aneurysms and compared with 2720 healthy UK controls. For both polymorphisms, the distribution of the genotypes and estimated allele frequency were different between the control group and the aneurysm group. For -572G>C, a higher frequency of the C allele (p = 0.001) and more people homozygous for the C allele were found among those with aneurysms than among the controls (4.4% v 0.3%, p = 0.001). For -174G>C, more people homozygous for the C allele were found among the controls than among those with aneurysm (18% v 7%, p = 0.007). The 572C/174G haplotype was associated with an increased risk of aneurysms, with the relative risk compared with the common haplotype being 1.89 and that for the -572G/174C haplotype being 0.58 (p<0.0005).
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Nucleoside analogues are suspected of playing a role in peripheral fat loss in patients during long-term treatment with antiretroviral drugs. We compared the long-term effects of stavudine (10 microM), zidovudine (1 muM), didanosine (10 microM), abacavir (4 microM), lamivudine (10 microM), and tenofovir (1 microM), near their maximum concentration values, on the differentiation, lipid accumulation, survival and mitochondrial function of differentiating 3T3-F442A and differentiated 3T3-L1 adipocytes. None of the nucleoside reverse transcriptase inhibitors (NRTI) markedly altered the differentiation of 3T3-F442A cells, as shown by the unmodified percentage of cells with lipid droplets on day 7 and the expression of the early differentiation markers CCAAT/enhancer binding protein (C/EBP) beta (on day 2) and sterol regulatory element-binding protein. However, stavudine and zidovudine altered the lipid phenotype, decreasing the lipid content and expression of markers involved in lipid metabolism, namely C/EBPalpha, peroxisome proliferator-activated receptor gamma, adipocyte lipid binding protein 2, fatty acid synthase and acetyl-coenzyme A carboxylase. Stavudine and zidovudine, contrary to the other NRTI, drove 5-10% of 3T3-F442A cells towards apoptosis, and reduced the lipid content and survival of differentiated 3T3-L1 adipocytes. Stavudine and zidovudine increased mitochondrial mass by two to fourfold, and lowered the mitochondrial membrane potential (JC-1 stain) as did zalcitabine (0.2 microM). Co-treatment with zidovudine plus lamivudine, or zidovudine plus lamivudine and abacavir, did not increase the effect of zidovudine on cell viability or apoptosis.
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Does experimental acute lung injury induce multi-organ epigenetic modifications in key angiogenic genes implicated in sepsis-associated endothelial dysfunction?
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The Tie2/angiopoietin (Tie2/Ang) and vascular endothelial growth factor receptor-ligand systems (VEGFR/VEGF) are recognized to play important roles in the regulation of microvascular endothelial function. Downregulation of these genes during sepsis has been implicated in the pathogenesis of sepsis-related microvascular leak and multiple organ dysfunction syndrome. Mechanisms responsible for dysregulation of angiogenic genes in sepsis are poorly defined. Western blot, reverse transcription-polymerase chain reaction, and multiplex chromatin immunoprecipitation platform (Matrix ChIP) were used to investigate serum albumin leak, changes in gene expression, and associated epigenetic alterations in a murine model of acute lung injury-induced sepsis (ALI-sepsis). Experimental ALI-sepsis induced microvascular leak and downregulation of expression of Angpt1 (Ang1), Tek (Tie2), and Kdr (Vegfr2 or Flk-1) genes in the lung, kidney, and liver. These changes correlate with a decrease in RNA polymerase II density at these genes, and the greatest response was observed in the lung. ALI-sepsis reduced levels of transcription-permissive histone H3 lysine acetylation (H3KAc) at these loci in all examined tissues. Decreases in permissive H3K4m3 and H3Km2 marks were detected only in the lung. In contrast, only minimal alterations in transcription-repressive histone modifications (H3K27m3, H3K9m2, H3K9m3, and H4K20m3) were observed in all tissues.
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Photodynamic therapy with aminolevulinic acid (ALA-PDT) is effective therapy for acne vulgaris; however, relatively strong side effects limit its wide usage. We have previously demonstrated that ALA-induced protoporphyrin IX distribution with lower concentrations and shorter contact time of ALA resulted in focused damage in sebaceous glands in vivo. We have formulated a protocol for ALA-PDT using 5% ALA with 2 hours contact time. The objective of this study was to establish the effectiveness and side effect profile of the new protocol in humans. Eleven Japanese patients (Fitzpatrick's skin type III - IV, mean age 23.7±7.2) with facial acne received topical application of 5% ALA for 2 hours with subsequent illumination by a broadband light (600 - 1100 nm, 15J/cm(2), 60 mW/cm(2)). Subjects were evaluated prior to the procedure, 1 month, and 3 months after the treatment by a blinded dermatologist using the global acne grading system (GAGS). Side effects were monitored through the treatment period. The mean GAGS score decreased from 22.1±3.8 at baseline to 19.4 at 1 month, and to 16.3 at 3 months after PDT (P<0.05). Ten of eleven patients experienced local side effects, such as erythema, which were of minimal to mild severity. However, most side effects were of minimal to mild severity, and all of them resolved within several days without post inflammatory hyper pigmentation.
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Does icodextrin impact infectious and culture-negative peritonitis rates in peritoneal dialysis patients : a 2-year multicentre , comparative , prospective cohort study?
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Icodextrin is a glucose polymer derived by hydrolysis of cornstarch. The different biocompatibility profile of icodextrin-containing peritoneal dialysis (PD) solutions may have a positive influence on peritoneal host defence. Furthermore, cases of sterile peritonitis potentially associated with icodextrin have been reported. The primary objective of this multicentre, longitudinal, observational, non-interventional, prospective cohort study, which included 722 PD patients, was to evaluate the incidence of overall peritonitis in patients treated with icodextrin-containing PD solutions (Extraneal) used during one long-dwell exchange/day compared with those treated with non-icodextrin-containing PD solutions. The secondary objective was to determine if culture-negative peritonitis rates differed between patients treated with icodextrin from two independent manufacturers. All peritonitis episodes were assessed by a Steering Committee in a blind manner. There was no significant difference between icodextrin-treated and control patients in the adjusted overall, culture-positive or culture-negative peritonitis rates. When stratified by the icodextrin supplier, there was no significant difference in the adjusted rate of culture-negative peritonitis episodes between groups.
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The mitogen-activated protein kinases (MAPKs) have been shown to participate in a wide array of cellular functions. A role for some MAPKs (e.g., extracellular signal-regulated kinase, Erk1/2) has been documented in response to certain physiological stimuli, such as ischemia, visceral pain and electroconvulsive shock. We recently demonstrated that restraint stress activates the Erk MAPK pathway, but not c-Jun-N-terminal kinase/stress-activated protein kinase (JNK/SAPK) or p38MAPK, in several rat brain regions. In the present study, we investigated the effects of a different stressor, acute forced swim stress, on the phosphorylation (P) state of these MAPKs in the hippocampus, neocortex, prefrontal cortex, amygdala and striatum. In addition, effects on the phosphorylation state of the upstream activators of the MAPKs, their respective MAPK kinases (MAPKKs; P-MEK1/2, P-MKK4 and P-MKK3/6), were determined. Finally, because the Erk pathway can activate c-AMP response element (CRE) binding (CREB) protein, and swim stress has recently been reported to enhance CREB phosphorylation, changes in P-CREB were also examined. A single 15 min session of forced swimming increased P-Erk2 levels 2-3-fold in the neocortex, prefrontal cortex and striatum, but not in the hippocampus or amygdala. P-JNK levels (P-JNK1 and/or P-JNK2/3) were increased in all brain regions about 2-5-fold, whereas P-p38MAPK levels remained essentially unchanged. Surprisingly, levels of the phosphorylated MAPKKs, P-MEK1/2 and P-MKK4 (activators of the Erk and JNK pathways, respectively) were increased in all five brain regions, and much more dramatically (P-MEK1/2, 4.5 to > 100-fold; P-MKK4, 12 to approximately 300-fold). Consistent with the lack of forced swim on phosphorylation of p38MAPK, there appeared to be no change in levels of its activator, P-MKK3/6. P-CREB was increased in all but cortical (prefrontal, neocortex) areas.
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Do glutaminase-containing microvesicles from HIV-1-infected macrophages and immune-activated microglia induce neurotoxicity?
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HIV-1-infected and/or immune-activated microglia and macrophages are pivotal in the pathogenesis of HIV-1-associated neurocognitive disorders (HAND). Glutaminase, a metabolic enzyme that facilitates glutamate generation, is upregulated and may play a pathogenic role in HAND. Our previous studies have demonstrated that glutaminase is released to the extracellular fluid during HIV-1 infection and neuroinflammation. However, key molecular mechanisms that regulate glutaminase release remain unknown. Recent advances in understanding intercellular trafficking have identified microvesicles (MVs) as a novel means of shedding cellular contents. We posit that during HIV-1 infection and immune activation, microvesicles may mediate glutaminase release, generating excessive and neurotoxic levels of glutamate. MVs isolated through differential centrifugation from cell-free supernatants of monocyte-derived macrophages (MDM) and BV2 microglia cell lines were first confirmed in electron microscopy and immunoblotting. As expected, we found elevated number of MVs, glutaminase immunoreactivities, as well as glutaminase enzyme activity in the supernatants of HIV-1 infected MDM and lipopolysaccharide (LPS)-activated microglia when compared with controls. The elevated glutaminase was blocked by GW4869, a neutral sphingomyelinase inhibitor known to inhibit MVs release, suggesting a critical role of MVs in mediating glutaminase release. More importantly, MVs from HIV-1-infected MDM and LPS-activated microglia induced significant neuronal injury in rat cortical neuron cultures. The MV neurotoxicity was blocked by a glutaminase inhibitor or GW4869, suggesting that the neurotoxic potential of HIV-1-infected MDM and LPS-activated microglia is dependent on the glutaminase-containing MVs.
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The objective of this study was to evaluate the predictive value of prostate biopsies that were obtained 24 months after the completion of radiotherapy (RT) with respect to disease-free survival (DFS) in a randomized trial that compared 3 months versus 8 months of neoadjuvant hormone therapy before conventional dose external RT. From February 1995 to June 2001, 378 men were randomized to receive either 3 months or 8 months of combined flutamide and goserelin before they received 66 Gray of RT at 4 participating centers. By risk group, 26% of patients were categorized as low risk, 43% were categorized as intermediate risk, and 31% were categorized as high risk. The 2 treatment arms were balanced in terms of age, Gleason score, clinical tumor classification, risk group, and presenting prostate-specific antigen level. The median follow-up for the patients who remained alive was 6.6 years (range, 1.6-10.1 years). Of 361 evaluable patients, 290 patients remained alive. Post-RT prostate biopsies were performed between 24 and 30 months after the completion of RT in 3 of the 4 centers. Biopsies that had residual tumor with severe treatment effect were considered indeterminate, and biopsies that had minimal or no treatment effect were considered positive. The 5-year rate of actuarial freedom from any failure for the 3-month arm versus the 8-month arm was 72% versus 75% (P = .18). The DFS for patients who had negative and indeterminate biopsies was similar. Two-year post-treatment biopsy status was a strong predictor of 5-year DFS rate (82% and 83% for negative and indeterminate biopsies, respectively, vs 27% for positive biopsies; P < .0001). Multivariate analysis indicated that biopsy status (P < .0001) and Gleason score (P < .0001) were the strongest determinates of biochemical DFS.
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Do transient lower esophageal sphincter relaxations result from passive opening of the cardia by gastric distention?
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Transient lower esophageal sphincter relaxation is the main mechanism for gastroesophageal reflux. Although there is evidence that transient lower esophageal sphincter relaxations are neurally mediated, another school of thought is that transient lower esophageal sphincter relaxations result from gastric distention, which shortens the sphincter to the point where it opens and the pressure decreases. We assessed the relationship of transient lower esophageal sphincter relaxation to gastroesophageal junction opening in an unsedated human model. Seven healthy volunteers (6 men and 1 woman, aged 18-53 years) were studied while they were sitting. Manometry was performed by using a sleeve catheter passed through 1 nostril. A 5.3-mm endoscope was placed through the other nostril to obtain a retroflexed view of the cardia. The biopsy channel was connected to a barostat to distend the stomach with air at 15 mm Hg for 30 minutes. Manometric and endoscopic video-recording times were synchronized but scored independently. The transient lower esophageal sphincter relaxation onset invariably preceded gastroesophageal junction opening (median, 5.0 seconds; range, 0.5-20.7 seconds; P < .001). The transient lower esophageal sphincter relaxation nadir also typically occurred before gastroesophageal junction opening (median, 2.1 seconds; range, -4.2 to +19.5 seconds; P < .001). Once open, the gastroesophageal junction moved proximally for the duration of the transient lower esophageal sphincter relaxation. Termination of transient lower esophageal sphincter relaxations occurred about the time the time of gastroesophageal junction closure.
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Expression of CD56 has been associated with poor prognosis in acute myeloid leukemia and aggressive lymphoma. We analyzed the impact of CD56 expression in a cohort of 452 newly diagnosed adult T-cell acute lymphoblastic leukemia (T-ALL) patients; clinical data were available for 306 patients. Treatment was according to the GMALL study protocols 06/99 and 07/03 stipulating stratification into standard (thymic T-ALL) and high risk (pre- and mature T-ALL) groups. CD56 expression was detected in 63/452 (13.9%) patients. CD56(+) T-ALL were predominantly of non-thymic (pre-T 35%, mature 41%) immunophenotypic subtypes, whereas 53% of the CD56(-) cases were thymic T-ALL (p=0.00002). CD13, CD33, CD34 and HLA-DR were significantly more frequently expressed. A clonal T-cell receptor rearrangement was detected in 22/23 CD56(+) ALL. No major clinical differences were observed at presentation. Treatment of CD56(+) ALL resulted in a lower rate of complete remissions (70% vs. 88%) (p=0.001) and a higher rate of resistant disease (21% vs. 8%) (p=0.004). CD56 expression had no significant influence on overall (48% vs. 59%) and disease free survival (67% vs. 57%) at three years.
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Does posttraumatic stress disorder influence the nociceptive and intrathecal cytokine response to a painful stimulus in combat veterans?
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Although posttraumatic stress disorder (PTSD) and chronic pain frequently occur in tandem, the pathophysiological mechanisms mediating this comorbidity are poorly understood. Because excessive inflammation occurs in both conditions, we examined the cerebrospinal fluid (CSF) concentrations of inflammatory response mediators interleukin 1-beta (IL-1β), interleukin 6 (IL-6), interleukin 8 (IL-8), tumor necrosis factor-alpha (TNFα) and interleukin 10 (IL-10) after prolonged suprathreshold pain stimulus in 21 male combat veterans; 10 with PTSD and 11 combat controls (CC). After completing baseline quantitative sensory testing (QST) and psychological profiling, all patients received an injection of capsaicin into the quadriceps muscle. Spontaneously reported pain was measured for 30min after the capsaicin injection. The evoked pain measure of temporal summation was tested between 70 and 110min post capsaicin injection. Inflammatory (IL-1β, IL-6, IL-8 TNFα) and anti-inflammatory (IL-10) CSF cytokines were measured before (baseline) and after capsaicin injection over a time frame of 110min. Following intramuscular capsaicin injection, pro-inflammatory cytokines [TNFα, IL-6, IL-8] significantly increased (percent rise from baseline) in both groups, whereas IL-1β significantly increased in the PTSD group only. The anti-inflammatory cytokine IL-10 showed an immediate (within 10min) increase in the CC group; however, the IL-10 increase in the PTSD group was delayed and not consistently elevated until 70min post injection.
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To investigate if placental Doppler velocimetry can predict the recurrence of a small-for-gestational age (SGA) fetus in subsequent pregnancies. Retrospective study. City cohort over 15 years attending a university hospital. A total of 196 pregnancies suspected of a SGA fetus (<3rd percentile) evaluated by uterine and umbilical artery Doppler velocimetry. Blood velocity waveform was analyzed for pulsatility index (PI) as well as the uterine artery waveform for notching in early diastole. The occurrence of a SGA newborn during the succeeding pregnancy by Doppler results from the previous pregnancy. In the group of 196 pregnancies suspected for SGA, 27 (13.8%) delivered a SGA newborn in the following pregnancy. Thirty-seven (18.9%) of the 196 had an abnormally high PI in the uterine arteries in their first pregnancy, 12 (32.4%) of these delivered a SGA child in the next pregnancy (relative risk 3.44, p<0.001). The corresponding figure for those with normal uterine artery PI was 15 (9.4%). Abnormal umbilical artery Doppler was a worse predictor of recurrence of SGA (p=0.051). Uterine artery notching was not related to a SGA newborn during next pregnancy.
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Does [ Interference of osteopontin expression inhibit the invasion and metastasis of human hepatocellular carcinoma cell lines ]?
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To investigate the effect of osteopontin (OPN) on the invasion and metastasis of human hapatocellular carcinoma (HCC). HCC cell lines (HCC-LM3) were transfected with the chemically synthesized small interfering RNA (siRNA). Real-time PCR and Western blot were used to quantify the mRNA and OPN protein levels. The malignant phenotypes including cellular growth, colony formation and invasion capability of the HCC cells were analyzed. The OPN mRNA and proteins levels were decreased by 75% and 80% in OPN siRNA treated cells. Colony formation and migratory capability were reduced in OPN siRNA treated cells (P < 0.05).
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Patients with acute myocardial infarction (AMI) whose culprit lesion lies in a branch of the 3 major coronary arteries have well-preserved cardiac function. A first MI with preserved cardiac function is a risk factor for left ventricular free wall rupture (LVFWR), so the aim of this study was to investigate the possible relationship between AMI with branch segment occlusion and LVFWR. The 439 patients with AMI were retrospectively studied. They were divided into 2 groups: group B (n=70; segments 4 atrioventricular node artery, 4 posterior descending coronary artery, 8, 9, 10, 12, 14, or 15 according to the AHA classification), and group P (n=369; segments 1, 2, 3, 5, 6, 7, 11, or 13). Primary percutaneous coronary intervention (PCI) was more often performed in group P (75% vs 57%; P=0.0018). In-hospital mortality tended to be lower in group B (1.4% vs 6.2%; P=0.105). The incidence of LVFWR was significantly higher in group B (10.0% vs 1.6%; P=0.0002).By multivariate logistic regression analysis, 1-vessel disease, absence of primary PCI, branch segment occlusion, and age were identified as independent predictors of LVFWR.
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Are memory disturbances in `` Ecstasy '' users correlated with an altered brain serotonin neurotransmission?
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Methylenedioxymethamphetamine (MDMA) is known to damage brain pre-synaptic serotonin (5-HT) neurons. Since loss of 5-HT neurons has been implicated in memory loss, it is important to establish whether MDMA use may produce changes in postsynaptic 5-HT receptors and memory function in humans. To investigate whether MDMA use leads to compensative alterations in post-synaptic 5-HT2A receptors and whether there is a relation with memory disturbances. Brain cortical 5-HT2A receptor densities were studied with [123I]-5-I-R91150 SPECT in five abstinent MDMA users and nine healthy controls. Memory performance was assessed using RAVLT. [123I]-5-I-R91150 binding ratios were significantly higher in the occipital cortex of MDMA users than in controls, indicating up-regulation. Mean cortical 5-HT2A receptor binding correlated positively with RAVLT-recall in MDMA users.
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Whether or not to perform intraoperative cholangiography (IOC) with laparoscopic cholecystectomy is controversial. The decision to perform IOC should depend on the individual surgeon's preference for the management of choledocholithiasis. An initial experience of 525 patients undergoing laparoscopic cholecystectomy done without IOC is reviewed. Suspected or proven choledocholithiasis was managed by endoscopic retrograde cholangiography with sphincterotomy if necessary. There were no bile duct injuries or bile leaks, and 9% (47) of patients underwent endoscopic investigation or treatment. There have been no secondary operations for duct stones.
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Is increased cycle length during long-duration ventricular fibrillation caused by decreased upstroke velocity as well as prolonged refractoriness?
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Cycle length (CL) increases as ventricular fibrillation (VF) progresses. The purpose of this study was to test the hypotheses that increased CL is due to increased diastolic interval (DI), not increased action potential duration (APD), and that the DI increase is not solely due to increased postrepolarization refractoriness. In 10 swine, VF was recorded for 20 minutes using a floating microelectrode through a hole in a 504-electrode epicardial plaque. Mean APD, DI, action potential amplitude (APA), maximum change in voltage during the AP upstroke (V(max)), and CL were calculated from the floating microelectrode recordings each minute of VF. The refractory period was estimated from the minimum DI (DI(min)). In two animals, rapid pacing was performed to gauge refractoriness. As VF progressed, CL, DI, and DI(min) increased (P <.05), whereas APD, V(max), and APA decreased (P <.05). At 20 minutes, DI(min) was not different from mean DI at VF onset. Pacing captured, but 53% of paced wavefronts blocked within the plaque.
