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['Recent studies suggest an association between vitamin D activity and cardiometabolic risk.', 'We investigated vitamin D status and its association with subclinical atherosclerosis in a population-based cohort study, the Korean Longitudinal Study on Health and Aging (KLoSHA).', 'Participants were 439 men and 561 women aged 65 yr or older who were recruited by random stratified sampling for KLoSHA.', 'Anthropometric and biochemical parameters, the concentration of 25-hydroxyvitamin D (25-OHD), and intact PTH were measured.', 'We evaluated the coronary artery calcium score and stenosis using multidetector-row cardiac computed tomography, the intima-media thickness using carotid sonography, pulse wave velocity, and the ankle-brachial index.', 'Among the participants, 49.8, 44.2, and 6.0% had 25-OHD deficiency (<15 ng/ml), insufficiency (15-29.9 ng/ml), and adequacy (≥30 ng/ml), respectively. The frequency of coronary artery stenosis (>50%) differed between 25-OHD categories: 18.5, 12.9, and 1.9% in the 25-OHD-deficient, -insufficient, and -adequate groups, respectively (P < 0.05). After adjusting for cardiometabolic risks and intact PTH concentration, multivariate regression analysis showed that participants with a low 25-OHD concentration had a higher risk of significant coronary artery stenosis; the odds ratios were 2.08 for 25-OHD concentration of 15-29.9 ng/ml vs. at least 30 ng/ml and 3.12 for 25-OHD concentration below 15 ng/ml vs. at least 30 ng/ml (both P < 0.05).'] |
['Pancreatic neuritis is a histopathological hallmark of pancreatic neuropathy and correlates to abdominal neuropathic pain sensation in pancreatic adenocarcinoma (PCa) and chronic pancreatitis (CP). However, inflammatory cell subtypes that compose pancreatic neuritis and their correlation to the neuropathic pain syndrome in PCa and CP are yet unknown.', 'Inflammatory cells within pancreatic neuritis lesions of patients with PCa (n = 20) and CP (n = 20) were immunolabeled and colorimetrically quantified with the pan-leukocyte marker CD45, with CD68 (macrophages), CD8 (cytotoxic T-lymphocytes), CD4 (T-helper cells), CD20 (B-lymphocytes), NCL-PC (plasma cells), neutrophil elastase, PRG2 (eosinophils), anti-mast cell (MC) tryptase and correlated to pain sensation. Perineural mast cell subtypes were analyzed by double immunolabeling with MC chymase. Expression and neural immunoreactivity of protease-activated receptor type 1 (PAR-1) and type 2 (PAR-2) were analyzed in PCa and CP and correlated to pain status of the patients.', 'In PCa and CP, nerves were predominantly infiltrated by cytotoxic T-lymphocytes (PCa: 35% of all perineural inflammatory cells, CP: 33%), macrophages (PCa: 39%, CP: 33%) and MC (PCa: 21%, CP: 27%). In both entities, neuropathic pain sensation was associated with a specific increase of perineural MC (PCa without pain: 14% vs. PCa with pain: 31%; CP without pain: 19% vs. CP with pain: 34%), not affecting the frequency of other inflammatory cell subtypes. The vast majority of these MC contained MC chymase. PAR-1 and PAR-2 expression did not correlate to the pain sensation of PCa and CP patients.'] |
['In Canada, staging of carcinoid tumors is largely based on computed tomography (CT) imaging sometimes complemented with somatostatin receptor scintigraphy (SRS). This study assessed the diagnostic accuracy of 6-[¹⁸F]fluoro-3,4-dihydroxyphenylalanine (¹⁸F-FDOPA) PET/CT in neuroendocrine tumors.', 'We prospectively included 27 patients with either suspected carcinoid (n=6, with all prior tests negative) or with an established diagnosis of intestinal carcinoid tumor (n=21) from two Canadian treatment centers. Findings of ¹⁸F-FDOPA PET/CT were compared with SRS, CT, and combined SRS/CT using a composite reference standard comprising all available imaging, biochemistry, surgery, and follow-up data. Sensitivity was calculated per patient, per body region, and per lesion. The contribution to patient management was estimated from the feedback of attending physicians.', 'In documented carcinoid patients, ¹⁸F-FDOPA PET/CT identified disease in 20 of 21 patients (patient-based sensitivity 95%). In 56 positive regions, ¹⁸F-FDOPA PET/CT detected 53, CT detected 34, SRS detected 34, and CT+SRS detected 39 regions, leading to region-based sensitivities of 95, 61, 62, and 71%, respectively. Lesion-based sensitivities were 96, 69, 50, and 72%, respectively. In the six patients with suspected disease only, one CT scan was positive, but ¹⁸F-FDOPA PET/CT was negative for all. ¹⁸F-FDOPA PET contributed to patient management in 12/21 patients (57%).'] |
['Thrombospondin type I domain containing 7A (THSD7A) is a novel neural protein that is known to affect endothelial migration and vascular patterning during development. To further understand the role of THSD7A in angiogenesis, we investigated the post-translational modification scheme of THS7DA and to reveal the underlying mechanisms by which this protein regulates blood vessel growth.', 'Full-length THSD7A was overexpressed in human embryonic kidney 293T (HEK293T) cells and was found to be membrane associated and N-glycosylated. The soluble form of THSD7A, which is released into the cultured medium, was harvested for further angiogenic assays. We found that soluble THSD7A promotes human umbilical vein endothelial cell (HUVEC) migration and tube formation. HUVEC sprouts and zebrafish subintestinal vessel (SIV) angiogenic assays further revealed that soluble THSD7A increases the number of branching points of new vessels. Interestingly, we found that soluble THSD7A increased the formation of filopodia in HUVEC. The distribution patterns of vinculin and phosphorylated focal adhesion kinase (FAK) were also affected, which implies a role for THSD7A in focal adhesion assembly. Moreover, soluble THSD7A increased FAK phosphorylation in HUVEC, suggesting that THSD7A is involved in regulating cytoskeleton reorganization.'] |
['The vaginal microbiota can impact the susceptibility of women to bacterial vaginosis (BV) and sexually transmitted infections (STIs). BV is characterized by depletion of Lactobacillus spp., an overgrowth of anaerobes (often dominated by Gardnerella vaginalis) and a pH\u2009>\u20094.5. BV is associated with an increased risk of acquiring STIs such as chlamydia and gonorrhea. While these associations have been identified, the molecular mechanism(s) driving the risk of infections are unknown. An ex vivo porcine vaginal mucosal model (PVM) was developed to explore the mechanistic role of Lactobacillus spp. in affecting colonization by G. vaginalis and Neisseria gonorrhoeae.', 'The data presented here demonstrate that all organisms tested can colonize and grow on PVM to clinically relevant densities. Additionally, G. vaginalis and N. gonorrhoeae form biofilms on PVM. It was observed that lactic acid, acetic acid, and hydrochloric acid inhibit the growth of G. vaginalis on PVM in a pH-dependent manner. N. gonorrhoeae grows best in the presence of lactic acid at pH 5.5, but did not grow well at this pH in the presence of acetic acid. Finally, a clinical Lactobacillus crispatus isolate (24-9-7) produces lactic acid and inhibits growth of both G. vaginalis and N. gonorrhoeae on PVM.'] |
