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['The methotrexate (MTX) polyglutamate assay has been validated in adults with arthritis.', 'We sought to assess clinical response rates and the value of the methotrexate polyglutamate assay in MTX-treated children with inflammatory skin diseases.', 'In this retrospective review, 46 MTX-treated children with a diagnosis of atopic dermatitis, psoriasis, or psoriasis-eczema overlap were serially assessed with the methotrexate polyglutamate assay.', 'In all, 38 children (83%) achieved good to excellent response: 27 (59%) within 12 weeks and 11 (24%) after dose-adjustment. Good to excellent responses were highest for psoriasis/overlap: 15 of 16 (94%), compared with 23 of 30 (77%) with atopic dermatitis. Mean maximum polyglutamate levels were 31.5 nmol/L for responders versus 18.1 nmol/L for nonresponders (P\xa0= .035). This difference was also significant for the subset with atopic dermatitis, but not for those with psoriasis/overlap. After dose modification, late\xa0responders ultimately achieved a significantly higher mean maximum methotrexate polyglutamate assay (41.9 nmol/L) compared with nonresponders (P\xa0= .002).']
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['Surgeon-performed ultrasonography is increasingly becoming part of the initial evaluation of patients after blunt or penetrating trauma. Currently, most institutions obtain a subxyphoid or subcostal view of the heart and pericardial space, and a three-view ultrasonogram of the abdomen to detect blood in the pericardial sac or in three dependent abdominal areas.', 'A left parastemal standard transverse transthoracic view is described in addition to the aforementioned views. This facilitates the visualization of the pericardial sac when a subxyphoid or subcostal view cannot be obtained because of anatomical reasons (narrow subxyphoid space) or local factors (pain, fractures, subcutaneous emphysema, or chest wall contusion).', 'The transthoracic view can be useful in patients where the subxyphoid view is difficult to obtain through the conventional approach. In most patients an excellent view of the pericardial sac and ventricles can be obtained and, therefore, expedites the diagnosis and treatment of patients with hemopericardium.']
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['Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a macrophage-synthesized lipase that is primarily bound to small electronegative low-density lipoproteins (LDLs). Lipoprotein-associated phospholipase A2 oxidatively modifies LDL and generates the proinflammatory byproducts oxidized fatty acids (ox-FAs) and lysophosphatidylcholine. Fenofibrate reduces Lp-PLA2 mass; however, it remains unknown whether the anti-inflammatory effects of fenofibrate are related to changes in LDL subclasses.', 'This was a randomized, double-blind, controlled clinical trial designed to investigate the effects of 3-month treatment with fenofibrate (160 mg/d) on Lp-PLA2 mass, LDL subclasses, and ox-FAs among 55 hypertriglyceridemic (> or = 1.7 and < 6.78 mmol/L) subjects with the metabolic syndrome.', 'Fenofibrate treatment lowered fasting Lp-PLA2 mass by 13.2% (-19.0 to -7.7) versus placebo (2.3% [-5.0 to 4.1], P = .0002) and total ox-FA by 15.5% (-34.2 to +1.4) versus an 11.5% increase with placebo (P = .0013). In age-, sex-, and treatment-adjusted models, changes in Lp-PLA2 mass were associated with reductions in chemical LDL cholesterol (r = 0.59, P < .01) and measured total LDL particles (LDL-Ps) (r = 0.64, P < .01) and small LDL-Ps (r = 0.57, P < .01). In models that included small LDL, effects of fenofibrate on Lp-PLA2 mass were attenuated (P = .125), but not in models that included LDL cholesterol (P < .0001) and LDL-Ps (P = .005). Changes in Lp-PLA2 mass were not significantly associated with changes in ox-FA or inflammatory markers.']
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['Neoadjuvant systemic therapy (NST) is an established strategy to reduce tumor size in breast cancer patients prior to breast-conserving therapy. The effect of NST on tumor cell dissemination in these patients is not known. The aim of this study was to investigate the incidence of disseminated tumor cells (DTC), including apoptotic DTC, in breast cancer patients after NST, and to investigate the correlation of DTC status with therapy response.', 'Bone marrow aspiration was performed in 157 patients after NST. DTC were detected by immunocytochemistry using the A45-B/B3 anticytokeratin antibody. To detect apoptotic DTC the antibody M30 (Roche Diagnostics, Germany) was used, which detects a neo-epitope expressed only after caspase cleavage of cytokeratin 18 during early apoptosis.', 'The incidence of DTC in breast cancer patients was 53% after completion of NST. Tumor dissemination was observed more frequently in patients with no change/progressive disease (69%) than in patients with partial remission or complete remission of the primary tumor (46%) (P < 0.05). Ten out of 24 patients with complete remission, however, were still bone marrow positive. Apoptotic DTC were present in 36 of 157 (23%) breast cancer patients. Apoptotic cells only were detected in 14% of the patients with partial remission or complete remission, but were detected in just 5% of the patients with stable disease. Apoptotic DTC were detectable in none of the patients with tumor progression.']
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['A subset of colorectal carcinomas are due to a deficiency in the DNA mismatch repair system. The molecular mechanisms of tumorigenesis in these tumors is not yet well understood. Deregulation of the cell cycle, specifically of the G(1) and S phases, is a hallmark of human cancers. Transition from the G(1) to the S phase is accelerated by increased cyclin E protein expression, and recent studies suggest that overexpression of cyclin E leads to chromosomal instability. The overexpression of cyclin E in a variety of human cancers, for example in colorectal, gastric, lung, breast, and kidney cancer, provides evidence that cyclin E plays a pivotal role in the cell cycle and replication. We examined whether the overexpression of cyclin E is related to the status of the mismatch repair system in colorectal carcinomas.', 'Frozen tumor samples and adjacent normal colon mucosa obtained from 100 patients were subjected to microsatellite analysis, RT-PCR, western blot analysis and immunohistochemistry.', 'High microsatellite instability was detected in 13 tumors, and in 10 of these (77%) cyclin E protein was overexpressed at least twofold compared to normal mucosa. In contrast, only 28 of the remaining 87 microsatellite stable tumors (32%) overexpressed cyclin E. Lower molecular weight cyclin E proteins were present in 7 of 87 microsatellite stable carcinoma (8%), compared to 7 cases exhibiting lower molecular weight isoforms of 13 MSI carcinoma (54%).']
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['It is now generally admitted that penetrance of the common HFE p.C282Y/p.C282Y genotype is incomplete, and identification of modifier genes is the concern of a growing number of research projects. We recently identified a significant association between pretherapeutic serum ferritin level and the common rs235756 single nucleotide polymorphism (SNP) of the BMP2 gene region. Our results further suggested an interactive effect between the BMP2 rs235756 SNP and the rs16827043 SNP in HJV, with a small additive effect of the rs4901474 SNP in BMP4.', 'The present study has been designed as a replication study in an independent cohort of 450 HFE p.C282Y homozygous patients from a nearby French region (Brittany). Information on individual alcohol consumption and amount of iron removed by phlebotomy being available for a substantial part of this cohort, additional analyses were conducted.', 'Only the use of the Amount of Iron Removed by phlebotomy (AIR) as marker of iron burden has provided positive results. Indeed, a significant association was detected between rs235756 and AIR adjusted for sex and age, with a mean AIR increasing with the number of BMP2 T alleles in the genotype groups. The effect of rs235657 was not strong enough to detect effects of gene combinations. Still, the trend in two-locus genotype risks involving BMP2 and HJV for AIR was concordant with the specific interactive effect described in the initial study.']
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['This study assessed functional performance, calf muscle characteristics, peripheral nerve function, and quality of life in asymptomatic persons with peripheral arterial disease (PAD).', 'PAD participants (n=465) had an ankle brachial index <0.90. Non-PAD participants (n=292) had an ankle brachial index of 0.90 to 1.30. PAD participants were categorized into leg symptom groups including intermittent claudication (n=215) and always asymptomatic (participants who never experienced exertional leg pain, even during the 6-minute walk; n=72). Calf muscle was measured with computed tomography. Analyses were adjusted for age, sex, race, ankle brachial index, comorbidities, and other confounders. Compared with participants with intermittent claudication, always asymptomatic PAD participants had smaller calf muscle area (4935 versus 5592 mm(2); P<0.001), higher calf muscle percent fat (16.10% versus 9.45%; P<0.001), poorer 6-minute walk performance (966 versus 1129 ft; P=0.0002), slower usual-paced walking speed (P=0.0019), slower fast-paced walking speed (P<0.001), and a poorer Short-Form 36 Physical Functioning score (P=0.016). Compared with an age-matched, sedentary, non-PAD cohort, always asymptomatic PAD participants had smaller calf muscle area (5061 versus 5895 mm(2); P=0.009), poorer 6-minute walk performance (1126 versus 1452 ft; P<0.001), and poorer Walking Impairment Questionnaire speed scores (40.87 versus 57.78; P=0.001).']
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['To investigate the effects of fenofibrate, an activator of peroxysome proliferator activated receptor (PPAR) alpha, on vascular endothelium and on hemostasis in a rabbit endotoxic shock model.', 'Prospective laboratory study in a university laboratory.', '36 male New Zealand rabbits weighing 2.5-3 kg.', 'We determined in vitro vascular reactivity, endothelium CD31-platelet/endothelial cell adhesion molecule (PECAM) 1 immunohistochemistry, plasma coagulation factors, and monocyte tissue factor expression 5 days after onset of endotoxic shock (0.5 mg/kg intravenous bolus, Escherichia coli lipopolysaccharide) with or without treatment by fenofibrate (mixed in the chow at a concentration of 0.5%) for 15 days before lipopolysaccharide injection and 5 days afterward.', 'Metabolic acidosis and coagulation activation confirmed presence of shock. Fenofibrate decreased monocyte tissue factor expression. It improved endothelial-dependent relaxation at 5 days (Emax=68.2+/-3.3%, vs. 44.2+/-2.5% in the non-treated group). Endotoxin-induced deendothelialization was significantly decreased by fenofibrate at 5 days (8.5+/-1.3% vs. 19.2+/-3.1% in the nontreated group) .']
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['Long noncoding RNAs (lncRNAs) have been identified as having functional roles in cancer biology and are deregulated in many cancers. The present study aimed to determine the expression, roles and functional mechanisms of a long noncoding RNA CCAT1 in the progression of hepatocellular carcinoma (HCC).', 'CCAT1 expression levels in 66 pairs of HCC tissues and pair-matched noncancerous hepatic tissues were tested by real-time PCR. The effects of CCAT1 on HCC cells proliferation and migration were assessed using in vitro cell proliferation and migration assays. A computational screen of microRNAs (miRNAs) target sites in CCAT1 was conducted to search for specific miRNAs binding to CCAT1. The specific binding between CCAT1 and miRNAs was confirmed by RNA immunoprecipitation assay combined with luciferase reporter assay.', 'CCAT1 levels are markedly increased in HCC tissues compared with pair-matched noncancerous hepatic tissues. Up-regulation of CCAT1 is correlated with tumor size, microvascular invasion, AFP and poor prognosis. CCAT1 promotes the proliferation and migration of HCC cells. CCAT1 functions as a molecular sponge for let-7, antagonizes its functions, and leads to the de-repression of its endogenous targets HMGA2 and c-Myc. The effect of CCAT1 on HCC cell proliferation and migration is dependent upon its competitively binding to let-7.']
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['We assessed the association between herpes zoster (HZ) and herpes simplex (HS) occurrence whilst controlling for risk factors of HZ.', 'Using a Belgian general practitioner network, a retrospective cohort study with 3736 HZ patients and 14,076 age-gender-practice matched controls was performed, covering over 1.5 million patient-years. Multiple logistic regression was used with HZ as outcome and several diagnoses (malignancy, depression, diabetes mellitus, auto-immune diseases, asthma, multiple sclerosis, HIV, fractures), medications (systemic corticosteroids, biologicals, vaccination), HS and other infections as variables.', 'HS was significantly associated with HZ for all analysed time intervals (up to five years) post HZ (OR of 3.51 [2.09 5.88] 95%CI one year post HZ) and to a lesser extent for time ranges pre HZ. Registration of other infections was significantly associated with HZ in all time intervals pre and post HZ (OR up to 1.37). Malignancy up to five years pre HZ, depression up to one year pre or post HZ, fractures up to two years pre HZ, asthma, auto-immune diseases, and immunosuppressive medication one year pre or post HZ were also associated with HZ.']
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['The elevated plus-maze and the light/dark box are two established anxiety tests in rodents, which are useful to screen putative anxiogenic effects of drugs.', "Caffeine is well known to promote anxious behaviour in humans and animal models, but the precise site of action of the drug is still a matter of debate. The present study investigated whether the anxiogenic effects of caffeine observed in mice depend on the blockade of A(2A) receptor. First, the effects induced by the non-selective drug caffeine were compared with those elicited by two selective A(2A) receptor antagonists over a wide range of doses in the same experimental conditions. The effects of A(2A) or A(1 )adenosine receptor agonists and of a selective A(1) adenosine receptor antagonist were also investigated. Second, wild-type and A(2A) receptor knockout mice offered another approach to delineate the role played by A(2A) receptor in caffeine's anxiogenic effects.", 'Mice were exposed to the elevated plus-maze or to the light/dark box for 5 min after acute or chronic administration of tested drugs.', 'Caffeine acutely administered (50 or 100 mg/kg IP) induced anxiety-like effects in both procedures. Its chronic administration (50 mg/kg IP twice daily) for 1 week or consumption in the drinking water (0.3 g/l) for 8 days or 2 months were also anxiogenic in the plus-maze test. The A(2A) receptor antagonists ZM241385 (up to 60 mg/kg IP) and SCH58261 (up to 10 mg/kg IP) were devoid of acute effects in both tests. One week administration of ZM241385 (30 mg/kg IP) or SCH58261 (3 mg/kg IP) had no effects in the plus-maze test. An antagonist (DPCPX) and an agonist (CPA) at A(1) receptors had no acute effects on anxiety-related indices, whereas an A(2A) receptor agonist (CGS 21680) displayed non-specific motor effects in the plus-maze test. Acute administration of caffeine (50 mg/kg IP) induced no clear-cut anxiety-like effects in the plus-maze test in A(2A) receptor knockout mice that exhibited higher basal anxiety levels than wild-type mice. Chronic administration (50 mg/kg IP twice daily) for 1 week elicited less anxiety-like behaviour in A(2A) receptor knockout than in wild-type mice.']
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['T cells have been attributed an important role in modulating repair responses following vascular injury. The aim of this study was to investigate the role of different T cell subsets in this context.', 'A non-obstructive collar was introduced to inflict carotid artery injury in mice and subsequent activation of immune cells in draining lymph nodes and spleen were studied by flow cytometry. Carotid artery injury of wild type mice was associated with mobilization of both Th1 type CD4(+)IFNγ(+) and regulatory CD4(+)CD25(+)FoxP3(+) T cells in draining lymph nodes. Studies using FoxP3-green fluorescent protein (GFP) transgenic C57/Bl6 mice demonstrated scattered presence of regulatory T cells in the adventitial tissue of injured arteries as well as a massive emigration of regulatory T cells from the spleen in response to carotid injury. However, deletion of antigen presentation to CD4+ T cells (H2(0) mice), as well as deletion of regulatory T cells (through treatment with blocking anti-CD25 antibodies), did not affect neointima formation. Also deletion of antigen presentation to CD8(+) T cells (Tap1(0) mice) was without effect on carotid collar-induced neointima formation.']
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['To evaluate the relationship between osteopontin (OPN) in serum and plasma and parathyroid hormone-related protein (PTHrP) in serum, plasma and tumour tissue, and to assess the prognostic impact of OPN and PTHrP in human renal cell carcinoma (RCC).', 'The study included 269 patients with RCC. In 189 patients, immunohistochemical (IHC) PTHrP tumour tissue expression was evaluated, and OPN and PTHrP in serum were assessed. In 80 patients, plasma OPN and PTHrP were analysed. Tumour type, TNM stage, nuclear grade and RCC-specific survival were also registered. In a sub-group, IHC expression of CD 31 was assessed. The prognostic information of the factors was analysed using uni- and multivariate analyses.', 'The median OPN level was 2.3 times higher in plasma than in serum. Serum OPN was significantly higher in patients with papillary RCC compared to clear cell RCC and chromophobe RCC. Both serum and plasma OPN levels were positively correlated to TNM stage and nuclear grade. Multivariate analysis showed that serum and plasma OPN levels were independent prognostic factors for RCC-specific survival, along with TNM stage. Immunohistochemical expression of PTHrP associated to TNM stage but not to nuclear grade or serum OPN. Furthermore, IHC expression of PTHrP was positively correlated to serum PTHrP but inversely to tumour CD31 expression. Plasma PTHrP was increased in 20% of the patients and related to TNM stage but not to nuclear grade. Plasma OPN was significantly higher in patients with increased PTHrP levels, compared to those with normal levels.']