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To investigate the role of T helper-1 cell (Th1) activation in the induction of proinflammatory cytokine production and cartilage damage by rheumatoid arthritis (RA) synovial fluid mononuclear cells (SFMNC) and the subsequent possible beneficial role of the T helper-2 cell (Th2) cytokine interleukin-4 (IL-4) in the inhibition of this process. SFMNC were stimulated with bacterial antigen (hsp60) to activate Th1 cells. Th1 and Th2 specific cytokine profiles (interferon gamma (IFN gamma) and IL-4) and proinflammatory cytokines interleukin-1 (IL-1) and tumour necrosis factor alpha (TNF alpha) in the conditioned media were analysed. In addition, the conditioned media were tested for their ability to induce cartilage damage. The same parameters were measured in the presence of IL-4. Stimulation of SFMNC with bacterial antigen resulted in an increase in IFN gamma, IL-1, and TNF alpha production which was accompanied by the induction of cartilage damage. Th1 activation could be inhibited by IL-4 as shown by a reduction of IFN gamma. This was accompanied by a decrease in IL-1 and TNF alpha production and inhibition of cartilage damage.
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Does atorvastatin modulate Th1/Th2 response in patients with chronic heart failure?
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The T-helper (Th)1/Th2 imbalance has been demonstrated to be involved in chronic heart failure (CHF). We sought to determine whether atorvastatin exhibited any effect on CHF through modulating the Th1/Th2 response. We measured serum concentrations of interleukin (IL)-12, -18, interferon (IFN)-gamma, IL-4, and IL-10 from 20 controls and 72 patients with nonischemic CHF by enzyme-linked immunosorbent assay. To investigate the effect of atorvastatin in vivo, CHF patients were either classified into a usual therapy group (n = 35) or usual therapy plus atorvastatin (10 mg/day) group (n = 37). Patient serum levels of IFN-gamma and IL-4 were measured at time of admission and 2 weeks after treatment. Peripheral blood mononuclear cells from patients of CHF group were cultured in the presence or absence of atorvastatin (0, 0.4, 1, and 4 micromol/L) in vitro, and IFN-gamma and IL-4 levels were detected. Serum levels of IL-12, IL-18, and IFN-gamma were significantly higher in the CHF group than in the control group. The levels of IFN-gamma and the ratios of IFN-gamma:IL-4 were significantly decreased with atorvastatin treatment both in vivo and in vitro, whereas levels of IL-4 did not differ significantly.
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Cervical cancer continues to threaten women's health worldwide, and the incidence of cervical adenocarcinoma (AD) is rising in the developed countries. Previously, we showed that glucose-regulated protein 58 (Grp58) served as an independent factor predictive of poor prognosis of patients with cervical AD. However, the molecular mechanism underlying the involvement of Grp58 in cervical carcinogenesis is currently unknown. DNA microarray and enrichment analysis were used to identify the pathways disrupted by knockdown of Grp58 expression. Among the pathway identified, the WNT signaling pathway was one of those that were significantly associated with knockdown of Grp58 expression in HeLa cells. Our experiments showed that β-catenin, a critical effector of WNT signaling, was stabilized thereby accumulated in stable Grp58 knockdown cells. Membrane localization of β-catenin was observed in Grp58 knockdown, but not control cells. Using a transwell assay, we found that accumulated β-catenin induced by Grp58 knockdown or lithium chloride treatment inhibited the migration ability of HeLa cells. Furthermore, an inverse expression pattern of Grp58 and β-catenin was observed in cervical tissues.
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Is a new measurement method in Graf technique : prediction of future acetabular development possible in physiologically immature hips?
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Universal ultrasound screening has led to overtreatment and higher follow-up rates than are found with clinical examination alone because of high incidence of physiologically immature hips (type IIa) in the first weeks of life. The ability to predict future acetabular development in physiologically immature hips (type IIa) would therefore help to reduce overtreatment and unnecessary follow-up. We described the γ-angle to assess the femoral head coverage by the acetabular roof, which is measured between the baseline defined by Graf and the cartilaginous edge line connecting the inferior point of the iliac bone (lower limb) to the medial corner of the acetabular labrum. We retrospectively analyzed ultrasonographic findings of infants with developmental dysplasia of the hip diagnosed in our hospital and infants with normal hips screened in our hospital. Group 1 (35 hips) consists of type IIa hips at initial examination and went on to develop into dysplastic hips at follow-up. Group 2 (279 hips) consists of type IIa hips at initial examination and went on to develop into normal hips (type I) at follow-up. The γ-angles of type IIa hips that developed into type I hip at follow-up ranged between 77 and 82. The γ-angles of type IIa hips that developed into hip dysplasia ranged between 72 and 78. All type IIa hips that had γ-angles >78 degrees developed into normal hips. We also observed that all type IIa hips that had γ-angles <77 degrees developed into dysplasia.
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PS-341 (bortezomib, Velcade), the first proteasome inhibitor approved by the Food and Drug Administration for the treatment of patients with relapsed multiple myeloma, induces apoptosis in human cancer cell lines. Vitamin C (ascorbic acid) is an essential water-soluble vitamin required for many normal physiologic functions and has to be obtained through diet or supplemental tablets in humans. Here we studied the potential effect of vitamin C on the anticancer activity of PS-341 in human cancer cell lines. The effects of vitamin C on apoptosis induction by PS-341 alone and by PS-341 combined with tumor necrosis factor-related apoptosis-inducing ligand were studied. In addition, the effects of vitamin C and other antioxidants on PS-341-mediated proteasome inhibition were also examined. Finally, the direct chemical interaction between vitamin C and PS-341 was determined. Vitamin C abrogated the ability of PS-341 to induce apoptosis in various human cancer cell lines, to induce G(2)-M arrest, and to augment apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand. Moreover, vitamin C suppressed PS-341-mediated inhibition of proteasome activity. PS-341 itself did not induce generation of intracellular reactive oxygen species whereas other antioxidants failed to abrogate its biological activity. Importantly, we detected a direct chemical interaction between vitamin C and PS-341.
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Is gastric emptying in critically ill patients accelerated by adding cisapride to a standard enteral feeding protocol : results of a prospective , randomized , controlled trial?
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To investigate the effect of cisapride, a relatively new prokinetic agent, on gastric emptying in critically ill patients. Prospective, randomized, controlled study. Adult medical/surgical intensive care unit in a university hospital. Twenty-one consecutively enrolled patients, requiring prolonged mechanical ventilation and enteral feeding. Patients were randomized to receive either no cisapride or 10 mg of cisapride four times daily, which was added to a standard enteral nutrition feeding protocol. Gastric emptying was evaluated by daily measurements of gastric residue and on days 5 through 7 by bedside scintigraphy. Normal values for gastric clearance of a tracer-labeled test meal and for measurements obtained in the supine position were determined in ten healthy volunteers. The mean time at which 50% of the technetium 99m-labeled test meal was eliminated from the stomach (T 1/2) in this control group was 31 +/- 15 mins. In ten critically ill patients (enteral nutrition group), gastric emptying was markedly delayed after 5 to 7 days of enteral feeding (mean T 1/2 = 78 +/- 40 mins; p < .002 as compared with the control group). In contrast, patients treated with cisapride (cisapride group) showed an accelerated gastric emptying (mean T 1/2 = 18 +/- 7 mins; p > .05 as compared with controls; p < .005 as compared with enteral nutrition group). The mean gastric residue over a 1-wk period was also significantly lower in the cisapride group than in the enteral nutrition group (17.7 +/- 8.9 vs. 94.5 +/- 33.4 mL; p < .001).
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To investigate changes in gene expression in fibrillated and intact human osteoarthritis (OA) cartilage for evidence of an altered chondrocyte phenotype and hypertrophy. Paired osteochondral samples were taken from a high-load site and a low-load site from 25 OA joints and were compared with eight similar paired samples from age-matched controls. Gene expression of key matrix and regulatory genes was analysed by quantitative real-time reverse transcription-polymerase chain reaction on total RNA extracted from the cartilage. There was a major change in chondrocyte gene expression in OA cartilage. SOX9 (38-fold) and aggrecan (4-fold) gene expression were both lower in OA (p<0.001), and collagen I (17-fold) and II (2.5-fold) gene expression were each increased in a subset of OA samples. The major changes in gene expression were similar at the fibrillated high-loaded site and the intact low-loaded site. There was no evidence of a generalised change in OA to proliferative or hypertrophic phenotype as seen in the growth plate, as genes associated with either stage of differentiation were unchanged (PTHrPR), or significantly downregulated (collagen X (14-fold, p<0.002), VEGF (23-fold, p<0.02), BCL-2 (5.6-fold, p<0.001), matrilin-1 (6.5-fold, p<0.001)). In contrast MMP-13 was significantly upregulated in the OA cartilage samples (5.3-fold, p<0.003).
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Do professionalism deficiencies in a first-quarter doctor-patient relationship course predict poor clinical performance in medical school?
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The purpose of this study was to determine whether four types of professionalism deficiencies in medical students identified during a first-year course on doctor-patient relationships might predict poor performance in third-year clerkships. Preceptors identified students who had deficiencies in interviewing patients: extreme shyness, poor process skills, paternalism, or a negative attitude toward interviewing. Deficient students were matched by academic ability to a control group. Performance on third-year clerkships was compared. Students with paternalistic behavior or negative attitudes had significantly lower third-year grades.
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Iron can cause oxidative stress, and elevated iron levels have been associated with several neurodegenerative diseases including age-related macular degeneration (AMD). Transferrin, an iron transport protein, is expressed at high levels in the retina. The purpose of this study was to assess transferrin involvement in AMD by determining the expression profile of transferrin in retinas with AMD compared with retinas without evidence of disease. Postmortem retinas were obtained from AMD and non-AMD eyes. Expression of transferrin was assessed in a microarray dataset from 33 retinas of unaffected donors and 12 retinas of patients with AMD (six with neovascular AMD and six with non-neovascular AMD). Quantitative real-time RT-PCR (QPCR) was used to confirm the microarray results. Transferrin protein expression was assessed by semiquantitative Western blot analysis and immunohistochemistry. In comparison to unaffected retinas, mean transferrin mRNA levels, as measured by microarray analysis were elevated 3.5- and 2.1-fold in non-neovascular and neovascular AMD retinas, respectively. Semiquantitative Western blot analysis demonstrated a 2.1-fold increase in transferrin protein in AMD eyes. Immunohistochemistry showed more intense and widespread transferrin label in AMD maculas, particularly in large drusen, Müller cells, and photoreceptors.
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Is delay of airway epithelial wound repair in COPD associated with airflow obstruction severity?
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Airway epithelium integrity is essential to maintain its role of mechanical and functional barrier. Recurrent epithelial injuries require a complex mechanism of repair to restore its integrity. In chronic obstructive pulmonary disease (COPD), an abnormal airway epithelial repair may participate in airway remodeling. The objective was to determine if airway epithelial wound repair of airway epithelium is abnormal in COPD. Patients scheduled for lung resection were prospectively recruited. Demographic, clinical data and pulmonary function tests results were recorded. Emphysema was visually scored and histological remodeling features were noted. Primary bronchial epithelial cells (BEC) were extracted and cultured for wound closure assay. We determined the mean speed of wound closure (MSWC) and cell proliferation index, matrix metalloprotease (MMP)-2, MMP-9 and cytokines levels in supernatants of BEC 18 hours after cell wounding. In a subset of patients, bronchiolar epithelial cells were also cultured for wound closure assay for MSWC analyze. 13 COPD and 7 non COPD patients were included. The severity of airflow obstruction and the severity of emphysema were associated with a lower MSWC in BEC (p = 0.01, 95% CI [0.15-0.80]; p = 0.04, 95% CI [-0.77;-0.03] respectively). Cell proliferation index was decreased in COPD patients (19 ± 6% in COPD vs 27 ± 3% in non COPD, p = 0.04). The severity of COPD was associated with a lower level of MMP-2 (7.8 ± 2 10(5) AU in COPD GOLD D vs 12.8 ± 0.13 10(5) AU in COPD GOLD A, p = 0.04) and a lower level of IL-4 (p = 0.03, 95% CI [0.09;0.87]). Moreover, higher levels of IL-4 and IL-2 were associated with a higher MSWC (p = 0.01, 95% CI [0.17;0.89] and p = 0.02, 95% CI [0.09;0.87] respectively). Clinical characteristics and smoking history were not associated with MSWC, cell proliferation index or MMP and cytokines levels. Finally, we showed an association of the MSWC of bronchial and corresponding bronchiolar epithelial cells obtained from the same patients (p = 0.02, 95% CI [0.12;0.89]).
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The widespread increase in the use of contraception, due to multiple factors including improved access to modern contraception, is one of the most dramatic social transformations of the past fifty years. This study explores whether the global progress in the use of modern contraceptives has also benefited the poorest. Demographic and Health Surveys from 55 developing countries were analyzed using wealth indices that allow the identification of the absolute poor within each country. This article explores the macro level determinants of the differences in the use of modern contraceptives between the poor and the national averages of several countries. Despite increases in national averages, use of modern contraception by the absolute poor remains low. South and Southeast Asia have relatively high rates of modern contraception in the absolute poor, on average 17% higher than in Latin America. Over time the gaps in use persist and are increasing. Latin America exhibits significantly larger gaps in use between the poor and the averages, while gaps in sub-Saharan Africa are on average smaller by 15.8% and in Southeast Asia by 11.6%.
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Do ecological evidence that affect and perceptions of drink effects depend on alcohol expectancies?
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(1) To compare affective changes over drinking and non-drinking days among frequent drinkers and (2) to evaluate whether drinkers' expectations influence affective changes and perceived pleasure and relief from drinking. Observational study involving ecological momentary assessments collected via electronic diaries during the course of 3 weeks. Drinkers' usual settings in Columbia, MO, USA. A total of 400 adult, frequent drinkers, aged 18-70 years. Ecological assessments included morning reports, pre-drinking random prompts, user-initiated first-drink reports and device-prompted follow-ups over drinking episodes. Participants rated positive (enthusiastic, excited, happy) and negative (distressed, sad) affect and perceived pleasure and relief from drinking in real time. A self-report questionnaire completed at baseline evaluated expectancies for enhanced sociability and tension reduction from drinking. Relative to affective changes over non-drinking days, positive affect increased prior to drinking [95% confidence interval (CI) = 0.004, 0.023], and at first drink (95% CI = 0.238, 0.317), whereas negative affect decreased prior to drinking (95% CI = - 0.007, 0.000) and at first drink (95% CI = - 0.154, - 0.098). Sociability expectancies augmented increases in positive affect prior to drinking (95% CI = 0.009, 0.027) and at first drink (95% CI = 0.017, 0.169). Sociability expectancies also enhanced perceived pleasure from first drinks (95% CI = 0.046, 0.318). Tension-reduction expectancies attenuated decreases in negative affect at first drink (95% CI = - 0.133, - 0.029), but augmented perceived relief from first drinks (95% CI = 0.001, 0.304).
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Prostaglandin E(1) (PGE(1)), via cAMP, dilates the ductus arteriosus (DA). For patients with DA-dependent congenital heart disease (CHD), PGE(1) is the sole DA dilator that is used until surgery, but PGE(1) has a short duration of action, and frequently induces apnea. Most importantly, PGE(1) increases hyaluronan (HA) production, leading to intimal thickening (IT) and eventually DA stenosis after long-term use. The purpose of this study was therefore to investigate potential DA dilators, such as phosphodiesterase 3 (PDE3) inhibitors, as alternatives to PGE(1). Expression of PDE3a and PDE3b mRNAs in rat DA tissue was higher than in the pulmonary artery. I.p. milrinone (10 or 1mg/kg) or olprinone (5 or 0.5mg/kg) induced maximal dilatation of the DA lasting for up to 2h in rat neonates. In contrast, vasodilation induced by PGE(1) (10μg/kg) was diminished within 2h. No respiratory distress was observed with milrinone or olprinone. Most important, milrinone did not induce HA production, cell migration, or proliferation when applied to cultured rat DA smooth muscle cells. Further, high expression of both PDE3a and PDE3b was demonstrated in the human DA tissue of CHD patients.
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Is combinatory inhibition of VEGF and FGF2 superior to solitary VEGF inhibition in an in vitro model of RPE-induced angiogenesis?
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Choroidal neovascularisation (CNV) as a feature of exudative age-related macular degeneration (AMD) is partially regulated by retinal pigment epithelium (RPE). In this study, the effect of combinatory anti-angiogenic treatment was evaluated using a novel in vitro assay of RPE-induced angiogenesis. RPE isolated from surgically excised CNV-membranes (CNV-RPE) was used to stimulate sprouting of endothelial cell (EC) spheroids in a 3D collagen matrix. The anti-angiogenic effect of solitary anti-VEGF antibodies (bevacizumab) was compared to a combinatory treatment with anti-VEGF and anti-FGF2 antibodies. Anti-VEGF treatment inactivated all RPE-derived VEGF but was unable to fully inhibit EC sprouting induced by CNV-RPE. Combined anti-VEGF/anti-FGF treatment inactivated both growth factors and reduced EC sprouting significantly.
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The serum leptin level is elevated in patients undergoing peritoneal dialysis (PD) and associated with a loss of lean body mass. The nutritional status of PD patients may further be worsened following peritonitis. We investigated the association between hyperleptinaemia, inflammation and malnourishment in PD-related peritonitis. We conducted a prospective study on PD patients who developed peritonitis. Blood samples were obtained as baseline (D0) before the onset of peritonitis, and once peritonitis developed, leptin, adiponectin (ADPN) and other inflammatory markers were collected, on day 1 (D1), day 7 (D7) and day 42 (D42) of peritonitis. Patients were followed-up for any censor event or 1 year after peritonitis. Forty-two patients with a mean age of 62.9+/-13.2 years were recruited. Fourteen (33.3%) were diabetic. The serum leptin levels increased significantly from baseline to day 1 and 7, but fell back to the premorbid state at day 42. In contrast, the ADPN level decreased from a baseline value of 15.60+/-10.4 microg/ml to 13.01+/-8.1 microg/ml on day 1 (P=0.01) but rose to 14.39+/-8.9 microg/ml on day 7 (P=0.28) and 13.87+/-7.9 microg/ml on day 42 (P=0.21). High-sensitivity C-reactive protein (hs-CRP) increased significantly from baseline to day 1, 7 and even at day 42. The lean body mass (LBM) and nutritional markers decreased significantly after peritonitis. For patients with high hs-CRP (>3.0 mg/l) at day 42, there was a higher mortality rate than for those with lower hs-CRP (<3.0 mg/l, P=0.02), even if they were in clinical remission of peritonitis.
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Do logic models help make sense of complexity in systematic reviews and health technology assessments?
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To describe the development and application of logic model templates for systematic reviews and health technology assessments (HTAs) of complex interventions. This study demonstrates the development of a method to conceptualize complexity and make underlying assumptions transparent. Examples from systematic reviews with specific relevance to Sub-Saharan Africa (SSA) and other low- and middle-income countries (LMICs) illustrate its usefulness. Two distinct templates are presented: the system-based logic model, describing the system in which the interaction between participants, intervention, and context takes place; and the process-orientated logic model, which displays the processes and causal pathways that lead from the intervention to multiple outcomes.
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Prostate cancer is the world's leading cause of cancer and the second cause of cancer-related death in men after lung cancer. Differentiation of prostate adenocarcinoma from benign prostate lesions and hyperplasia sometimes cannot be done on the basis of morphologic findings. Considering the fact that in the prostate adenocarcinoma there is no basal cell layer, basal cell markers can help to differentiate prostate adenocarcinoma from cancer mimickers. We studied 98 prostate biopsy blocks (40 adenocarcinoma and 58 benign lesions) for basal cell marker expression. p63 and 34βE12 were negative in all prostate adenocarcinoma specimens, but all benign prostate hyperplasia and high grade intraepithelial neoplasia cases expressed them.
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Is visual impairment , but not hearing impairment , independently associated with lower subjective well-being among individuals over 95 years of age : A population-based study?