['To assess the relationship between the spectroscopically measured axonal damage in the normal-appearing white matter of the brainstem, the total brain T2-hyperintense lesion volume (T2LV), and disability in patients with early relapsing-remitting multiple sclerosis (RRMS).', 'Forty-three RRMS patients and 10 sex- and age-matched healthy controls were prospectively studied for 2 years. T2-weighted magnetic resonance (MR) images and proton MR spectroscopy were acquired at the time of recruitment and at year 2. Brainstem was considered, where large tracts join together, as a suitable region to detect early axonal damage. The T2LV was calculated with a semiautomatic program; N-acetylaspartate (NAA), creatine (Cr), and choline (Cho) resonances areas were integrated with the jMRUI program, and the ratios were calculated for the sum of the volume elements represented at brainstem.', 'The basal NAA/Cho ratio was significantly decreased in patients compared with controls. After 2-year follow-up, there was a decrease in the NAA/Cho (-9%; p = 0.002) and NAA/Cr (-13%; p = 0.001) ratios, and an increase in the T2LV (19%; p = 0.043) in multiple sclerosis patients, whereas control subjects had no significant metabolic changes. Significant NAA/Cr ratio decreases were observed in both patients, with and without relapses, whereas T2LV only increased in patients with relapses. The final Expanded Disability Status Scale (EDSS) score correlated with T2LV at baseline, but no significant correlations were found between metabolic values, T2LV change, or EDSS score over the study period.'] |
['Oral administration of live Lactobacillus casei strain GG is associated with the reduction of duration of diarrhea in children admitted to the hospital because of diarrhea. The purposes of this work were to investigate the clinical efficacy of oral administration of Lactobacillus in children with mild diarrhea who were observed as outpatients, and to see whether Lactobacillus GG can reduce the duration of rotavirus excretion.', 'Duration of diarrhea was recorded in 100 children seen by family pediatricians and randomly assigned to receive oral rehydration or oral rehydration followed by the administration of lyophilized Lactobacillus casei, strain GG. Rotavirus was looked for in the stools of all children and in those in whom results were positive, stools were examined again 6 days after the onset of diarrhea.', 'In 61 children results were positive for rotavirus and in 39 results were negative. Duration of diarrhea was reduced from 6 to 3 days in children receiving Lactobacillus GG, with a similar pattern in rotavirus-positive and -negative children. Six days after the onset of diarrhea, stools in only 4 out of 31 children that received Lactobacillus GG were positive for rotavirus compared with positive findings in 25 out of 30 control subjects.'] |
['The purpose of this study was to compare aortic valve function and morphology in adult wild-type (WT) mice and in low-density lipoprotein receptor-deficient (LDLr-/-) mice fed or not fed a high-fat/high-carbohydrate (HF/HC) diet.', 'Observations suggest a link between degenerative aortic valve stenosis (AS) and atherosclerosis. Aortic valve stenosis has been successfully induced in animal models of extreme hypercholesterolemia, but these models are less relevant to humans. It is not known if a proatherogenic HF/HC diet without added cholesterol could have the same negative impacts.', 'Forty C57BL/6J mice were divided into four groups: WT + normal diet, WT + HF/HC diet, LDLr-/- with a normal diet, and LDLr-/- with a HF/HC diet. Aortic valve function and histology were evaluated by echocardiography after four months.', 'Wild-type mice on a HF/HC diet became mildly hypercholesterolemic, obese, and hyperglycemic. As expected, LDLr-/- mice became severely hypercholesterolemic. Both WT and LDLr-/- mice on a HF/HC diet displayed smaller valve areas and higher transvalvular velocities (p < 0.01) after four months. Aortic valve leaflets were thicker and infiltrated with lipids and macrophages in both HF/HC groups.'] |
['Large full thickness skin defects caused by trauma or surgery require skin grafting, often in conjunction with dermal scaffolds such as INTEGRA(®). Due to the size and severity of these procedures, complications such as infection may occur. This can lead to poor healing outcomes.', 'To identify early biomarkers of complications during INTEGRA(®) healing.', 'Levels of EGF, TGF-β1, FGF-2, VEGF, IFN-α, GM-CSF, IL-4 and IL-8 were measured pre-surgery and at days 1, 7 and 25 post-surgery in peripheral blood of 15 pediatric patients treated with INTEGRA(®) for reconstructive procedures. The levels of these molecules were analysed with respect to the occurrence of complications.', 'Complications (local infection) occurred in a group of 4 patients. This resulted in a reduced INTEGRA(®) take rate comparing to the group without complications (71.5±5.4% vs. 98.1±0.7%). In cases with complications there were significantly higher plasma concentrations of IL-4 and FGF-2 on day 7 (p=0.037 and p=0.008 respectively). Other markers were not significantly different between groups or at very low level at all time-points. WCC and CRP remained within normal ranges at all time-points.'] |
['To test the hypothesis that somatosensory stimulation would enhance the effects of training functional hand tasks immediately after practice and 1 day later in chronic subcortical stroke patients.', 'Single-blinded and randomized, crossover study.', 'Human research laboratory.', 'Nine chronic subcortical stroke patients.', 'Three separate sessions of motor training preceded by (1) synchronous peripheral nerve stimulation (PNS), (2) no stimulation, or (3) asynchronous PNS.', 'Time to complete the Jebsen-Taylor Hand Function Test (JTHFT time) and corticomotor excitability tested with transcranial magnetic stimulation.', 'After familiarization practice, during which all patients reached a performance plateau, training under the effects of PNS reduced JTHFT time by 10% beyond the post-familiarization plateau. This behavioral gain was accompanied by a specific reduction in GABAergically mediated intracortical inhibition in the motor cortex. These findings were not observed after similar practice under the influence of no stimulation or asynchronous PNS sessions.'] |
['Liver kinase B1 (LKB1) and its downstream effector AMP-activated protein kinase (AMPK) play critical roles in polarity establishment by regulating membrane trafficking and energy metabolism. In collagen sandwich-cultured hepatocytes, loss of LKB1 or AMPK impaired apical ABCB11 (Bsep) trafficking and bile canalicular formation. In the present study, we used liver-specific (albumin-Cre) LKB1 knockout mice (LKB1(-/-) ) to investigate the role of LKB1 in the maintenance of functional tight junction (TJ) in vivo. Transmission electron microscopy examination revealed that hepatocyte apical membrane with microvilli substantially extended into the basolateral domain of LKB1(-/-) livers. Immunofluorescence studies revealed that loss of LKB1 led to longer and wider canalicular structures correlating with mislocalization of the junctional protein, cingulin. To test junctional function, we used intravital microscopy to quantify the transport kinetics of 6-carboxyfluorescein diacetate (6-CFDA), which is processed in hepatocytes into its fluorescent derivative 6-carboxyfluorescein (6-CF) and secreted into the canaliculi. In LKB1(-/-) mice, 6-CF remained largely in hepatocytes, canalicular secretion was delayed, and 6-CF appeared in the blood. To test whether 6-CF was transported through permeable TJ, we intravenously injected low molecular weight (3 kDa) dextran in combination with 6-CFDA. In wild-type mice, 3 kDa dextran remained in the vasculature, whereas it rapidly appeared in the abnormal bile canaliculi in LKB1(-/-) mice, confirming that junctional disruption resulted in paracellular exchange between the blood stream and the bile canaliculus.'] |