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['Bone mineral density (BMD) testing is a key tool used to diagnose and treat osteoporosis. We assessed the rate of scheduling BMD tests among health plan members at risk for osteoporosis who received interactive voice response (IVR) calls.', 'Cohort study.', 'Study patients included persons age 45 years with either a prior fracture or 90 days of glucocorticoid use and all women age 65 years during the 2-year baseline period. The IVR call provided educational content and then offered members an opportunity to transfer to schedule a BMD test. The primary outcome was scheduling a BMD test.', "We targeted 1402 health plan members, and 708 (50%) were successfully contacted. Of 54 patients who transferred to schedule a BMD test, only 3 actually did so. Because so few patients scheduled a BMD test, predictors of transfer were examined as a secondary end point. In a multivariate model, only self-reported intention to schedule a BMD test was a significant predictor (odds ratio = 4.4, 95% confidence interval = 2.2, 8.8). Members' age, sex, history of a prior fracture, self-report of a BMD test in the previous 2 years, acknowledgement of barriers to BMD testing, and discussion of BMD testing with one's physician were not related to transferring to schedule a BMD test."]
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['To assess compliance with established consensus derived guidelines for ondansetron therapy and to estimate the cost of any non-guideline use.', "All inpatients (including paediatric patients) at Christchurch Hospital who received ondansetron during August 1993 were identified by daily review of medication charts. Outpatients who received ondansetron prescriptions were identified from pharmacy records. All patients' medical records were then examined and ondansetron therapy was compared with the guideline recommendations for indication and dosage. The total cost of ondansetron for each patient was also calculated.", "Ondansetron was prescribed for 64 patients (41 female, 23 male) during the one month period. Fifty patients received ondansetron therapy in accordance with all indication and dosage aspects of the guidelines. The main guideline indication for use was highly emetogenic chemotherapy with 28 patients. Fifteen patients received ondansetron because of failure of standard antiemetic therapy and nine because they were paediatric chemotherapy patients. Of the 12 patients who received ondansetron outside the guidelines indications, nine had received 'moderately highly' emetogenic chemotherapy (whereas the guidelines state 'highly' only), two had severe asthma, one received radiotherapy. Two patients did not comply with the dosage recommendations as they received ondansetron more than 24 hours after the initial cytotoxic dose. Total ondansetron expenditure for the period was $12,789 (inpatient $8492 outpatient $4297). Expenditure related to the nonguideline usage was $536 (4.2% of the total monthly ondansetron expenditure)."]
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['Ischemic postconditioning (PoC) is a cardio-protective strategy in which initial reperfusion is interrupted by episodes of ischemia. It is unclear whether PoC can be achieved in the Langendorff perfused rat heart model. We investigated (1) whether postconditioning occurs in Langendorff perfused rat heart and (2) whether there is a gender-specific response to PoC.', 'Male/female rat hearts (n = 8/group) were subjected to 30 min of equilibration, 30 min of ischemia, and 120 min of reperfusion (Control). PoC was induced by 6 cycles (PoC 6c10s), 3 cycles (PoC 3c10s), or 2 cycles (PoC 2c10s) of 10 s reperfusion/10 s ischemia. Rate pressure product (RPP) and infarct size were measured. Male rats (n = 7/group) were subjected in vivo to 30 min left coronary ligation followed by 24 h of reperfusion (Control) or PoC 6c10s and 24 h of reperfusion.', 'Recovery of RPP was 18% ± 4% in male Control versus 17% ± 2% for 6c10s, 16% ± 1% for 3c10s, and 15% ± 3% for 2c10s. Female Control hearts recovered 25% ± 3% of their RPP versus 21% ± 2% for 6c10s. Infarct size was 25% ± 3% for male Control versus 26% ± 3% for 6c10s, 30% ± 2% for 3c10s, 28% ± 1% for 2c10s, and 30% ± 2% for female Control versus 29% ± 2% in 6c10s. In vivo infarct size for Control and PoC 6c10s was 44% ± 3% and 28% ± 5%, respectively (P < 0.05).']
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["Non-Hodgkin's B-cell lymphomas account for approximately 70% of B-cell lymphomas. While its incidence is dramatically increasing worldwide, the disease is still associated with high morbidity due to ineffectiveness of conventional therapies, creating an urgent need for novel therapeutic approaches. Unconventional compounds, including polyphenols and the cytokine TRAIL, are being extensively studied for their capacity to restore apoptosis in a large number of tumors, including lymphomas.", "Molecular mechanisms of TRAIL-resistance and reactivation of the apoptotic machinery by quercetin in non-Hodgkin's lymphoma cell lines were determined by Hoescht, flow cytometry, Western blot, qPCR, by use of siRNA or pharmacological inhibitors of the mitochondrial pathway and by immunoprecipitation followed by post-translational modification analysis.", 'Results demonstrate that quercetin, a natural flavonoid, restores TRAIL-induced cell death in resistant transformed follicular lymphoma B-cell lines, despite high Bcl-2 expression levels due to the chromosomal translocation t(14;18). Quercetin rescues mitochondrial activation by inducing the proteasomal degradation of Mcl-1 and by inhibiting survivin expression at the mRNA level, irrespective of p53. Restoration of the TRAIL pathway requires Bax and Bak but is independent of enhanced TRAIL DISC formation.']
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['To determine the prevalence of foot vein incompetence in a group of patients with chronic venous insufficiency and to assess the association of this, with venous ulceration located on the forefoot.', 'A total of 20 consecutive patients (21 limbs) with active or healed venous ulceration was prospectively studied with duplex ultrasound of the superficial and plantar foot veins. In these, four extremities had venous ulceration involving the forefoot. Specifically, the superficial venous arch near the metatarsal heads, the foot portion of the great and small saphenous veins, the anterior arch veins on the foot dorsum, and the plantar veins were interrogated with a 12-MHz probe.', 'Reflux was found in 32% of pedal vein segments in CEAP C5, C6 legs, with ulceration involving only the gaiter area (mean number of incompetent foot segments, 1.6 ± 1.2). Pedal reflux was present in 65% of foot vein segments when forefoot ulceration was present (mean number of incompetent foot segments, 3.3 ± 1.3). Student t-test for the difference in the mean number of incompetent foot vein segments was significant (P < .004).']
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['High levels of plasma homocysteine have been reported to be toxic to the vascular endothelium, thereby creating an environment of hypercoagulability and occlusion. Elevated homocysteine has been reported as a risk factor for young adult central retinal vein occlusion (CRVO) cases. This study aimed to see if oxidative stress is an independent risk factor or is homocysteine dependent.', '23 young adult CRVO patients and 54 age and sex-matched controls were included in the study. Oxidative stress markers thiobarbituric acid-reacting substance (TBARS), superoxide dismutase (SOD), total thiols, glutathione peroxidase and total antioxidant capacity (TAC) were estimated. The effect of homocysteine (25-200 μM) on cultured bovine retinal endothelial cells (BREC) on oxidative stress parameter TBARS was measured.', 'There was a significant increase in the plasma TBARS in CRVO cases compared with controls (p=0.000). SOD and TAC were significantly lower in CRVO cases than controls (p=0.000, p=0.022). There was a significant negative correlation between TAC and TBARS (p=0.00) and a significant positive correlation between homocysteine and TBARS (p=0.029). Nominal regression analysis showed that TAC and homocysteine influence TBARS significantly. The in-vitro study in BREC cells revealed that homocysteine increased the TBARS dose and time dependently.']
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['Prostate-specific antigen (PSA) is a serine protease secreted as a zymogen. Previously, cell-free biochemical studies have identified various kallikreins (KLK) as candidate activating proteases. In this study, KLK2-mediated activation of PSA in cell-based in vitro, xenograft, and transgenic models was evaluated.', 'Du145-derived PSA- or KLK2-expressing clones were coincubated in vitro and in vivo to evaluate KLK2-induced PSA activity. While mice possess orthologs of KLK4-15, they do not have functional orthologs of PSA or KLK2. Therefore, transgenic animals expressing PSA or both PSA and KLK2 were generated to assess orthotopic PSA activation.', 'PSA is activated by KLK2 when the cells are physically in contact, and through co-conditioned media. In vivo, the free (inactive PSA) to total (active + inactive PSA) ratio in the blood is decreased when PSA and KLK2-expressing cells are co-inoculated subcutaneously, suggesting increased active PSA. Additionally, double-transgenic mice expressing both genes in the prostate produce more active PSA compared to single transgenic animals. A longitudinal evaluation over a 2-year period demonstrated no morphologic changes (i.e., no PIN or prostate cancer) due to PSA or PSA/KLK2 double transgene expression relative to non-transgenic mice.']
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["The rate of iatrogenic pneumothorax associated with thoracic central venous catheterization in community emergency departments (EDs) is poorly described, although such information is vital to inform the procedure's risk/benefit analysis. We undertook this multicenter study to estimate the incidence of immediate catheter-related pneumothorax in community EDs and to determine associations with site of access, failed access, and positive pressure ventilation.", "This was a secondary analysis of 2 retrospective cohort studies of adults who underwent attempted thoracic central venous catheterization in 1 of 21 EDs. Pneumothorax was identified by postprocedural anteroposterior chest radiograph or emergent evacuation for presumed tension pneumothorax. Frequencies were compared using Fisher's exact test.", 'Among 1249 patient encounters, the initial vein of catheterization was internal jugular in 1054 cases (84.4%) and subclavian in 195 cases (15.6%). Success at the initial internal jugular vein was more common than at the initial subclavian vein (95.4% vs 83.6%, P < .001). Periprocedural positive pressure ventilation was administered in 316 patients (25.3%). We identified 6 pneumothoraces (0.5%; 95% confidence interval, 0.2%-1.1%). The incidence of pneumothorax was higher with the subclavian vein than the internal jugular vein (2.3% vs 0.1%, P < .001), with failed access at the initial vein (2.5% vs 0.3%, P = .05), and among patients receiving positive pressure ventilation (1.6% vs 0.1%, P < .01).']
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['We addressed whether patients with a family history of atrial fibrillation (AF) were diagnosed as having AF earlier in life, were more symptomatic, and had worse outcomes compared with those without a family history of AF.', 'Using the ORBIT-AF, we compared symptoms and disease characteristics in those with and without a family history of AF. A family history of AF was defined as AF in a first-degree family member and obtained by patient self-reporting. Multivariable Cox proportional hazard analyses were performed to compare the incidence of cardiovascular outcomes, AF progression, all-cause hospitalization, and all-cause death.', 'Among 9,999 patients with AF from 176 US outpatient clinics, 1,481 (14.8%) had a family history of AF. Relative to those without, those with a family history of AF developed AF 5 years earlier on average (median age 65 vs 70 years, P < .01), with less comorbidity, and had more severe AF-related symptoms. No differences were found between the 2 groups in the risk of AF progression (adjusted hazard ratio [HR] 0.98, 95% CI 0.85-1.14), stroke, non-central nervous system embolism, or transient ischemic attack (adjusted HR 0.95, 95% CI 0.67-1.34), all-cause hospitalization (adjusted HR 1.03, 95% CI 0.94-1.12), and all-cause death (adjusted HR 1.05, 95% CI 0.86-1.27).']
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['To evaluate the combination of CpG oligodeoxynucleotide (CpG ODN) and miltefosine for the treatment of experimental visceral leishmaniasis (VL).', 'The experiments were carried out using BALB/c mice and hamsters, infected with Leishmania donovani. CpG ODN was administered at various doses by the intraperitoneal (ip) route. The dose of CpG ODN (1 nM/single dose) showing best antileishmanial activity was given as free and liposomal forms with a subcurative dose of miltefosine, namely 2.5 and 5 mg/kg x 5 days in mice and hamsters, respectively.', 'Among the various groups of mice, co-administered liposomal CpG ODN and miltefosine showed the best inhibitory effect (85% inhibition) compared with free CpG ODN and miltefosine, and miltefosine, free CpG ODN and liposomal CpG ODN separately. Production of Th1 cytokines, nitric oxide (NO), reactive oxygen species (ROS) and H(2)O(2) was enhanced. A remarkable increase in the phagocytosis index was also observed, indicating overall immunological support to antileishmanial activity of miltefosine by CpG ODN. Similar responses were observed in hamsters.']
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['Hemobilia is an uncommon cause of gastrointestinal bleeding. The etiology is diverse, but most often, it is iatrogenic. The present study aims to reassess the clinical picture and the treatment of choice.', 'We describe a case series from a single center of patients who presented with nontraumatic iatrogenic hemobilia.', 'Over a period of 8 years, hemobilia occurred in 12 patients: following liver biopsy in six patients and after endoscopic biliary interventions in four patients, with a respective prevalence of 0.1 and 0.04%. The clinical presentation was characterized by an upper gastrointestinal bleeding (n=11) and/or biochemical signs of sudden biliary obstruction (n=9). The onset of the symptoms occurred after a median of 6 days (range: 1-23). Ultrasound and computed tomography scan missed the diagnosis in, respectively, 4/5 and 2/5 of patients. On arteriography, pseudoaneurysm (6/12) was the most common finding. Transcatheter arterial embolization controlled the bleeding in all cases (12/12) without major complications.']
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['We aimed to better discriminate metastasized (lymphogen/occult/both combined) from non-metastasized seminoma based on post-transcriptional changes examined in the peripheral blood.', 'Total RNAs including small RNAs were isolated from the peripheral blood of patients suffering from metastasized testicular tumours (lymphogen, n = 5, clinical stage IIb/c; occult, n = 5, clinical stage I) and non-metastasized patients (n = 5, clinical stage I). Small RNA next generation sequencing (SOLID, Life Technologies) was employed to examine post-transcriptional changes. We searched for small RNAs showing at least 50 reads and a significant\u2009 ≥ 2-fold difference using peripheral blood small RNAs of non-metastasized tumours as the reference group. Candidate small RNAs were examined in univariate logistic regression analysis and combinations of two small RNAs were further examined using support vector machines.', 'On average 1.3 x 10(7), 1.2 x 10(7) and 1.2 x 10(7) small RNA reads were detectable in non-metastasized, lymphogen and occult metastasized seminoma, respectively of which 73-76% remained after trimming. From these between 80-82% represented annotated reads and 7.2-7.8% (1.6-1.7 x 10(4)) were annotated small RNA tags. Of them 137 small RNAs showed > 50 reads and a ≥ two-fold difference to the reference. In univariate analysis we detected 33-35 different small RNAs which significantly discriminated lymphogen/occult/combined metastasized from non-metastasized seminoma and among these different comparisons it were the same small RNAs in 44-79%. Many combinations of two of these small RNAs completely discriminated metastasized from non-metastasized seminoma irrespective of the metastasis subtype.']
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['We hypothesized that among patients with chronic obstructive pulmonary disease, those who develop quadriceps contractile fatigue (QCF) after exhaustive submaximal cycle exercise would have a greater response to exercise training than those who do not develop QCF (NQCF).', 'Patients (N = 132) had measurement of QCF at baseline. Six-minute walk distance (6 MWD), maximal incremental cycle exercise testing, and quality of life measured by the Chronic Respiratory Questionnaire were obtained before and after pulmonary rehabilitation (PR).', 'Eighty of the 132 patients (60.6%) developed QCF following constant workload exhaustive cycle exercise. Patients who developed QCF had a significantly greater improvement in 6 MWD following PR (45.3 ± 45.2 m) than those who did not (27.5 ± 45.7 m; P= .032). When baseline differences between patients who developed QCF and NQCF were accounted for, the difference in 6 MWD remained significant. Patients who developed QCF were not more likely to identify leg fatigue as the factor limiting exercise (56.2% of QCF group stated that leg fatigue was the limiting factor compared with 47.9% in the NQCF group; P= .46). When baseline differences were accounted for, the symptom causing exercise termination was not a predictor of the response to PR.']