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Sensory impairment affects an increasing number of elderly adults, with a negative psychological impact. Our objective was to examine the associations of visual and hearing impairment with subjective well-being (SWB), an important psychological concept defined by life satisfaction [LS], positive affect [PA], negative affect [NA], and affect balance [AB] among long-lived individuals (LLIs) over 95 years of age. Data on 442 LLIs from the Rugao longevity cohort, a population-based study in Rugao, China, were analyzed. Graded classifications of visual and hearing impairment (none, mild, moderate, and severe) were constructed from self-reported items. Bivariate correlation and multiple regression analysis were performed to test the associations. Approximately 66.1% and 87.3% of the subjects reported varying degrees of visual and hearing impairment. Following the degree of vision impairment, LS, PA, and AB decreased linearly, whereas NA increased linearly (all p for trend<0.05). Vision was significantly related to LS (r=0.238, p<0.001), PA (r=0.142, p<0.01), NA (r=-0.157, p<0.001), and AB (r=0.206, p<0.001). After adjustment for multiple variables including functional ability, an important factor of SWB, the associations of vision impairment with LS, NA, and AB, while diminished, still existed.
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The SARS coronavirus (SARS-CoV) 3a protein functions as an ion channel, induces apoptosis and is important for viral pathogenesis. It is expressed on the cell surface and contains a tyrosine-based sorting motif and a di-acidic motif, which may be crucial for its intracellular trafficking. However the role of these motifs is not fully understood in the case of 3a protein. The subcellular distribution of the 3a protein was studied by immunofluorescence staining of cells transfected with wild type and mutant constructs along with markers for different intracellular compartments. Semi-quantitative RT-PCR was performed to estimate the mRNA where as western blotting was carried out to detect protein levels of wild type and mutant 3a proteins. In vitro transcription- translation was performed to estimate cell free protein synthesis. While the wild type 3a protein is efficiently transported to the plasma membrane, the protein with mutations in the tyrosine and valine residues within the YXXV motif (ΔYXXΦ) accumulated in the Golgi compartment. However the 3a protein with mutations within the EXD di-acidic motif (ΔEXD) showed an intracellular distribution similar to the wild type protein. Increased retention of the ΔYXXΦ protein in the Golgi compartment also increased its association with lipid droplets. The ΔYXXΦ protein also expressed at significantly lower levels compared to the wild type 3a protein, which was reversed with Brefeldin A and Aprotinin.
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Do inflammatory genes and psychological factors predict induced shoulder pain phenotype?
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The pain experience has multiple influences, but little is known about how specific biological and psychological factors interact to influence pain responses. The current study investigated the combined influences of genetic (pro-inflammatory) and psychological factors on several preclinical shoulder pain phenotypes. An exercise-induced shoulder injury model was used, and a priori selected genetic (IL1B, TNF/LTA region, and IL6 single nucleotide polymorphisms (SNP)) and psychological (anxiety, depression symptoms, pain catastrophizing, fear of pain, and kinesiophobia) factors were included as the predictors of interest. The phenotypes were pain intensity (5-d average and peak reported on numerical rating scale), upper extremity disability (5-d average and peak reported on the Quick Disabilities of the Arm, Shoulder and Hand instrument), and duration of shoulder pain (d). After controlling for age, sex, and race, the genetic and psychological predictors were entered separately as main effects and interaction terms in regression models for each pain phenotype. Results from the recruited cohort (n = 190) indicated strong statistical evidence for the interactions between 1) TNF/LTA SNP rs2229094 and depression symptoms for average pain intensity and duration and 2) IL1B two SNP diplotype and kinesiophobia for average shoulder pain intensity. Moderate statistical evidence for prediction of additional shoulder pain phenotypes included interactions of kinesiophobia, fear of pain, or depressive symptoms with TNF/LTA rs2229094 and IL1B.
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Tamoxifen, an endocrine therapy drug used to treat breast cancer, is designed to interrupt estrogen signaling by blocking the estrogen receptor (ER). However, many ER-positive patients are low reactive or resistant to tamoxifen. Metformin is a widely used anti-diabetic drug with noteworthy anti-cancer effects. We investigated whether metformin has the additive effects with tamoxifen in ER-positive breast cancer therapy. The efficacy of metformin alone and in combination with tamoxifen against ER-positive breast cancer was analyzed by cell survival, DNA replication activity, plate colony formation, soft-agar, flow cytometry, immunohistochemistry, and nude mice model assays. The involved signaling pathways were detected by western blot assay. When metformin was combined with tamoxifen, the concentration of tamoxifen required for growth inhibition was substantially reduced. Moreover, metformin enhanced tamoxifen-mediated inhibition of proliferation, DNA replication activity, colony formation, soft-agar colony formation, and induction of apoptosis in ER-positive breast cancer cells. In addition, these tamoxifen-induced effects that were enhanced by metformin may be involved in the bax/bcl-2 apoptotic pathway and the AMPK/mTOR/p70S6 growth pathway. Finally, two-drug combination therapy significantly inhibited tumor growth in vivo.
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Does smad4 expression in hepatocellular carcinoma differ by hepatitis status?
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Primary hepatocellular carcinoma (HCC) is a common malignancy often related to hepatitis viral infection. Smad4 is known to mediate the TGF-β pathway to suppress tumorigenesis. However, the function of Smad4 in HCC is still controversial. In this study we compared levels of Smad4 in HCC tissues with or without hepatitis virus infection and adjacent normal-appearing liver. Samples from HCC patients were analyzed for Smad4 protein and mRNA expression by immunohistochemistry (IHC), RT-PCR and Western blotting. We found that tumor tissues expressed less Smad4 mRNA and protein than the adjacent tissues. Most HCC tumor tissues were negative for Smad4 in IHC staining, while the majority of adjacent tissues were positively stained. Interestingly, protein levels were higher in HCC tissues with viral hepatitis than those without virus infection. Suppression of expression appeared closely related to HCC, so that Smad4 appears to function as a tumor suppressor gene (TSG).
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Experimental evidence suggests that flow-dependent dilatation of conduit arteries is mediated by nitric oxide (NO) and/or prostacyclin. The present study was designed to assess whether NO or prostacyclin also contributes to flow-dependent dilatation of conduit arteries in humans. Radial artery internal diameter (ID) was measured continuously in 16 healthy volunteers (age, 24 +/- 1 years) with a transcutaneous A-mode echo-tracking system coupled to a Doppler device for the measurement of radial blood flow. In 8 subjects, a catheter was inserted into the brachial artery for measurement of arterial pressure and infusion of the NO synthase inhibitor NG-monomethyl-L-arginine (L-NMMA; 8 mumol/min for 7 minutes; infusion rate, 0.8 mL/min). Flow-dependent dilatation was evaluated before and after L-NMMA or aspirin as the response of the radial artery to an acute increase in flow (reactive hyperemia after a 3-minute cuff wrist occlusion). Under control conditions, release of the occlusion induced a marked increase in radial blood flow (from 24 +/- 3 to 73 +/- 11 mL/min; P < .01) followed by a delayed increase in radial diameter (flow-mediated dilatation; from 2.67 +/- 0.10 to 2.77 +/- 0.12 mm; P < .01) without any change in heart rate or arterial pressure. L-NMMA decreased basal forearm blood flow (from 24 +/- 3 to 13 +/- 3 mL/min; P < .05) without affecting basal radial artery diameter, heart rate, or arterial pressure, whereas aspirin (1 g PO) was without any hemodynamic effect. In the presence of L-NMMA, the peak flow response during hyperemia was not affected (76 +/- 12 mL/min), but the duration of the hyperemic response was markedly reduced, and the flow-dependent dilatation of the radial artery was abolished and converted to a vasoconstriction (from 2.62 +/- 0.11 to 2.55 +/- 0.11 mm; P < .01). In contrast, aspirin did not affect the hyperemic response nor the flow-dependent dilatation of the radial artery.
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Is mutacin H-29B identical to mutacin II ( J-T8 )?
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Streptococcus mutans produces bacteriocins named mutacins. Studies of mutacins have always been hampered by the difficulties in obtaining active liquid preparations of these substances. Some of them were found to be lantibiotics, defined as bacterial ribosomally synthesised lanthionine-containing peptides with antimicrobial activity. The goal of this study was to produce and characterize a new mutacin from S. mutans strain 29B, as it shows a promising activity spectrum against current human pathogens. Mutacin H-29B, produced by S. mutans strain 29B, was purified by successive hydrophobic chromatography from a liquid preparation consisting of cheese whey permeate (6% w/v) supplemented with yeast extract (2%) and CaCO3 (1%). Edman degradation revealed 24 amino acids identical to those of mutacin II (also known as J-T8). The molecular mass of the purified peptide was evaluated at 3246.08 +/- 0.1 Da by MALDI-TOF MS.
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Sitosterolemia, a rare genetic disorder characterized by profoundly elevated plasma sitosterol concentrations, is associated with premature atherosclerosis in some individuals. This study was conducted to evaluate if the modest sitosterol elevations seen in the general population are also associated with the occurrence of coronary events. A nested case-control study using stored samples from male participants in the Prospective Cardiovascular Münster (PROCAM) study was performed. Each of 159 men who suffered a myocardial infarction or sudden coronary death (major coronary event) within 10 years of follow-up in PROCAM was matched with 2 controls (N = 318) by age, smoking status, and date of investigation. Analysis was performed using conditional logistic regression. Plasma sitosterol concentrations were elevated in cases compared with controls (4.94 +/- 3.44 micromol/L versus 4.27 +/- 2.38 micromol/L; P = 0.028). The upper quartile of sitosterol (>5.25 micromol/L) was associated with a 1.8-fold increase in risk (P < 0.05) compared with the lower three quartiles. Among men with an absolute coronary risk > or = 20% in 10 years as calculated using the PROCAM algorithm, high sitosterol concentrations were associated with an additional 3-fold increase in the incidence of coronary events (P = 0.032); a similar, significant relationship was observed between a high sitosterol/cholesterol ratio and coronary risk (P = 0.030).
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Does preoperative reverse transcriptase polymerase chain reaction for prostate specific antigen predict treatment failure following radical prostatectomy?
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We previously demonstrated than an enhanced reverse transcriptase-polymerase chain reaction assay for prostate specific antigen (PSA) can predict final pathological stage in radical prostatectomy patients. The potential role of the assay in predicting serum PSA recurrence after radical prostatectomy was explored. We evaluated 100 radical prostatectomy candidates by reverse transcriptase polymerase chain reaction preoperatively, and status was compared to serum PSA, Gleason score and final pathological results. Potential surgical failure was defined as tumor at the surgical margin or extending into the seminal vesicle. Patients were monitored postoperatively by serum PSA every 4 months. Kaplan-Meier analysis was used to evaluate the correlation between reverse transcriptase polymerase chain reaction and disease recurrence, defined as a PSA of 0.2 ng/ml. or greater. Enhanced reverse transcriptase polymerase chain reaction for PSA had a stronger correlation with potential surgical failure than preoperative serum PSA or Gleason score (relative risks 15.2, 5.9 and 3.2, respectively). The correlation between these modalities and PSA recurrence was evaluated during a mean followup of 13.6 months (range 5 to 26). Of 36 patients with positive reverse transcriptase polymerase chain reactions 9 had failure by PSA compared to 3 of 64 (4.7%) with negative polymerase chain reactions (p<0.0286). The relative risk for failure by reverse transcriptase polymerase chain reaction was 3.6. Gleason score and serum PSA had higher correlations with postoperative PSA elevations (relative risk 13.2 and 7.6, respectively). A Cox regression analysis model demonstrated that reverse transcriptase polymerase chain reaction for PSA can be used in conjunction with Gleason score and provides statistically significant risk information.
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Duchenne muscular dystrophy (DMD) is a devastating muscle disease caused by a mutation in DMD encoding dystrophin. Oxidative stress accounts for dystrophic muscle pathologies in DMD. We examined the effects of molecular hydrogen in mdx mice, a model animal for DMD. The pregnant mother started to take supersaturated hydrogen water (>5 ppm) ad libitum from E15.5 up to weaning of the offspring. The mdx mice took supersaturated hydrogen water from weaning until age 10 or 24 weeks when they were sacrificed. Hydrogen water prevented abnormal body mass gain that is commonly observed in mdx mice. Hydrogen improved the spontaneous running distance that was estimated by a counter-equipped running-wheel, and extended the duration on the rota-rod. Plasma creatine kinase activities were decreased by hydrogen at ages 10 and 24 weeks. Hydrogen also decreased the number of central nuclei of muscle fibers at ages 10 and 24 weeks, and immunostaining for nitrotyrosine in gastrocnemius muscle at age 24 weeks. Additionally, hydrogen tended to increase protein expressions of antioxidant glutathione peroxidase 1, as well as anti-apoptotic Bcl-2, in skeletal muscle at age 10 weeks.
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Does intrathecal amitriptyline act as an N-methyl-D-aspartate receptor antagonist in the presence of inflammatory hyperalgesia in rats?
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Amitriptyline and other tricyclic antidepressants exhibit high affinity binding to N-methyl-D-aspartate (NMDA) receptors in vitro and inhibit NMDA receptor activation-induced neuroplasticity in hippocampal slices. Because spinal NMDA receptor activation is believed to be central to generation and maintenance of hyperalgesic pain, the purpose of this study was to test whether intrathecal amitriptyline reduced inflammation-induced hyperalgesia in the rat. Rats were prepared with chronic lumbar intrathecal and femoral intravenous catheters and nociceptive threshold was assessed by hind paw withdrawal to a radiant heat stimulus. Rats received an injection of carrageenin in one hind paw followed by thermal paw withdrawal testing 3 hr later and intrathecal amitriptyline and/or intravenous morphine injection. In other rats, intrathecal NMDA injection was preceded by either intrathecal saline or 60 micrograms amitriptyline. Intrathecal amitriptyline reversed thermal hyperalgesia in a dose-dependent manner, but had no effect on withdrawal latency of the contralateral, noninjected paw. Intrathecal phentolamine plus methysergide did not alter amitriptyline's effect, except at the lowest dose. Intravenous morphine increased paw withdrawal latency in both inflamed and control paws in a dose-dependent fashion, and morphine interacted additively with intrathecal amitriptyline to reverse hyperalgesia. Thermal hyperalgesia induced by NMDA was completely antagonized by intrathecal amitriptyline.
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Several studies have reported on an association between hepatitis C virus (HCV) antibody status and the development of chronic kidney disease (CKD), but the role of HCV viremia and genotype are not well defined. Patients with at least three serum creatinine measurements after 1 January 2004 and known HCV antibody status were included. Baseline was defined as the first eligible estimated glomerular filtration rate (eGFR) (Cockcroft-Gault equation), and CKD was either a confirmed (>3 months apart) eGFR of 60 ml/min per 1.73 m or less for patients with a baseline eGFR more than 60 ml/min per 1.73 m or a confirmed 25% decline in eGFR for patients with a baseline eGFR of 60 ml/min per 1.73 m or less. Incidence rates of CKD were compared between HCV groups (anti-HCV-negative, anti-HCV-positive with or without viremia) using Poisson regression. Of 8235 patients with known anti-HCV status, 2052 (24.9%) were anti-HCV-positive of whom 983 (47.9%) were HCV-RNA-positive, 193 (9.4%) HCV-RNA-negative and 876 (42.7%) had unknown HCV-RNA. At baseline, the median eGFR was 97.6 (interquartile range 83.8-113.0) ml/min per 1.73 m. During 36123 person-years of follow-up (PYFU), 495 patients progressed to CKD (6.0%) with an incidence rate of 14.5 per 1000 PYFU (95% confidence interval 12.5-14.9). In a multivariate Poisson model, patients who were anti-HCV-positive with HCV viremia had a higher incidence rate of CKD, whereas patients with cleared HCV infection had a similar incidence rate of CKD compared with anti-HCV-negative patients. There was no association between CKD and HCV genotype.
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Does corn silk maysin induce apoptotic cell death in PC-3 prostate cancer cells via mitochondria-dependent pathway?
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Despite recent advances in prostate cancer diagnostics and therapeutics, the overall survival rate still remains low. This study was aimed to assess potential anti-cancer activity of maysin, a major flavonoid of corn silk (CS, Zea mays L.), in androgen-independent human prostate cancer cells (PC-3). Maysin was isolated from CS of Kwangpyeongok, a Korean hybrid corn, via methanol extraction and preparative C18 reverse phase column chromatography. Maysin cytotoxicity was determined by either monitoring cell viability in various cancer cell lines by MTT assay or morphological changes. Apoptotic cell death was assessed by annexin V-FITC/PI double staining, depolarization of mitochondrial membrane potential (MMP), expression levels of Bcl-2 and pro-caspase-3 and by terminal transferase mediated dUTP-fluorescein nick end labeling (TUNEL) staining. Underlying mechanism in maysin-induced apoptosis of PC-3 cells was explored by evaluating its effects on Akt and ERK pathway. Maysin dose-dependently reduced the PC-3 cell viability, with an 87% reduction at 200 μg/ml. Maysin treatment significantly induced apoptotic cell death, DNA fragmentation, depolarization of MMP, and reduction in Bcl-2 and pro-caspase-3 expression levels. Maysin also significantly attenuated phosphorylation of Akt and ERK. A combined treatment with maysin and other known anti-cancer agents, including 5-FU, etoposide, cisplatin, or camptothecin, synergistically enhanced PC-3 cell death.
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Epidemiological data on personality disorders, comorbidity and associated use of services are essential for health service policy. To measure the prevalence and correlates of personality disorder in a representative community sample. The Structured Clinical Interview for DSM-IVAxis II disorders was used to measure personality disorder in 626 persons aged 16-74 years in households in England, Scotland and Wales, in a two-phase survey. The weighted prevalence of personality disorder was 4.4% (95% CI 2.9-6.7). Rates were highest among men, separated and unemployed participants in urban locations. High use of healthcare services was confounded by comorbid mental disorder and substance misuse. Cluster B disorders were associated with early institutional care and criminality.
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Do lifestyle risk factors predict healthcare costs in an aging cohort?
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While the U.S. elderly population uses a disproportionate amount of healthcare resources, there is limited knowledge from prospective studies regarding the impact of lifestyle-related factors on costs in this group. The association was examined between smoking, drinking, exercise, body mass index (BMI), and changes in these risk factors, and healthcare costs after 4 years among 68- to 95-year-olds. A total of 1323 participants completed annual surveys providing information on lifestyle factors (1986-1994) and health utilization (1994-1998). Healthcare costs in nine categories were ascertained from validated utilization. The relationships between risk factors and costs were examined in 2004 using linear regression models. Fewer cigarette pack-years and lower BMI were the most significant predictors of lower total costs in 1998 (p<0.001), controlling for baseline sociodemographic factors, costs, and conditions. Associations with smoking were strongest for hospitalizations, diagnostic tests, and physician and nursing-home visits. Those who reduced smoking by one pack per day experienced cost savings of 1160 dollars (p<0.05). The costs for normal weight compared to minimally obese seniors were approximately 1548 dollars lower, with diagnostic testing, physician visits, and medications accounting for much of this difference. Daily walking, measured at baseline, also predicted lower costs for hospitalizations and diagnostic testing.
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In sheep and cattle, trophoblast-derived interferons serve as signals for the maternal recognition of pregnancy and may regulate the immunologic relationship between the fetus and mother. In this study, soluble extracts prepared from human hydatidiform mole decidua (DE) and trophoblast (HME) were screened for immunosuppressive activity using an interleukin (IL)-2-dependent T-cell line (CTLL2). Antibody neutralization studies were performed with monoclonal antibodies to alpha- and beta-interferon (IFN). HME suppressed (P < 0.05) IL-2-stimulated (2 IU/well) CTLL2 proliferation at doses ranging from 500 (52 +/- 2% of control) to 100 (74 +/- 5%) micrograms/ml concentrations. DE also suppressed (P < or = 0.05) CTLL2 proliferation in a dose-related fashion from 500 (20 +/- 6% of control) to 100 (71 +/- 8%) micrograms/ml doses. Preincubation with the alpha- and beta-IFN antibody preparations had no effect on CTLL2 suppression by the DE sample. In contrast, the beta-IFN antibody partially neutralized the suppressive activity of HME at each of the dilutions tested. The monoclonal antibody to alpha-IFN failed to neutralize HME suppression at any of the doses tested.
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Does oscillatory Characteristics of the Vocal fold Across the Tenor Passaggio?