['The aim was to investigate assisted reproductive technology (ART) outcomes after routine use of EmbryoGlue(®) as a human embryo transfer (ET) medium with high concentration of hyaluronan (HA, hyaluronic acid).', 'A cohort of total 229 patients was retrospectively enrolled for the present study. They were subjected for embryo transfer on day 2 either in EmbryoGlue(®) (n = 117) as study group or in conventional ET medium with low concentration of HA as control group (n = 112).', 'Patients in the both groups, in regards to the mean level of day 3 FSH, the etiology of infertility, the history of implantation failure and the rate of good quality embryos showed similar characteristics. There were no significant differences between two groups in terms of clinical and ongoing pregnancies, implantation, delivery and live birth rates. In spite of a decreased abortion and increased multiple pregnancy rates in the study group compared to the control group (15.8 vs. 19 % and 20.6 vs. 15.6 respectively), the differences were not statistically significant.'] |
['To investigate the relationship among angiogenic cytokines, inflammatory markers, and fibrinolytic activity in tuberculous pleural effusion (TBPE) and their clinical importance.', 'Forty-two patients diagnosed with TBPE were studied. Based on chest ultrasonography, there were 26 loculated and 16 nonloculated TBPE patients. The effusion size radiological scores and effusion vascular endothelial growth factor (VEGF), interleukin- (IL-) 8, plasminogen activator inhibitor type-1 (PAI-1), and tissue type plasminogen activator (tPA) were measured. Treatment outcome and pleural fibrosis, defined as radiological residual pleural thickening (RPT), were assessed at 6-month follow-up.', 'The effusion size and effusion lactate dehydrogenase (LDH), VEGF, IL-8, PAI-1, and PAI-1/tPA ratio were significantly higher, while effusion glucose, pH value, and tPA were significantly lower, in loculated than in nonloculated TBPE. VEGF and IL-8 correlated positively with LDH and PAI-1/tPA ratio and negatively with tPA in both loculated and nonloculated TBPE. Patients with higher VEGF or greater effusion size were prone to develop RPT (n=14; VEGF, odds ratio 1.28, P=0.01; effusion size, odds ratio 1.01, P=0.02), and VEGF was an independent predictor of RPT in TBPE (receiver operating characteristic curve AUC=0.985, P<0.001).'] |
['CD133 has been suggested to be a cancer stem cell (CSC) marker in various types of cancers. The present study assessed the relationship between CD133 expression and clinicopathological features of gastric cancer. In addition, the prognostic value of CD133 for gastric cancer was evaluated.', 'In total, 100 advanced gastric cancer patients who received curative gastrectomy and adjuvant chemotherapy were included. CD133 expression was determined by immunohistochemistry and clinicopathological results, including survival, were analyzed.', 'CD133 was expressed in 23% of advanced gastric cancer patients (23/100). CD133 expression was significantly associated with serosal exposure (P\u2009=\u20090.036), venous invasion (P\u2009=\u20090.047), well and moderate differentiation (P\u2009=\u20090.002), and intestinal-type Lauren classification (P\u2009=\u20090.001). CD133-positive patients had a significantly worse 5-year disease-free (28.1% vs. 65.8%, P\u2009=\u20090.002) and overall (47.5% vs. 74.0%, P\u2009=\u20090.037) survival rate than those who were CD133-negative. A multivariate analysis suggested that CD133 expression significantly affected the 5-year disease-free and overall survival.'] |
['Nurses and physicians often describe critical care that is not expected to provide meaningful benefit to a patient as futile, and providing treatments perceived as futile is associated with moral distress.', "To explore concordance of physicians' and nurses' assessments of futile critical care.", 'A focus group of clinicians developed a consensus definition of "futile" critical care. Daily for 3 months, critical care physicians and nurses in a health care system identified patients perceived to be receiving futile treatment. Assessments and patients\' survival were compared between nurses and physicians.', 'Nurses and physicians made 6254 shared assessments on 1086 patients. Nurses and physicians assessed approximately the same number of patients as receiving futile treatment (110 for nurses vs 113 for physicians, P = .82); however, concordance was low as to which patients were assessed as receiving futile treatment (κ = 0.46). The 110 patients categorized by nurses as receiving futile treatment had lower 6-month mortality than did the 113 patients so assessed by physicians (68% vs 85%, P = .005). Patients who were assessed as receiving futile treatment by both providers were more likely to die in the hospital than were patients assessed as receiving futile treatment by the nurse alone (76% vs 32%, P < .001) or by the physician alone (76% vs 57%, P = .04).'] |
['To investigate the role of Th17/Treg unbalance in the pathogenesis of experimental autoimmune encephalomyelitis (EAE).', 'EAE was modeled in mice and the number of regulatory T cells (Tregs) in spleen of EAE mice was detected by flow cytometry. The expressions of Foxp3 and RoR-γt mRNA in the spleen of EAE mice and IL-17 mRNA in the brain of EAE mice were evaluated by real-time quantitative PCR and the levels of IL-6, TGF-β and IL-17 in the serum of EAE mice were examined by ELISA.', 'Compared with control group, the number of CD4(+)CD25(+) Foxp3(+) Tregs and the expression of Foxp3 mRNA in the spleen of EAE mice dramatically decreased in the early and peak stage of EAE (P<0.05), but increased in chronic stage of EAE (P<0.05); the RoR-γt mRNA expression from mouse spleen at the early stage of EAE was significant raised (P<0.05), but was not significantly different at the peak and chronic stage of EAE from that in control group (P>0.05). The levels of IL-6 and TGF-β in the serum of EAE group dramatically increased compared with control group (P<0.05). With the development of EAE, the level of IL-6 gradually decreased, and there was no statistical difference in the chronic stage of EAE compared with control group (P>0.05). However, the level of TGF-β was higher than that in control group in the chronic stage of EAE (P<0.05). Compared with those in control group, the concentration of IL-17A and the expression of IL-17 mRNA dramatically increased in different stages of EAE group, especially in peak stage (P<0.05).'] |