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['To investigate the preventive and therapeutic effects and the possible mechanisms of Dilingdan Decoction (DLDD), a compound Chinese herbal medicine, on rats with renal tubulointerstitial fibrosis induced by unilateral ureteral obstruction (UUO).', 'Sixty SD rats were randomly divided into sham-operated group, untreated group, enalapril-treated group and DLDD-treated group. Blood urea nitrogen (BUN), serum creatinine (SCr), urine protein quantization in 24 hours and pathological changes of the obstructed kidney were observed. The expressions of transforming growth factor-beta1 (TGF-beta1), alpha-smooth muscle actin (alpha-SMA), fibronectin (FN) and laminin (LN) were detected by immunohistochemical method and colored-multimedia pathological image analysis system.', 'Massive inflammatory infiltrates and collagen expression in renal interstitial in the untreated group were observed on the 7th day. Compared with the sham-operated group, percentages of area of TGF-beta1, alpha-SMA, FN and LN expressions in the untreated group were markedly increased (P<0.05), while the percentage of area of interstitial fibrosis was decreased in the DLDD-treated group as compared with the untreated group (P<0.05). On the 14th day, the percentages of area of TGF-beta1, alpha-SMA, FN and LN expressions were declined in two treated groups as compared with the untreated group (P<0.05), but had no statistical difference in biochemical indicators, including BUN, SCr and 24-hour urinary protein. On the 21st day, the level of SCr and the percentage of area of TGF-beta1 expression in the DLDD-treated group were lower than those of the enalapril-treated group (P<0.05).']
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['B-cell chronic lymphocytic leukemia (B-CLL) is characterized by the accumulation of monoclonal mature B cells. The G protein Galphas subunit has been linked to proapoptotic processes in cancer cell lines. The TT genotype of the GNAS1 T393C polymorphism is associated with increased Galphas transcript levels and a more favorable clinical course in different solid cancers.', 'We retrospectively genotyped 144 patients with B-CLL to examine a potential association between T393C genotypes with progression-free survival (time from diagnosis to initiation of chemotherapy) and overall survival.', 'The C-allele frequency in the patient group was 0.57 and not significantly different from that of healthy blood donors. Median progression-free survival was significantly different between genotypes (TT 130 months; TC 100 months; CC 31 months; P = 0.0066). Multivariable analysis showed that besides of ZAP-70 (P = 0.005) and Binet stage (P < 0.001), the T393C polymorphism was an independent prognostic factor for progression-free survival [hazard ratio (HR) CC versus TT 2.7; P = 0.010]. In Binet A stages, ZAP-70-positive patients with CC genotypes had a HR of 4.4 to receive first therapy compared with ZAP-70-negative patients with T-alleles (P = 0.0001). Regarding overall survival, CC genotypes (median overall survival, 197 months) were at highest risk for death compared with T-alleles (median overall survival, 310 months) in both univariate (HR, 4.8; P < 0.0001) and multivariable analysis (HR, 5.6; P = 0.002).']
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['Preterm birth is a major cause of infant morbidity and long-term disability, and is associated with numerous central nervous system (CNS) deficits. Infants exposed to intrauterine inflammation, specifically chorioamnionitis, are at risk for very early preterm birth and neurological complications including cerebral palsy, epilepsy, and behavioral and cognitive deficits. However, placenta-brain axis abnormalities and their relationship to subsequent permanent CNS injury remain poorly defined.', 'Intrauterine injury was induced in rats on embryonic day 18 (E18) by transient systemic hypoxia-ischemia (TSHI) and intra-amniotic lipopolysaccharide (LPS) injection. Placenta, brain and serum were collected from E19 to postnatal day 0 (P0). Histology, TUNEL staining, western blot and multiplex immunoassays were used to quantify placental and brain abnormalities, and fetal serum cytokine levels.', 'Prenatal TSHI + LPS caused acute and subacute placental injury hallmarked by inflammatory infiltrate, edema, hemorrhage and cell death along with placental increases in IL-1β and TNFα. TSHI + LPS increased a diverse array of circulating inflammatory proteins including IL-1β, TNFα, IL-6, IL-10, IL-4, IFNγ and CXCL1, both immediately after TSHI + LPS and in live born pups. CNS inflammation was characterized by increased CXCL1.']
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['Prognostic value of myocardial fibrosis in patients with non-ischemic idiopathic dilated cardiomyopathy (DCM) is not well-defined. We sought to assess the association of focal and diffuse myocardial fibrosis with left ventricular reversed remodeling (LVRR).', 'Patients with DCM who underwent cardiac MRI with baseline and subsequent follow-up echocardiography were included in the study. Post-contrast T1 times were corrected for renal function, body size, gadolinium dose and time after Gadolinium injection. Patients were followed over a median time of 29months to evaluate changes of left ventricular end-systolic volume (LVESV). A Linear Mixed Model was used to assess the relationship between the LVESV during follow-up, corrected post-T1 value delayed hyperenhancement (DHE), and modified Seattle Heart Failure Score (SHFS).', 'A total of 103 patients (mean age 51±15years, 61% male) were evaluated. The mean LVEF was 33±11%, LVESVi 62±39ml/m(2), and T1 time 416±98. DHE was identified in 45 patients (44%). Patients with focal DHE (n=45) had higher LVESVi at baseline and during follow-up (p=0.024). Post T1 value >450 was an independent predictor of LVRR at the follow-up (Δ=24.6ml/m(2) SE 14.6ml/2, p=0.0480) in patients despite the presence of DHE, even after adjusting for their SHFS.']
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['betaig-h3 is an extracellular matrix protein whose expression in several cell types is greatly increased by transforming growth factor-beta (TGF-beta). TGF-beta is believed to be involved in the development of diabetic nephropathy and thus we have assessed the possibility that betaig-h3 may be a downstream molecule in this pathogenic process.', 'Immunoblotting and immunohistochemistry were done using an antibody against mouse betaig-h3 protein. betaig-h3 and TGF-beta concentrations were measured by enzyme-linked immunosorbent assay (ELISA). Cell adhesion and migration were assessed by measuring activity of N-acetyl-beta-d-glucosaminidase and using a transwell plate, respectively.', "Immunohistochemistry revealed that betaig-h3 occurs mainly in the basement membrane of proximal tubules, particularly the S3 segment but also to lesser extents in the basement membranes of the cortical thick ascending limb cells and the parietal glomerular epithelial cells in Bowman's capsule. Immunoblotting revealed that approximately 68 kD bands were seen only in the cortex + the outer stripe of the outer medulla. Rats with streptozotocin (STZ)-induced diabetes exhibited a marked and sustained increase in renal betaig-h3 abundance. This was mirrored by urinary betaig-h3 levels. In vitro experiments with human primary renal proximal tubular epithelial cells revealed that their expression of betaig-h3 was greatly increased by either TGF-beta or glucose. High glucose levels also stimulated TGF-beta production by renal proximal tubular epithelial cells and the high glucose-induced betaig-h3 expression was almost completely blocked by anti-TGF-beta antibody. betaig-h3 mediated renal proximal tubular epithelial cells adhesion and migration."]
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['Intracerebral hemorrhage (ICH) is one of the most common clinical manifestations of human brain arteriovenous malformation (BAVM). However, the hemorrhagic mechanism of BAVM is still unclear. Leptin, first discovered in obesity research, has not been systematically studied in BAVM and ICH. We investigated expression and effect of leptin on human BAVM.', 'Specimens were obtained from 6 BAVM patients, who had been divided into either hemorrhagic or non-hemorrhagic groups. Leptin, leptin receptor, and signal transducers and activators of transcription-3 (STAT3) were analyzed by different methods, such as gene chips, reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry, and Western blot. Perinidal brain tissue around each BAVM served as control.', 'Gene chips and RT-PCR found transcriptional leptin raised at least 2 levels in hemorrhagic BAVM. Immunohistochemical slices also showed higher expression of leptin, leptin receptor, and STAT3 on nidus part of hemorrhagic BAVM than non-hemorrhagic ones. On Western blot analysis, hemorrhagic BAVMs had higher levels of leptin (p < 0.01).']
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['To characterize phenotypes of T cells that accumulated in multiple sclerosis (MS) lesions, to compare the lesional T-cell receptor (TCR) repertoire of T-cell subsets to peripheral blood, and to identify paired α and β chains from single CD8(+) T cells from an index patient who we followed for 18 years.', 'We combined immunohistochemistry, laser microdissection, and single-cell multiplex PCR to characterize T-cell subtypes and identify paired TCRα and TCRβ chains from individual brain-infiltrating T cells in frozen brain sections. The lesional and peripheral TCR repertoires were analyzed by pyrosequencing.', 'We found that a TCR Vβ1(+) T-cell population that was strikingly expanded in active brain lesions at clinical onset comprises several subclones expressing distinct yet closely related Vα7.2(+) α chains, including a canonical Vα7.2-Jα33 chain of mucosal-associated invariant T (MAIT) cells. Three other α chains bear striking similarities in their antigen-recognizing, hypervariable complementarity determining region 3. Longitudinal repertoire studies revealed that the TCR chains that were massively expanded in brain at onset persisted for several years in blood or CSF but subsequently disappeared except for the canonical Vα7.2(+) MAIT cell and a few other TCR sequences that were still detectable in blood after 18 years.']
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['Determine the incidence of hepatitis C virus antibodies among a cohort of prisoners.', 'Follow-up study of a random sample of prisoners who participated in a cross-sectional survey in 1996.', '29 correctional centres in New South Wales (Australia).', '181 adult prisoners (163 men and 18 women).', 'The incidence of hepatitis C virus antibody among the 90 inmates who were seronegative at the first test in 1996 was 7.1 per 100 person-years (16 seroconverters). Among the 90 inmates, 37 had re-entered the prison system following release into the community and 53 had been continuously detained. The seroconversion rate was higher among the re-entrants compared with those who had been continuously incarcerated (10.8 vs. 4.5 per 100 person-years, p=0.07). However, when the data was stratified by injecting status, the serocon-version rate in the two groups was similar. Most of the seroconverters had histories of injecting drug users (14/16). The overall incidence among injectors was 19.3 per 100 person years (95% CI: 9.1-29.2).']
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['Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been regarded as a promising candidate for cancer therapy. However, most of oral cancer cell lines are resistant to the TRAIL-induced cytotoxicity. The aim of this study was to investigate the ability of phenethyl isothiocyanate (PEITC) to sensitize TRAIL-induced apoptosis in TRAIL-resistant oral cancer cells and xenografts.', 'Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay, Western blotting, and a mouse xenograft model were used to study the effects of PEITC and TRAIL on two TRAIL-resistant human oral cancer cells, SAS and Ca9-22.', 'PEITC upregulated death receptor 4 (DR4) and DR5 protein expression and increased reactive oxygen species (ROS) production in both SAS and Ca9-22 cells. Antioxidant N-acetyl-L-cysteine (NAC) and c-Jun NH2-terminal kinase (JNK) inhibitor SP600125 inhibited PEITC-induced DR4 and DR5 expression. Inhibitor experiments showed that PEITC induced apoptosis through ROS-mediated JNK activation and upregulation of DR4 and DR5. Furthermore, treatment with PEITC significantly increased TRAIL-induced apoptosis in both cells. Combined treatment with PEITC and TRAIL had greater effect on the inhibition of tumor growth than either agent alone.']
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['Human papillomavirus (HPV) testing has become an essential part of current clinical practice in the management of cervical cancer and precancerous lesions. We reviewed the most important validation studies of a next-generation real-time polymerase chain reaction-based assay, the RealTime High Risk HPV test (RealTime)(Abbott Molecular, Des Plaines, IL, USA), for triage in referral population settings and for use in primary cervical cancer screening in women 30 years and older published in peer-reviewed journals from 2009 to 2013. RealTime is designed to detect 14 high-risk HPV genotypes with concurrent distinction of HPV-16 and HPV-18 from 12 other HPV genotypes. The test was launched on the European market in January 2009 and is currently used in many laboratories worldwide for routine detection of HPV.', 'We concisely reviewed validation studies of a next-generation real-time polymerase chain reaction (PCR)-based assay: the Abbott RealTime High Risk HPV test.', 'Eight validation studies of RealTime in referral settings showed its consistently high absolute clinical sensitivity for both CIN2+ (range 88.3-100%) and CIN3+ (range 93.0-100%), as well as comparative clinical sensitivity relative to the currently most widely used HPV test: the Qiagen/Digene Hybrid Capture 2 HPV DNA Test (HC2). Due to the significantly different composition of the referral populations, RealTime absolute clinical specificity for CIN2+ and CIN3+ varied greatly across studies, but was comparable relative to HC2. Four validation studies of RealTime performance in cervical cancer screening settings showed its consistently high absolute clinical sensitivity for both CIN2+ and CIN3+, as well as comparative clinical sensitivity and specificity relative to HC2 and GP5+/6+ PCR.']
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['The aim of this study was to investigate the influence of clinicopathological and biological characteristics on prognosis, disease free survival (DFS) and overall survival (OS), of very young patients (≤35 years of age) with breast cancer.', 'We retrospectively collected information of 150 women diagnosed with breast cancer, aged ≤35 years, who were operated and treated at two University Hospitals in Serbia between January 2009 and February 2011.', 'After a median follow up of 44 months patients ≤30 had shorter DFS and OS compared to patients aged 31-35 years (p=0.004 and p=0.037, respectively). The differences in DFS and OS were significant with decreased survival associated with higher tumor grade (p=0.005 and p=0.0001, respectively). Tumor size and number of positive nodes were predictors of outcome with decreased survival associated with higher tumor size (p=0.0019 for DFS and p<0.0001 for OS) and increasing number of nodes (p<0.0001 for both). HER 2 receptor did not seem to have a prognostic influence while patients with hormonal receptors (HRs) positive tumors had a better DFS (p=0.034) and OS (p=0.046) than those with HRs negative tumors. In univariate survival analysis, a significant difference in DFS (p=0.0003) and OS (p=0.0003) was found between patients with vs without lymphovascular invasion (LVI).']
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['Motor learning is the core cognitive function in neurorehabilitation and in various other skill-training activities (e.g. sport, music). Therefore, there is an increasing interest in the use of transcranial magnetic stimulation (TMS) methods for its enhancement. However, although usually assumed, a potential placebo effect of TMS methods on motor learning has never been systematically investigated.', 'Improvement of performance on the Purdue Pegboard Task over three test-blocks (T0, T1, and T2), separated by >20 min, was used to evaluate motor learning. In Experiment-1, two groups of 10 participants each were compared: one group immediately before T1 received a sham intermittent theta burst stimulation procedure (P-iTBS group), while another did not have any intervention at all (control - CON group). In Experiment-2, a third group of participants (six subjects) who received sham high-frequency repetitive TMS procedure before T1 (P-rTMS group) was compared with P-iTBS group.', 'All three groups showed significant learning over time, but without any difference between them, either in Experiment-1 between P-iTBS and CON, or in Experiment-2 between P-rTMS and P-iTBS.']
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['To date, studies with ingenol mebutate gel have used clinical clearance, not histological clearance, as a primary efficacy endpoint.', 'This phase I, multicentre, single-arm, open-label study sought to confirm histologically the clinical clearance of actinic keratoses (AKs) to support a treatment effect deep in the epidermis.', 'Patients (n = 108) aged ≥ 18 years with histologically confirmed AK within a 25-cm', 'The observed agreement rate between clinical and histological assessments of clearance of a single AK was 81·9% and the positive predictive value of a clinical assessment of clearance was 87%. Agreement between the two pathologists was 88%. The common composite 8-week complete clearance rate was 41% (95% confidence interval 32-50). Observed agreement rates between RCM and pathologist I and II assessments of clearance were 72·9% and 81·4%, respectively. Overall, 30 patients (27·8%) experienced 38 adverse events (AEs). Application-site pain (four patients, 3·7%) was the most common treatment-related AE inside the treatment area.']
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['Oxidative stress and fibrosis is implicated in cardiac remodeling and failure. We tested whether allopurinol could decrease myocardial oxidative stress and attenuate cardiac fibrosis and left ventricular diastolic dysfunction in angiotensin II (AngII)-induced hypertensive mice.', 'We used 8-week-old male C57BL/6J mice, in which angiotensin II was subcutaneously infused for 4 weeks to mimic cardiac remodeling and fibrosis. They were treated with either normal saline or allopurinol in daily doses, which did not lower blood pressure.', 'Allopurinol improved diastolic dysfunction in angiotensin II-induced hypertensive mice, which was associated with the amelioration of cardiac fibrosis. However, allopurinol showed no effect on the increased systolic blood pressure by angiotensin II infusion. The ratio of reduced glutathione (GSH) to oxidized glutathione (GSSG) [GSH/GSSG] was decreased and malondialdehyde levels were increased in the hearts of AngII-treated mice. Allopurinol also inhibited both the decrease in the GSH/GSSG ratio and the increase in malondialdehyde levels in the heart. Infusion of AngII-induced upregulation of transfer growth factor (TGF)-β1, Smad3 expression and downregulation of Smad7 expression. Treatment with allopurinol reduced cardiac levels of TGF-β1, Smad3, and increased Smad7 expression.']