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Recent research has revealed that classically trained tenors tend to constrict epilaryngeal structures when singing in and above the passaggio (ie, the frequency region where register events typically occur). These constrictions complicate visibility of vocal fold oscillatory patterns with transoral rigid high-speed video endoscopy, thus limiting the current understanding of laryngeal dynamics in the passaggio region of tenors. This investigation analyzed seven professionally trained western classical tenors using high-speed digital imaging (HSDI) at 20,000 frames per second via transnasal flexible endoscopy. The participants produced transitions (a) from modal to falsetto register and (b) from modal to stage voice above the passaggio (SVaP) during ascending pitch glides from A3 (220 Hz) to A4 (440 Hz) on vowel /i/. HSDI data were complemented by simultaneous acoustic and electroglottographic recordings. For many subjects both transition types were associated with constrictions of the epilaryngeal structures during the pitch glide. These constrictions appeared to be more distinct for the SVaP than for falsetto. No major irregularities of vocal fold oscillations in the sense of fundamental frequency jumps were observed for either transition type. However, during the transitions, the open quotient derived from the glottal area waveform (OQ
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There have been many studies that evidence the health hazards of sunlight exposure, but less study on sun safe intervention model, especially in China. Our aim was to evaluate the cognitive and behavioral effects of a peer education model-based intervention to sun safe in children. Cluster random control intervention was conducted in one district in Chongqing, China. Two primary schools, selected through stratified clustered sampling approach (two grades in each school, three classes in each grade) were designated as intervention (n=304) and control schools (n=305) randomly. 36 students, selected as peer educators in intervention group, were trained for one month. Educational activities such as discussions were organized by peer educator for one month. There was no sun safe education to participants in control school during the project period. The evaluation of changes of sun safe knowledge (the primary outcome), attitude and behavior (the secondary outcome measures) were conducted before intervention and at months of 0, 1 and 6 of the intervention to two groups using quantitative and qualitative methods. After the intervention, sun safe knowledge score which gained by the students from intervention group has been remarkably improved, compared to baseline survey (24.48±6.17 vs. 29.51±6.75) (P<0.001), and it kept this high level (29.02±7.96 and. 28.65±8.96), while control group students' scores have made no difference (P=0.410). Most of students have changed their sun safe behavior after the intervention.
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Does generation of IL-8 and TNF-alpha in platelet concentrate during storage?
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Platelet transfusion is accompanied by febrile nonhemolytic transfusion reactions. The generation of cytokines (like IL-1 beta, IL-6, IL-8, and TNF-alpha) in platelet concentrates by white cells is suggested to be responsible for febrile nonhemolytic transfusion reactions. The number of white cells in the platelet concentrates is crucial to cytokine generation. This study was performed to determine whether WBC reduction in platelet concentrates by prestorage leukodepletion filters or inactivation by gamma radiation reduced the levels of these cytokines during storage for 3 days. Each of the platelet concentrates (n = 54) was prepared from a single random donor by platelet-rich plasma. This was then divided into four groups: 1) unfiltered, nonirradiated random-donner platelet concentrates (n = 13); 2) unfiltered, gamma-irradiated random-donner platelet concentrates (n = 16); 3) filtered, nonirradiated random-donner platelet concentrates (n = 14); and 4) filtered, gamma-irradiated random-donner platelet concentrates (n = 11). Cytokine levels in platelet concentrates supernatants were measured by ELISA kits according to the manufacturer's recommendations. Our results showed that IL-8 was detected in unfiltered, nonirradiated, and gamma-irradiated random-donner platelet concentrates but not in the filtered random-donner platelet concentrates. TNF-alpha was only detected in unfiltered, nonirradiated units. Compared with unfiltered platelet concentrates, prestorage filtration prevented a rise in the IL-8 and TNF-alpha on day 3 of storage. The concentration of IL-1 beta was lower than the minimum concentration value of the kit used for this purpose. IL-6 was detected only in 7 units of all filtered platelet concentrates on day 3.
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MiR-506 is a miRNA involved in carcinogenesis of several kinds of cancer. In this study, we explored whether miR-506 played a critical role in hepatocellular carcinoma (HCC). Twenty HCC and adjacent normal liver tissue samples were collected. Human hepatoma cell lines HepG2 and H7402 were used for in vitro studies. The expression of miR-506 and transcriptional co-activator YAP was examined using qRT-PCR. Western blot analysis was used to measure the expression of YAP and its target genes. Luciferase reporter gene assay was used to identify YAP as a target gene of miR-506. MTT and EdU assays were carried out for functional analysis. The expression of miR-506 was significantly lower in HCC than in adjacent normal liver tissues. Bioinformatics analysis revealed that YAP mRNA might be one of the targets of miR-506, and miR-506 in HCC tissues was found to be negatively correlated with YAP (r=-0.605). In both HepG2 and H7402 cells, miR-506 dose-dependently down-regulated YAP and its target genes c-Myc and the connective tissue growth factor (CTGF). Luciferase reporter gene assays demonstrated that miR-506 targeted the wild type 3'UTR of YAP mRNA, but not a 3'UTR with a mutant seed site. Furthermore, miR-506 significantly inhibited the proliferation of HepG2 and H7402 cells, while anti-miR-506 enhanced the cell proliferation, which was blocked by YAP siRNA.
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Does down-regulation of microRNA-155 attenuate retinal neovascularization via the PI3K/Akt pathway?
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We aimed to investigate the anti-angiogenic properties of miR-155 via in vitro and in vivo studies. miR-155 was knocked down using lentivirus-mediated RNA interference. The proliferation, migration, and tube formation of human retinal microvascular endothelial cells (HRMECs) were measured using BrdU, Transwell, and Matrigel assays, respectively. An oxygen-induced retinopathy (OIR) model was induced using neonatal C57BL/6J pups. Anti-miR-155 was intravitreally injected on postnatal day 12, and the retinal non-perfused areas and extent of neovascularization were measured on postnatal day 18 using transcardiovascular fluorescein isothiocyanate (FITC)-dextran perfusion and retina sections. A laser-induced choroidal neovascularization (CNV) model was induced in adult C57BL/6J mice. To evaluate the leakage areas, fundus fluorescein angiography was performed on day 14 after anti-miR-155 intravitreal injection. The neovascularization area of the CNV model was also examined in confocal and retina section studies. The expression levels of SHIP1 and p-Akt (Thr308, Ser473, and Thr450) were evaluated both in vitro and in vivo. The expression of miR-155 was elevated in HRMECs after treatment with vascular endothelial growth factor (VEGF) and in neovascularized mouse model retinas. Anti-miR-155 lentivirus reduced the VEGF-induced proliferation, migration, and tube formation abilities of HRMECs. Anti-miR-155 attenuated retinal neovascularization in in vivo CNV and OIR models. In VEGF-treated HRMECs and retina neovascularization models, p-Akt (Ser473) was significantly upregulated, while SHIP1 was downregulated. Conversely, the inhibition of miR-155 restored the expression of SHIP1 and reduced the phosphorylation of effectors in the Akt (Ser473) signaling pathway.
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To test the aerobic plate count examining capability of microbiology laboratories, to ensure the accuracy and comparability of quantitative bacteria examination results, and to improve the quality of monitoring. The 4 different concentration aerobic plate count piece samples were prepared and noted as I, II, III and IV. After homogeneity and stability tests, the samples were delivered to monitoring institutions. The results of I, II, III samples were logarithmic transformed, and evaluated with Z-score method using the robust average and standard deviation. The results of IV samples were evaluated as "satisfactory" when reported as < 10 CFU/piece or as "not satisfactory" otherwise. Pearson χ2 test was used to analyze the ratio results. 309 monitoring institutions, which was 99.04% of the total number, reported their results. 271 institutions reported a satisfactory result, and the satisfactory rate was 87.70%. There was no statistical difference in satisfactory rates of I, II and III samples which were 81.52%, 88.30% and 91.40% respectively. The satisfactory rate of IV samples was 93.33%. There was no statistical difference in satisfactory rates between provincial and municipal CDC.
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Is laparoscopy Safe and Accurate to Evaluate Peritoneal Surface Metastasis Prior to Cytoreductive Surgery?
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Completeness of cytoreduction is a significant predictor of long-term outcome after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Imaging has limited sensitivity to identify peritoneal metastases and therefore predict whether complete cytoreduction is possible. We reviewed our experience using laparoscopy to determine candidates for complete cytoreduction and HIPEC. This single-center, retrospective study examined patients from 2007 to 2014 who underwent laparoscopy to determine complete cytoreduction (CC-0/1)/HIPEC candidacy. Preoperative, intraoperative, and postoperative data were collected. A total of 145 laparoscopies were performed on 141 patients, 72 (51.1 %) of whom were female, with a median age of 53 years (range 20-79). The primary site was appendiceal in 67 (47.5 %) patients, colorectal in 43 (30.5 %), mesothelioma in 17 (12.1 %), unknown in 9 (6.4 %), small bowel in 3 (2.1 %), gastric in 1, and ovarian in 1 (0.7 % each). Overall, 115 (81.6 %) patients had prior abdominal surgery, 111 (76.6 %) had evidence of disease on imaging, and 117 (80.7 %) underwent prior chemotherapy, with a median of 5.9 weeks between the last treatment and laparoscopy (0.9-498.9 weeks). Four (2.8 %) intraoperative complications were observed (one liver laceration, two enterotomies, and one air embolus), and nine (6.2 %) postoperative complications [four (2.8 %) Clavien grade (CG) I, three (2.8 %) CG II, one (0.7 %) CG III (return to operating room) and one (0.7 %) CG IV (transient ischemic attack)]. Forty-eight patients deemed candidates by laparoscopy underwent CRS/HIPEC (positive predictive value 82.8 %).
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Rhesus macaques serve a critical role in the study of human biomedical research. While both Indian and Chinese rhesus macaques are commonly used, genetic differences between these two subspecies affect aspects of their behavior and physiology, including response to simian immunodeficiency virus (SIV) infection. Single nucleotide polymorphisms (SNPs) can play an important role in both establishing ancestry and in identifying genes involved in complex diseases. We sequenced the 3' end of rhesus macaque genes in an effort to identify gene-based SNPs that could distinguish between Indian and Chinese rhesus macaques and aid in association analysis. We surveyed the 3' end of 94 genes in 20 rhesus macaque animals. The study included 10 animals each of Indian and Chinese ancestry. We identified a total of 661 SNPs, 457 of which appeared exclusively in one or the other population. Seventy-nine additional animals were genotyped at 44 of the population-exclusive SNPs. Of those, 38 SNPs were confirmed as being population-specific.
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Does preoperative posterior leaflet angle accurately predict outcome after restrictive mitral valve annuloplasty for ischemic mitral regurgitation?
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Ischemic mitral regurgitation (MR) often persists after restrictive mitral valve annuloplasty, in which case it is associated with worse clinical outcomes. The goal of the present study was to determine whether persistence of MR and/or clinical outcome could be predicted from preoperative analysis of mitral valve configuration. In 51 consecutive patients undergoing restrictive annuloplasty for ischemic MR, posterior leaflet (PL) angle, anterior leaflet angle, coaptation distance, and tenting area were quantified by echocardiography before surgery (6+/-3 days), and MR severity was assessed before and early after surgery (9+/-4 days). Postoperatively, persistence of mild to moderate MR (vena contracta > 3 mm) was observed in 11 (22%) of the patients. The best predictor of postoperative persistence of MR was a PL angle > or = 45 degrees (sensitivity 100%, specificity 97%, positive predictive value 92%, negative predictive value 100%). Patients with persistent MR had markedly lower 3-year event-free survival (26+/-20%) compared with those with nonpersistent MR (75+/-12%, P=0.01). Preoperative presence of a PL angle > or = 45 degrees also was associated with a markedly lower 3-year event-free survival (22+/-17% versus 76+/-12%; P<0.001).
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Human osteoclast formation from mononuclear phagocyte precursors involves interactions between tumor necrosis factor (TNF) ligand superfamily members and their receptors. LIGHT is a transmembrane protein expressed and shed from the surface of activated T cells. Since activated T cells have been implicated in osteoclastogenesis in rheumatoid arthritis (RA), this study sought to determine whether LIGHT can regulate RANKL/cytokine-induced osteoclast formation, to identify the mechanism by which LIGHT influences osteoclastogenesis, and to investigate the presence of LIGHT in the serum of RA patients. The effect of LIGHT on human and murine osteoclast formation was assessed in the presence and absence of neutralizing reagents to known osteoclastogenic factors. Serum levels of LIGHT in RA patients were measured by enzyme-linked immunosorbent assay. In the presence and absence of RANKL, LIGHT induced osteoclast formation from both human peripheral blood mononuclear cells and murine macrophage precursors, in a dose-dependent manner, whereas no inhibition was observed by adding osteoprotegerin, RANK:Fc, TNFalpha, or interleukin-8 or by blocking the LIGHT receptors herpesvirus entry mediator or lymphotoxin beta receptor. However, formation of osteoclasts was significantly decreased by the soluble decoy receptor for LIGHT, DcR3, and by blocking antibodies to the p75 component of the TNF receptor. A significant increase in LIGHT levels in the serum of RA patients compared with normal controls was also noted.
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Does endothelial alpha-1-antitrypsin attenuate cigarette smoke induced apoptosis in vitro?
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Deficiency of the antiprotease alpha-1-antitrypsin (AAT) and exposure to cigarette smoke (CS) contribute to the development of early onset emphysema. CS-induced apoptosis of alveolar cells including endothelial cells plays critical role in the lung destruction. AAT deficiency is associated with increased lung tissue destruction as well. We hypothesize that AAT protects lung alveoli from noxious environmental stimuli such as CS-induced apoptosis. Porcine pulmonary artery endothelial cells (PAEC) were exposed to CS in the presence or absence of AAT (20 microM). AAT internalization and markers for apoptosis were assessed by confocal microscopy. Flow cytometry was performed in parallel to quantify the number of AAT-loaded and apoptotic cells. We demonstrated that exogenous AAT accumulated in PAEC and protected cells from CS-induced apoptosis. AAT-loaded CS-exposed cells exhibited increased amounts of chaperone HSP-70 in their cytosol and less apoptosis inducing factor in their nuclei compared to AAT-untreated, CS-exposed cells.
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The purpose was to investigate whether patient-specific factors (PSF) and surgically modifiable factors (SMF), measured by means of a computer-assisted navigation system, can predict the Knee Society Scores (KSS) after total knee arthroplasty (TKA). Data from 99 patients collected during a randomized clinical trial were used for this secondary data analysis. The KSS scores of the patients were measured preoperatively and at 4-years follow-up. Multiple regression analyses were performed to investigate which combination of variables would be the best to predict the 4-years KSS scores. When considering SMF alone the combination of four of them significantly predicted the 4-years KSS-F score (p = 0.009), explaining 18 % of its variation. When considering only PSF the combination of age and body weight significantly predicted the 4-years KSS-F (p = 0.008), explaining 11 % of its variation. When considering both groups of predictors simultaneously the combination of three PSF and two SMF significantly predicted the 4-years KSS-F (p = 0.007), explaining 20 % of its variation.
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Does optimal number of needle pass in endoscopic ultrasound-guided fine needle aspiration for pancreatic lesions?
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Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) is accurate in cytological diagnosis of pancreatic lesions. Our aim was to determine optimal number of needle passes in EUS-FNA for pancreatic lesions without onsite cytopathologist, who is not routinely available to participate in the procedure. Results of all needle passes in EUS-FNAs for 117 pancreatic neoplasms in 115 patients were reviewed retrospectively. Factors that required 2 or more needle passes for correct diagnosis were identified by multivariate logistic regression analysis. In each lesion group defined by the factors that required 2 or more passes and were known at the time of EUS-FNA, number of needle passes was regarded as optimal when an increase in diagnostic sensitivity by an additional needle pass did not reach 10%. Size of 15 mm or less (OR 4.58, 95% CI 1.70-12.3, P < 0.01), location of head (OR 5.02, 95% CI 1.82-13.9, P < 0.01), and neuroendocrine tumor (NET) (OR 5.04, 95% CI 1.38-18.4, P = 0.01) independently required 2 or more needle passes. Optimal numbers of needle passes for lesions of 15 mm or less in the head, those of more than 15 mm in the head, those of 15 mm or less in the body or tail, and those of more than 15 mm in the body or tail were 3, 2, 2, and 1, respectively. When these numbers of needle passes were performed, 93% of pancreatic lesions were correctly diagnosed.
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Traumatic brain injury (TBI) is a complex process that increasing evidence has demonstrated that reactive oxygen species contribute to brain injury. Revesterol (RVT), which exhibits significant antioxidant properties, is neuroprotective against excitotoxicity, ischemia, and hypoxia. Our aim was to evaluate the neuroprotective effects of RVT on the hippocampus in a rat model of TBI. Seven rats were divided into four. A moderate degree of head trauma was induced using Feeney's falling weight technique. Group1 (control) underwent no intervention. Head trauma was induced in the Group 2 (trauma) and, no drug was administered. Head trauma was induced in the Group 3 rats and low-dose RVT (50 mg/kg per day) was injected and in the fourth group, high-dose RVT (100 mg/kg per day) was used. Brain tissues were extracted immediately after perfusion without damaging the tissues. Histopathological and biochemistry parameters were studied. Brain tissue malondialdehyde (MDA) levels in the trauma group were significantly higher than those in the control, low-dose RVT-treated, and high-dose-RVT-treated groups. The superoxide dismutase (SOD) levels in the control group were significantly higher than those in the trauma, low-dose RVT-treated, and high-dose RVT-treated groups. Glutathione peroxidase (GSH-Px) levels in the control group were significantly higher than those in the trauma and low-dose RVT-treated groups. The level of oxidative DNA damage (8-OHdG/106 dG) in the trauma group was higher than that in the control group, low-dose RVT-treated, and high-dose RVT-treated groups.
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Does intestinal transformation result in transforming growth factor-beta-dependent alteration in tumor cell-cell matrix interactions?
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An alteration in the expression of and response to transforming growth factor-beta 1 (TGF-beta 1) appears to be an important event during colorectal carcinogenesis. However, the precise role of TGF-beta 1 in colorectal carcinogenesis is not clear. We have previously described in detail the changes in cell proliferation and differentiation caused by chronic exposure to TGF-beta 1. In this study we sought to better characterize the changes in tumor cell-cell matrix interactions seen during TGF-beta 1-mediated intestinal transformation. Rat intestinal epithelial cells (RIE) and RIE cells transformed by chronic exposure to TGF-beta 1 (RIE-Tr) were treated with TGF-beta 1 and production of components of the plasmin/plasminogen system measured by ELISA and Western blotting. TGF-beta 1 effects on invasion and adhesion were determined in vitro. The role of urokinase on TGF-beta 1-mediated invasion and adhesion were determined using immunoneutralization. The role of COX-2 was determined using a specific COS-2 inhibitor. TGF-beta 1 had no effect on RIE-1 adhesion to collagen types I and IV, fibronectin, and laminin, or invasion through collagen types I and IV. However, 5 ng/mL TGF-beta 1 significantly increased the invasiveness and decreased the adhesiveness of RIE-Tr. This effect of TGF-beta 1 on RIE-Tr was associated with a significant increase in plasmin activity secondary to increased expression of uPA. TGF-beta 1 had no effect on either uPA receptor or PAI-1 in this system. Antibodies to uPA completely blocked the TGF-beta 1-mediated invasiveness of the RIE-Tr cells and returned their adhesiveness to basement membrane proteins to baseline. Addition of the selective Cox-2 inhibitor SC-58125 resulted in a dose-dependent decrease in TGF-beta 1-mediated invasion and uPA expression.
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The appropriate duration of cardiopulmonary resuscitation (CPR) for patients who experience out-of-hospital cardiac arrest (OHCA) remains unknown. This study aimed to evaluate the duration of CPR in emergency departments (EDs) and to determine whether the institutions' median duration of CPR was associated with survival-to-discharge rate. A cohort of adult patients from a nationwide OHCA registry was retrospectively evaluated. The main variable was the median duration of CPR for each ED (institutional duration), and the main outcome was survival to discharge. Multivariable logistic regression analysis was performed to adjust for individual and aggregated confounders. Among the 107,736 patients who experienced OHCA between 2006 and 2010, 30,716 (28.5%) were selected for analysis. The median age was 65 years, and 67.1% were men. The median duration of CPR for all EDs was 28 min, ranging from 11 to 45 min. EDs were categorized into 3 groups according to their institutional duration of CPR: groups A (< 20 min), B (20-29 min), C (≥ 30 min). The observed survival rates of the 3 groups were 2.11%, 5.20%, and 5.62%, respectively. Compared with group B, the adjusted difference (95% confidence interval) for survival to discharge was 3.01% (1.90-4.11, P<0.001) for group A, and 0.33% (-0.64 to 1.30, P=0.51) for group C.
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Is phosphorylation of Akt involved in protocatechuic acid-induced neurotrophic activity?