['During erythrocytic schizogony, Plasmodium falciparum interacts with the human erythrocyte membrane when it enters into, grows within and escapes from the erythrocyte. An interaction between the P. falciparum M18 aspartyl aminopeptidase (PfM18AAP) and the human erythrocyte membrane protein spectrin was recently identified using phage display technology. In this study, recombinant (r) PfM18AAP was characterized and the interaction between the enzyme and spectrin, as well as other erythrocyte membrane proteins, analyzed.', 'rPfM18AAP was produced as a hexahistidine-fusion protein in Escherichia coli and purified using magnetic bead technology. The pI of the enzyme was determined by two-dimensional gel electrophoresis and the number of subunits in the native enzyme was estimated from Ferguson plots. The enzymatic activity over a pH and temperature range was tested by a coupled enzyme assay. Blot overlays were performed to validate the spectrin-PfM18AAP interaction, as well as identify additional interactions between the enzyme and other erythrocyte membrane proteins. Sequence analysis identified conserved amino acids that are expected to be involved in cofactor binding, substrate cleavage and quaternary structure stabilization.', 'rPfM18AAP has a molecular weight of ~67 kDa and the enzyme separated as three entities with pI 6.6, 6.7 and 6.9. Non-denaturing gel electrophoresis indicated that rPfM18AAP aggregated into oligomers. An in vitro coupled enzyme assay showed that rPfM18AAP cleaved an N-terminal aspartate from a tripeptide substrate with maximum enzymatic activity at pH 7.5 and 37 degrees C. The spectrin-binding region of PfM18AAP is not found in Homo sapiens, Saccharomyces cerevisiae and otherPlasmodium species homologues. Amino acids expected to be involved in cofactor binding, substrate cleavage and quaternary structure stabilization, are conserved. Blot overlays with rPfM18AAP against spectrin and erythrocyte membrane proteins indicated that rPfM18AAP binds to spectrin, as well as to protein 4.1, protein 4.2, actin and glyceraldehyde 3-phosphate dehydrogenase.'] |
['The genetic polymorphism with an isoleucine-to-methionine substitution at position 148 (rs738409 C>G) in the patatin-like phospholipase domain protein 3 (PNPLA3) gene confers risk of steatosis. PNPLA3 polymorphism is shown to be associated with alcoholic liver disease (ALD). We performed a systematic review and meta-analysis to examine association of this genetic polymorphism with ALD spectrum and its severity.', "Medline, Embase, and Cochrane Library were searched for studies on association of PNPLA3 polymorphism and ALD spectrum: alcoholic fatty liver (AFL), alcoholic liver injury (ALI), alcoholic cirrhosis (AC), and hepatocellular carcinoma (HCC). Pooled data are reported as odds ratio (OR) with 95% confidence interval. Heterogeneity was assessed using the I(2) statistics and publication bias using Egger's test and Begg and Mazumdar's test. Individual participant data obtained from five studies were used for subgroup analyses.", 'Among 10 studies included in this pooled analysis, compared with controls, OR for rs738409 CG and GG among ALI patients was 1.45 (1.24-1.69) and 2.22 (1.50-3.28), respectively, compared with CC. Respective OR among AC patients was 2.09 (1.79-2.44) and 3.37 (2.49-4.58) and among AC patients with HCC was 2.87 (1.61-5.10) and 12.41 (6.99-22.03). Data for AFL were inconsistent. Among ALD patients, OR of CG and GG genotypes was 2.62 (1.73-3.97) and 8.45 (2.52-28.37), respectively, for AC compared with fatty liver (FL) patients. Similar OR for AC compared with ALI was 1.98 (1.24-3.17) and 3.86 (1.18-12.60). The OR for CG and GG genotypes among AC patients for HCC occurrence was 1.43 (0.76-2.72) and 2.81 (1.57-5.01), respectively. Individual participant data analysis showed age to predispose to AC among ALI patients.'] |
['Vascular endothelial growth factor (VEGF) is one of the most potent angiogenic mitogens specific for vascular endothelial cells. It also induces vascular hyperpermeability and protein leakage into the extracellular space. Leukotriene D(4) (LTD(4)), one of the cysteinyl leukotrienes (CysLTs), is known to be one of the key molecules of allergic inflammation. The interaction between LTD(4) and VEGF production in human monocytes/macrophages is not well characterized.', 'We examined VEGF production by THP-1 cells, a human monocytic leukemia cell line, and human peripheral blood CD14+monocytes/macrophages stimulated with LTD(4) and/or tumor necrosis factor-α (TNF-α). We also determined the inhibitory effects of pranlukast, a CysLT(1) receptor antagonist, on VEGF production by LTD(4) stimulation.', 'LTD(4) significantly induced VEGF production and enhanced TNF-α-induced VEGF release in THP-1 cells and human peripheral blood CD14+monocytes/macrophages. VEGF mRNA expression was also induced by stimulation of THP-1 cells with LTD(4) and TNF-α. In addition, 10(-7)-10(-10)M pranlukast completely inhibited VEGF production enhanced by LTD(4). The 50% inhibitory concentration (IC50) for VEGF production in THP-1 cells was 10(-10)-10(-11)M.'] |
['The voltage gated sodium channel Na(v) 1.8 has a highly restricted expression pattern to predominantly nociceptive peripheral sensory neurones. Behaviourally Na(v) 1.8-null mice show an increased acute pain threshold to noxious mechanical pressure and also deficits in inflammatory and visceral, but not neuropathic pain. Here we have made in vivo electrophysiology recordings of dorsal horn neurones in intact anaesthetised Na(v) 1.8-null mice, in response to a wide range of stimuli to further the understanding of the functional roles of Na(v) 1.8 in pain transmission from the periphery to the spinal cord.', 'Na(v) 1.8-null mice showed marked deficits in the coding by dorsal horn neurones to mechanical, but not thermal, -evoked responses over the non-noxious and noxious range compared to littermate controls. Additionally, responses evoked to other stimulus modalities were also significantly reduced in Na(v) 1.8-null mice where the reduction observed to pinch > brush. The occurrence of ongoing spontaneous neuronal activity was significantly less in mice lacking Na(v) 1.8 compared to control. No difference was observed between groups in the evoked activity to electrical activity of the peripheral receptive field.'] |
['Few studies have reported on the relative ratio between the depths to which acupuncture needles are inserted in therapy (therapeutic depth) and safety depth (the distance from the surface of the skin of the acupoint to the transverse fascia). This ratio may be of clinical importance because it may have an impact on the safety and the therapeutic effectiveness of acupuncture.', 'We retrospectively studied children aged 7 to 15 years who underwent abdominal computed tomography (CT) at our hospital during the period January 1997-March 2006. Twelve (12) abdominal acupuncture points (CV-3, CV-4, CV-6, CV-10, CV-12, CV-14, KI-12, ST-24, ST-25, SP-15, LV-13, and LV-4) were measured directly on the CT images. The ratio between the therapeutic depth and safe depth of the 12 abdominal acupoints with factors sex, body weight, age, and waist girths were analyzed by one-way analysis of variance and multiple linear regression analysis.', 'A total of 204 patients were included in this study. There was no significant difference in the therapeutic depth over safety depth ratio (T/S ratio) between genders. The T/S ratio of these 12 acupuncture points ranged from 0.67 to 0.88 and increased significantly with body weight, age, and waist girth (p < 0.001).'] |