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['Decreased heart rate variability (HRV) and abnormal nonlinear HRV shortly after myocardial infarction (MI) are risk factors for mortality. Traditional HRV predicts mortality in patients with a range of times post-MI, but the association of nonlinear HRV and outcome in this population is unknown.', 'HRV was determined from 740 tapes recorded before antiarrhythmic therapy in Cardiac Arrhythmia Suppression Trial patients with ventricular premature contractions (VPCs) suppressed on the first randomized treatment. Patients were 70 +/- 121 days post-MI. Follow up was 362 +/- 241 days (70 deaths). The association between traditional time and frequency-domain HRV and mortality and nonlinear HRV and mortality were compared for the entire population (ALL), those without coronary artery bypass graft post-MI (no CABG), and those without CABG or diabetes (no CABG, no DIAB) using univariate and multivariate Cox regression analysis. Strength of association was compared by P values and Wald Chi-square values. Nonlinear HRV included short-term fractal scaling exponent, power law slope, and SD12 (Poincare dimension). For ALL and for no CABG, increased daytime SD12 had the strongest association with mortality (P=0.002 ALL and P <0.001 no CABG). For no CABG, no DIAB increased 24-hour SD12 hours had the strongest association (P <0.001) with mortality. Upon multivariate analysis, increased SD12, decreased ln ULF (ultra low frequency), and history of prior MI and history of congestive heart failure each remained in the model.']
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['Clinical joint activity is a strong predictor of joint damage in rheumatoid arthritis (RA), but progression of damage might increase despite clinical inactivity of the respective joint (silent progression). The aim of this study was to evaluate the prevalence of silent joint progression, but particularly on the patient level and to investigate the duration of clinical inactivity as a marker for non-progression on the joint level.', '279 patients with RA with any radiographic progression over an observational period of 3-5\u2005years were included. We obtained radiographic and clinical data of 22 hand/finger joints over a period of at least 3\u2005years. Prevalence of silent progression and associations of clinical joint activity and radiographic progression were evaluated.', '120 (43.0%) of the patients showed radiographic progression in at least one of their joints without any signs of clinical activity in that respective joint. In only 7 (5.8%) patients, such silent joint progression would go undetected, as the remainder had other joints with clinical activity, either with (n=84; 70.0%) or without (n=29; 24.2%) accompanying radiographic progression. Also, the risk of silent progression decreases with duration of clinical activity.']
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['Although interleukin-17 (IL-17)-producing gamma/delta T cells were reported to play pathogenic roles in collagen-induced arthritis (CIA), their characteristics remain unknown. The aim of this study was to clarify whether gamma/delta T cells or CD4+ T cells are the predominant IL-17-producing cells, and to determine what stimulates gamma/delta T cells to secret IL-17 in mice with CIA. The involvement of IL-17-producing gamma/delta T cells in SKG mice with autoimmune arthritis and patients with rheumatoid arthritis (RA) was also investigated.', 'IL-17-producing cells in the affected joints of mice with CIA were counted by intracellular cytokine staining during 6 distinct disease phases, and these cells were stimulated with various combinations of cytokines or specific antigens to determine the signaling requirements. Similar studies were performed using SKG mice with arthritis and patients with RA.', 'Gamma/delta T cells were the predominant population in IL-17-producing cells in the swollen joints of mice with CIA, and the absolute numbers of these cells increased in parallel with disease activity. IL-17-producing gamma/delta T cells expressed CC chemokine receptor 6, were maintained by IL-23 but not by type II collagen in vitro, and were induced antigen independently in vivo. Furthermore, IL-17 production by gamma/delta T cells was induced by IL-1beta plus IL-23 independently of T cell receptor. In contrast to what was observed in mice with CIA, IL-17-producing gamma/delta T cells were nearly absent in the affected joints of SKG mice and patients with RA, and Th1 cells were predominant in the joints of patients with RA.']
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['To determine genome-wide methylation profiles of bone from patients with hip osteoarthritis (OA) and those with osteoporotic (OP) hip fractures.', 'Trabecular bone pieces were obtained from the central part of the femoral head of 27 patients with hip fractures and 26 patients with hip OA. DNA was isolated, and methylation was explored with Illumina methylation arrays. RNA was extracted, pooled, and deep-sequenced to obtain the whole transcriptome. Differentially methylated regions were identified, and connections between genes with differentially methylated regions were explored by pathway and text-mining analyses.', 'After quality control, methylation of 23,367 CpG sites (13,463 genes) was analyzed. There was a genome-wide inverse relationship between methylation and gene expression in both patient groups. Comparison of OP and OA bones revealed 241 CpG sites, located in 228 genes, with significant differences in methylation (false discovery rate<0.05). Of them, 217 were less methylated in OP than in OA. The absolute methylation differences were >5% in 128 CpG sites and >10% in 45 CpG sites. The differentially methylated genes were enriched for association with bone traits in the genome-wide association study catalog. Pathway analysis and text-mining analysis with Gene Relationships Across Implicated Loci software revealed enrichment in genes participating in glycoprotein metabolism or cell differentiation, and particularly in the homeobox superfamily of transcription factors.']
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['The weightbearing axis of the limb goes from the pelvis to the ground and includes the hindfoot. However, the influence of hindfoot alignment on mechanical axis and overall limb alignment after TKA is unclear.', 'We therefore addressed the following questions: (1) Does hindfoot alignment change after TKA for knee osteoarthritis? (2) What factors influence hindfoot alignment after TKA? (3) Does deviation of the mechanical axis from the center of the knee vary when the hindfoot is considered (ground mechanical axis) as compared with when it is not (conventional mechanical axis) after TKA?', 'We prospectively reviewed the radiographs of 125 patients who underwent 165 TKAs. We evaluated the preoperative and postoperative hip-knee-ankle (HKA) angle, conventional mechanical axis deviation, ground mechanical axis (mechanical axis which included the hindfoot) deviation, and tibiocalcaneal angle.', 'The preoperative hindfoot valgus alignment decreased after TKA. Preoperative hindfoot alignment was the only factor that influenced hindfoot alignment after TKA. The conventional mechanical axis showed less deviation from the center of the knee when compared with ground mechanical axis which showed lateral deviation after TKA. Despite limb alignment being restored to within 3° of neutral of the conventional mechanical axis after TKA, 29% of limbs had a postoperative ground mechanical axis deviation of 10 mm or greater.']
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['Renal failure is a frequent complication of juxtarenal abdominal aortic aneurysm (JAA)-repair. During this operation, suprarenal aortic-clamping is followed by infrarenal aortic-clamping (below renal arteries) to restore renal flow, while performing the distal anastomosis. We hypothesized that infrarenal aortic-clamping, despite restoring renal perfusion provokes additional renal damage.', 'We studied three groups of rats. After 45min of suprarenal aortic-clamping, group 1 had renal reperfusion for 90min without aortic-clamps (n=7). In group 2, 45min of suprarenal aortic-clamping with a distal clamp on the aortic-bifurcation was followed by 20min of infrarenal aortic-clamping. Renal reperfusion was continued for 70min without aortic-clamps (i.e. 90\u2003min of renal reperfusion; n=8). The sham-group had no clamps (n=7). We measured renal haemodynamics, functional parameters and tissue damage.', 'On suprarenal aortic-clamp removal, renal artery flow, cortical flow and arterial pressures were higher in group 2 than in group 1. We detected increased tubular brush border damage, luminal lipocalin-2 and 30-60% higher renal protein nitrosylation in group 2 when compared to group 1 (P<0·05). Group 2 showed more release of asymmetrical dimethylarginine (ADMA) from the kidneys in the renal vein, therefore indicating diminished clearing capacity (P<0·001). Arginine/ADMA-ratio, which defines the bio-availability of nitric oxide, tended to be lower in group 2 and correlated with renal flow. Furthermore, there were no significant differences found in creatinine levels and renal leucocyte accumulation between group 1 and 2.']
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['Delayed drainage on diuretic renography is an accepted sign of obstruction in adults and symptomatic children. We investigated how to analyze the diuretic challenge as well as assess the significance of impaired drainage.', 'We followed 24 children with a unilateral prenatal diagnosis of pelvic dilatation up to a minimum of 2 years. A total of 91 diuretic renograms were performed. All children had stable differential renal function and renal pelvic diameter did not change by greater than 9 mm. on sequential ultrasound. Kidneys with stable differential function and no increase in dilatation were considered not obstructed. Analysis of the diuretic challenge included half-time, a post-void image with a change in posture, that is the child erect for 5 to 7 minutes, and drainage considering renal function using the pelvic excretion efficiency. Prolonged drainage was defined as a half-time of greater than 20 minutes or a post-void pelvic excretion efficiency of less than 71%.', 'Median patient age at presentation was 0.32 years and median followup was 3.07 years. The affected nonobstructed hydronephrotic kidney showed impaired drainage in 68% of the children using the half-time parameter, and in 80% and 44% using pelvic excretion efficiency before and after voiding, respectively. Variability in drainage was documented on sequential diuretic renography.']
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["To evaluate the educational and clinical effectiveness of the 'Brief Evidence-Based Assessment of Research' (BEAR), a template to assist residents in searching, evaluating and integrating relevant medical literature into daily practice.", 'We completed a descriptive analysis of BEARs submitted by first year residents between 2005 and 2007 at the University of Alberta Family Medicine Residency program.', '317 BEARs were analyzed. The most common type of question for which information was searched was therapy (59%). Residents searched Pubmed most often (38%) followed by Summary (i.e. Clinical Evidence) (22%) and Filtered sites (i.e. ACP Journal Club) (19%). Original research articles were the largest resource category used to answer questions (41%). Secondary peer-reviewed resources (filtered articles, summary sites, reviews/meta-analysis and guidelines) accounted for 48% of all resources used. 19% of residents reported a large change in practice with completion of the BEAR, 50% reported a small change, 12% stated they were reassured and 8% reported that the intervention was of no help to them.']
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['Osteosarcoma is the most common primary bone malignancy with high local aggressiveness and rapid metastasizing potential, resulting in poor survival. Increasing reports suggest that deregulated microRNAs (miRNAs) might provide novel therapeutic targets for cancers. However, the expression of miR-26a and miR-27a in osteosarcoma need further investigation in clinical samples. In our study, we evaluate the expression of these miRNAs in osteosarcoma tissues and compared with paired adjacent non-tumor bone tissues using RT-qPCR.', 'Total RNA was purified from patients with osteosarcoma and noncancerous bone tissues. Real-time PCR was applied to quantify the expression level of miR-26a and miR-27a. Moreover, the correlation of these markers with clinicopathological characteristics was also evaluated in osteosarcoma patients. A cox proportional hazards model was performed to assess multivariate analyses of prognostic values.', 'Our result suggested that miR-26aexpression level in osteosarcoma bone tissue was significantly lower than that in the paired noncancerous bone tissues. MiR-27a expression was higher in osteosarcoma bone tissue in comparison with paired noncancerous bone tissues. The results indicated that low expression level of miR-26a and high expression of miR-27a were associated with high TNM stage (P\u2009=\u20090.001; P\u2009=\u20090.012), tumor grade (P\u2009=\u20090.007; P\u2009=\u20090.016), and distant metastasis (P\u2009=\u20090.004; P\u2009=\u20090.001). Kaplan-Meier analysis and log-rank test indicated that patients with low expression of miR-26a and high expression of miR-27a had shorter overall survival (log-rank test: P\u2009<\u20090.001). Multivariate Cox proportional hazards model analysis showed that low expression of miR-26a and high expression of miR-27a (P\u2009=\u20090.021; P\u2009=\u20090.011), high TNM stage (P\u2009=\u20090.001; P\u2009=\u20090.003), tumor grade (P\u2009=\u20090.005; P\u2009=\u20090.01), and distant metastasis.(P\u2009=\u20090.002; P\u2009=\u20090.005) were independent prognostic factors for overall survival patients with osteosarcoma cancer.']
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['p-cresol (PC) and p-cresyl sulfate (PCS) are responsible for many of the uremia clinical consequences, such as atherosclerosis in Chronic Kidney Disease (CKD) patients.', 'We investigate the in vitro impact of PC and PCS on monocyte chemoattractant protein-1 (MCP-1) expression via NF-kappa B (NF-κB) p65 in VSMC.', 'PCS was synthesized by PC sulfatation. VSMC were extracted by enzymatic digestion of umbilical cord vein and characterized by immunofluorescence against α-actin antibody. The cells were treated with PC and PCS at their normal (n), uremic (u) and maximum uremic concentrations (m). Cell viability was assessed by MTT. MCP-1 expression was investigated by ELISA in cells supernatants after toxins treatment with or without the NF-κB p65 inhibitor.', 'There was no significant difference in cell viability after toxins treatment for all concentrations tested. There was a significant increase in MCP-1 expression in cells treated with PCu and PCm (p < 0.001) and PCSn, PCSu and PCSm (p < 0.001), compared with the control. When VSMC were treated with the NF-κB p65 inhibitor plus PCu and PCm, there was a significant decrease in MCP-1 production (p < 0.005). This effect was not observed with PCS.']
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['Critically ill patients require transfusions because of acute blood loss and the anemia of critical illness. In critically ill burn patients, typically, no distinction is made between transfusions related to acute surgical blood loss and those related to the anemia of critical illness. We sought to identify the percentage of blood transfusions due to the anemia of critical illness and the clinical characteristics associated with these transfusions in severely burned patients.', 'Sixty adult patients with ≥20% total body surface area (TBSA) burn who were transfused at least 1 unit of packed red blood cells during their hospitalization were studied. Clinical variables including age, %TBSA burn, Acute Physiology and Chronic Health Evaluation (APACHE) II score, number of ventilator days, inhalation injury, and number of operative events were correlated with the total number of packed red blood cell units and percentage of nonsurgical transfusions in these patients. Nonsurgical transfusions were defined as transfusions occurring after postoperative day 1 for each distinct operative event and were classified as being caused by the anemia of critical illness.', 'Patients were transfused an average of 16.6 units ± 21.2 units. Nonsurgical transfusions accounted for 52% of these transfusions. APACHE II score, %TBSA burn, number of ventilator days, and number of operative events, all correlated with total transfusions. However, nonsurgical transfusions correlated with only APACHE II score (p = 0.01) and number of ventilator days (p = 0.03). There was no correlation between nonsurgical transfusions and other clinical variables.']
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['Hydrogen sulphide (H(2) S) is gaining acceptance as a gaseous signal molecule. However, mechanisms regarding signal termination are not understood. We used stigmatellin and antimycin A, inhibitors of sulphide quinone reductase (SQR), to test the hypothesis that the catabolism of H(2) S involves SQR.', 'H(2) S production and consumption were determined in living and intact mouse brain, liver and colonic muscularis externa using gas chromatography and HPLC. Expressions of SQR, ethylmalonic encephalopathy 1 (Ethe1) and thiosulphate transferase (TST; rhodanese) were determined by RT-PCR and immunohistochemistry.', 'In the colonic muscularis externa, H(2) (35) S was catabolized to [(35) S]-thiosulphate and [(35) S]-sulphate, and stigmatellin reduced both the consumption of H(2) (35) S and formation of [(35) S]-thiosulphate. Stigmatellin also enhanced H(2) S release by the colonic muscularis externa. In the brain, catabolism of H(2) (35) S to [(35) S]-thiosulphate and [(35) S]-sulphate, which was stigmatellin-insensitive, partially accounted for H(2) (35) S consumption, while the remainder was captured as unidentified (35) S that was probably bound to proteins. Levels of mRNA encoding SQR were higher in the colonic muscularis externa and the liver than in the brain.']
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['Patients with rheumatoid arthritis (RA) have shared care between rheumatologists and general practitioners (GPs). Rheumatologists guide immunosuppressive therapy, whilst GPs rely on analgesia and glucocorticoid (GC) therapy to manage active disease. The objective of this study was to describe patterns of GC prescribing for patients with RA in primary care and to determine the influence of patient characteristics and prescriber.', 'Incident RA patients were identified within the Clinical Practice Research Datalink, a United Kingdom (UK) primary care research database. Descriptive statistics identified patterns of oral GC prescribing. Prescribers were categorised by their tendency to prescribe GCs (high/low). Logistic regression was used to identify baseline characteristics associated with GC prescriptions during follow-up and to examine whether baseline characteristics influenced prescribing differently in high versus low prescribers.', 'A total of 7777 patients (47%) received ≥1 GC prescription during follow-up. The average daily dose was 7.5 mg (IQR 5-15.3 mg). Of those who received GCs, >50% were prescribed >10 mg/day and 20 % >30 mg/day. The median proportion of time spent on GCs was 26.3% (IQR 3.8-70.0%). Age and cardiovascular disease (CVD) were associated with increased likelihood of receiving GCs. High prescribers more commonly prescribed GC therapy in older patients and patients with hypertension.']