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To investigate the mechanisms underlying protocatechuic acid (PCA)-induced neurotrophic effects on cultured cortical neurons. The mRNA expression of microtubule-associated protein 2 (MAP2) and brain-derived neurotrophic factor (BDNF) were measured by real-time quantitative PCR (qPCR). Subsequently, antagonists were used to study the signaling pathways activated by PCA and western blotting was used to detect the phosphorylation level of kinase-related protein. The mRNA expression of MAP2 and BDNF were upregulated in neurons treated with PCA compared with vehicle control. PCA-induced neurite outgrowth and neuronal survival in cultured cortical neurons were significantly inhibited by ZM241385 (an A(2A) receptor antagonist) and LY294002 (a PI3K inhibitor), but not by K252a (a TrkA receptor antagonist), GÖ6976 (a protein kinase C inhibitor) and PD98059 (a MEK inhibitor). PCA enhanced the phosphorylation of Akt, which could be blocked by LY294002.
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Sophorae radix (SR) has been used for various diseases including atherosclerosis and arrhythmias. Atherosclerosis induced by hyperglycemia is an important factor in the promotion of diabetic complications. An early event in atherosclerosis is the adhesion of monocytes to endothelium via adhesion molecules. Among them, vascular cell adhesion molecule-1 (VCAM-1) expression mediates the binding of monocytes and lymphocytes to vascular endothelial cells. The study was performed on vascular endothelial cells (ECV304 cells) that were pretreated with various concentrations of SR extract for 3 h before exposure with high glucose (55.5 mmol/l) for 48 h. The protein expression of VCAM-1 was measured by enzyme-linked immunosorbent assay (ELISA) and its mRNA expression was by reverse transcription polymerase chain reaction (RT-PCR). SR extract significantly inhibited high glucose-induced expression of VCAM-1 in a dose-dependent manner and reduced the level of VCAM-1 mRNA through interfering with translocation of nuclear factor-kappaB (NF-kappaB). Decreased VCAM-1 expression by SR extract was associated reduction of adherence between high glucose-stimulated ECV304 cells and human monocyte-like HL-60 cells.
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Is leg extension power a pre-disaster modifiable risk factor for post-traumatic stress disorder among survivors of the Great East Japan Earthquake : a retrospective cohort study?
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Post-traumatic stress disorder (PTSD) is a common psychological problem following natural disasters. Although pre-disaster risk factors are important for early detection and proactive support, the examination of such has been limited to sociodemographic factors, which were largely unaffected by the disasters. We examined the association between pre-disaster physical functioning and lifestyle and PTSD symptoms five months after the earthquake in the Great East Japan Earthquake survivors who were participating in a pre-existing cohort study. We designed a retrospective cohort study of a cooperative association in Sendai from August 2010 to August 2011. In 2010, lifestyle, physical condition, and sociodemographic factors were examined by self-reported questionnaires completed by 522 employees of this organization. We also measured the leg extension power of all the participants. PTSD symptoms were evaluated by the Japanese version of the Impact of Event Scale-Revised (IES-R-J) following the earthquake of 2011. In multivariate linear regression analysis, leg extension power (β = -0.128, P = 0.025), daily drinking (β = 0.203, P = 0.006), and depressive symptoms (β = 0.139, P = 0.008) were associated with total score of the IES-R-J among men. Moreover, for the IES-R-J subscale, leg extension power was also negatively associated with Intrusion (β = -0.114, P = 0.045) and Hyperarousal (β = -0.163, P = 0.004) after adjusting for all other significant variables. For women, hypertension (β = 0.226, P = 0.032) and depressive symptoms (β = 0.205, P = 0.046) were associated with the total score of the IES-R-J.
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This study is to characterize the antifungal effects of pyridoxatin (PYR), a small natural product isolated from an endolichenic fungus. The susceptibility tests in vitro and in vivo by using Caenorhabditis elegans as an infectious model were performed to evaluate the antifungal efficacy of PYR against Candida species. The cytotoxicity of PYR against normal human cells was tested using MTT assay. The transcriptional levels of genes related to sterol synthesis and cell cycle regulation were measured using real-time quantitative PCR (qPCR). The contents ergosterol, squalene, lanosterol were detected by liquid chromatography/tandem mass spectrometry (LC/MS). PYR was effective against four tested Candida species with its minimal inhibitory concentrations (MICs) ranging from 1-4μg/ml. No obvious cytotoxicity was observed for PYR against normal human cells. PYR inhibited the growth of Candida albicans, preventing the biofilm formation. And the antifungal action was independent on efflux pumps. The in vivo test showed PYR greatly prolonged the survival of infected C. elegans. qPCR results revealed that most of the genes related to sterol biosynthesis were considerably down-regulated in PYR-treated cells. Determination of the sterol content found that PYR inhibited the ergosterol synthesis dose dependently and caused the accumulation of squalene and lanosterol. Moreover, analysis of the structure-activity relationship revealed the heterocyclic hydroxamic acid in PYR was the key group for the antifungal action.
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Do dietary gangliosides enhance in vitro lipid uptake in weanling rats?
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The intestine adapts morphologically or functionally in response to environmental stimuli. Dietary lipids modify brush border membrane (BBM) permeability and nutrient transporter activities. Gangliosides (GANG) are glycolipids in human milk that are present only in low amounts in infant formula. Exogenous GANG are incorporated into cell membranes and increase their permeability. The objective of this study was to determine whether feeding a GANG-enriched diet alters in vitro intestinal lipid absorption. Weanling rats were fed either (1) GANG-enriched diet; (2) diet enriched with polyunsaturated long-chain fatty acids; or (3) isocaloric control diet for 2 weeks, after which in vitro intestinal lipid uptake was measured. Feeding GANG did not alter weight gain or intestinal morphology. Enhanced uptake of stearic acid (18:0) in the ileum and stearic and linoleic acid (18:2) in the jejunum was not associated with a change in the abundance of the ileal lipid binding protein (ILBP), the intestinal fatty acid binding protein (I-FABP), or the liver fatty acid binding protein (L-FABP).
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Acute kidney injury (AKI) is an established indicator of all-cause mortality in a coronary care unit (CCU), and evaluating the risks of renal dysfunction can guide treatment decisions. In this study we used the Society of Thoracic Surgeons (STS) score to predict the incidence of AKI in CCU patients who had not undergone coronary artery bypass surgery (CABG) after a cardiac angiogram. The study cohort comprised 126 patients diagnosed with 2 or 3 coronary vessels disease who did not receive CABG during their hospital course. This study was performed in the CCU of a tertiary referral university hospital between September 2012 and August 2013. The STS score was evaluated with adjustment in all patients and the outcomes of the risk of mortality, morbidity, or mortality and renal failure were selected for predicting assessment. Furthermore, the performance of the STS scores was compared with that of other scoring systems. A total of 28.5% (36 of 126) of the patients had AKI of varying severity. For predicting AKI, the STS renal failure score was excellent, with areas under the receiver operating characteristic curve of 0.851 ± 0.039, p < 0.001. When compared with other scoring systems, the STS renal failure score demonstrated the highest discriminatory power, the most favorable Youden index, and the highest overall correctness of prediction.
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Does ezetimibe inhibit lymphatic transport of esterified cholesterol but not free cholesterol in thoracic lymph duct-cannulated rats?
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Ezetimibe has been shown to inhibit dietary cholesterol absorption in animal models and humans, but studies on lymphatic lipid transport have not yet been performed. Rats subjected to permanent lymph duct cannulation were used to investigate the effects of ezetimibe on lipid transport. Rats were fed diets with and without ezetimibe (5.0 mg/kg), and their lymph was collected after feeding to quantify lymphatic lipid levels. Total cholesterol content in the intestinal mucosa was also measured. Rats that consumed ezetimibe had significantly lower lymphatic total cholesterol transport with the reduction of esterified cholesterol transport. According to the calculation based on cholesterol consumption, ezetimibe reduced the total cholesterol lymphatic recovery rate by 54 %. We also determined that ezetimibe significantly reduced the total cholesterol content in the intestinal mucosa.
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Early detection of pathophysiological factors associated with permanent and severe brain damage in preterm infants requiring intensive care is a major issue in neonatal neurology. The aim of this study was to investigate if an abnormal CO2 reactivity of cerebral blood flow in high risk very low birth weight infants is associated with severe brain injury demonstrated at autopsy or by neurodevelopment examination at 18 months. The CO2 reactivity of cerebral blood flow (xenon-133) was measured in 18 mechanically ventilated, severely ill, very low birthweight infants (gestational age 26-32 weeks, birthweight: 630-1360 g) during the first 36 hours of life. Cerebral outcome was assessed on autopsy findings (n = 8) or at the age of 18 months using Bayley developmental scales (n = 10). Eight infants with normal development at 18 months (within mean +/- 2.5 SD of reference group) and two infants with normal cerebral autopsy findings had a median CO2 reactivity of 24.4%/kPa CO2 (interquartile range 14.7-41.2). Two infants with abnormal development (> 2.5 SD below mean) and six infants with hypoxic-ischaemic encephalopathy at autopsy has a median CO2 reactivity of 3.4%/kPa CO2 (interquartile range 8.0-11.7).
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Do total serum homocysteine levels identify cognitive dysfunction in multimorbid elderly patients?
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Total blood homocysteine (Hcys) and folate levels have been investigated in association with cognitive dysfunction in healthy but not in multimorbid elderly patients. We hypothesized that total serum Hcys is an adequate marker to identify multimorbid elderly patients with cognitive dysfunction assessed by the Short Cognitive Performance Test (SKT) and Mini-Mental State Examination (MMSE). Cross-sectional study. The study center was an acute geriatric hospital. A total of 189 multimorbid elderly patients were recruited. Cognitive dysfunction was determined according to the SKT and MMSE. Biochemical parameters (Hcys, folate, vitamin B12, hemoglobin), nutritional status (BMI, Mini Nutritional Assessment, nutritional intake), and activities of daily living were assessed. According to the SKT, 25.4% of patients showed no cerebral cognitive dysfunction, 21.2% had suspected incipient cognitive dysfunction, 12.7% showed mild cognitive dysfunction, 9.0% had moderate cognitive dysfunction, and 31.7% of patients were demented. The median plasma Hcys value was elevated by approximately 20% in multimorbid elderly patients, independent of cognitive dysfunction. Serum folate and vitamin B12 concentrations were within normal ranges. We did not find significant differences in nutritional status, activities of daily living, numbers of diseases or medications, or selected biochemical parameters between the SKT groups.
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Electroporation has been shown to increase the efficacy of intramuscular injection of plasmid DNA, resulting in a higher level of foreign gene expression. Using this technique, we examined the effect of viral IL-10 gene transfer on the prevention of tracheal allograft stenosis in an animal model. On the day of tracheal transplantation, recipient Lewis rats were intramuscularly injected with either plasmid pCAGGS-LacZ or plasmid pCAGGS-viral IL-10, followed immediately by electroporation. Tracheas from Brown Norway donors were transplanted into the backs of Lewis recipients, and the histology of the grafts were assessed 2 and 4 weeks after transplantation. The serum level of IL-10 peaked at 2000 pg/ml one day after injection; the level then slowly decreased, but was maintained above 1000 pg/ml until 8 days after injection. At Day 28, the airway lumina of the tracheal allografts were almost completely obliterated by fibroproliferative tissue in the control pCAGGS-LacZ-treated rats. In rats injected once with pCAGGS-viral IL-10, luminal obliteration was significantly decreased compared with the control pCAGGS-LacZ-treated rats (mean luminal opening 46.8% vs 0% p<0.05). The loss of epithelial cells lining the airway was also decreased in the IL-10-treated group (mean epithelial coverage 42% vs 5% p<0.05). Multiple injections with pCAGGS-viral IL-10 did not further improve the histological changes.
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Does n-pentyl-nitrofurantoin induce apoptosis in HL-60 leukemia cell line by upregulating BAX and downregulating BCL-xL gene expression?
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Nitrofurantoin is a nitroderivative antibiotic that has bactericidal activity against pathogens causing urinary tract infection. A few studies have reported that nitrofurantoin has cytotoxic activity against cancer cells; however, nitrofurans remain a poorly explored class of compounds with respect to their anticancer potential. The aim of this study was to investigate the anticancer effects of a nitrofurantoin derivative, n-pentyl-nitrofurantoin (NFP), on HL-60 leukemia cells. Cytotoxicity was assayed by the MTT assay. Cell morphology and phosphatidylserine externalization were visualized after Giemsa-May-Grunwald and annexin V staining, respectively. DNA content and mitochondrial depolarization were measured by flow cytometry. BAX and BCL-xL expression was examined by RT-PCR. NFP was 3.8-fold more cytotoxic against HL-60 leukemia cells than against normal cells. NFP reduced the number of viable cells 24h after the treatment with a concomitant increase in the number of apoptotic cells indicated by the externalization of phosphatidylserine, DNA fragmentation, and mitochondrial depolarization. The mRNA levels of BAX increased, whereas the mRNA levels of BCL-xL decreased.
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Diagnostic criteria for binge eating disorder (BED) appear in Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition as "criteria for further study." Few epidemiological studies of BED have been conducted. Our aim was to describe the prevalence and correlates of BED, as assessed by the Patient Health Questionnaire (PHQ) in a community sample. Descriptive epidemiology from a survey of 910 randomly ascertained participants residing in the greater metropolitan area of St Louis, Mo. Sixty individuals (6.6%) screened positive for current BED, as assessed by the PHQ (BED+). Men were as likely to screen positive as women. BED+ subjects were at substantially elevated odds for depression, generalized anxiety disorder, panic attacks, and past suicide attempts; individuals with obesity who screened negative for BED (BED-) were not at elevated odds for these syndromes. BED+ subjects, but not other obese individuals, exhibited substantially lower scores on measures of mental health-related quality of life. Personality traits associated with BED symptoms included high Novelty Seeking, high Harm Avoidance, and low Self-directedness. Personality and psychiatric profiles in obese, BED- individuals were closer to those for normal-weight, BED- individuals, suggesting that BED is distinct from typical obesity. BED+ subjects reported mean body mass index of 34.1, more than 6 units above BED- subjects.
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Is ileum resection the most predictive factor for osteoporosis in patients with Crohn 's disease?
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Crohn's disease is associated with a host of factors potentially increasing the risk for osteoporosis and fractures. The aim of our study was to identify the most predictive factors for skeletal pathology in this patients. Using a cross-sectional study design, 146 randomly selected patients with Crohn's disease of variable disease activity who were given standard therapy to control disease activity, including glucocorticoids, and who attended the outpatient clinic of the Gastroenterology Unit on regular follow-up visits were studied. Bone mineral density (BMD) measurements and lateral X-rays of the spine were performed, and biochemical parameters of bone turnover, gonadal hormones and C-reactive protein (CRP) as markers of disease activity were measured in all patients. There were 61 men and 85 women, with a mean age of 43 years and mean disease duration of 20 years. The majority of patients (86%) had been treated with glucocorticoids at some stage during their illness at a median dose of 7.5 mg/day, 43% were currently using these agents and 66% had undergone an intestinal resection. Twenty-one percent of patients had below-normal 25-hydroxy vitamin D levels. Osteoporosis was documented in 26% of patients, predominantly at the femoral neck, but also at the lumbar spine or at both sites; osteopenia was documented in 45% of patients. Prevalence of vertebral and non-vertebral fractures was, respectively, 6% and 12%. Ileum resection was the most predictive factor for osteoporosis: RR 3.84 (CI 1.24-9.77, p=0.018), followed by age: RR 1.05 (CI 1.02-1.08, p<0.001) and current or past glucocorticoid use: RR 1.94 (CI 0.92-4.10, p=0.08).
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Hypothermia has been shown to be neuroprotective in the therapy of ischemic stroke in the brain. To date no studies exist on the level of the inner retina and it is unclear if hypothermia would prolong the ischemic tolerance time of retinal ganglion cells, which are decisive in many ischemic retinopathies. Bovine eyes were enucleated and stored either at 21°C or 37°C for 100 or 340 minutes, respectively. Afterwards the globes were dissected, the retina was prepared and either the spontaneous ganglion cell responses were measured or the retina was incubated as an organotypic culture for additional 24 hours. After incubation the retina was either processed for histology (H&E and DAPI staining) or real-time PCR (Thy-1 expression) was performed. Hypothermia prolonged ganglion cell survival up to 340 minutes under ischemic conditions. In contrast to eyes kept at 37°C the eyes stored at 21°C still showed spontaneous ganglion cell spiking (56.8% versus 0%), a 5.8 fold higher Thy-1 mRNA expression (not significant, but a trend) and a preserved retinal structure after 340 minutes of ischemia.
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Is eGFR expression associated with poor outcome in cutaneous squamous cell carcinoma?
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Cutaneous squamous cell carcinoma (CSCC) is the second most frequent cancer in humans, after basal cell carcinoma, and its incidence is dramatically rising. CSCC is rarely problematic, but given its high frequency, the absolute number of complicated cases is also high. It is necessary to identify molecular markers to recognize those CSCC with poor prognosis. There is controversy concerning the role of EGFR (epidermal growth factor receptor) as a marker of prognosis in CSCC. In addition, EGFR-targeted therapies have emerged in recent years and a better understanding of the role of EGFR in CSCC may help some patients in predicting prognosis and guide curative management. We evaluated clinical and histopathological features, including events of bad clinical evolution, in a series of 94 CSCC. We also analysed EGFR expression by immunohistochemistry, FISH and QPCR. We detected EGFR in 85 (90.4%) cases, with overexpression in 33 (35.1%) cases, and aberrant EGFR expression in the cytoplasm in 50 (53.1%) cases. EGFR overexpression in the primary tumours was associated with lymph node progression, TNM stage progression and proliferation (Ki-67 staining) in CSCC. EGFR overexpression and poor grade of differentiation were the strongest independent variables defining lymph node metastasis and progression in CSCC in a logistic regression model.
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The risk of transfusion-transmitted bacterial infections as a result of the presence of bacteria in blood is one of the major concerns in transfusion medicine. The purpose of this study was to investigate whether bacteria inoculated into red blood cell concentrates can be inactivated by the INACTINE PEN110 pathogen-reduction process. Four bacterial species were chosen for the study: anaerobic Gram-positive Clostridium perfringens and Propionibacterium acnes, known to be transfusion-transmitted; and two Gram-negative species, Acinetobacter johnsonii and Acinetobacter lwoffii, recently reported to be a common cause of transfusion-associated infections in Europe. Identical units of leucoreduced red cell concentrates were inoculated with A. johnsonii, A. lwoffii, C. perfringens, or P. acnes. The 4 degrees C control units were put on storage immediately after receiving the spike. The test units were subjected to PEN110 treatment and then stored. The bacterial titre in all units was monitored during a 6-week storage period. The PEN110 inactivation of all tested bacterial strains was time- and titre-dependent. For A. johnsonii and A. lwoffii, no viable bacteria were detected in the units spiked with up to 10(4) colony-forming units (CFU)/ml and treated with PEN110. For red cell units spiked with 10(4)-10(5) CFU/ml of C. perfringens and P. acnes, no viable bacteria were detected in the units treated with PEN110. In control units, there was a gradual decrease in A. johnsonii, A. lwoffii and C. perfringens titres during cold storage, while P. acnes titres remained stable.
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Does deletion of the Serotonin Receptor Type 3A in Mice lead to Sudden Cardiac Death During Pregnancy?
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The serotonin receptor type 3 (Htr3) blocker is associated with QT prolongation and torsades de pointes. However, little is known about effects of Htr3 on the heart arrhythmia. An electrophysiological study Involving knock-out (KO) female mice lacking functional Htr3a (Htr3a(-/-)) and their wild-type littermates during non-pregancy (NP) and late pregnancy (LP) was performed. Htr3a mRNA was present in the wild-type, but not in the Htr3a(-/-)mouse hearts. Serotonin and tryptophan hydroxylase 1 (Tph1), a rate-limiting enzyme of serotonin synthesis in hearts, is increased during pregnancy. The heart weight and size were increased in the pregnant mice regardless of a mutation. The QTc intervals were prolonged after pregnancy in both the wild (NP: 171.2±16.8 vs. LP: 247.7±14.3 ms; P<0.001) and Htr3a(-/-)mice (NP: 187.9±18.7 vs. LP: 275.6±11.0 ms, P<0.001). Compared with wild-type LP mice, Htr3a(-/-)LP mice had increased spontaneous ventricle tarchycardia (VT; 56% vs. 0%, P=0.002), VT inducibility (66% vs. 25%, P=0.002) and mortality (56% vs. 0%, P=0.002). Pharmacologic administration of serotonin and Htr3 agonists (m-CPBG) decreased the QT interval in wild mice, but not in Htr3a(-/-)mice.