['An elevated preoperative C-reactive protein/albumin (CRP/Alb) ratio has been reported to be associated with a poor prognosis for hepatocellular carcinoma. The aim of the present study was to investigate the prognostic value of the preoperative CRP/Alb ratio and compare it with other systemic inflammatory response markers in patients with gastric cancer (GC).', 'A retrospective study was performed in 455 patients with GC undergoing curative resection. We investigated the correlations between the preoperative CRP/Alb ratio and overall survival (OS). Kaplan-Meier and Cox regression models were used to assess independent prognostic factors. The area under the curve was used to compare the prognostic value of different markers.', 'On multivariate analysis, the CRP/Alb ratio were independently associated with OS in patients with GC (hazard ratio: 1.626; 95% confidence interval: 1.191-2.219; P = .002), along with age (P = .003), preoperative body weight loss (P = .001), tumor location (P = .008), metastatic lymph node ratio (P < .001), and seventh tumor-nodes-metastasis stage (American Joint Committee on Cancer) (P = .007). However, several other systemic inflammation-based prognostic scores (neutrophil lymphocyte ratio, platelet lymphocyte ratio and systemic immune-inflammation index, Glasgow Prognostic Score, modified Glasgow prognostic score, and high-sensitivity modified Glasgow prognostic score) were not. In addition, the CRP/Alb ratio had a higher area under the curve value (0.625) compared with several other systemic inflammation-based prognostic scores (P < .001).'] |
['Our objective was to assess whether there is an association between the presence of allelic variants of the gene for cytochrome P450 (CYP) 2C9 and anticoagulation problems during the initial 3 to 6 months of acenocoumarol treatment.', 'A prospective follow-up study was performed at 2 anticoagulation clinics in the Netherlands. Included subjects started with a standard dose regimen as follows: 6 mg on the first day, 4 mg on the second day, and 2 mg on the third day. CYP2C9 genotypes were assessed, and data on international normalized ratio (INR), comedication, and comorbidity were collected.', 'The CYP2C9 genotype of 231 subjects was assessed. Of these, 147 (63.6%) were wild-type subjects (CYP2C9*1/*1), 38 (16.5%) were carriers of CYP2C9*2, and 46 (19.9%) were carriers of CYP2C9*3. Compared with wild-type subjects, carriers of the CYP2C9*3 allele had (1) a lower chance to achieve stability in the first 6 months of therapy (hazard ratio, 0.62; 95% confidence interval, 0.42-0.91; P <.05) and (2) an increased risk of severe overanticoagulation (INR >6.0) (hazard ratio, 3.80; 95% confidence interval, 1.54-9.39; P <.01). For both outcomes, there was no significant difference between carriers of the CYP2C9*2 allele and wild-type subjects.'] |
['Erythropoietin (EPO) is a cytokine that regulates the proliferation, differentiation, and survival of erythroid progenitor cells. EPO has recently been demonstrated to have a tissue-protective role by mediating anti-apoptotic signals through the erythropoietin receptor (EPOR) in various tissues, including brain, liver, and heart. We have previously examined pancreatic β-cell line NIT-1 cells for the expression of EPOR by real-time PCR and determined that these cells were protected by EPO against cytokine-induced apoptosis. The precise underlying anti-apoptotic mechanisms in pancreatic β-cells are poorly understood. The purpose of this study is to examine erythropoietin receptor expression in the NIT-1 pancreatic beta-cell line and the intracellular pathway related with its anti-apoptosis effect in NIT-1 cells.', 'we examined the expression of EPOR by western blot. We investigate the role of erythropoietin in the survival of these cells, and whether the PI3K/AKT pathway is involved in this protective process.', 'NIT-1 cells expressed EPOR and, in the presence of certain cytokines, exposure of NIT-1 cells to recombinant human erythropoietin (rhEPO) significantly improved the impaired insulin secretion and inhibited cytokine-induced apoptosis. RhEPO caused a rapid activation of Akt and increased expression of Bcl-2. The protective anti-apoptotic effect of rhEPO was significantly abolished by a specific phosphatidylinositol 3-kiniase (PI3K) inhibitor, LY294002.'] |
['Posttraumatic stress disorder (PTSD) is a complex disorder associated with an intricate biological and psychological symptom profile and various common comorbidities. Despite an existing myriad of evidence-based and experimental treatments, PTSD is often difficult to treat. This reality necessitates a discussion of the potential of emerging treatments.', 'A literature search using PubMed and PsychInfo was done using the following keywords: randomized clinical trials, treatment guidelines, pharmacotherapy and psychotherapy, all in addition to PTSD. A comprehensive treatment review establishes that early intervention approaches have not yet been found to prevent PTSD in trauma survivors. However, psychotherapy research provides substantial support for cognitive behavioral therapies and eye movement desensitization and reprocessing for chronic PTSD, and psychopharmacological approaches are myriad - although at present there is FDA approval only for sertraline and paroxetine. However, the efficacy of these treatments varies and, unfortunately, not everyone will achieve remission.'] |
['There is conflicting data as to whether obesity is an independent risk factor for mortality in severe pandemic (H1N1) 2009 influenza (A(H1N1)pdm09). It is postulated that excess inflammation and cytokine production in obese patients following severe influenza infection leads to viral pneumonitis and/or acute respiratory distress syndrome.', 'Demographic, laboratory and clinical data prospectively collected from obese and non-obese patients admitted to nine adult Australian intensive care units (ICU) during the first A(H1N1)pdm09 wave, supplemented with retrospectively collected data, were compared.', 'Of 173 patients, 100 (57.8%), 73 (42.2%) and 23 (13.3%) had body mass index (BMI) <30 kg/m(2), ≥30 kg/m(2) (obese) and ≥40 kg/m(2) (morbidly obese) respectively. Compared to non-obese patients, obese patients were younger (mean age 43.4 vs. 48.4 years, p\u200a=\u200a0.035) and more likely to develop pneumonitis (61% vs. 44%, p\u200a=\u200a0.029). Extracorporeal membrane oxygenation use was greater in morbidly obese compared to non-obese patients (17.4% vs. 4.7%, p\u200a=\u200a0.04). Higher mortality rates were observed in non-obese compared to obese patients, but not after adjusting for severity of disease. C-reactive protein (CRP) levels and hospital length of stay (LOS) were similar. Amongst ICU survivors, obese patients had longer ICU LOS (median 11.9 vs. 6.8 days, p\u200a=\u200a0.017). Similar trends were observed when only patients infected with A(H1N1)pdm09 were examined.'] |
['Management of antiplatelet therapy at the time of device implantation remains controversial. This study aimed to assess the risk of bleeding complications in patients receiving clopidogrel at the time of cardiac device surgery.', 'We performed a retrospective case-control study. Between 2004 and 2010, 101 consecutive patients receiving clopidogrel underwent cardiac device surgery (pacemaker or implantable cardioverter-defibrillator implantation, and generator replacement) in our institution. Controls were 1:1 matched on age, sex, device, type of procedure, number of leads implanted, and venous approach (cephalic or subclavian). A significant bleeding complication was defined as pocket hematoma requiring surgical evacuation or prolonged hospitalization, hemothorax, pericardial effusion, or tamponade.', 'Bleeding complications occurred more frequently in patients receiving clopidogrel at the time of device procedure: 11.9% versus 4.0% (P = 0.037; odds radio [OR] 3.27 [1.02-10.5]). Significant bleeding complications were noted in 12 patients (11.9%) receiving clopidogrel, including two patients with pericardial effusion and one patient with hemothorax. Four controls (4.0%) had bleeding complications (three pocket hematomas and one pericardial effusion). The single factor associated with increased bleeding complications in patients receiving clopidogrel was subclavian puncture (P = 0.008). In the entire cohort (n = 202), multivariate analysis identified two independent predictors of significant bleeding complications: clopidogrel treatment at the time of surgery (P = 0.03; OR 3.7 [1.1-12.6]) and subclavian venous puncture (P = 0.03; OR 3.44 [1.1-10.4]).'] |