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['The 2007 World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) guidelines encourage cancer survivors to follow its cancer prevention recommendations. We evaluated whether adherence to the WCRF/AICR guidelines for cancer prevention was associated with lower mortality among older female cancer survivors.', "From 2004 to 2009, 2,017 participants in the Iowa Women's Health Study who had a confirmed cancer diagnosis (1986-2002) and completed the 2004 follow-up questionnaire were followed. Adherence scores for the WCRF/AICR guidelines for body weight, physical activity, and diet were computed assigning one, 0.5 or 0 points to each of eight recommendations depending on the degree of adherence. All-cause (n = 461), cancer-specific (n = 184), and cardiovascular disease (CVD)-specific mortality (n = 145) were compared by the total adherence score and by adherence scores for each of the three components of the recommendations.", 'Women with the highest (6-8) versus lowest (0-4) adherence score had lower all-cause mortality [HR = 0.67; 95% confidence of interval (CI), 0.50-0.94]. Meeting the physical activity recommendation was associated with lower all-cause (Ptrend < 0.0001), cancer-specific (Ptrend = 0.04), and CVD-specific mortality (Ptrend = 0.03). Adherence to dietary recommendations was associated with lower all-cause mortality (Ptrend < 0.05), whereas adherence to the body weight recommendation was associated with higher all-cause mortality (Ptrend = 0.009).']
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['Endothelial adhesion molecules ICAM-1 (CD54) and VCAM-1 (CD106) mediate cellular adhesion and transcellular migration. Cell adhesion and diapedesis have a key role in the course of shock and sepsis. During severe sepsis, adrenoceptor agonist levels may be increased due to endogenous production or due to intensive care treatment. As yet, the influence of β1 or β2 agonists on adhesion molecule formation on endothelial cells has remained unclear.', 'Cultured human umbilical vein endothelial cells were stimulated with E. coli. Following bacterial stimulation the cells were incubated with either β2 receptor agonist terbutaline or β1 agonist norepinephrine. ICAM-1 and VCAM-1 expression were examined using flow cytometry.', 'Administration of norepinephrine did not cause increases of both CD54 and CD106 in stimulated HUVEC. Compared to negative controls the bacterial stimulation itself led to an increase of adhesion molecules. Following administration of terbutaline no significant increase in CD54 expression was found.']
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['Life-long insulin is the standard treatment for type 1 diabetes mellitus (T1DM). The role of traditional Chinese medicine (TCM) in T1DM is still not clear. The aim of this study is to explore the prescription pattern of TCM and its impact on the risk of diabetic ketoacidosis (DKA) in patients with T1DM.', 'We retrieved samples from the registry for catastrophic illness patients from the National Health Insurance Research Database (NHIRD). Based on a frequency (1:4) matched case-control design, patients with T1DM in 2000-2011 were designated as cases (TCM users) and controls (non-TCM users). TCM treatment for patients with T1DM was analyzed. The incidence of DKA and the annual costs of emergency visits and hospitalizations were evaluated for all causes.', 'Overall, 416 subjects were TCM users, whereas a total of 1608 matched subjects were classified as non-TCM users. The most common Chinese herbal formula and single herb is Liu-wei-di-huang-wan (Six-ingredient pill of Rehmannia) and Huang-qi (Radix Astragali; Astragalus membranaceus (Fisch.) Bunge, Astragalus membranaceus var. mongholicus (Bunge) P.K.Hsiao), respectively. Compared with non-TCM users, we found a 33% reduction in DKA incidence for all TCM users (aHR 0.67, 95% CI 0.56-0.81, p <0.000) and a 40% reduction for users receiving TCM treatment for more than 180 days (aHR 0.58, 95% CI 0.41-0.82, p <0.01). There were no significant differences between TCM users and non-users in the frequency and medical costs of emergency visits and hospitalizations.']
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['During asymmetric cell division in the Drosophila nervous system, Numb segregates into one of two daughter cells where it is required for the establishment of the correct cell fate. Numb is uniformly cortical in interphase, but in late prophase, the protein concentrates in the cortical area overlying one of two centrosomes in an actin/myosin-dependent manner. What triggers the asymmetric localization of Numb at the onset of mitosis is unclear.', 'We show here that the mitotic kinase Aurora-A is required for the asymmetric localization of Numb. In Drosophila sensory organ precursor (SOP) cells mutant for the aurora-A allele aurA(37), Numb is uniformly localized around the cell cortex during mitosis and segregates into both daughter cells, leading to cell fate transformations in the SOP lineage. aurA(37) mutant cells also fail to recruit Centrosomin (Cnn) and gamma-Tubulin to centrosomes during mitosis, leading to spindle morphology defects. However, Numb still localizes asymmetrically in cnn mutants or after disruption of microtubules, indicating that there are two independent functions for Aurora-A in centrosome maturation and asymmetric protein localization during mitosis. Using photobleaching of a GFP-Aurora fusion protein, we show that two rapidly exchanging pools of Aurora-A are present in the cytoplasm and at the centrosome and might carry out these two functions.']
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['We investigated the longitudinal association of depression, with and without cognitive dysfunction, with hemoglobin A1c (HbA1c), systolic blood pressure (SBP), and low-density lipoprotein (LDL) in a predominantly minority cohort.', 'There were 613 participants. Presence of depression was defined by a score ≥7 on the Short-CARE depression scale. We tested participants for executive dysfunction using the Color Trails Test (CTT), part 2, and for memory dysfunction using the total recall task of the Selective Reminding Test (TR-SRT). We classified performance in these tests as abnormal based on standardized score cutoffs (<16th percentile and one standard deviation below the sample mean). Random effects models were used to compare repeated measures of the diabetes control measures between those with depression versus those without depression and ever versus never cognitively impaired.', 'Baseline depression was present in 36% of participants. Over a median follow-up of 2 years, depression was not related to worse HbA1c, SBP, or LDL. The presence of (1) abnormal performance on a test of executive function and depression (n=57) or (2) abnormal performance on a test of verbal recall and depression (n=43) was also not associated with clinically significant worse change in diabetes control.']
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['The precise mechanism by which the immune system is adversely affected in cancer patients remains poorly understood, but the accumulation of immune suppressive/pro-tumorigenic myeloid-derived suppressor cells (MDSCs) is thought to be one prominent mechanism contributing to immunologic tolerance of malignant cells in epithelial ovarian cancer (EOC). To this end, we hypothesized genetic variation in MDSC pathway genes would be associated with survival after EOC diagnoses.', 'We measured the hazard of death due to EOC within 10 years of diagnosis, overall and by invasive subtype, attributable to SNPs in 24 genes relevant in the MDSC pathway in 10,751 women diagnosed with invasive EOC. Versatile Gene-based Association study (VEGAS) and the Admixture Likelihood method (AML), were used to test gene and pathway associations with survival.', 'We did not identify individual SNPs that were significantly associated with survival after correction for multiple testing (p<3.5 x 10-5), nor did we identify significant associations between the MDSC pathway overall, or the 24 individual genes and EOC survival.']
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['Lithium is the most widely prescribed mood stabilizer, but the precise mechanism of lithium is unresolved.', 'We examine the effects of the administration of therapeutically relevant concentrations of lithium on the expression of brain-derived neurotrophic factor (BDNF) and its receptor, Trk B, as well as glia-derived neurotrophic factor (GDNF) and its receptors, RET and GDNFR-alpha, in the rat brain. In addition, we also examined the effect of another well-prescribed mood stabilizer, valproate, on the expression of BDNF and GDNF.', 'Rats were kept on a 0.2% lithium carbonate-containing diet for 1, 7, 14, or 28 days or treated with valproate (400 mg/kg per day i.p.) for 1 or 14 days. After the brains were rapidly removed, the levels of BDNF, GDNF, and their receptors were measured by ELISA or western blot analysis.', 'Chronic lithium treatment for 14 and 28 days significantly increased the expression of BDNF in the hippocampus and temporal cortex. In addition, chronic lithium treatment for 14 days significantly increased the expression of BDNF in the frontal cortex. In contrast, acute or chronic dietary lithium treatment did not alter GDNF expression in these brain regions. In addition, acute or chronic lithium treatments did not change the levels of Trk B, RET, or GDNFR-alpha immunoreactivity. As well as lithium, repeated administration of valproate also increased the expression of BDNF in the frontal cortex and hippocampus.']
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['To determine the influence of N-acetylcysteine on endotoxin-induced leukocyte-endothelial cell adhesion, vascular leakage, and venular microhemodynamics.', 'Randomized, blinded, controlled trial.', 'Experimental laboratory.', 'Thirty male Wistar rats.', 'After pretreatment with N-acetylcysteine (150 mg/kg; n = 40; group A) or 0.9% saline solution (n = 10; group B) animals were given an intravenous infusion of endotoxin (Escherichia coli lipopolysaccharide 026:B6; 2 mg/kg/hr) over 120 mins. Animals in the control group (n = 10; group C) received a volume-equivalent infusion of 0.9% saline solution.', 'Leukocyte adherence, red cell velocity (VRBC), vessel diameters, venular wall shear rate, and macromolecular leakage were determined in mesenteric postcapillary venules using in vivo videomicroscopy at baseline and at 30, 50, 90, and 120 mins after the start of the endotoxin challenge. Endotoxin exposure induced a marked increase in adherent leukocytes (group B: baseline, 391 +/- 24 cells/mm2; 120 mins, 1268 +/- 131 cells/mm2; p < .01). N-acetylcysteine pretreatment attenuated the adherence of leukocytes during endotoxemia (baseline, 366 +/- 28 cells/mm2; 120 mins, 636 +/- 49 cells/mm2; p < .01 vs. baseline; p < .01 vs. group B). Leukocyte adherence in control animals (group C) did not increase significantly. Administration of N-acetylcysteine did not influence the decrease in VRBC observed during endotoxemia. In group B1 VRBC decreased during the infusion of endotoxin from 2.0 +/- 0.2 mm/sec at baseline to 1.1 +/- 0.2 mm/ sec after 120 mins (p < .01 vs. baseline; p < .05 vs. group C), and in group A from 2.2 +/- 0.2 mm/sec to 1.1 +/- 0.1 mm/sec after 120 mins (p < .01 vs. baseline; p < .05 vs. group C). In group C, VRBC remained unchanged (baseline, 1.7 +/- 0.2 mm/sec; at 120 mins, 1.5 +/- 0.2 mm/sec). The venular diameters remained unchanged in all groups during the entire study period. After 120 mins, the venular wall shear rate decreased from 502 +/- 62 secs-1 at baseline to 272 +/- 46 sec-1 in group B (p < .01), and from 563 +/- 45 secs-1 at baseline to 283 +/- 31 secs-1 in group A (p < .01). No differences in venular wall shear rate were observed between these groups. In group C, the venular wall shear rate remained unchanged (baseline, 457 +/- 54 secs-1; at 120 mins, 409 +/- 51 secs-1). Macromolecular leakage, expressed as perivenular/intravenular fluorescence intensity after injection of fluorescence-labeled albumin, increased from 0.29 +/- 0.03 to 0.58 +/- 0.03 (p < .01) during the infusion of endotoxin in group B. In contrast, pretreatment with N-acetylcysteine diminished the extravasation of albumin (baseline, 0.27 +/- 0.01; at 120 mins, 0.37 +/- 0.02; p < .01 vs. baseline; p < .01 vs. group B).']
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['MitoQ is a mitochondria-targeted derivative of the antioxidant ubiquinone, with antioxidant and anti-apoptotic functions. Reactive oxygen species are involved in many inflammatory diseases including inflammatory bowel disease. In this study, we assessed the therapeutic effects of MitoQ in a mouse model of experimental colitis and investigated the possible mechanisms underlying its effects on intestinal inflammation.', 'Reactive oxygen species levels and mitochondrial function were measured in blood mononuclear cells of patients with inflammatory bowel disease. The effects of MitoQ were evaluated in a dextran sulfate sodium-induced colitis mouse model. Clinical and pathological markers of disease severity and oxidative injury, and levels of inflammatory cytokines in mouse colonic tissue were measured. The effect of MitoQ on inflammatory cytokines released in the human macrophage-like cell line THP-1 was also analyzed.', 'Cellular and mitochondrial reactive oxygen species levels in mononuclear cells were significantly higher in patients with inflammatory bowel disease (P <0.003, cellular reactive oxygen species; P <0.001, mitochondrial reactive oxygen species). MitoQ significantly ameliorated colitis in the dextran sulfate sodium-induced mouse model in vivo, reduced the increased oxidative stress response (malondialdehyde and 3-nitrotyrosine formation), and suppressed mitochondrial and histopathological injury by decreasing levels of inflammatory cytokines IL-1 beta and IL-18 (P <0.001 and P <0.01 respectively). By decreasing mitochondrial reactive oxygen species, MitoQ also suppressed activation of the NLRP3 inflammasome that was responsible for maturation of IL-1 beta and IL-18. In vitro studies demonstrated that MitoQ decreases IL-1 beta and IL-18 production in human THP-1 cells.']
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['Chronic obstructive pulmonary disease (COPD) is a syndrome of progressive airflow limitation caused by the abnormal inflammatory reaction of the airway and lung parenchyma. Osteoporosis is one of the major extrapulmonary manifestations of COPD. The, prevalence of osteoporosis in COPD patients in Indian population is unknown.', 'To study the prevalence of osteoporosis in COPD and to define various risk factors associated with reduced bone mineral density (BMD) in COPD.', 'The study was done in the department of Pulmonary Medicine of a tertiary care hospital. All the diagnosed cases of COPD according to the Global Initiative for Obstructive Lung Disease (GOLD) guidelines were included in this study. The present study was a prospective study in for a period of 1 year. A brief history of the patients was taken, especially regarding duration of illness, number of exacerbations in the past 3 years, smoking in pack years, and history of steroid use (both systemic and inhaled steroids) after which cumulative dose of steroids was calculated. Spirometry was done in all these patients to stage the severity of COPD according to GOLD criteria. DEXA scan of the lumbar spine was done using bone densitometer to determine osteoporosis. A world Health Organization (WHO) criterion for definition of osteoporosis was applied and patients with T-score of > -2.5 standard deviation (SD) were diagnosed to have osteoporosis, -1 SD to -2.5 SD were diagnosed to have osteopenia and < -1 SD as normal. Statistical analysis for association of COPD with osteoporosis was done using chi-square test. Risk factors for osteoporosis were identified by univariate and multivariate logistic regression analysis.', 'A total of 102 COPD patients were included in the study. Among these, 68 patients (66.6%) had osteoporosis and 20 patients (19.6%) had osteopenia. Majority (64.7%) of the patients who had osteoporosis had stage III and stage IV COPD disease. It was observed that as the severity grade of COPD increased, the risk of osteoporosis also increased. The bone mineral density (BMD) showed a significant difference among different stages of COPD. As the severity of the stage of COPD increased, BMD decreased. It was also observed that patients with lower body mass index (BMI) had higher prevalence of osteoporosis (37.3%) as compared to overweight patients. On univariate analysis, it was observed that risk factors for osteoporosis were female sex, higher number of exacerbations, BMI, and severity of COPD. After using multivariate logistic regression analysis, stage IV COPD (odds ratio (OR): 34.48, 95% confidence interval (CI): 1.59-1,000, P < 0.02), number of acute exacerbations >3 (OR: 30.3, 95% CI: 4.74-200, P < 0.01), and steroid cumulative dose >1,000 mg (OR: 7.35, 95% CI: 0.92-58.5, P < 0.04) were observed to be significant risk factors for osteoporosis in COPD patients.']
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['Recent studies have demonstrated the genetic significance of insertions, deletions, and other more complex structural variants (SVs) in the human population. With the development of the next-generation sequencing technologies, high-throughput surveys of SVs on the whole-genome level have become possible. Here we present split-read identification, calibrated (SRiC), a sequence-based method for SV detection.', 'We start by mapping each read to the reference genome in standard fashion using gapped alignment. Then to identify SVs, we score each of the many initial mappings with an assessment strategy designed to take into account both sequencing and alignment errors (e.g. scoring more highly events gapped in the center of a read). All current SV calling methods have multilevel biases in their identifications due to both experimental and computational limitations (e.g. calling more deletions than insertions). A key aspect of our approach is that we calibrate all our calls against synthetic data sets generated from simulations of high-throughput sequencing (with realistic error models). This allows us to calculate sensitivity and the positive predictive value under different parameter-value scenarios and for different classes of events (e.g. long deletions vs. short insertions). We run our calculations on representative data from the 1000 Genomes Project. Coupling the observed numbers of events on chromosome 1 with the calibrations gleaned from the simulations (for different length events) allows us to construct a relatively unbiased estimate for the total number of SVs in the human genome across a wide range of length scales. We estimate in particular that an individual genome contains ~670,000 indels/SVs.']