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Chronic inflammation in periodontal disease is associated with increased plasminogen activation and elevated levels of chemokines. It is unknown whether chemokines can regulate the activation of plasminogen via modulation of plasminogen activators (PA) and the corresponding plasminogen activator inhibitors (PAI) in periodontal tissue. To establish a link between chemokines and activation of plasminogen, human periodontal ligament fibroblasts (PDL) and gingival fibroblasts (GF) were incubated with IL-8, monocyte chemoattractant protein-1, macrophage inflammatory protein-1alpha, and platelet factor-4, either alone or in the presence of the inflammatory mediators TGF-beta and IL-1. The potential of the cell lysates to activate plasminogen was based on kinetic studies with the substrate casein. Casein zymography was performed to determine the molecular sizes of the PA. Total PAI-1 in the cell-conditioned medium was quantified by immunoassay. We report that the chemokines did not affect activation of plasminogen by PDL and GF. Even in the presence of TGF-beta which suppressed, and IL-1 which stimulated plasminogen activation, the chemokines had no direct effect. Inhibition of PA and plasmin, but not of matrix metalloproteinases and cysteine proteinases prevented caseinolysis. The plasminogen activation capacity of the cell lysates was represented by a single band with features of uPA. The immunoassay showed that the release of PAI-1 in PDL and GF remained unaffected by the chemokines, also when stimulated with TGF-beta.
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Does rilmenidine prevent blood pressure increase in rats with compromised nitric oxide production?
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To search tools of high blood pressure in the model of nitric oxide (NO)-defective hypertension, and the study focused on the effect of rilmenidine, agonist of imidazoline receptors, which was suggested to modulate central sympathetic outflow. Three experimental groups, each consisting of 7 rats, were used: (I) rats with inhibition of NO synthase (NOS) by N(G)-nitro-L-arginine methyl ester (L-NAME) 40 mg.kg(-1).d(-1) for 4 weeks in drinking water, (II) rats with inhibited NOS as in group I , plus agonist of imidazoline receptors rilmenidine 3 mg.kg(-1).d(-1) for 4 weeks by gavage, and (III) control rats. Systolic blood pressure was measured weekly noninvasively. At the end of experiment aortic ring isometric tension was followed, NOS expression (aorta, left ventricle), and NOS activity (left ventricle and brain) were determined. In the group I systolic blood pressure increased significantly, aortic ring relaxation to acetylcholine was significantly attenuated. Rilmenidine administered simultaneously with L-NAME (group II) prevented the increase of blood pressure which did not differ significantly from control values; aortic ring relaxation to acetylcholine did not differ from control. No change in NOS expression (aorta and left ventricle) was found in groups I and II. Significant decline in NOS activity (left ventricle and brain) was found in groups I and II.
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Current prognostic molecular markers for epithelial ovarian cancer (EOC) are insufficient. The aim of the current study was to investigate the role of Sox11 in EOC. Using an in silico transcriptomic screen, Sox11 was identified as a potential EOC biomarker. Sox11 protein expression was evaluated using immunohistochemistry (IHC) in 76 EOC cases, which were analysed using automated algorithms to develop a quantitative scoring model. Sox11 mRNA expression was upregulated in EOC compared to normal tissues. Automated analysis of Sox11 in the EOC cohort revealed high expression of Sox11, in 40% of tumours, who had an improved recurrence-free survival (RFS) (p=0.002). Multivariate analysis confirmed that Sox11 was an independent predictor of improved RFS after controlling for stage and grade.
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Is [ Glycine involved in the modulation of respiratory rhythmical discharge activity in neonatal rat medullary brain slices ]?
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To determine the role of glycine (Gly) in the generation and modulation of basic respiratory rhythm. Neonatal (0-3 days) SD rats of either sex were used in this study. The medulla oblongata brain slice containing the medial region of the nucleus retrofacialis (mNRF) and the hypoglossal nerve rootlets was prepared, and the surgical procedure was performed in the modified Kreb's solution (MKS) with continuous carbogen (95% O(2) and 5% CO(2)) within 3 min. The rhythmical respiratory discharge activity (RRDA) of the hypoglossal nerve rootlets was recorded using suction electrode. Eighteen medulla oblongata slice preparations were divided into 3 groups and treated for 20 min with Gly receptor specific agonist Gly (10 micromol/L), Gly receptor antagonist strychnine (STR, 1 micromol/L), or Gly+STR after a 20 min Gly application. The changes in RRDA of the hypoglossal nerve rootlets were observed. Gly significantly decreased the inspiratory time and integral amplitude (IA), but the changes of respiratory cycle (RC) and expiratory time (TE) were not statistically significant. STR induced a decrease in expiratory time and respiratory cycle without significantly affecting the inspiratory time or integral amplitud. The effect of Gly on the respiratory rhythm was partially reversed by additional application of STR.
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The majority of acute coronary syndromes are caused by plaque ruptures. Proteases secreted by macrophages play an important role in plaque ruptures by degrading extracellular matrix proteins in the fibrous cap. Matrix metalloproteinases have been shown to be markers for cardiovascular disease whereas the members of the cathepsin protease family are less studied. Cathepsin D, cathepsin L and cystatin B were measured in plasma at baseline from 384 individuals who developed coronary events (CEs), and from 409 age-matched and sex-matched controls from the Malmö Diet and Cancer cardiovascular cohort. Cathepsin D (180 (142-238) vs 163 (128-210), p<0.001), cathepsin L (55 (44-73) vs 52 (43-67), p<0.05) and cystatin B levels (45 (36-57) vs 42 (33-52), p<0.001) were significantly increased in CE cases compared to controls. In addition, increased cathepsin D (220 (165-313) vs 167 (133-211), p<0.001), cathepsin L (61 (46-80) vs 53 (43-68), p<0.05) and cystatin B (46 (38-58) vs 43 (34-54), p<0.05) were associated with prevalent diabetes. Furthermore, cathepsin D and cystatin B were increased in smokers. The HRs for incident CE comparing the highest to the lowest tertile(s) of cathepsin D and cystatin B were 1.34 (95% CI 1.02 to 1.75) and 1.26 (95% CI 1.01 to 1.57), respectively, after adjusting for age, sex, low-density lipoprotein/high-density lipoprotein ratio, triglycerides, body mass index, hypertension and glucose, but these associations did not remain significant after further addition of smoking to the model. In addition, cathepsin D was increased in incident CE cases among smokers after adjusting for cardiovascular risk factors.
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Is polycystic ovary syndrome associated with elevated plasma soluble CD40 ligand , a marker of coronary artery disease?
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To determine the level of plasma soluble CD40 ligand (sCD40L) in patients with polycystic ovary syndrome (PCOS). Prospective study. Baskent University School of Medicine in Turkey. Thirty-one patients with PCOS and 31 non-PCOS (control) patients. Determination of plasma sCD40L and homocysteine levels. Plasma sCD40L, fasting glucose, fasting insulin, homeostatic model assessment insulin resistance index (HOMA-IR), LH, FSH, E(2), total T, DHEAS, total cholesterol, high- and low-density lipoprotein cholesterol, triglyceride, homocysteine, and high-sensitivity C-reactive protein (hsCRP). The mean serum fasting insulin and HOMA-IR levels were significantly higher in the PCOS group. The mean serum homocysteine level was significantly higher in the PCOS group. Despite a trend for higher high-sensitivity C-reactive protein levels in the PCOS group, the difference did not reach statistical significance. The mean plasma sCD40L level in the PCOS group was significantly higher than that in the control group (5.14 +/- 3.65 ng/mL vs. 3.45 +/- 2.64 ng/mL, respectively).
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The aim of this study was to evaluate two-lung high-frequency jet ventilation during esophagectomy and evaluate the influence of high-frequency jet ventilation on pulmonary complications as compared with one-lung ventilation. A retrospective study. A single-center study in a university hospital. The authors analyzed the data of patients who had undergone an elective esophagectomy by transthoracic esophagectomy between January 2000 and December 2006. The patients had undergone a cervicothoracoabdominal subtotal esophagectomy via a right-sided thoracotomy. Patients with high-frequency jet ventilation were intubated with a single-lumen endotracheal tube, and an oxygen insufflation catheter was placed inside the endotracheal tube and connected to a high-frequency jet ventilator. Eighty-seven patients were enrolled, 30 with high-frequency jet ventilation and 57 with 1-lung ventilation. Both groups were adequately oxygenated, but patients in the one-lung ventilation group had a higher PaCO2 (42.75 +/- 7.5 mm Hg) compared with that for the high-frequency jet ventilation group (35.25 +/- 8.25 mm Hg) (p < 0.05). There were no differences in postoperative respiratory complications between the 2 groups. Mean blood loss was significantly lower for patients in the high-frequency jet ventilation group (1,243 +/- 787 mL).
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Does mitral regurgitation reduce systemic coagulation activity in patients with rheumatic heart disease?
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Severe mitral regurgitation (MR) reduces left atrial thrombus formation in patients with mitral stenosis (MS) and atrial fibrillation (AF). Plasma D-dimer levels represent a biochemical marker for fibrinolytic activity in prothrombotic states. The prothrombotic burden in patients with mitral valve disease and/or AF was assessed using plasma D-dimer levels. The study population included 89 patients with mitral valve disease, 21 with AF but normal valves, and 15 healthy controls. The mitral valve group was subdivided into patients with MS (n = 27), severe MR (n = 26), and MS with concomitant with severe MR (MS/MR; n = 36). These subgroups were further subdivided according to the atrial rhythm (sinus rhythm (SR)+AF). The mean left atrial size was increased in all groups with cardiac disease. D-dimer levels were highest in the MS+AF subgroup (527 +/- 134 microg/l). Patients with MS+AF, MS+SR, and nonvalvular AF had significantly higher D-dimer levels than controls (p < 0.01, by ANOVA). Patients with MR had normal levels of D-dimer. The atrial rhythm did not influence D-dimer levels in the MS/MR subgroup, or in the pure MR subgroup (p = NS).
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An effective HIV vaccine will likely require induction of both mucosal and systemic cellular and humoral immune responses. We investigated whether intramuscular (IM) delivery of electroporated plasmid DNA vaccine and simultaneous protein vaccinations by intranasal (IN) and IM routes could be combined to induce mucosal and systemic cellular and humoral immune responses to a model HIV-1 CN54 gp140 antigen in mice. Co-immunisation of DNA with intranasal protein successfully elicited both serum and vaginal IgG and IgA responses, whereas DNA and IM protein co-delivery did not induce systemic or mucosal IgA responses. Cellular IFNγ responses were preserved in co-immunisation protocols compared to protein-only vaccination groups. The addition of DNA to IN protein vaccination reduced the strong Th2 bias observed with IN protein vaccination alone. Luminex analysis also revealed that co-immunisation with DNA and IN protein induced expression of cytokines that promote B-cell function, generation of TFH cells and CCR5 ligands that can reduce HIV infectivity.
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Do subgenual cingulate and visual cortex responses to sad faces predict clinical outcome during antidepressant treatment for depression?
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Previous follow-up studies indicate that increased visual cortical, ventral cingulate and subcortical responses of depressed individuals to sad facial stimuli, but not happy stimuli could represent reversible markers of disease severity. We hypothesized that greater responses in these areas to sad stimuli, but not happy stimuli, would predict better subsequent clinical outcome. We also explored areas that would predict a poor outcome. Twelve melancholically depressed individuals in the early stages of antidepressant treatment in a secondary care setting participated in two experiments comparing responses to varying intensities of sad and happy facial stimuli, respectively, using event related functional MRI. They repeated the experiments after a mean delay of 12 weeks of treatment. There was a variation in response to treatment. Greater right visual cortex and right subgenual cingulate (R-BA25) responses to sad stimuli, but not happy stimuli, in the early stages of treatment were associated with a good clinical outcome. Greater ventrolateral prefrontal cortex responses to either stimulus type were associated with a relatively poor outcome.
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To evaluate the possibility of applying oligonucleotide microarrays for detection of the fusion genes in childhood acute lymphoblastic leukemia (ALL). To detect five types of fusion genes emerging frequently in childhood ALL including TEL/AML1, E2A/PBX1, BCR/ABLp190, BCR/ABLp210, MLL/AF4, probes were designed, synthesized and spotted on the chemical-material-coated-glass plates in array. The total RNAs were extracted from patients' bone marrow or peripheral blood cells at the beginning of diagnosis, analyzed by multiplex nested reverse-transcription-polymerase chain reaction (RT-PCR), and labeled by fluorescein. The products of RT-PCR were hybridized with microarray in order to detect specific types of fusion genes in leukemia cells. Distinctive hybridization signals were obtained for internal positive control and specific types of fusion genes. TEL/AML1 gene was found positive in 2 of the 36 cases, E2A/PBX1 gene in 3, BCR/ABLp190 gene in 2, BCR/ ABLp210 gene in one, and MLL/ AF4 gene in one. The results of the microarray and RT-PCR were consistent.
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Does heterogeneity of red blood cell velocity in skeletal muscle decrease with increased flow?
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Effective material exchange between blood and tissue depends on the heterogeneity of microvascular flow. The objective was to address inconsistencies between intravital studies regarding this dependency. We tested the hypothesis that heterogeneity of red blood cell velocity (VRBC) in capillary beds varies with the strength of metabolic stimulus and with capillary bed geometry. We used videomicroscopy to measure VRBC in a bed of 10-24 capillaries at the surface of extensor digitorum longus (EDL) muscle in anesthetized rats. The coefficient of variation (CV = standard deviation/mean; an index of spatial heterogeneity) was computed in the same bed before and after (i) 1, 2, 4, or 8 Hz supramaximal muscle contraction or (ii) adenosine superfusion (10(-7)-10(-3) M). Beds with or without arteriolar-venular capillary shunts were used. Although control VRBC differed between beds (shunt: 232 microns/s; no shunt: 130 microns/s), the percentage increases in postcontraction VRBC did not (range: 111-326%). In both beds, control CV varied greatly (overall range: 28-117%) and 2-8 Hz muscle contractions reduced CV significantly by 25%. Similar results were obtained for adenosine. In confirmatory experiments using the rat cremaster muscle, contractions (4 Hz) and adenosine (10(-4) M) also reduced CV. Based on all data, CV = 63-0.022 VRBC (r = 0.82, P < 0.001).
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Anxiety and depression are common features of coeliac disease. Depression is cause of non-compliance to treatment in chronic illness. To evaluate the useful of psychological support counselling to improve affective disorders and gluten-free diet adherence in coeliac disease with anxiety and depression. A total of 66 coeliac disease patients with state anxiety and current depression were enrolled. Patients were randomized in two groups: in group A psychological support was started at the beginning of gluten-free diet, while group B was free of psychological support. Both groups were followed every 2 weeks for 6 months. State and Trait Anxiety Inventory test Y-1 and the modified Zung self-rating depression scale were administered before (T0) and after 6 months of gluten-free diet (T1). At T1 no difference was found between groups in the percentage of state anxiety, while a significant lower percentage of depressed subjects was found in group A with respect to group B (15.1% vs. 78.8%; P=0.001). In the follow-up period, a significant lower compliance to gluten-free diet was found in group B with respect to group A (39.4% vs. 9.1%; P=0.02).
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Is acute systemic inflammation associated with an increase in peritoneal solute transport rate in chronic peritoneal dialysis patients?
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This study was performed to evaluate the effects of acute systemic inflammation on peritoneal solute transport rate (PSTR) in chronic peritoneal dialysis (CPD) patients. A baseline standard peritoneal equilibration test (PET) was performed on each patient every 6 months, and blood concentration of high-sensitivity C-reactive protein (hs-CRP) was assayed every 2 months in our peritoneal dialysis clinic. Acute systemic inflammation was defined as a greater than 10-fold increase in hs-CRP concentration compared with baseline value, in the absence of peritonitis, and returning to baseline level in 2 months. In patients with acute systemic inflammation, PET and hs-CRP concentration assays were performed during inflammation and after recovery. Ten patients with acute systemic inflammation were enrolled in the inflammation group and 42 other patients served as controls. There were no significant changes in hs-CRP and dialysate-to-plasma ratio of creatinine (D/Pcreat) in the control group during the study period. In the inflammation group, median hs-CRP levels at baseline, during acute inflammation, and at recovery were 2.3 mg/L (range 0.3 - 4.5 mg/L), 39.2 mg/L (range 15.1 - 117.4 mg/L), and 3.7 mg/L (range 0.9 - 8.9 mg/L), respectively. Median D/Pcreat increased significantly from baseline (0.64; range 0.55 - 0.98) to time of acute inflammation (0.72; range 0.60 - 0.96) (p < 0.05). The D/Pcreat at recovery was 0.67 (range 0.52 - 0.94), which decreased significantly from time of acute inflammation (p < 0.05). There was no correlation between changes in log (hs-CRP) and changes in D/Pcreat.
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General anesthesia induces long-lasting cognitive and learning deficits. However, the underlying mechanism remains unknown. The GluA1 subunit of AMPAR is a key molecule for learning and synaptic plasticity, which requires trafficking of GluA1-containing AMPARs into the synapse. Adult male rats were exposed to 1.8% isoflurane for 2 h and subjected to an inhibitory avoidance task, which is a hippocampus-dependent contextual fear learning paradigm (n = 16 to 39). The in vitro extracellular field potential of hippocampal synapses between the Schaffer collateral and the CA1 was evaluated using a multielectrode recorder (n = 6 per group). GluA1 expression in the synaptoneurosome was assessed using Western blotting (n = 5 to 8). The ubiquitination level of GluA1 was evaluated using immunoprecipitation and Western blotting (n = 7 per group). Seven days after exposure to 1.8% isoflurane for 2 h (Iso1.8), the inhibitory avoidance learning (control vs. Iso1.8; 294 ± 34 vs. 138 ± 28, the mean ± SEM [%]; P = 0.002) and long-term potentiation (125.7 ± 6.1 vs. 105.7 ± 3.3; P < 0.001) were impaired. Iso1.8 also temporarily increased GluA1 in the synaptoneurosomes (100 ± 9.7 vs. 138.9 ± 8.9; P = 0.012) and reduced the GluA1 ubiquitination, a main degradation pathway of GluA1 (100 ± 8.7 vs. 71.1 ± 6.1; P = 0.014).
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Does danzhi Xiaoyao San ameliorate depressive-like behavior by shifting toward serotonin via the downregulation of hippocampal indoleamine 2,3-dioxygenase?
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Danzhi Xiaoyao San (DXS) is a canonical Chinese medicine formula from Principles of Internal Medicine, which was written during the Ming dynasty. This formula is approved and commercialized for use in the prevention and treatment of affective disorders. This study is aimed to investigate the hypothesis that DXS treats depressive-like behavior by shifting the balance of the kynurenine (Kyn)/serotonin (5-HT) pathway toward the 5-HT pathway through the downregulation of hippocampal indoleamine 2,3-dioxygenase (IDO). Chemical fingerprints of gardenoside, paeoniflorin, ferulic acid, paeonol, and ligustilide in standard extraction were used as the material bases of DXS. Rats with depressive-like behavior induced by chronic unpredictable mild stress (CUMS) were randomly divided into four groups, namely the control, model, DXS, and fluoxetine groups. Cytokines, IDO, and tryptophan (Trp) catabolites were analyzed by enzyme-linked immunosorbent assay, western blot, and liquid chromatography-electrospray ionization tandem mass spectrometry, respectively. DXS significantly increased crossing grid numbers, sucrose consumption, and body weight. This treatment significantly decreased the serum levels of tumor necrosis factor-α and interleukin 6 (IL-6). However, DXS elicited no significant effects on IL-1β, IL-2, and interferon γ. DXS downregulated the activity of IDO and subsequent production of Kyn in the hippocampus. This treatment upregulated the hippocampal contents of Trp and 5-HT but did not influence 5-HT turnover.
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The goals of this study were to evaluate the complication rate for intraoperative placement of a long-term central venous catheter (CVC) using intraoperative ultrasound (US) and fluoroscopy and to examine the feasibility for eliminating routine postprocedure chest X-ray. Retrospective data pertaining to operative insertion of long-term CVC were collected and the rate of procedural complications was determined. From January 2008 to August 2013, 351 CVCs were placed via the internal jugular vein using US. Of these, 93% had a single, successful internal jugular vein insertion. The complications included 4 arterial sticks (1.14%). Starting in October 2012, postprocedure chest radiography (CXR) was eliminated in 170 cases, with no complications. A total of $29,750 in charges were deferred by CXR elimination.
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Does ketamine antagonize nitric oxide release from cerebral cortex after middle cerebral artery ligation in rats?