['Critically ill patients including trauma patients are at high risk of urinary tract infection (UTI). The composition of urine in trauma patients may be modified due to inflammation, systemic stress, rhabdomyolysis, life support treatment and/or urinary catheter insertion.', 'Prospective, single-centre, observational study conducted in patients with severe trauma and without a history of UTIs or recent antibiotic treatment. The 24-hour urine samples were collected on the first and the fifth days and the growth of Escherichia coli in urine from patients and healthy volunteers was compared. Biochemical and hormonal modifications in urine that could potentially influence bacterial growth were explored.', 'Growth of E. coli in urine from trauma patients was significantly higher on days 1 and 5 than in urine of healthy volunteers. Several significant modifications of urine composition could explain these findings. On days 1 and 5, trauma patients had an increase in glycosuria, in urine iron concentration, and in the concentrations of several amino acids compared to healthy volunteers. On day 1, the urinary osmotic pressure was significantly lower than for healthy volunteers.'] |
['to investigate the effects of Vitamin D calcitriol/1,25(OH)2D3 on NETosis in systemic lupus erythematosus (SLE) patients with hypovitamin D.', 'neutrophlis of five SLE patients with hypovitamin D were divided into 4 groups, P0 (0 nM/control), P1 (1 nM), P2 (10 nM), and P3 (100 nM) as cultured samples. Phorbol Myristate Acetate (PMA) was used to stimulate NETs formation. The supernatant was separated and cocultured with HUVECs. Externalization of Neutrophil Elastase (NE) and Myeloperoxidase (MPO) during NETosis was measured by immunofluorescence and ELISA respectively. Early and late apoptosis of endothelial cell was measured by flowcytometry using cell death kit (Annexin V and PI antibody).', 'this study showed significant decrease in early apoptosis with 10 nM of 1,25(OH)2D3 compared to control group. Significance of NE externalization found in all treatment groups (p<0.05), while MPO absorbance in the same tendency but not statistically significant. Further analysis also found a moderate positive correlation between NE externalizations with early apoptosis.'] |
['Gestational zinc deficiency has been confirmed to impair the infant immune function. However, knowledge about effects of maternal mild zinc deficiency during pregnancy on hepatitis B vaccine responsiveness in offspring is limited. In this report, we aimed to examine how maternal zinc deficiency during pregnancy influences humoral and cellular immune responses to hepatitis B vaccination in offspring of BALB/c mice.', 'From day 1 of pregnancy upon delivery, maternal mice were given a standard diet (30 mg/kg/day zinc), zinc deficient diet (8 mg/kg/day zinc), or combination of zinc deficient diet (8 mg/kg/day zinc in the first 2 weeks of gestation) and zinc supplement diet (150 mg/kg/day zinc for the last week of pregnancy), respectively. Newborn pups of these maternal mice were immunized with hepatitis B vaccine at postnatal weeks 0, 2 and 4. Then, splenocytes and blood samples from the offspring mice were harvested for detection of serum zinc concentrations, humoral and cell-mediated immune responses, expression of cytokines using ELISA, CCK-8 and flow cytometric analysis. Results from the present study demonstrated that gestational zinc deficiency inhibited antibody responses, and decreased the proliferative capacity of T cells in offsprings immunized with hepatitis B vaccine. Additionally, HBsAg-specific cytokines analysis revealed that gestational zinc deficiency could inhibit secretion of IFN-γ from splenocytes, and decrease IFN-γ expression of CD4(+) and CD8(+) T cells.'] |
['The pathogenesis of insulin resistance involves dysregulated gene expression and function in multiple cell types, including endothelial cells (ECs). Post-transcriptional mechanisms such as microRNA-mediated regulation of gene expression could affect insulin action by modulating EC function.', 'To determine whether microRNA-181b (miR-181b) affects the pathogenesis of insulin resistance by regulating EC function in white adipose tissue during obesity.', "MiR-181b expression was reduced in adipose tissue ECs of obese mice, and rescue of miR-181b expression improved glucose homeostasis and insulin sensitivity. Systemic intravenous delivery of miR-181b robustly accumulated in adipose tissue ECs, enhanced insulin-mediated Akt phosphorylation at Ser473, and reduced endothelial dysfunction, an effect that shifted macrophage polarization toward an M2 anti-inflammatory phenotype in epididymal white adipose tissue. These effects were associated with increased endothelial nitric oxide synthase and FoxO1 phosphorylation as well as nitric oxide activity in epididymal white adipose tissue. In contrast, miR-181b did not affect insulin-stimulated Akt phosphorylation in liver and skeletal muscle. Bioinformatics and gene profiling approaches revealed that Pleckstrin homology domain leucine-rich repeat protein phosphatase, a phosphatase that dephosphorylates Akt at Ser473, is a novel target of miR-181b. Knockdown of Pleckstrin homology domain leucine-rich repeat protein phosphatase increased Akt phosphorylation at Ser473 in ECs, and phenocopied miR-181b's effects on glucose homeostasis, insulin sensitivity, and inflammation of epididymal white adipose tissue in vivo. Finally, ECs from diabetic subjects exhibited increased Pleckstrin homology domain leucine-rich repeat protein phosphatase expression."] |
['We determined the contribution of the desmosomal cadherin desmoglein-2 to cell-cell cohesion in cardiomyocytes. In the intercalated disc, providing mechanical strength and electrical communication between adjacent cardiomyocytes, desmoglein-2 is closely associated with N-cadherin and gap junctions.', 'We studied intercalated discs of HL-1 cardiomyocytes by immunostaining of desmoglein-2 and N-cadherin. Cohesion was measured using a liberase-based dissociation-assay and compared with cell-free single-molecule atomic force microscopy measurements. L-tryptophan caused irregular desmoglein-2 condensation, weakened cell-cell cohesion and impaired both homophilic desmoglein-2 and N-cadherin trans-interaction, whereas l-phenylalanine had no effect. L-tryptophan did not affect N-cadherin localization and its inhibitory effect on cell-cohesion and desmoglein-2 binding, but not on N-cadherin interaction, was blocked by a desmoglein-specific tandem peptide. Moreover, Ca(2+)-depletion, desmoglein-2 knockdown, a desmoglein-specific single peptide and certain desmoglein-2 mutations associated with arrhythmogenic cardiomyopathy reduced cell-cell cohesion, whereas cell adhesion was strengthened by desmoglein-2 overexpression. Since single peptide did not interfere with N-cadherin trans-interaction, these data indicate that (i) desmoglein-2 binding is crucial for cardiomyocyte cohesion and (ii) L-tryptophan reduced both desmoglein-2 and N-cadherin binding, whereas single and tandem peptide can be used to specifically target desmoglein-2-mediated adhesion. L-tryptophan and single peptide also induced ultrastructural alterations of areae compositae. Functional analyses at the organ level revealed reduced cardiomyocyte function and inefficient response to adrenergic stimulation in both L-tryptophan- and single peptide-challenged murine Langendorff hearts paralleled by redistribution of connexin 43 in L-tryptophan-treated heart slices.'] |