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['Although ventricular septal aneurysm may diminish or even close the shunt through the ventricular septal defect (VSD), developing a left ventricular-to-right atrial (LV-RA) shunt may be unfavorable. This study sought to clarify this issue on the basis of an extended observation of such patients.', 'Sixty-eight patients (1201 patient-years) who had small perimembranous VSD and LV-RA shunt and were not operated on before 6 years of age were studied.', 'The onset age of LV-RA shunt was 5.8 +/- 3.3 years, with clinical improvement later observed in 23 (34%). The murmur disappeared and showed spontaneous closure in 5 (7%). Seven episodes of infective endocarditis occurred in 6 (8.7%, or 58 per 10000 patient-years), with 2 receiving surgery. Another 4 received surgery during follow-up. With echocardiography, aneurysmal transformation involving the anterior and septal leaflets of tricuspid valve (double sac) was found in 56 (85%), whereas only the septal leaflet (single sac) was involved in 10. Patients with double sac were less likely to show improvement, whereas patients who had superior QRS axis and were female showed clinical improvement more frequently.']
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['Recent longitudinal studies have emphasised the prognostic value of noninvasive tests of liver fibrosis and cross-sectional studies have shown their combination significantly improves diagnostic accuracy.', 'To compare the prognostic accuracy of six blood fibrosis tests and liver biopsy, and evaluate if test combination improves the liver-prognosis assessment in chronic hepatitis C (CHC).', 'A total of 373 patients with compensated CHC, liver biopsy (Metavir F) and blood tests targeting fibrosis (APRI, FIB4, Fibrotest, Hepascore, FibroMeter) or cirrhosis (CirrhoMeter) were included. Significant liver-related events (SLRE) and liver-related deaths were recorded during follow-up (started the day of biopsy).', 'During the median follow-up of 9.5 years (3508 person-years), 47 patients had a SLRE and 23 patients died from liver-related causes. For the prediction of first SLRE, most blood tests allowed higher prognostication than Metavir F [Harrell C-index: 0.811 (95% CI: 0.751-0.868)] with a significant increase for FIB4: 0.879 [0.832-0.919] (P = 0.002), FibroMeter: 0.870 [0.812-0.922] (P = 0.005) and APRI: 0.861 [0.813-0.902] (P = 0.039). Multivariate analysis identified FibroMeter, CirrhoMeter and sustained viral response as independent predictors of first SLRE. CirrhoMeter was the only independent predictor of liver-related death. The combination of FibroMeter and CirrhoMeter classifications into a new FM/CM classification improved the liver-prognosis assessment compared to Metavir F staging or single tests by identifying five subgroups of patients with significantly different prognoses.']
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['Cerebral revascularization may be indicated either for blood flow preservation or flow augmentation, often in clinical situations where neither endovascular nor standard surgical intervention can be performed. Cerebral revascularization can be performed by using a temporary occlusive or a non-occlusive technique. Both of these possibilities have their specific range of feasibility. Therefore non-occlusive revascularization techniques have been developed. To further reduce the risks for patients, less time consuming, sutureless techniques such as laser tissue soldering are currently being investigated.', 'In the present study, a new technique for side-to-side anastomosis was developed. Using a "sandwich technique", two vessels are kept in close contact during the laser soldering. Thoraco-abdominal aortas from 24 different rabbits were analyzed for laser irradiation induced tensile strength. Two different irradiation modes (continuous and pulsed) were used. The results were compared to conventional, noncontact laser soldering. Histology was performed using HE, Mason\'s Trichrome staining.', 'The achieved tensile strengths were significantly higher using the close contact "sandwich technique" as compared to the conventional adaptation technique. Furthermore, tensile strength was higher in the continuously irradiated specimen as compared to the specimen undergoing pulsed laser irradiation. The histology showed similar denaturation areas in both groups. The addition of a collagen membrane between vessel components reduced the tensile strength.']
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['Normalization of serum prolactin concentrations in patients with prolactinomas is an accepted endpoint of therapy. Clinical signs and symptoms of hyperprolactinemia are usually resolved when prolactin levels are lowered to within the normal range. While most patients are treated with dopamine agonist drugs, some patients require surgical resection of their tumors. We sought to determine whether preoperative treatment with dopamine agonists alters the outcome of surgical intervention.', 'We present an analysis of 253 patients with prolactinomas treated surgically during the period of time when dopamine agonist therapy was first introduced and prior to its widespread use as first-line therapy. We compared both short- and long-term outcomes of patients treated with dopamine agonists prior to surgery with those undergoing surgery as their initial treatment modality. Our data showed that that patients treated with dopamine agonists prior to surgery experienced greater reductions in prolactin levels, had lower prolactin levels, were more likely to have normal prolactin levels at long term follow-up, and were less likely to require additional therapy to control their prolactin levels.']
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['Metronidazole is the most commonly used antimicrobial for Bacteroides fragilis infections and is recommended for prophylaxis of colorectal surgery. Metronidazole resistance is increasing and the mechanisms of resistance are not clear.', 'A transposon mutant library was generated in B. fragilis 638R (BF638R) to identify the genetic loci associated with resistance to metronidazole.', 'Thirty-two independently isolated metronidazole-resistant mutants had a transposon insertion in BF638R_1421 that encodes the ferrous transport fusion protein (feoAB). Deletion of feoAB resulted in a 10-fold increased MIC of metronidazole for the strain. The metronidazole MIC for the feoAB mutant was similar to that for the parent strain when grown on media supplemented with excess iron, suggesting that the increase seen in the MIC of metronidazole was due to reduced cellular iron transport in the feoAB mutant. The furA gene repressed feoAB transcription in an iron-dependent manner and disruption of furA resulted in constitutive transcription of feoAB, regardless of whether or not iron was present. However, disruption of feoAB also diminished the capacity of BF638R to grow in a mouse intraperitoneal abscess model, suggesting that inorganic ferrous iron assimilation is essential for B. fragilis survival in vivo.']
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['High levels of total and allergen-specific IgE levels are a key feature in allergic diseases. The high-affinity receptor for IgE, which is composed of one alpha (FCER1A), one beta (FCER1B), and two gamma (FCER1G) subunits, represents the central receptor of IgE-induced reactions. In a genome-wide association scan, we recently identified associations between functional FCER1A variants and total serum IgE levels. Previous studies had reported linkage and association of FCER1B variants with IgE and atopic traits. The FCER1G gene has not yet been investigated with regard to atopy. Filaggrin (FLG) is the strongest known risk gene for eczema, in particular the allergic subtype of eczema.', 'We investigated the association of FCER1A, FCER1B, and FCER1G variants with IgE in a large population-based cohort (n = 4261) and tested for epistatic effects using the model-based multifactor dimensionality reduction (MB-MDR) method. In addition, we investigated a potential interaction between FLG and FCER1A variants in a large collection of eczema cases (n = 1018) and population controls.', 'Three strongly correlated FCER1A polymorphisms were significantly associated with total and specific IgE levels as well as allergic sensitization. No associations were seen for FCER1B and FCER1G. After adjustment for FLG effects, a significant epistatic effect of the FCER1A variants rs10489854 and rs2511211 on eczema risk was detected.']
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['IL-24 (melanoma differentiation-associated gene-7 (mda-7)), a member of the IL-10 cytokine family, possesses the properties of a classical cytokine as well as tumor suppressor effects. The exact role of IL-24 in the immune system has not been defined but studies have indicated a role for IL-24 in inflammatory conditions such as psoriasis. The tumor suppressor effects of IL-24 include inhibition of angiogenesis, sensitization to chemotherapy, and p38 mitogen-activated protein kinase (MAPK)-mediated apoptosis. Current knowledge on the regulation of IL-24 expression is sparse. Previous studies have suggested that mRNA stabilization is of major importance to IL-24 expression. Yet, the mechanisms responsible for the regulation of IL-24 mRNA stability remain unidentified. As p38 MAPK is known to regulate gene expression by interfering with mRNA degradation we examined the role of p38 MAPK in the regulation of IL-24 gene expression in cultured normal human keratinocytes.', "In the present study we show that anisomycin- and IL-1beta- induced IL-24 expression is strongly dependent on p38 MAPK activation. Studies of IL-24 mRNA stability in anisomycin-treated keratinocytes reveal that the p38 MAPK inhibitor SB 202190 accelerates IL-24 mRNA decay suggesting p38 MAPK to regulate IL-24 expression by mRNA-stabilizing mechanisms. The insertion of the 3' untranslated region (UTR) of IL-24 mRNA in a tet-off reporter construct induces degradation of the reporter mRNA. The observed mRNA degradation is markedly reduced when a constitutively active mutant of MAPK kinase 6 (MKK6), which selectively activates p38 MAPK, is co-expressed."]
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['Patients with an implanted cardioverter defibrillator (ICD) and ventricular arrhythmias leading to ICD therapies have poor clinical outcomes and quality of life. Antiarrhythmic agents and catheter ablation are needed to control these arrhythmias. Dofetilide has only been approved for the treatment of atrial fibrillation. The role of dofetilide in the control of ventricular arrhythmias in patients with an ICD has not been established.', 'Evaluate the safety and efficacy of dofetilide in a consecutive group of patients with an ICD and recurrent ventricular tachycardia (VT) and/ or ventricular fibrillation (VF) after other antiarrhythmic drugs have failed to suppress these arrhythmias.', 'We studied 30 patients (age 59 ± 11; 5 women) with symptomatic VT or VF and ICDs for secondary prevention of sudden cardiac death. These patients had an average of 1.8 ± 4.5 episodes of VT/VF per month despite antiarrhymic therapy. Twenty-one patients (70%) had recurrent appropriate ICD therapies prior to initiation of dofetilide, and 9 (30%) VTs below the programmed detection rate of the ICD. Twenty-three patients (77%) had coronary artery disease. Mean ejection fraction was 30 ± 14% and 26/30 (87%) had congestive heart failure. All patients had previously failed 2 ± 1 antiarrhythmic drugs including amiodarone (n = 19) and sotalol (n = 10).', 'During the first month of treatment, 25 patients (83%) had complete suppression of VT/VF and of the 21 patients with ICD therapies 16 (76%) had no therapies during the first month of treatment. During a follow-up period of 32 ± 32 months, dofetilide reduced the monthly episodes of VT/VF from 1.8 ± 4.5 to 1.0 ± 3.5 (P = 0.006). Monthly ICD therapies decreased from 0.9 ± 1.4 to 0.4 ± 1.7 (P = 0.037). In 9 patients that presented with slow VTs under the ICD detection zone, dofetilide reduced monthly VT/VF episodes from 0.7 ± 0.6 to 0.1 ± 0.1 (P = 0.01) and 6 (67%) had no further ICD therapies. Dofetilide was discontinued in 13 patients (43%) after 24 ± 30 months due to failure to control VT/VF (n = 7), placement of a left ventricular assist device (n = 3), catheter ablation (n = 1), heart transplantation (n = 1), and left ventricular restoration surgery (n = 1). There were 7 documented deaths (2 patients died suddenly; 3 patients of progressive heart failure; and 2 of non-cardiac causes).']
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['The study aimed to investigate patient and spouse perception of cognitive functioning 1 to 2 years after coronary artery bypass grafting.', 'Seventy-six married patients who had undergone coronary artery bypass grafting were selected and sex- and age-matched with 75 concurrent married patients who had undergone percutaneous transluminal coronary angioplasty. Couples received a letter of explanation and then completed telephone interviews. Forty-seven questions assessed memory, concentration, general health, social functioning, and emotional state. Response choices were: improved, unchanged, or deteriorated function after coronary artery bypass grafting/percutaneous transluminal coronary angioplasty.', 'Patients who had undergone coronary artery bypass grafting did not differ in subjective ratings on any measure from patients who had undergone percutaneous transluminal coronary angioplasty. There were no differences between spouses in the respective groups; spouse ratings also did not differ from patient ratings. Only in memory function did patients and spouses report a postprocedural decline.']
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['P21(WAF1/Cip1) binds to cyclin-dependent kinase complexes and inhibits their activities. It was originally described as an inhibitor of cancer cell proliferation. However, many recent studies have shown that p21 promotes tumor progression when accumulated in the cell cytoplasm. So far, little is known about the correlation between cytoplasmic p21 and drug resistance. This study was aimed to investigate the role of p21 in the cisplatin resistance of ovarian cancer.', 'RT-PCR, western blot and immunofluorescence were used to detect p21 expression and location in cisplatin-resistant ovarian cancer cell line C13* and its parental line OV2008. Regulation of cytoplasmic p21 was performed through transfection of p21 siRNA, Akt2 shRNA and Akt2 constitutively active vector in the two cell lines; their effects on cisplatin-induced apoptosis were evaluated by flow cytometry. Tumor tissue sections of clinical samples were analyzed by immunohistochemistry.', 'p21 predominantly localizes to the cytoplasm in C13* compared to OV2008. Persistent exposure to low dose cisplatin in OV2008 leads to p21 translocation from nuclear to cytoplasm, while it had not impact on p21 localization in C13*. Knockdown of cytoplasmic p21 by p21 siRNA transfection in C13* notably increased cisplatin-induced apoptosis through activation of caspase 3. Inhibition of p21 translocation into the cytoplasm by transfection of Akt2 shRNA into C13* cells significantly increased cisplatin-induced apoptosis, while induction of p21 translocation into the cytoplasm by transfection of constitutively active Akt2 in OV2008 enhanced the resistance to cisplatin. Immunohistochemical analysis of clinical ovarian tumor tissues demonstrated that cytoplasmic p21 was negatively correlated with the response to cisplatin based treatment.']
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['Angiogenesis is essential for tumors to grow and metastasize. Lymphatic metastasis is also an important means of tumor spread. In non-small cell lung carcinoma, the relationship of lymphangiogenesis with lymph node metastasis and, ultimately, patient prognosis is unknown.', 'To evaluate whether lymphangiogenesis is related to lymph node metastasis and/or overall survival.', 'Seventy-eight cases of non-small cell lung carcinoma diagnosed from 1987 to 2004 were retrospectively analyzed for intratumoral, peritumoral, and uninvolved adjacent lung tissue lymphatic vessel density (LVD) by D2-40 immunostaining. Lymphatics in 6 cases of squamous dysplasia/carcinoma in situ were similarly evaluated. Appropriate statistical methods were used.', 'Intratumoral and peritumoral LVD was significantly higher than in the uninvolved adjacent lung but showed no significant association with lymph node stage at the time of tumor resection. Survival in patients with above average D2-40 values was not significantly different when compared with those who had below average values (median survival, 895 vs 1131 days; P = .97). Furthermore, patients with affected lymph nodes had significantly shorter survival (median survival, 467 vs 1425 days; P = .002). Overall, regardless of lymph node status, there was a significantly higher intratumoral (P < .001) and peritumoral (P < .001) LVD when compared with the adjacent uninvolved lung LVD. There was a trend toward increasing LVD with higher grade of squamous dysplasia.']
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['Cerebral microbleeds (CMBs) are a marker of small vessel diseases, including hypertensive arteriopathy and cerebral amyloid angiopathy, and may be associated with cognitive impairment. The relationship between CMBs and cognitive function in ischemic cerebrovascular disease remains uncertain. We, therefore, investigated the cognitive impact of CMBs in a cohort of patients with ischemic stroke or transient ischemic attack.', 'All patients underwent detailed and comprehensive neuropsychological testing and standardized MRI, including fluid attenuation inversion recovery, T1, T2, and gradient-recalled echo T2*-weighted sequences. CMBs, white matter changes, lacunes, and territorial cortical infarcts (defined by standardized criteria) were identified, and associations with cognition assessed.', 'Three hundred twenty patients with a diagnosis of ischemic stroke or transient ischemic attack were included. Of these, 72 (22.5%) had at least 1 CMB. Of all the cognitive domains tested, only executive impairment was more prevalent in patients with CMBs than without (38% versus 25%; P=0.039). In univariate analysis, the presence of strictly lobar (but not deep) CMBs was associated with executive impairment (odds ratio, 2.49; 95% confidence interval, 1.16-5.36; P=0.019). In adjusted multivariate analyses, the presence (OR, 2.34; 95% confidence interval, 1.08-5.09; P=0.031) and number (OR, 1.33; 95% confidence interval, 1.04-1.69; P=0.022) of strictly lobar CMBs were significantly associated with executive impairment. CMBs were not associated with impairment in other cognitive domains.']