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Ischemia or hypoxia activates N-methyl-D-aspartate (NMDA) receptors and results in nitric oxide (NO) production. The purpose of this study was to investigate whether an NMDA channel blocker can inhibit NO production during ischemia. Temporary cerebral ischemia was induced by middle cerebral artery ligation while common carotid arteries were clamped bilaterally for 40 minutes in urethane-anesthetized rats. Extracellular NO concentration in the cortex was recorded through Nafion- and porphyrine-coated carbon fiber electrodes. Ketamine, and NMDA channel blocker, was administered (50 mg/kg) intraperitoneally 15 minutes before the cerebral artery ligation. During middle cerebral artery ligation, cortical NO was increased to its peak (18.76+/-3.36 nmol/L) in 7 minutes and then declined. The overflow of NO can be antagonized by pretreatment with ketamine, dizocilpine maleate (MK801), or N(G)-nitro-L-arginine methyl ester (L-NAME). Local application of nitroprusside also induced NO production. However, this effect was not antagonized by ketamine.
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Increased C-reactive protein levels have been found in all active inflammations, including periodontitis. This study aims to assess the C-reactive protein levels in periodontal disease progression. Forty-five patients were divided into the following three groups (n=15) based on gingival index, probing pocket depth, and clinical attachment level: healthy (group I), gingivitis (group II), and chronic periodontitis (group III). Gingival crevicular fluid and serum samples were quantified for C-reactive protein using enzyme-linked immunosorbent assay. The mean C-reactive protein concentration in gingival crevicular fluid and serum was found to be highest in group III (1233.33ng/mL for gingival crevicular fluid, 5483.33ng/mL for serum), and least in group I (60 ng/mL and 413 ng/mL for gingival crevicular fluid and serum, respectively) The mean C-reactive protein concentration in group II (453.33ng/mL for gingival crevicular fluid and 3565.33 ng/mL for serum) was found to be intermediate.
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Does a modified Glenn shunt reduce right ventricular stroke work during left ventricular assist device therapy?
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Right ventricular (RV) failure is a major cause of morbidity and mortality after left ventricular assist device (LVAD) placement and remains hard to predict. We hypothesized that partial surgical exclusion of the RV with a modified Glenn shunt during LVAD treatment would reduce RV stroke work. An LVAD was implanted in eight pigs and a modified Glenn shunt was constructed. A conductance pressure-volume catheter was placed in the right ventricle through the apex. Haemodynamic data and pressure-volume loops were obtained at the following time periods: (i) baseline, (ii) open shunt, (iii) LVAD with closed shunt and (iii) LVAD and open shunt. During LVAD therapy, the right atrial (RA) pressure increased from 9 mmHg (9-9) to 15 mmHg (12-15), P = 0.01. RV stroke volume increased from 30 ml (29-40) to 51 ml (42-53), P < 0.01. Also, RV stroke work increased to 708 mmHg ml (654-1193) from 535 mmHg ml (424-717), P = 0.04, compared with baseline. During LVAD therapy in combination with a Glenn shunt, the RA pressure decreased from 15 mmHg (12-15) to 10 mmHg (7-11) when compared with LVAD therapy only, P = 0.01. A decrease in RV stroke work from 708 mmHg ml (654-1193) to 465 mmHg ml (366-711), P = 0.04, was seen when the LVAD was combined with a shunt, not significantly different from the baseline value (535 mmHg ml). The developed pressure in the right ventricle decreased from 29 mmHg (26-32) to 21 mmHg (20-24), P < 0.01. The pressure-volume loops of the RV show a significant reduction of RV stroke work during the use of the shunt with LVAD treatment.
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To perform immunohistochemical (IHC) analysis of molecular drivers related to the development and maintenance of melanoma and to assess their value as diagnostic and prognostic melanoma biomarkers in routine clinical practice. Tissue microarrays constructed from a cohort of primary melanomas (n=355), benign naevi (n=37) and melanoma metastases (n=14) were evaluated for IHC expression of c-KIT, BRAF(V600E), MITF, p16, p53 and PTEN, as well as for pERK, a surrogate marker for mitogen-activated protein kinase pathway activation. The results were correlated with clinicopathological parameters and clinical outcome. Absent p16 expression and reduced MITF expression were both associated with the adverse prognostic markers ulceration (p=0.009 and p<0.0001, respectively), advanced tumour stage (p<0.0001 and p=0.001, respectively) and higher Breslow thickness (both p<0.0001), as well as with an adverse overall relapse-free survival (p<0.0001 and p=0.003, respectively). Absence of p16 expression predicted overall relapse-free (p=0.02) and distant metastasis-free (p=0.04) survival, independently of Breslow thickness, ulceration and tumour stage.
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Do environmental rRNA inventories miss over half of protistan diversity?
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The main tool to discover novel microbial eukaryotes is the rRNA approach. This approach has important biases, including PCR discrimination against certain rRNA gene species, which makes molecular inventories skewed relative to the source communities. The degree of this bias has not been quantified, and it remains unclear whether species missed from clone libraries could be recovered by increasing sequencing efforts, or whether they cannot be detected in principle. Here we attempt to discriminate between these possibilities by statistically analysing four protistan inventories obtained using different general eukaryotic PCR primers. We show that each PCR primer set-specific clone library is not a sample from the community diversity but rather from a fraction of this diversity. Therefore, even sequencing such clone libraries to saturation would only recover that fraction, which, according to the parametric models, varies between 17 +/- 4% to 49 +/- 10%, depending on the set of primers. The pooled data is thus qualitatively richer than individual libraries, even if normalized to the same sequencing effort.
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We aimed to investigate whether and how the total flavonoid extracts (TFE) from Inula britannica L. block neointimal hyperplasia induced by balloon injury in rats. Rats were administered orally TFE doses of 12.5, 25 and 50 mg/kg/d by gastric gavage from 3 days before balloon injury to 14 days after the injury. The ratio of intima (I) to media (M) thickness (I/M) in carotid arteries was examined by morphological analyses. The MDA content and SOD activity in plasma were measured. The O(2)(-) production in vascular tissues was detected in situ. The expression of p47(phox) in carotid arteries was analyzed by Western blot analysis and immunohistochemistry. The rats treated with TFE 50 mg/kg/d showed a reduction in neointimal hyperplasia, and the ratio of I/M of balloon injured-carotid arteries was significantly reduced by over 70% after TFE treatment, compared with the injured group. The inhibitory effect of TFE on neointimal hyperplasia was almost consistent with that of atorvastatin, a positive control. The plasma SOD activity was obviously increased by TFE treatment (P<0.01), while plasma MDA production was markedly decreased by TFE treatment (P<0.05). On day 14 after balloon injury, the carotid arteries showed an increase in O(2)(-) production that was most evident in the neointimal and medial layer of the vessel. Thus, TFE significantly inhibited injury-induced O(2)(-) production and p47(phox) expression in carotid arteries.
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Does ketamine attenuate endotoxin-induced leukocyte adherence in rat mesenteric venules?
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To determine the influence of ketamine on endotoxin-induced leukocyte adherence and venular microhemodynamics. Randomized, controlled trial. Experimental laboratory. Thirty male Wistar rats. The rats were pretreated with ketamine (10 mg/kg iv) or 0.9% saline, and both groups were given endotoxin (Escherichia coli lipopolysaccharide; 5 mg/kg iv). The control group received two doses of 0.9% saline. The rates of leukocyte adherence and changes in microhemodynamics were monitored in rat mesenteric venules, using in vivo video microscopy. The number of adherent leukocytes was determined on-line in 10-min intervals from 60 mins before until 2 hrs after endotoxin administration. Venular diameters, red blood cell velocity, volumetric blood flow, and the venular wall shear rate were monitored before and at 10, 30, and 60 mins after endotoxin exposure. A 6.3-fold increase in the number of adherent leukocytes was observed 10 mins after administration of endotoxin when compared with control animals (5.87 +/- 0.69 vs. 0.93 +/- 0.21 adherent cells/100 microns; p < .001). This increase remained unchanged for 120 mins. In ketamine-pretreated rats, a 2.6-fold increase in leukocyte adherence occurred during the first 20 mins after endotoxin exposure (2.40 +/- 0.46 vs. 0.93 +/- 0.21 adherent cells/100 microns; p < .01). However, no difference in the number of adherent leukocytes between ketamine-pretreated and control animals was found after this 20-min period. In animals of the control group, no increase in leukocyte adherence occurred during the entire observation time. Diameters of mesenteric venules did not change after endotoxin exposure in any of the groups. Red blood cell velocity and venular blood flow in the endotoxin-treated groups decreased 10 mins after the injection of endotoxin when compared with controls, but these values did not show any difference when they were compared between ketamine and saline-pretreated animals. Similarly, venular wall shear rate in the endotoxin-treated groups decreased 10 and 30 mins after injection of endotoxin. However, no significant difference occurred between ketamine and saline-pretreated animals.
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Large copy number variations (CNV) can contribute to increased burden for neurodegenerative diseases. In this study, we analyzed the genome-wide burden of large CNVs > 100 kb in primary open angle glaucoma (POAG), a neurodegenerative disease of the eye that is the largest cause of irreversible blindness. Genome-wide analysis of CNVs > 100 kb were analyzed in a total of 1720 individuals, including an Indian cohort (347 POAG cases and 345 controls) and a Caucasian cohort (624 cases and 404 controls). All the CNV data were obtained from experiments performed on Illumina 660W-Quad (infinium) arrays. We observed that for both the populations CNVs > 1 Mb was significantly enriched for gene-rich regions unique to the POAG cases (P < 10(-11)). In the Indian cohort CNVs > 1 Mb (39 calls) in patients influenced 125 genes while in controls 31 such CNVs influenced only 5 genes with no overlap. In both cohorts we observed 1.9-fold gene enrichment in patients for deletions compared to duplications, while such a bias was not observed in controls (0.3-fold). Overall duplications > 1 Mb were more than deletions (Del/Dup = 0.82) confirming that the enrichment of gene-rich deletions in patients was associated with the disease. Of the 39 CNVs > 1 Mb from Indian patients, 28 (72%) also were implicated in other neurodegenerative disorders, like autism, schizophrenia, sensorineural hearing loss, and so forth. We found one large duplication encompassing CNTN4 gene in Indian and Caucasian POAG patients that was absent in the controls.
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Do type I interferon and T helper 17 cells co-exist and co-regulate disease pathogenesis in lupus patients?
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T-helper 17 cells (Th17) and type I interferon (IFN-I) play a critical role in the pathogenesis of systemic lupus erythematosus (SLE). Previous studies have suggested that IFN-I suppresses Th17 development under autoimmune settings. Therefore, the main objective of this study was to define the association between IFN-I and Th17 pathways in SLE. Peripheral blood samples and disease activity measures were collected from 31 patients fulfilling the American College of Rheumatology revised criteria for SLE. Serum was evaluated for IFN-α bioactivity and interleukin (IL)-6 levels by cell-based bioluminescence assay and enzyme-linked immunosorbent assay, respectively. The frequency of Th17 cells in peripheral blood was determined by intracellular cytokine staining for IL-17. IFN-α bioactivity in the serum of lupus subjects (mean ± SD: 6.510 ± 3.686) was significantly higher (P = 0.001) compared to healthy controls (2.9 ± 1.061). Additionally, 58.1% and 41.9% of SLE subjects displayed high and low IFN-α bioactivity, respectively. We observed a significant increase (P = 0.04) in the percentage of Th17 cells in lupus subjects with high IFN-α bioactivity (1.9 ± 1.0) compared to lupus subjects with low IFN-α bioactivity (1.2 ± 0.9). Lupus subjects with high IFN-α bioactivity and Th17 cells had significantly higher disease activity (P = 0.04) and serum IL-6 levels (P = 0.01) compared to patients with low IFN-α activity and low Th17 cells.
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Nitric oxide (NO) bioavailability is reduced in the setting of heart failure. Nitrite (NO2) is a critically important NO intermediate that is metabolized to NO during pathological states. We have previously demonstrated that sodium nitrite ameliorates acute myocardial ischemia/reperfusion injury. No evidence exists as to whether increasing NO bioavailability via nitrite therapy attenuates heart failure severity after pressure-overload-induced hypertrophy. Serum from patients with heart failure exhibited significantly decreased nitrosothiol and cGMP levels. Transverse aortic constriction was performed in mice at 10 to 12 weeks. Sodium nitrite (50 mg/L) or saline vehicle was administered daily in the drinking water postoperative from day 1 for 9 weeks. Echocardiography was performed at baseline and at 1, 3, 6, and 9 weeks after transverse aortic constriction to assess left ventricular dimensions and ejection fraction. We observed increased cardiac nitrite, nitrosothiol, and cGMP levels in mice treated with nitrite. Sodium nitrite preserved left ventricular ejection fraction and improved left ventricular dimensions at 9 weeks (P<0.001 versus vehicle). In addition, circulating and cardiac brain natriuretic peptide levels were attenuated in mice receiving nitrite (P<0.05 versus vehicle). Western blot analyses revealed upregulation of Akt-endothelial nitric oxide-nitric oxide-cGMP-GS3Kβ signaling early in the progression of hypertrophy and heart failure.
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Is hypoxia-induced resistance to cisplatin and doxorubicin in non-small cell lung cancer inhibited by silencing of HIF-1alpha gene?
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Hypoxia is associated with human non-small cell lung cancers (NSCLC), which are highly resistant to chemotherapy. The hypoxia inducible factor (HIF) as a transcription factor in response to hypoxia indicates that it could be a novel, tumor-specific target for anticancer therapy. We hypothesized that disruption of HIF pathway through lentiviral vector-mediated HIF-1alpha RNA interference (RNAi) could reverse the hypoxia-induced resistance to chemotherapy. We transfected Human NSCLC cell lines, SPCA1 and A549 with HIF-1alpha specific RNAi lentiviral vectors as well as controls. HIF-1alpha silenced cells [SPCA1/HIF-1alpha(-) and A549/HIF-1alpha(-)] were screened by blasticidin. They were incubated in 19 or 0.5% O2 for 16 h followed by the assessment of chemosensitivity to cisplatin and doxorubicin with MTT and clonogenic assays. Quantitative RT-PCR and Western blot analysis were used to detect the expressions of HIF-1alpha mRNA and protein, respectively. Moreover, flow cytometry was used to monitor the expression of P-glycoprotein. Exposure of SPCA1 and A549 cells to 0.5% O2 significantly increased resistance to cisplatin and doxorubicin, in contrast to cells incubated in normoxia. Transduction of SPCA1 with HIF-1alpha RNAi vector resulted in sequence specific silencing with 87.2 and 84.6% decreases of HIF-1alpha mRNA transcription and 97.3 and 94.8% of protein expressions in normoxia and hypoxia, respectively. Correspondingly, they are 89.2, 89.9% and 97.2, 88.4% decreases in A549 cells. Hypoxia-induced resistance to cisplatin and doxorubicin were reversed in SPCA1/HIF-1alpha(-) and A549/HIF-1alpha(-) cells. There was no significant P-glycoprotein increase induced by hypoxia in NSCLC cells.
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To assess the effects of soft contact lens base curve radius (BCR), sex, ethnicity, central corneal curvatures, and vertical palpebral aperture size (PAS) on the postlens tear thickness (PLTT). The PLTT was measured using optical pachometry on 114 experienced lens wearers who were fitted with lathe-cut soft lenses (Alden 47, polymacon, 35.5% H2O, -2.00 diopter, and 14.0 mm). Each subject was randomly allocated to one lens group receiving a BCR of 7.9, 8.3, or 8.7 mm. Pachometry measurements were taken at 30 min after lens insertion. Vertical PAS and keratometry readings were measured for 94 of the 114 subjects. The mean (95% confidence interval) PLTT was 15.7 microm (13.2-18.0 microm), 12.8 microm (10.9-14.7 microm), and 12.1 microm (10.2-14.0 microm) for the 7.9-mm, 8.3-mm, and 8.7-mm BCR groups, respectively. The differences in PLTT among the three BCR groups was significant (analysis of variance F-test; P=0.039). Post hoc testing using the Tukey honestly significant difference statistic showed that only the two extreme BCR groups (7.9 mm and 8.7 mm) were significantly different. Sex had no effect on the PLTT; however, the PLTT was significantly thinner for the Asian compared with non-Asian eyes (P=0.0001). The Asian PLTT did not vary with different soft lens BCRs. The non-Asian PLTT was thicker with lenses of the steep BCR compared with the flat BCR.
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Does bi-level CPAP improve gas exchange when compared with conventional CPAP for the treatment of neonates recovering from respiratory distress syndrome?
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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.
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Sonic hedgehog (Shh) and components of its signalling pathway have been identified in human prostate carcinoma and increased levels of their expression appear to correlate with disease progression and metastasis. The mechanism through which Shh signalling could promote metastasis in bone, the most common site for prostate carcinoma metastasis, has not yet been investigated. The present study determined the effect of Shh signalling between prostate cancer cells and pre-osteoblasts on osteoblast differentiation, a requisite process for new bone formation that characterizes prostate carcinoma metastasis. LNCaP human prostate cancer cells modified to overexpress Shh (designated LNShh cells) and MC3T3 mouse pre-osteoblasts were maintained as mixed populations within the same culture chamber. In this non-conventional mixed culture system, LNShh cells upregulated the expression of Shh target genes Gli1 and Patched 1 (Ptc1) in MC3T3 cells and this was inhibited by cyclopamine, a specific chemical inhibitor of hedgehog signalling. Concomitantly, MC3T3 cells exhibited time-dependent decreased cell proliferation, upregulated alkaline phosphatase Akp2 gene expression, and increased alkaline phosphatase activity indicative of early phase osteoblast differentiation. LNShh cell-induced differentiation was inhibited in MC3T3 cells stably transfected with a dominant negative form of Gli1, a transcription factor that mediates Shh signalling. Interestingly, LNShh cells did not significantly increase the endogenous expression of the osteoblast differentiation transcription factor Runx2 and its target genes osteocalcin and osteopontin. Consistent with these results, exogenous Shh peptide did not upregulate Runx2 expression in MC3T3 cells. However, Runx2 levels were increased in MC3T3 cells by ascorbic acid, a known stimulator of osteoblast differentiation.
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Does combination of isoliquiritigenin and tumor necrosis factor-related apoptosis-inducing ligand induce apoptosis in colon cancer HT29 cells?
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Isoliquiritigenin is a chalcone derivative with potential in cancer chemoprevention. Although tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising anti-cancer agent, some cancer cells are resistant to TRAIL treatment. Current studies have tried to overcome TRAIL-resistant cancer cells. Here, we show for the first time that isoliquiritigenin overcomes TRAIL resistance in colon cancer HT29 cells. HT29 cells were treated with isoliquiritigenin and/or TRAIL, and apoptosis induction was detected by flow cytometry and fluorescence microscopy. Protein expression relating to the TRAIL pathway was analyzed by Western blotting. A single treatment with isoliquiritigenin scarcely induced apoptosis in HT29 cells. Combined treatment with suboptimal concentrations of isoliquiritigenin and TRAIL markedly induced apoptosis, however. The effect was blocked by a pan-caspase inhibitor and a caspase-3, 8, 9, or 10 inhibitor, suggesting that the combination facilitates caspase-dependent apoptosis. Furthermore, the apoptosis induced by isoliquiritigenin and TRAIL was blocked by a dominant negative form of the TRAIL receptor. This result indicates that the combined effect is caused by specific interaction between TRAIL and its receptors. Isoliquiritigenin increased the amount of DR5 protein among TRAIL receptors. Isoliquiritigenin did not significantly increase levels of the Bcl-2 family proteins Bcl-2, Bcl-xL, and BAX.
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Operation notes are an important part of medical records for clinical, academic and medicolegal reasons. This study audited the quality of operative note keeping for total knee replacements against the standards set by the British Orthopaedic Association (BOA). A prospective review of all patients undergoing total knee replacement at a district general hospital over 8 months. Data recorded were compared with those required by the BOA good-practice guidelines. Change in practice was implemented and the audit cycle completed. Data were statistically analysed. A total of 129 operation notes were reviewed. There was a significant improvement in the mean number of data points recorded from 9.6 to 13.1. The least well recorded data were diagnosis, description of findings, alignment and postoperative flexion range. All had a significant improvement except description of findings. The operating surgeon writing the note improved from 56% to 67%. Detailed postoperative instructions also improved in quality.
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Do qT Dispersion and T Wave Peak-to-end Interval Dispersion in Children with Kawasaki Disease?