['Angiotensin (Ang) II, a major regulatory factor for left ventricular mass, is generated from Ang I by ACE. ACE levels are associated with an insertion/deletion (I/D) polymorphism in the ACE gene. The ACE polymorphism should result in varied Ang II concentrations and hence affect left ventricular mass. We therefore investigated whether ACE genotype is a predictor of heart weight.', 'From 693 consecutive patients autopsied between 1994 and 1998 in our hospital, patients with valvular disease, myocardial infarction, or cardiomyopathy were excluded. The remaining 443 autopsy patients were the subjects of our study. The heart weight at autopsy was corrected for body surface area. Genomic DNA was purified from the kidney, and ACE genotype was determined by polymerase chain reaction. Heart weight in the DD genotype (249. 9+/-49.9 g/m(2)) was significantly higher than that in the ID (230. 0+/-51.2 g/m(2); P<0.05) and II (226.8+/-49.8 g/m(2); P<0.01) genotypes. Heart weight was also positively related to age (r=0.145, P<0.0001) and coronary stenosis index (r=0.147, P=0.0019). Multiple regression analysis showed that a history of hypertension (P<0.0001), age (P=0.0001), and DD genotype (P=0.0154) were independent predictors of heart weight.'] |
['The underlying mechanisms of steatosis, the first stage of non-alcoholic fatty liver disease (NAFLD) that is characterized by the accumulation of lipids in hepatocytes, remain unclear. Our study aimed to investigate the hypothesis that cigarette smoke is known to change circulating lipid profiles and thus may also contribute to the accumulation of lipids in the liver.', 'Mice and cultured hepatocytes were exposed to sidestream whole smoke (SSW), a major component of "second-hand" smoke and a variety of cellular and molecular approaches were used to study the effects of cigarette smoke on lipid metabolism.', "SSW increases lipid accumulation in hepatocytes by modulating the activity of 5'-AMP-activated protein kinase (AMPK) and sterol response element binding protein-1 (SREBP-1), two critical molecules involved in lipid synthesis. SSW causes dephosphorylation/ inactivation of AMPK, which contributes to increased activation of SREBP-1. These changes of activity lead to accumulation of triglycerides in hepatocytes."] |
["Recent advances in antiretroviral therapy have led to effective but increasingly complex strategies for the treatment of HIV infection. In a previous study, we demonstrated that physicians' experience in the care of patients with AIDS improves survival. We conducted this study to determine whether greater physician experience is associated with earlier adoption and appropriate use of new antiretroviral treatment regimens.", 'Retrospective medical record review of a population-based sample of HIV-infected individuals who received antiretroviral treatment between December 1995 and May 1997 by primary care physicians practicing throughout the state of Washington. We classified antiretroviral regimens observed into one of four categories based on national treatment guidelines.', "The use of new antiretroviral treatment regimens significantly increased during the study period; 22% of patients were treated with a protease inhibitor (PI)-based regimen or an alternative PI- or nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimen between December 1995 and November 1996, compared with 57% between April and May 1997 (p < .001). After controlling for CD4 count and the calendar period of treatment, patients cared for by physicians with greater HIV experience were significantly more likely to receive PI-based regimens or alternative PI- or NNRTI-based antiretroviral regimens (p = .02). Use of PI-based regimens was also associated with lower CD4 count (p < .001) and treatment after January 1997 (p = .02), but independent of patient demographic characteristics and the geographic location of physicians' practices."] |
['Tetrahydrobiopterin (BH4), an essential cofactor for the synthesis of NO, improves endothelial dysfunction after ischemia/reperfusion. Therefore, we hypothesized that reduction of BH4 is involved in the attenuation of endothelium-dependent vasodilation in atherosclerosis, and we investigated the effect of alterations of the BH4 level on the vasodilatory potential of coronary resistance vessels from humans and pigs with atherosclerosis.', 'Coronary arterioles were obtained from patients undergoing CABG (atherosclerosis group) or valve replacement (control group) and from pigs fed either a standard diet (control group) or atherogenic diet (atherosclerosis group). After isolation, vessels were cannulated, pressurized, and placed on the stage of an inverted microscope. Dose-response curves were investigated in response to the endothelium-dependent agonists histamine, serotonin, and acetylcholine (for pigs, substance P) and to the endothelium-independent agonist sodium nitroprusside (SNP) under control conditions and before and after incubation of the vessels with sepiapterin (substrate for BH4 synthesis). In vessels from patients and from animals with atherosclerosis, compared with vessels from the control groups, there was a significant (P:<0.05) reduction of vasodilation to all tested endothelium-dependent agonists but not to SNP. After application of sepiapterin, the responses to the endothelium-dependent agonists but not to SNP were significantly improved in vessels from the atherosclerosis groups. Sepiapterin did not influence vascular reactivity in the control groups.'] |
['The increase in obesity, especially the increase of visceral fat, has been directly associated with health risk. Additionally, a waist-to-height ratio (WHtR) (0.5) has been proposed as an indicator of early health risk.', 'To test the association between anthropometric measurements and inflammatory mRNA expression and to evaluate the effectiveness of WHtR to predict inflammatory risk in children.', 'Anthropometric measurements and fasting blood samples were collected in 94 Brazilian children (46 boys) aged 9-11 years. Children were identified as being at inflammatory risk based on cytokine mRNA expression levels at and above the 75', 'Body mass index (BMI), waist circumference (WC) and WHtR showed moderate-to-strong association with inflammatory cytokine mRNA gene expression. WHtR 0.51 was the most accurate cut-off point in distinguishing children at inflammatory risk. Compared with children with WHtR\u2009<\u20090.51, children with a WHtR≥0.51 presented an odds ratio of 2.643 (95% CI, 1.749-3.994) for both diagnosed IL-6 and MCP-1 above the 75'] |