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['Quinolones cause obvious cartilaginous lesions in juvenile animals by chondrocyte apoptosis, which results in the restriction of their use in pediatric and adolescent patients. Studies showed that chondrocytes can be induced to produce TNFα, and the cisternae of the endoplasmic reticulum in quinolone-treated chondrocytes become dilated. We investigated whether TNF/TNFR₁ pathway and endoplasmic reticulum stress (ERs) are involved in ofloxacin (a typical quinolone)-induced apoptosis of juvenile canine chondrocytes.', 'Canine juvenile chondrocytes were treated with ofloxacin. Cell survival and apoptosis rates were determined with MTT method and flow cytometry, respectively. The gene expression levels of the related signaling molecules (TNFα, TNFR₁, TRADD, FADD and caspase-8) in death receptor pathways and main apoptosis-related molecules (calpain, caspase-12, GADD153 and GRP78) in ERs were measured by qRT-PCR. The gene expression of TNFR₁ was suppressed with its siRNA. The protein levels of TNFα, TNFR₁ and caspase-12 were assayed using Western blotting.', 'The survival rates decreased while apoptosis rates increased after the chondrocytes were treated with ofloxacin. The mRNA levels of the measured apoptosis-related molecules in death receptor pathways and ERs, and the protein levels of TNFα, TNFR₁ and caspase-12 increased after the chondrocytes were exposed to ofloxacin. The downregulated mRNA expressions of TNFR₁, Caspase-8 and TRADD, and the decreased apoptosis rates of the ofloxacin-treated chondrocytes occurred after TNFR₁-siRNA interference.']
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['Aberrant expression of trk receptor kinases and enhanced expression of various neurotrophins (NTs) have been implicated in the development and progression of human prostatic carcinoma and pancreatic ductal adenocarcinoma. We examined the antitumor efficacy of administration of NT neutralizing antibodies on the growth of established human prostatic carcinoma and pancreatic ductal adenocarcinoma xenografts in nude mice.', 'In initial studies, tumor-bearing nude mice were treated with a mixture of NT antibodies [100 microg each of anti-nerve growth factor (NGF), anti-brain-derived neurotrophic factor, anti-NT-3, and anti-NT-4/5] or normal rabbit IgG (400 microg) intratumorally and peritumorally three times/week over a 15-day dosing period. In subsequent studies, tumor-bearing nude mice were treated with individual NT antibodies (100 microg), affinity-purified anti-NGF (0.1, 1.0, or 10.0 microg), or normal rabbit IgG (100 microg) using the same dosing schedule.', 'Treatment with the antibody mixture inhibited significantly the growth of TSU-Pr1 and AsPC-1 xenografts as compared with IgG-treated controls (maximal inhibition of 53 and 53%, respectively), whereas this treatment caused significant regression in PC-3 xenografts. Treatment of TSU-Pr1 xenografts with either anti-NGF or anti-NT-3 resulted in maximal tumor growth inhibition of 67 and 64%, respectively, whereas anti-brain-derived neurotrophic factor and anti-NT-4/5 did not inhibit tumor growth in this tumor model. Administration of various concentrations (0.1, 1.0, or 10.0 microg) of affinity-purified anti-NGF resulted in maximal TSU-Pr1 tumor growth inhibition of 49, 62, and 66%, respectively.']
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['Despite widespread interest in stem cells, their clinical application is largely limited owing to safety and cost concerns. We intended to overcome these limitations by evaluating whether the secretome of human adipose tissue-derived stem cells (ASCs) could be used to reverse ischemia/reperfusion (IR) injury in mice.', 'After establishment of hepatic IR injury in BALB/c mice, the mice were infused with saline solution (saline group), 1.0 × 10⁶ human ASCs (ASC group), 25-fold-concentrated ASC-conditioned medium (ASC-secretome group), which was the same volume as used for the ASC infusion, or concentrated control medium (medium-only group). After reperfusion, we obtained serum and liver specimens and compared parameters reflecting the degree of injury and mechanisms between the groups.', 'At 6 hours after reperfusion, serum interleukin (IL)-6 levels were decreased in both ASC and ASC-secretome groups (P < .05). At 12 and 24 hours after reperfusion, both ASC and ASC-secretome groups also demonstrated lesser histologic scores than did their controls (P < .05). In addition, the decreases in the expression of the cell adhesion markers intercellular adhesion molecule-1 and platelet-endothelial cell adhesion molecule-1 and in neutrophil infiltration into the liver were noted in the ASC-secretome group as well as in the ASC group.']
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['Sputum induction is a safe, well tolerated means of obtaining lower airway secretions from children with cystic fibrosis (CF), particularly for assessment of airway inflammation but the clinical value in diagnosing outpatient infections has not been extensively studied.', 'Investigate the success rate and microbiologic yield of induced sputum (IS) compared to oropharyngeal swabs (OP) and expectorated sputum (ES) samples in children with CF, and determine if IS culture results impact treatment.', 'Two cohorts were included in this prospective, longitudinal comparative study. In one cohort, simultaneously collected OP, ES, and IS specimens were obtained from 17 CF children at three visits over 1\u2009year. In the second group, sputum induction was performed in 35 CF subjects at four annual visits, and culture results were compared to their nearest respiratory culture within 4\u2009months. Antimicrobial treatment regimens were captured retrospectively.', 'Sputum induction was successful in 149 of 158 (94%) visit encounters. Polymicrobial infection (combined P\u2009=\u20090.005) and gram negative organisms (combined P\u2009=\u20090.003) were detected more frequently in IS samples compared to OP, as were the individual pathogens Pseudomonas aeruginosa (combined P\u2009=\u20090.04) and Stenotrophomonas maltophilia (combined P\u2009=\u20090.05). The microbiologic yield of serial IS samples collected over 1\u2009year was stable. IS culture results led to antibiotic changes in 6% of visit encounters. However, based on current practice 13% of visits could have resulted in treatment changes.']
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['Cardiovascular proteomics investigation reveals the characterization and elucidation of the novel therapeutic targets and strategies to prevent the development of heart failure associated diabetic complication by using 2DE and MS.', 'The experimental animals were made diabetic with a single intraperitoneal injection of alloxan (150 mg/kg of bw). Albino rats were randomly divided into four individual groups: Group-I control (n=6), group-II alloxan-induced diabetic rats, untreated (n=6), group-III (n=6) and group-IV (n=6) alloxan-induced diabetic rats were treated with aqueous and ethanolic extracts of Cynodon dactylon for 15 days, respectively. Animals were euthanized to collect the heart tissues and blood samples. 2DE sample preparation, gel running and staining (n=6: each groups) were performed at the same time to avoid variation. The result of six gel images from each group were analyzed and evaluated as one match set with 2D software (P<0.05).', 'The above experiment revealed two up-regulated proteins in group-II i.e. NTF4 and ETFB.']
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['Effective physician communication about prognosis is a critical aspect of quality care for families affected by terminal illness. This is particularly important for spousal caregivers of terminally ill parents of dependent children, who may have unique needs for communication about anticipated death. The objective of this study was to explore end-of-life prognostic communication experiences reported by bereaved fathers whose wives died from cancer.', "From October 2012 to November 2013 we surveyed widowed fathers whose wives died from cancer through an open-access educational website. The survey included the following open-ended questions regarding prognostic communication: 'What is the most important thing you would like us to know about whether/how your wife's doctors communicated with you about her anticipated death? What do you wish had been different, if anything?' We performed traditional content analysis of responses. Two researchers coded and categorized the data.", 'Two hundred forty-four men responded to the survey questions on prognostic communication. Major themes addressed by respondents were the importance of clear and honest communication and physician bedside manner. They also identified unmet information needs, including wanting to know prognosis sooner. Relevant sub-themes included death coming as a surprise, avoidance, and caregiver regret.']
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['To evaluate whether the presence of insulin antibodies (IAs) may preclude the optimization of metabolic control during pregnancy and affect outcome in women with IDDM.', "IAs were measured by radiobinding assay in 44 women with IDDM referred to the Diabetes and Pregnancy Outpatients' Clinic during 46 pregnancies. Age, duration of IDDM, metabolic control (HbA1c, mean pre- and postprandial capillary blood glucose, frequency of hypo- or hyperglycemia), insulin requirement at 1st and 3rd trimester of pregnancy, BM1, and weight gain were recorded. Neonatal variables such as gestational age, weight, length, and the presence at birth of either hypoglycemia, hypocalcemia, or jaundice requiring phototherapy were also considered.", 'IAs correlated positively with insulin requirement (P < 0.05) and negatively with HbA1c at term (P < 0.01). Patients with IA levels > or = 40% insulin binding (8 of 46) had a higher insulin requirement and lower preprandial capillary blood glucose at the beginning of pregnancy but not at term (P < 0.005), whereas they had lower HbA1c at term than did patients with low IA levels (P < 0.01). IA levels decreased slightly at term (P = 0.007). IA levels > or = 40% were not associated with a higher rate of hypo- or hyperglycemic episodes or with diabetic complications or thyreopathy. No correlation was found between 1A levels and any of the neonatal variables considered.']
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['Mixed cryoglobulinemia (MC) is one of the most common and severe symptoms in chronic hepatitis C patients. The aim of this study was to investigate whether mixed cryoglobulinemia is a factor associated with sustained virological response in chronic hepatitis C patients treated with combination therapy of pegylated interferon alpha-2a and ribavirin.', 'This is a single-center study including 57 chronic hepatitis C patients who received combination treatments of pegylated interferon alfa-2a and ribavirin. Serum cryoglobulin was detected by cryoprecipitation prior to treatment. Serum hepatitis C virus (HCV) RNA levels were checked before treatment, during the fourth and 12th week of treatment, and during the 24th week after cessation of treatment. The genotype of HCV was determined at baseline. Logistic regression analysis was used to assess the factors associated with sustained virological response.', 'Twenty-five patients were with MC (43.9%). Twenty-four weeks after cessation of antiviral treatment, sustained virological response achievement in MC(+) patients was significantly lower than that in MC(-) patients (32.0% vs. 75.0%, P = 0.001). Univariate Logistic regression analysis and multivariate Logistic regression analysis found that only MC (odds ratio: 6.375; 95% CI: 1.998- 20.343, P = 0.002) was negatively associated with sustained virological response achievement.']
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['Besides its toxic effects, bilirubin has been demonstrated to have antioxidant properties to counteract oxidative stress, which has been suggested to play a role in the pathophysiology of schizophrenia.', 'This study investigated the potential association between changes in psychopathology measured by the Lindenmayer model of the Positive and Negative Syndrome Scale (PANSS) and changes in total plasma bilirubin concentrations. Data of patients with schizophrenia (ICD-10) starting monotherapy with a new-generation antipsychotic were analyzed at baseline (N = 52) and 2 (n = 40), 4 (n = 46), and 12 weeks (n = 30) after the initiation of treatment. Data were collected between December 1997 and October 2007 and analyzed retrospectively.', 'The PANSS total score decreased significantly from baseline to weeks 2, 4, and 12 of treatment (all P values ≤ .001). Total plasma bilirubin concentration also dropped significantly from baseline to week 2 (P = .015) and decreased further until week 4 (P = .013); no significant decrease was observed between baseline and week 12. Spearman rank correlation revealed a significant association of bilirubin concentration with the PANSS positive (r = 0.371, P = .007) and excitement (r = 0.322, P = .020) components at baseline. No further correlations were found. From baseline to weeks 2, 4, and 12, changes in the PANSS positive component correlated significantly with changes in plasma bilirubin concentration (all P values < .05), whereas correlations between changes in the remaining PANSS components and bilirubin were less consistent.']
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['QT hysteresis phenomenon exists in healthy subjects, and is more exaggerated in patients with coronary artery disease (CAD) and long QT syndrome. The purpose of this study was to establish an appropriate method to evaluate the magnitude of QT hysteresis, and assess the value of QT hysteresis index in the treadmill exercise test (TET) in predicting CAD. METHODS\u2004AND\u2004RESULTS: A total of 138 subjects with suspected CAD and referred for TET and selective coronary angiography (SCA) were divided into positive (n=77) and negative (n=61) SCA groups. Dynamic ECG were recorded during TET. QT/RR curves were constructed and QTp (Q-Tpeak) and QTe (Q-Tend) hysteresis indices were calculated for each subject. SYNTAX score in the positive SCA group was determined. The QTp and QTe hysteresis indices in the positive SCA group were significantly higher than in the negative SCA group. The combination of QTe hysteresis index and conventional TET criteria had the highest sensitivity and negative predictive value according to receiver operating characteristic curve, and was an independent predictor on multivariate logistic regression. QT hysteresis indices significantly correlated with SYNTAX score in the positive SCA group.']
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['In contrast to platelet-rich white thrombi, red thrombi in the heart are rich in fibrin and trapped erythrocytes. The magnetic susceptibility effect of deoxygenated hemoglobin in red thrombi may result in hypointense signals on T2*-weighted gradient echo imaging (GRE). We tested the hypothesis that a GRE susceptibility vessel sign (SVS) is specific for cardioembolic stroke.', 'This retrospective study examined data from acute ischemic stroke patients who underwent diffusion-weighted imaging, GRE and magnetic resonance angiography (MRA) within 24 hours of stroke onset and who had symptomatic occlusion of large intracranial arteries in the circle of Willis. Hypointense signals within vascular cisterns on GRE corresponding to symptomatic vascular occlusion were termed "GRE SVS." Recanalization was assessed on follow-up MRA performed within 7 days of onset. The relationships between GRE SVS and stroke subtypes and subsequent recanalization were explored.', 'Of the 95 patients who met the inclusion criteria, GRE SVS was observed in 45 (47.4%). GRE SVS was more commonly associated with cardioembolic stroke patients (31 of 40, 77.5%) than with other stroke subtypes (14 of 55, 25.5%; P<0.001). In 66 patients who underwent follow-up MRA, GRE SVS was associated with subsequent recanalization (P<0.001). Multivariate analysis showed that GRE SVS was an independent predictor of cardioembolic stroke and subsequent recanalization (odds ratio, 10.75 and 4.26; 95% CI, 3.68 to 31.47 and 1.12 to 16.30).']
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['This report examines the < or =30-day postoperative mortality and morbidity in our first 190 duodenal switch (DS) patients.', 'DS is the most weight loss effective and the most difficult to perform bariatric procedure. Indeed, certain surgeons have advocated a 2-stage approach to minimize complications, especially in the super obese (body mass index [BMI] > or =50 kg/m(2)).', 'DS procedures were performed (n = 190) by either open (n = 168) or laparoscopic/robotic surgery in an academic setting: common channel 75 to 125 cm, sleeve gastrectomy (approximately 100 mL gastric pouch), closed duodenal stump, end-to-side duodenoileostomy hand-sewn in 2 layers, with most staple lines oversewn, and all mesentery defects closed.', 'For the 190 patients, 149 were female (78%) and the mean age was 43 years (range, 16-71). Mean preoperative weight 151.4 kg (range, 74.1-332.7); mean preoperative BMI 53.4 kg/m(2) (range, 32-107), with 100 (52.6%) of the patients super obese (BMI > or =50 kg/m(2)). Seventy-four patients had concurrent procedures, eg, cholecystectomy (n = 22), ventral or umbilical hernia repair (n = 19), and hiatus hernia repair (n = 10). Mean operating room time was 337 minutes (range, 127-771); mean hospitalization time was 6 days (range, 2-38). There were no deaths. Serious < or =30-day complications (n = 18 in 14 patients) consisted of 2 leaks (1.0%), which responded to drainage, and intra-abdominal bleeding (n = 3), splenectomy (n = 1), acute pancreatitis (n = 2), gastric outlet obstruction (n = 1), acute renal failure (n = 2), pneumonia (n = 2), respiratory failure (n = 3), acute myocardial infarction (n = 1), and duodenoileostomy stricture requiring endoscopic dilation (n = 1). The serious complication rate in patients with a BMI <50 kg/m(2) was 6.7% (6 of 90) and 12% (12 of 100) with a BMI > or =50 kg/m(2) (NS). Surgical site infections occurred in 7 patients with a BMI <50 kg/m(2) and in 12 with a BMI > or =50 kg/m(2) (NS). Overall complication rate in patients with a BMI <50 kg/m(2) was 14.4% (13 of 90) and 24% (24 of 100) with a BMI > or =50 kg/m(2) (NS).']