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The main complication of Kawasaki disease is the Coronary Artery (CA) involvement and long term follow up of patients depends on the severity of coronary arterial aneurysms, ischemia, and thrombosis. Early diagnosis of these complications can lead to a more desirable outcome for patients. Myocardial ischemia can prolong QT dispersion and increase the risk of cardiac arrhythmias as well as sudden cardiac arrests. Also, T wave peak-to-end (Tp-Te) interval dispersion, which provides a valuable index of transmural dispersion of repolarization, can trigger the arrhythmia. We evaluated the non-corrected QT interval dispersion (QTD) and the corrected QT (QTc) dispersion and measured Tp-Te interval dispersion in 49 Iranian children (28 males and 21 females) with the diagnosis of Kawasaki disease (KD) in the acute phase and 49 age-matched controls in a prospective study from 2009 to 2012. Student's t-test and Pearson correlation were used to analyze the data. All the statistical analyses were performed through the SPSS 16. Besides, P<0.05 was considered as statistically significant. Patients with KD had significantly longer QTc dispersion (0.099±0.055 s versus. 0.040±0.018 s; P<0.001), non-corrected QT dispersion (0.075±0.046 versus 0.042±0.019; P<0.001), and Tp-Te dispersion (0.047±0.054 versus 0.022±0.011; P=0.015). The patients with elevation in white blood cell count (above 15000) had a statistically significant increased in QTD (P=0.011). No significant correlation was found between coronary involvement and repolarization indexes.
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Small cell carcinoma of the ovary is a rare, highly malignant tumor that often exhibits a paraneoplastic hypercalcemia. A 27-year-old female presented with pancreatitis and altered mental status with hypercalcemia. Further investigation revealed a left ovarian mass and a small cell carcinoma of the ovary, hypercalcemic type was found. Hysterectomy with bilateral salpingo-oophorectomy was performed, and the patient underwent chemotherapy with carboplatin and paclitaxel. Hypercalcemia resolved after tumor resection. The patient has retroperitoneal lymph node recurrence at 16 months.
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Are thoracic epidural local anesthetics ineffective in alleviating post-thoracotomy ipsilateral shoulder pain?
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This study was conducted to estimate the incidence and clinical predictors of post-thoracotomy shoulder pain and to determine the effectiveness of thoracic epidural block in alleviating this pain. A prospective clinical trial. University teaching hospital. Thirty-two adult patients undergoing elective thoracic surgery consented to participate in the study. All operations were open thoracotomies done by the same team of surgeons and anesthesiologists. A thoracic (T6) epidural catheter was placed before induction of general anesthesia. Each patient received 7 mL of lidocaine 2% epidurally and repeated doses of 5 mL of lidocaine 2% every half hour during the operation. Postoperatively, the occurrence of incision or ipsilateral shoulder pain was observed and treated with a maximal dose of 5 mL of lidocaine 2%. If ineffective, indomethacin suppository (nonsteroidal anti-inflammatory drug [NSAID]) was given. Variables such as patient's age, sex, American Society of Anesthesiologists physical status, type, site and duration of surgery, duration of anesthesia, the resection of main bronchus, and the use of thoracostomy tubes were recorded. Postoperatively, 10 patients (31%) had shoulder pain, 4 patients (12.5%) complained of incision pain, and 2 (6.3%) complained of both incision and shoulder pain. A bolus of 5 mL of lidocaine 2% in the epidural catheter relieved incision pain in all the patients, but was ineffective for shoulder pain. Indomethacin suppository was effective in these patients. No correlation was found between any variable and the occurrence of shoulder pain.
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The tumor necrosis factor (TNF) gene is located within the highly polymorphic major histocompatibility complex region, exhibiting the -308 GA promoter region polymorphism and six microsatellites (TNFa-f) spanning the region nearby the TNF locus. In the present study, we evaluated the frequency of -308 GA and TNFa-e polymorphisms and respective haplotypes (in chromosomal sequence: TNFd-TNFe-308GA-TNFc-TNFa-TNFb), in 222 patients with AIDS, 52 of whom exhibited cytomegalovirus retinitis, and in 202 healthy HIV-negative individuals. TNF microsatellite and single nucleotide polymorphism typings were performed by PCR followed by polyacrylamide gel electrophoresis. The TNF-308A allele and the 4-3-G-2-7-1 haplotype were associated with susceptibility to AIDS, whereas the TNFb4 allele and the 3-3-G-1-11-4 haplotype were associated with protection against AIDS development. The TNFc2 allele and the 4-1-G-2-2-1 haplotype, which contains the TNFc2 allele, were associated with cytomegalovirus retinitis.
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Does therapeutic hypothermia preserve antioxidant defenses after severe traumatic brain injury in infants and children?
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Oxidative stress contributes to secondary damage after traumatic brain injury (TBI). Hypothermia decreases endogenous antioxidant consumption and lipid peroxidation after experimental cerebral injury. Our objective was to determine the effect of therapeutic hypothermia on oxidative damage after severe TBI in infants and children randomized to moderate hypothermia vs. normothermia. Prospective randomized controlled study. Pediatric intensive care unit of Pittsburgh Children's Hospital. The study included 28 patients. We compared the effects of hypothermia (32 degrees C-33 degrees C) vs. normothermia in patients treated in a single center involved in a multicentered randomized controlled trial of hypothermia in severe pediatric TBI (Glasgow Coma Scale score <or=8). The patients randomized to hypothermia (n = 13) were cooled to target temperature within approximately 6 to 24 hours for 48 hours and then rewarmed. Antioxidant status was assessed by measurements of total antioxidant reserve and glutathione. Protein oxidation and lipid peroxidation were assessed by measurements of protein thiols and F2-isoprostane, respectively, in ventricular cerebrospinal fluid (CSF) samples (n = 76) obtained on day 1-3 after injury. The association between Glasgow Coma Scale score, age, gender, treatment, temperature, time after injury, and CSF antioxidant reserve, glutathione, protein-thiol, F2-isoprostane levels were assessed by bivariate and multiple regression models. Demographic and clinical characteristics were similar between the two treatment groups. Mechanism of injury included both accidental injury and nonaccidental injury. Multiple regression models revealed preservation of CSF antioxidant reserve by hypothermia (p = 0.001). Similarly, a multiple regression model showed that glutathione levels were inversely associated with patient temperature at the time of sampling (p = 0.002). F2-isoprostane levels peaked on day 1 after injury and were progressively decreased thereafter. Although F2-isoprostane levels were approximately three-fold lower in patients randomized to hypothermia vs. normothermia, this difference was not statistically significant.
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Chronic inflammatory conditions, such as granulomas, are associated with angiogenesis. Mast cells represent the main cell type orchestrating angiogenesis, through the release of their granule content. Therefore, compounds able to modulate mast cell behaviour may be considered as a new pharmacological approach to treat angiogenesis-dependent events. Here, we tested the effect of selective cannabinoid (CB) receptor agonists in a model of angiogenesis-dependent granuloma formation induced by lambda-carrageenin in rats. Granulomas were induced by lambda-carrageenin-soaked sponges implanted subcutaneously on the back of male Wistar rats. After 96 h, implants were removed and granuloma formation was measured (wet weight); angiogenesis was evaluated by histological analysis and by the measurement of haemoglobin content. Mast cells in the granulomas were evaluated histologically and by RT-PCR and immunoblotting analysis for mast cell-derived proteins (rat mast cell protease-5 (rMCP-5) and nerve growth factor). Selective CB1 and CB2 receptor agonists(,) ACEA and JWH-015 (0.001-0.1 mg mL(-1)), were given locally only once, at the time of implantation. The CB1 and CB2 receptor agonists decreased the weight and vascularization of granulomas after 96 h. This treatment also reduced mast cell number and activation in granulomatous tissue. Specifically, these compounds prevented the transcription and expression of rMCP-5, a protein involved in sprouting and advance of new blood vessels.
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Does geometry of the carotid bifurcation predict its exposure to disturbed flow?
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That certain vessels might be at so-called geometric risk of atherosclerosis rests on assumptions of wide interindividual variations in disturbed flow and of a direct relationship between disturbed flow and lumen geometry. In testing these often-implicit assumptions, the present study aimed to determine whether investigations of local risk factors in atherosclerosis can indeed rely on surrogate geometric markers of disturbed flow. Computational fluid dynamics simulations were performed on carotid bifurcation geometries derived from MRI of 25 young adults. Disturbed flow was quantified as the surface area exposed to low and oscillatory shear beyond objectively-defined thresholds. Interindividual variations in disturbed flow were contextualized with respect to effects of uncertainties in imaging and geometric reconstruction. Relationships between disturbed flow and various geometric factors were tested via multiple regression. Relatively wide variations in disturbed flow were observed among the 50 vessels. Multiple regression revealed a significant (P<0.002) relationship between disturbed flow and both proximal area ratio (beta approximately 0.5) and bifurcation tortuosity (beta approximately -0.4), but not bifurcation angle, planarity, or distal area ratio. These findings were shown to be insensitive to assumptions about the flow conditions and to the choice of disturbed flow indicator and threshold.
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5-fluorouracil-(5-FU)-based adjuvant chemotherapy is widely used for the treatment of colorectal cancer. However, 5-FU resistance in the course of treatment has become more common. Therefore, new therapeutic strategies and/or new adjuvant drugs still need to be explored. Two colon-cancer-derived cell lines, colon26 and HT29, were used to investigate the effect of 5-FU, 3-methyladenine (3-MA, an autophagy inhibitor), or their combination on apoptotic cell death and autophagy. MTT assay, Hochest plus propidium iodide (PI) staining, and DNA fragmentation assay were used to observe apoptosis. Meanwhile, monodansylcadaverine (MDC) was used to detect autophagy. Finally, immunoblotting assay was used to explore the molecular change that occurred. We observed the apoptosis induced by 5-FU in colon cancer cells. Meanwhile, autophagy was also stimulated. The combination treatment of 3-MA and 5-FU significantly increased the apoptotic cell death. By isolating the subcellular fractions of mitochondria and cytosol, we observed that the release of cytochrome c was increased in combination-treated cells. Cytochrome c resulted in the activation of caspase-3, thus activating PARP. Moreover, the anti-apoptotic protein, Bcl-xL, was significantly downregulated by 3-MA.
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Do eugonadal male patients with adrenal incidentalomas and subclinical hypercortisolism have increased rate of vertebral fractures?
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Subclinical hypercortisolism (SH) is suggested to exert a deleterious effect on bone. This effect and the role of gonadal status in male subjects are not fully elucidated. We evaluated bone mineral density (BMD) and prevalence of vertebral fractures in eugonadal male subjects with adrenal incidentalomas (AI) and without SH. This 12-month observational multicentre study was performed between January and December 2006 on inpatient basis in three referral Italian centres. Eighty-eight consecutive eugonadal male patients with AI and 90 matched control subjects were studied. All subjects underwent the determination of BMD by dual-energy X-ray absorptiometry at lumbar spine (LS) and femoral neck (FN), and spinal radiograph. In AI patients SH was diagnosed in the presence of two of the following: urinary free cortisol > 193.1 nmol/l, cortisol after 1 mg dexamethasone suppression test > 82.8 nmol/l, ACTH levels < 2.2 pmol/l. As compared to patients without SH (SH-, n = 66) and controls, patients with SH (SH+, n = 22) had lower BMD at LS (Z-score: SH+, -1.04 +/- 1.84; SH-, 0.19 +/- 1.34, Controls 0.20 +/- 1.28, P = 0.001 and FN (Z-score: SH+, -0.63 +/- 1.01; SH-, 0.01 +/- 1.01, Controls 0.26 +/- 1.06, P = 0.002) and higher prevalence of fractures (SH+, 72.7%; SH-, 21.2%, Controls 20.0%, P = 0.0001). Multivariable analyses showed that SH was associated to BMD at LS (beta = -0.378, P = 0.0001) and vertebral fractures (OR = 7.81, 95% CI 1.96-31.17, P = 0.004).
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We hypothesized that miR-194 may control Forkhead box protein M1 (FoxM1) expression in gastric cancer cells and therefore may have therapeutic potential in gastric cancer. The expression level of miR-194 was examined using real-time PCR in human gastric cancer and noncancerous gastric tissues, gastric cancer cell and normal gastric mucosal epithelial cell. We examined whether the miR-194 regulates cell migration and invasion, and the epithelial-mesenchymal transition Phenotype by inhibiting FoxM1 in gastric cancer cells. The expression of miR-194 was significantly lower in gastric cancer compared with non-cancerous gastric tissues and cells. Exogenous expression of miR-194 inhibited cell migration, invasion, and the epithelial-mesenchymal transition phenotype in gastric cancer cells. Moreover, we discovered a novel post-transcriptional regulatory mechanism of FoxM1 expression that is mediated by miR-194.
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Does quantified corticospinal tract diffusion restriction predict neonatal stroke outcome?
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Neonatal arterial ischemic stroke occurs in > or =1:4000 births. Many children experience motor deficits but acute predictors of outcome are lacking. Diffusion-weighted MRI changes in descending corticospinal tracts remote from arterial ischemic stroke may represent pre-Wallerian degeneration. We verify and quantify this signal and correlate it with motor outcome. Fourteen neonates with acute arterial ischemic stroke and > or =12 months follow-up with the Pediatric Stroke Outcome Measure were included. Quantitative measurements of descending corticospinal tracts diffusion-weighted MRI signal were developed using Image J software. Ipsilesional descending corticospinal tract diffusion-weighted MRI signal was abnormal in 10 neonates with decreased apparent diffusion coefficients (P<0.001). Poor outcome correlated with: (1) percentage of peduncle (P=0.002); (2) length of descending corticospinal tracts P<0.001); and (3) volume of descending corticospinal tracts (P=0.002). None of: (1) any peduncle; (2) any posterior limb of the internal capsule; or (3) infarct volume correlated with outcome. All children without descending corticospinal tracts signal had normal outcome. Chronic Wallerian degeneration was seen in all children with hemiparesis. Software-assisted analysis was superior to visual inspection with excellent reliability (intra-class correlation coefficient > or =0.9).
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Antigen-specific immunotherapy (SIT) has been widely practiced in treating allergic diseases such as asthma. However, this therapy may induce a series of allergic adverse events during treatment. Peptide immunotherapy (PIT) was explored to overcome these disadvantages. We confirmed that multiple antigen peptides (MAPs) do not cause autoimmune responses, which led to the presumption that MAPs intervention could alleviate allergic airway inflammation without inducing adverse effects. In this study, synthesized OVA323-339MAP octamers were subcutaneously injected into ovalbumin (OVA)-sensitized and -challenged Balb/c mice to observe its effect on allergic airway inflammation, Th2 immune response, and immune regulating function. It was confirmed that OVA sensitization and challenge led to significant peritracheal inflammatory, cell infiltration, and intensive Th2 response. Treatment of OVA323-339MAP octomers in the airway inflammation mice model increased CD4+CD25+Foxp3+ T regulatory (Treg) cells and their regulatory function in peripheral blood, mediastinal draining lymph nodes, and the spleen. Furthermore, OVA323-339MAP increased IL-10 levels in bronchial alveolar lavage fluid (BALF); up-regulated the expression of IL-10, membrane-bound TGF-β1, as well as Foxp3 in lung tissues; and up-regulated programmed death-1 (PD-1) and cytotoxic T lymphocyte associated antigen 4 (CTLA-4) on the surface of Treg cells. These results were further correlated with the decreased OVA specific immunoglobulin E (sIgE) level and the infiltration of inflammatory cells such as eosinophils and lymphocytes in BALF. However, OVA323-339 peptide monomers did not show any of the mentioned effects in the same animal model.
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Does sSeCKS/Gravin/AKAP12 attenuate expression of proliferative and angiogenic genes during suppression of v-Src-induced oncogenesis?
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SSeCKS is a major protein kinase C substrate with kinase scaffolding and metastasis-suppressor activity whose expression is severely downregulated in Src- and Ras-transformed fibroblast and epithelial cells and in human prostate, breast, and gastric cancers. We previously used NIH3T3 cells with tetracycline-regulated SSeCKS expression plus a temperature-sensitive v-Src allele to show that SSeCKS re-expression inhibited parameters of v-Src-induced oncogenic growth without attenuating in vivo Src kinase activity. We use cDNA microarrays and semi-quantitative RT-PCR analysis to identify changes in gene expression correlating with i) SSeCKS expression in the absence of v-Src activity, ii) activation of v-Src activity alone, and iii) SSeCKS re-expression in the presence of active v-Src. SSeCKS re-expression resulted in the attenuation of critical Src-induced proliferative and pro-angiogenic gene expression including Afp, Hif-1alpha, Cdc20a and Pdgfr-beta, and conversely, SSeCKS induced several cell cycle regulatory genes such as Ptpn11, Gadd45a, Ptplad1, Cdkn2d (p19), and Rbbp7.
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Centella asiatica (CA) leaves extract has been shown therapeutic potential. However, safety information is lacking. To evaluate acute oral toxicity (AOT), sub-chronic toxicity, and mutagenic potential of standardized extract of CA (L.) Urban leaves (INDCA). For the acute toxicity study, INDCA was orally administered to Sprague-Dawley rats at a dose range of 0-2000 mg/kg. For the repeated dose toxicity study, the rats of either sex were orally administered with INDCA at the doses of 250, 500, and 1000 mg/kg/day for a period of 90 days. The effects on body weight, food and water consumption, organ weight, hematology, clinical chemistry as well as histology were studied. The mutagenic potential of INDCA was tested using reverse mutation assay (Ames test). Data of each parameter were analyzed by one-way ANOVA followed by Dunnett's test to compare the difference between treated groups. The administration of INDCA did not produce mortality or significant changes in the clinical signs included but not limited to changes in the skin and fur, eyes and mucous membranes, and also respiratory, circulatory, autonomic and central nervous systems, somatomotor activity, and behavior pattern. The appearance, progress, and disappearance of these signs were recorded. The lethal dose and no observable adverse effect level of INDCA were 2000 mg/kg and 1000 mg/kg, respectively. There were no significant differences in the organ weights, hematological parameters, clinical chemistry values, or gross and microscopic appearance of the organs from the treatment groups as compared to the control group. It was found to be nonmutagenic in reverse mutation assay.
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Are glenoid version and inclination risk factors for anterior shoulder dislocation?
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Although the contribution of the capsuloligamentous structures and dynamic muscle balance to shoulder stability has been well documented, the role of the osseous anatomy of the glenoid has not been thoroughly evaluated. This study investigated glenoid version and inclination in patients with a documented anterior shoulder dislocation and compared it with a control group. We hypothesized that patients with a prior anterior dislocation would have more anterior version and increased inferior inclination of the glenoid. Patients aged younger than 40 years who underwent arthroscopic shoulder stabilization (study group) were compared with patients (control group) who had previously undergone magnetic resonance imaging (MRI) for a different shoulder condition. Version was measured on axial images, and inclination was measured on coronal images of a T2-weighted spin-echo scan. The MRIs of 128 study group patients (mean age, 24.5 ± 8.6 years) with a confirmed traumatic anterior shoulder dislocation were compared with the MRIs of 130 control group patients (mean age, 30.9 ± 7 years). The mean version in the study group was -1.7° ± 4.5° (retroversion); the mean inclination was 1.6° ± 5.9° (inferior). The mean version in the control group was -5.8° ± 4.6° (retroversion); the mean inclination was -4.0° ± 6.8° (superior). The between-group differences were significant for version (P = .00001) and inclination (P = .00001).
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Serum concentrations of soluble tumor necrosis factor-alpha (TNF-alpha) receptor 2 (sTNFR2) are associated with insulin resistance. In a recent study, we provided evidence for the existence of a biologically active form of sTNFR2 produced by alternative splicing (DS-TNFR2). We aimed to evaluate whether this circulating DS-TNFR2 is associated with insulin action in humans. Real time PCR (light cycler technology) evaluated DS-TNFR2 expression in monocytes. DS-TNFR2 was measured using a monoclonal antibody against an epitope present in TNFR2 (first 14 residues of the juxtamembrane region) but predicted to be absent in soluble proteolytic cleavage-produced TNFR2. Insulin sensitivity was measured using euglycemic hyperinsulinemic clamp (n = 76) and homeostatic model of assessment (HOMA) value in a replication study of 223 subjects. Real time PCR confirmed gene expression of DS-TNFR2 in monocytes from healthy subjects. A significant and positive association was found between serum DS-TNFR2 concentration and insulin sensitivity (P = 0.032, n = 76). This association was most significant in subjects with normal glucose tolerance (r = 0.44, P = 0.002). The subjects in whom DS-TNFR2 was detectable were more insulin sensitive than those with undetectable DS-TNFR2 (42.12+/-22.08 vs 31.71+/- 16.95 micromol x kg(-1) x min(-1), P = 0.039). DS-TNFR2 was inversely associated with body mass index, waist-to-hip ratio, systolic and diastolic blood pressure, fasting serum glucose, serum triglycerides and serum uric acid concentration and with the HOMA value (P = 0.03) in the replication study. Circulating DS-TNFR2 declined with increased number of components of the metabolic syndrome.
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