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['Nocturnal hypertension is associated with a high risk of morbidity and mortality. A blunted nocturnal surge in melatonin excretion has been described in nondipping hypertensive patients. We therefore studied the potency of melatonin to reduce nighttime blood pressure (BP) in treated hypertensive patients with nocturnal hypertension.', 'Thirty-eight treated hypertensive patients (22 males, mean age 64+/-11 years) with confirmed nocturnal hypertension (mean nighttime systolic BP >125 mm Hg), according to repeated 24-hour ambulatory blood pressure monitoring (ABPM), were randomized in a double-blind fashion to receive either controlled release (CR)-melatonin 2 mg or placebo 2 hours before bedtime for 4 weeks. A 24-hour ABPM was then performed.', 'Melatonin treatment reduced nocturnal systolic BP significantly from 136+/-9 to 130+/-10 mm Hg (P=.011), and diastolic BP from 72+/-11 to 69+/-9 mm Hg (P=.002), whereas placebo had no effect on nocturnal BP. The reduction in nocturnal systolic BP was significantly greater with melatonin than with placebo (P=.01), and was most prominent between 2:00 AM and 5:00 AM (P=.002).']
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['Stimulation of soluble guanylyl cyclase (sGC) is a valuable therapeutic strategy for the treatment of several cardiovascular diseases. The sGC stimulator riociguat has been approved for the treatment of two forms of pulmonary hypertension. Platelets contain large amounts of sGC and play a key role in the regulation of haemostasis. Therefore, we investigated the effects of riociguat on platelet function.', 'The effect of riociguat treatment on human platelet activation and aggregation was investigated. The sGC-specific effects of riociguat were determined by comparing wild-type and platelet-specific sGC-knockout mice.', 'Riociguat induced cGMP synthesis and subsequent PKG activation in human platelets, suggesting that the inhibitory effects are mediated by cGMP signalling. This finding was confirmed when sGC-knockout platelets were not inhibited by riociguat. In washed human platelets, 100\u2009nM riociguat reduced ADP-induced GPIIb/IIIa activation, while a 10-fold higher concentration was required to reduce convulxin-stimulated GPIIb/IIIa activation. Riociguat inhibited ADP-induced platelet shape change and aggregation, while ATP-induced shape change remained unaffected. However, in PRP and whole blood, 50-100\u2009μM riociguat was required to inhibit platelet activation and aggregation. Riociguat in combination with iloprost significantly inhibited platelet aggregation, even in whole blood.']
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['Prostate-specific membrane antigen (PSMA) provides an attractive target for monoclonal antibody targeted therapies in the treatment of prostate cancer (PC). In this study, we generated an immunotoxin by linking a humanized anti-PSMA monoclonal antibody (hJ591) to the ribosome-inactivating protein toxin saporin. The hJ591-saporin immunoconjugate was evaluated for antitumor activity against PC cells.', 'PSMA-positive cell lines, LNCaP and CWR22Rv1 and a PSMA-negative cell line, PC-3, were used in these experiments. The hJ591 was biotinylated and mixed with streptavidin-saporin (SAZAP). The binding ability of hJ591-SAZAP and the extent of internalization into the cells were tested. The viability of cells treated with hJ591-SAZAP was also examined and the apoptotic cells were measured. Lastly, the anticancer effect of hJ591-SAZAP was investigated in vivo.', 'The binding ability of hJ591-SAZAP to PSMA was equivalent to that of unconjugated J591. Internalization of hJ591-SAZAP was clearly detected in PSMA-positive, but not in PSMA-negative cell lines. IC(50) of hJ591-SAZAP was 0.14 nM, 1.99 nM, and more than 100 nM in LNCaP, CWR22Rv1, and PC-3 cells, respectively. After 72 hr of hJ591-SAZAP treatment, the percentage of apoptotic cells was 60.29% and 40.73% in LNCaP and CWR22Rv1 cells, respectively, compared to 4.70% in PC-3 cells. The hJ591-SAZAP also had anticancer activity in a LNCaP xenograft model.']
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['Cardiovascular disease is a major cause of mortality in chronic kidney disease patients. Oxidative stress and nitric oxide (NO) deficiency play an important role in vascular endothelial cell dysfunction in chronic kidney disease. To determine if the uremic toxin indoxyl sulfate (IS) induces oxidative stress and inhibits NO production and cell viability in human umbilical vein endothelial cells (HUVEC).', 'The production of reactive oxygen species (ROS), superoxide, NO and peroxynitrite was measured using a fluorescence microplate reader. The expression of NADPH oxidases (Nox4, Nox2) was analyzed by quantitative reverse transcription-polymerase chain reaction. Cell viability was examined by 4-[3-(4-iodophenyl)-2-(4-nitrophenyl)-2H-5-tetrazolio]-1,3-benzene disulfonate assay.', 'IS induced ROS generation in HUVEC. An inhibitor of NADPH oxidase showed an inhibitory effect on IS-induced ROS production. However, the inhibitors of xanthine oxidase, mitochondrial electron transport and NO synthase did not show any significant effect on IS-induced ROS production. Antioxidants such as vitamin E, N-acetyl-L-cysteine and vitamin C inhibited IS-induced ROS production. IS induced the expression of Nox4 mRNA and the production of superoxide and peroxynitrite in HUVEC. IS inhibited NO production in HUVEC. IS inhibited cell viability, and antioxidants preserve the inhibitory effect of IS on cell viability.']
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['Searching for two-dimensional (2D) structural similarities is a useful tool to identify new active compounds in drug-discovery programs. However, as 2D similarity measures neglect important structural and functional features, similarity by 2D might be underestimated. In the present study, we used combined 2D and three-dimensional (3D) similarity comparisons to reveal possible new functions and/or side-effects of known bioactive compounds.', 'We utilised more than 10,000 compounds from the SuperTarget database with known inhibition values for twelve different anti-cancer targets. We performed all-against-all comparisons resulting in 2D similarity landscapes. Among the regions with low 2D similarity scores are inhibitors of vascular endothelial growth factor receptor (VEGFR) and inhibitors of poly ADP-ribose polymerase (PARP). To demonstrate that 3D landscape comparison can identify similarities, which are untraceable in 2D similarity comparisons, we analysed this region in more detail. This 3D analysis showed the unexpected structural similarity between inhibitors of VEGFR and inhibitors of PARP. Among the VEGFR inhibitors that show similarities to PARP inhibitors was Vatalanib, an oral "multi-targeted" small molecule protein kinase inhibitor being studied in phase-III clinical trials in cancer therapy. An in silico docking simulation and an in vitro HT universal colorimetric PARP assay confirmed that the VEGFR inhibitor Vatalanib exhibits off-target activity as a PARP inhibitor, broadening its mode of action.']
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['Adhesion molecules play an integral role in tumor growth, invasion, and metastasis and have been shown to influence the immune response to malignant cells. The interaction of intercellular adhesion molecule-1 (ICAM-1) with lymphocyte function antigen-1 (LFA-1) is important for the adhesion of leukocytes, monocytes and lymphocytes to endothelial cells in vitro and in vivo. In order to explore the role of the ICAM-1/LFA-1 interaction in liver metastases, we utilized homozygous deletionally mutant (gene knockout) mice for ICAM-1 or LFA-1 which had been derived from the C57BL6/J background.', 'Wild-type C57BL6/J mice were used as controls. Animals were anesthetized and underwent a 1-cm midline lower abdominal incision. The ileocolic vein was identified and B16 melanoma cells (10(4)) were injected. The incisions were closed with skin clips. Two weeks following surgery, mice were sacrificed and their livers resected for gross and histological analysis.', 'LFA-1 deficient mice developed 13 times the number of metastases compared to wild-type controls and ICAM-1 deficient mice developed 7 times that number [13.5 (n = 17) vs 1.0 (n = 19) and 36 (n = 10) vs 5.0 (n = 16), P values of 0.0003 and 0.0002 by Wilcoxon Rank Sum Test, respectively]: Histologically, multiple areas of inflammatory cells consisting of T-cells and macrophages were noted in wild-type mice. Only sparse inflammatory cells were noted surrounding the metastases in the null mice.']
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['Chondroitin sulfate proteoglycan-4 (CSPG4) is commonly expressed in melanoma cells and induces melanoma cell proliferation and migration by enhancement of activation of the extracellular signal-regulated kinase 1, 2 (ERK1,2) pathway. The phosphoinositide 3-kinase (PI3K) -protein kinase B (AKT) and mammalian target of rapamycin (mTOR) pathways are also frequently de-regulated in melanoma. We hypothesized that CSPG4, by sustained activation of PI3K, may reduce the effect of the dual inhibition of PI3K-AKT and mTOR pathways.', 'CSPG4-negative melanoma cell line WM1552C was transfected with CSPG4 and CSPG4 lacking cytoplasmic domain (melanoma-associated chondroitin sulfate proteoglycan (MCSP)ΔCD). To assess the effect of CSPG4 on the mTOR pathway, PF-5212384, a dual PI3K/mTOR inhibitor was used. Cell proliferation and downstream signaling from mTOR was assayed in the presence of CSPG4.', 'Forced CSPG4 expression did not provide any protection to melanoma cells from the pharmacological inhibition of mTOR pathway in vitro. In addition, we demonstrated that inhibition of signaling molecules downstream of AKT and mTOR was not diminished in the presence of CSPG4 when the cells were treated with the PI3K/mTOR inhibitor.']
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['Idiopathic epilepsies are considered to have relatively good prognoses and normal or near normal developmental outcomes. Nevertheless, accumulating studies demonstrate memory and psychosocial deficits in this population, and the prevalence, severity and relationships between these domains are still not well defined. We aimed to assess memory, psychosocial function, and the relationships between these two domains among children with idiopathic epilepsy syndromes using an extended neuropsychological battery and psychosocial questionnaires.', 'Cognitive abilities, neuropsychological performance, and socioemotional behavior of 33 early adolescent children, diagnosed with idiopathic epilepsy, ages 9-14years, were assessed and compared with 27 age- and education-matched healthy controls.', 'Compared to controls, patients with stabilized idiopathic epilepsy exhibited higher risks for short-term memory deficits (auditory verbal and visual) (p<0.0001), working memory deficits (p<0.003), auditory verbal long-term memory deficits (p<0.0021), and more frequent psychosocial symptoms (p<0.0001). The severity of auditory verbal memory deficits was related to severity of psychosocial symptoms among the children with epilepsy but not in the healthy controls.']
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['The retinal pigment epithelium (RPE), an important tissue monolayer of retina, sustains visual function and retinal homeostasis. In disease conditions such as Retinitis Pigmentosa (RP) and Age related Macular degeneration (AMD), the integrity and functional capacity of RPE monolayer is compromised. Human embryonic stem cells derived RPE (hESC-RPE) is ideal for cell based therapy because of their ability to morphologically and functionally mimic native fetal and adult RPE. However protocols for optimum culture of hESC-RPE are not well established.', 'To describe a simplified protocol for differentiating human embryonic stem cells (hESC) into retinal pigment epithelial cells.', 'hESC (WA09-DL-11) cell lines were grown with standard stem cell culture protocol. After cell colonies were established, basic fibroblast growth factor (bFGF) was deprived (day 0). hESC colonies expressing pigmentation were characterized for expression of RPE65 and Zonular occludens--1 (ZO-1) with immunocytochemistry on days 0, 36, 42, 56 and 70 and western blot analysis on days 0, 40, 48, 53 and 63. In addition, morphological assessment was conducted on transformed cells longitudinally.', 'Pigmented cells were noted 36 days after deprivation of bFGF from growth media. Immunofluorescence demonstrated progressive up regulation of RPE specific proteins (ZO-1 & RPE 65). Immunofluorescence of ZO-1 (in pixels) was (3.08 ± 0.31) on day 42, (5.33 ± 0.89, p = 0.0001) on day 56 and (4.87 ± 0.57, p = 0.0011) on day 70. Similarly expression of RPE 65 was (2.44 ± 0.31) on day 42, which continued to increase (4.23 ± 0.60, p = 0.0011) on day 56 and (5.59 ± 0.36, p < 0.0001) on day 70. Protein expression patterns using western blot confirmed the trends seen in immunofluorescence. Western blot analysis of ZO-1 expression (in optical density unit) was 272.57 ± 31.75 on day 40, 4212.20 ± 911.31 (p = 0.0004) on day 48, 5182.43 ± 1230.38 (p = 0.030) on day 53 and 5848.76 ± 241.04 (p < 0.0001) on day 63. Protein expression of RPE 65 was 1607.64 ± 247.76 on day 40, 2448.07 ± 152.66 on day 48 and (2341.15 ± 52.84) on day 63. hESC-RPE cells displayed a series of specific morphological changes (cytoplasmic, nuclear pigmentary and cell shape) over the course of time frame. By day 70, cells with hexagonal pattern, dark dense nucleus and uniform cytoplasm were noted in densely pigmented RPE colonies.']
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['Hyperhomocysteinaemia has been associated with reduced pulse wave velocity (PWV) in patients with end-stage renal disease and in those with hypertension. The aim of this study was to examine the association between total homocysteine (tHcy) concentrations, the biochemical and genetic determinants of tHcy and PWV in healthy young adults.', 'A total of 489 subjects aged 20-25 years participated. A fasting blood sample was taken and PWV measured using a non-invasive optical method. tHcy did not correlate with PWV, whether assessed at the aorto-iliac segment (P = 0.18), the aorto-radial segment (P = 0.39) or the aorto-dorsalis-pedis segment (P = 0.22). When tHcy was classified into normal (<15) and high (> or =15micromol/l), PWV did not differ between the two groups at any segment. PWV did not differ by MTHFR C677T or NOS3 G894T genotype, even when smoking and folate sub-groups were considered. Considering aortic PWV as a dependent variable, stepwise regression analysis showed that the only parameter entering the model for all segments was systolic blood pressure (aorto-iliac, P < 0.001; aorto-radial, P = 0.01; aorto-dorsalis-pedis, P = 0.001). Age, sex, COL1A1 genotype and triglycerides entered the model significantly for two of three segments.']
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['Osteonecrosis (ON) of the femoral head in childhood can lead to loss of femoral head architecture and subsequent deformity. When femoral head ON was surgically induced in 24 rats, zoledronic acid treatment and prophylaxis improved sphericity and maintenance of architecture at 6 weeks. This preliminary experiment supports the use of bisphosphonates in childhood ON.', 'We hypothesized that the bisphosphonate zoledronic acid could preserve femoral head structure while allowing bone repair.', 'Osteonecrosis (ON) was surgically induced in the right femoral head of 24 female Wistar rats. The rats were randomized into three treatment groups and dosed subcutaneously with saline, zoledronic acid (0.1 mg/kg) at 1 and 4 weeks postoperation (ZA post), or zoledronic acid (0.1 mg/kg) given 2 weeks preoperation and at 1 and 4 weeks postoperation (ZA pre-post). After death at 6 weeks postoperation, undecalcified specimens were analyzed by DXA and standardized histomorphometric analysis.', 'Seventy-one percent of saline-operated femoral heads were aspherical (Mose score > 1), whereas only 13% and 0% of operated heads in the ZA-treated groups were aspherical (p < 0.05). DXA-measured bone mineral density in saline-treated femoral heads was reduced by 34% and 43% compared with the ZA-treated groups (p < 0.01). Histomorphometry showed decreases of 12% and 17% in bone volume (BV/TV) in saline groups compared with ZA post and ZA pre-post (p < 0.05), and a decrease in trabecular number (Tb.N) of 18% and 14% (p < 0.05), respectively. Bone formation rate (BFR) was increased by 56% in saline-treated operated heads over ZA post and was 4.8 times increased over the ZA pre-post group (p < 0.05). The differences in BV/TV and Tb.N in treated groups must therefore be caused by a reduction in bone turnover. Observational histology confirmed the retention of necrotic architecture in treated groups.']
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["The aim of this study was to investigate the relationship of pretreatment serum IL-10 (sIL-10) levels with known prognostic factors and with failure-free survival (FFS) in patients with Hodgkin's lymphoma (HL).", 'Interleukin-10 (IL-10) levels were measured in the sera of 36 untreated patients with HL and were subsequently correlated with clinical and laboratory prognostic parameters as well as with FFS.', '36 untreated HL patients (21 men, median age 31 (18-62) years) were studied. Of the subjects, 19 (52.7%) had elevated IL-10 levels (> or = 10 pg/ml). High IL-10 correlated with bulky disease, high serum lactate dehydrogenase (LDH) and leukocytosis (P = 0.015 for all three variables). High IL-10 (P = 0.015) and low serum albumin (P = 0.001) were associated with worse FFS, but only high IL-10 emerged as an independent predictor of inferior FFS in multivariate analysis (P = 0.04, hazard ratio 2.21, 95% CI 1.12-14.67). Median FFS of IL-10-positive patients (30 (12-47) months) was significantly shorter compared to that of IL-10-negative ones (39 (12-58) months, log-rank test P = 0.0185).']
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