['Early vocal development of German-speaking cochlear implant recipients has rarely been assessed so far. There-fore the purpose of this study was to describe the early vocal development following successful implantation.', "A case study was designed to assess the temporal progression of early vocal development in a young cochlear implant recipient who was bilaterally implanted at the age of 8;3 months. Data were collected during one year by recording parent-child interactions on a monthly basis. The first recording was made before the onset of the signal-processors, the 12 following recordings were made during the first year of implant use. The child's vocalizations were classified according to the vocalization categories and developmental levels from the Stark Assessment of Early Vocal Development--Revised (SAEVD-R). This assessment tool was translated into German in this study and used with German-speaking children for the first time. It allows a coding of prelinguistic utterances via auditory perceptual analysis.", "The results show an overall decrease of early vocalizations and an increase of speech-like vowels and consonants. In the first six months no apparent progress took place; The child produced almost exclusively vocalizations from Levels 1-3. In the second half of the year an increase of canonical utterances (Level 4) and advanced forms (Level 5) was observed. However, vocalizations beyond the canonical babbling phase, especially vocants and closants as well as their combinations, continued to be dominant throughout the first year of implant use. The progress of development of the child investigated in this study is comparable to other children implanted at young age who had also been assessed with the SAEVD-R. In comparison to normal-hearing children, the implanted child's development seemed to progress slightly faster. Interrater- and intrarater-reliability using the SAEVD-R were measured for two independent observers and for a first and second coding procedure and revealed to be acceptable to good."] |
['Salidroside, the predominant component of a Chinese herbal medicine, Rhodiola rosea L., becomes an attractive bio-agent due to its multifunction. Although it is well proposed that this herbal medicine may have photoprotective effect according to the folk hearsay, the direct supportive experimental evidences linking the drug with skin ageing have rarely been reported so far. The study was conducted to investigate the photoprotective role of salidrosdie and its related mechanisms in vitro.', 'First, a premature senescence model induced by UVB irradiation (250 mJ cm(-2)) in human dermal fibroblasts (HDFs) was established, and senescent phenotypes were evaluated by cell morphology, cell proliferation, senescence-associated beta-galactosidase (SA-β-gal) activity and cell cycle distribution. Then the photoprotective effect of salidroside was investigated. Cells were pre-treated with various doses of salidroside (1, 5 and 10 μM) followed by the sublethal dosage of UVB exposure and then were harvested for various detections, including senescence-associated phenotypes and molecules, alteration of oxidative stress, matrix metalloproteinase-1 (MMP-1) secretion and inflammatory response.', 'Pre-treatment of salidroside dose dependently reversed the senescent state of HDFs induced by UVB as evidenced by elevated cell viability, decreased SA-β-gal activity and relieving of G1/G0 cell cycle arrest. UVB-induced increased protein expression of cyclin-dependent kinase (CDK) inhibitors p21(WAF) (1) and p16(INK) (4) was also repressed by salidrosdie treatment in a dose-dependent manner. Meanwhile, the increment of malondialdehyde (MDA) level in UVB-irradiated HDFs was inhibited upon salidroside treatment. Additionally, salidroside significantly attenuated UVB-induced synthesis of MMP-1 as well as the production of IL-6 and TNF-α in HDFs.'] |
['Pseudolaric acid B (PAB) is a diterpene acid isolated from the root and trunk bark of Pseudolaric kaempferi Gordon. Previous work has found that PAB has anti-inflammatory and anti-tumor effects in xenograft models of human hepatocellular carcinoma. The aim of this study is to evaluate the correlation between anti-cancer and anti-inflammatory effects of PAB and its molecular mechanisms on HT-29 cells.', 'Production of prostaglandin E2 (PGE2) in HT-29 cells was evaluated by ELISA. mRNA of cyclooxygenase-2 (COX-2) was analyzed by RT-PCR assay. High-content screening (HCS) method was adopted to detect the cytokine mixture (CM)-induced transcription activity of NF-κB and STAT3. Western blotting was used to evaluate the protein expression levels of inflammatory mediators induced by CM. After treatment with PAB in various concentrations, the inhibition rate of cell proliferation was measured with sulforhodamine B assays. For the in vivo studies, tumor-bearing models xenografted with HT-29 cells were developed in nude mice, and following oral administration with PAB, tumor inhibition rate was calculated.', 'PAB inhibited the PGE2 production in HT-29 cells significantly (P < 0.05) with similar results detected at the COX-2 mRNA level. Furthermore, PAB suppressed the COX-2 protein expression and significant nuclear translocation of NF-κB and STAT3 induced by CM, which correlated with a concomitant degradation of I-κB and a decrease in constitutive STAT3 phosphorylation (P < 0.05). Moreover, various concentrations of PAB inhibited the proliferation of HT-29 cells in a dose- and time-dependent manner. In vivo, after treatment with PAB for 17 days, the tumor weight of the 50 and 100 mg/kg treated groups was 0.62 ± 0.15 and 0.54 ± 0.06 g, respectively. When compared to the control group (0.82 ± 0.16 g), the inhibition rate of tumor weight was 24.2% at 50 mg/kg (P < 0.05) and 34.7% at 100 mg/kg (P < 0.001).'] |
['Recent evidence implicates endogenous interferon-gamma (IFN-gamma) in the host response to an immunogenic tumor (MCA105); antibody blockade of host IFN-gamma increased tumor growth rate (Doherty et al., Ann. Surg. Oncol. 3: 198-203, 1996). Those experiments did not attempt to determine the site of IFN-gamma activity (the host, the tumor, or both).', 'MCA101 murine tumor cells were transfected with a plasmid expression vector containing an antisense construct to the IFN-gamma receptor (IFN-gamma R) or a control construct. Clones were isolated and tested for IFN-gamma stimulation of MHC I expression, sensitivity to IFN-gamma growth effects in vitro, and specific [125I]IFN-gamma binding.', 'The antisense strategy was successful in decreasing the number of cell-surface IFN-gamma binding sites and in vitro response to IFN-gamma. Finally, in vivo experiments demonstrated significantly increased untransfected tumor growth rate in animals after blockade of endogenous IFN-gamma by a single dose of anti-IFN-gamma antibody and more rapid growth of the IFN-gamma R-deficient cells compared to controls.'] |
['NHS England deems 90-day readmission rates as a marker of quality of care. The causes of readmission have not been previously reported in the UK. The aim of this study was to examine the factors associated with 90-day readmission following colorectal cancer surgery at a hospital trust with a catchment population 1.2 million.', 'A retrospective review was performed of all patients undergoing resection for colorectal cancer between January 2012 and December 2013. Unplanned readmission was defined as an emergency admission to the trust for any cause within 90 days of surgery. Readmission analyses were restricted to patients discharged from hospital within 28 days of resection.', 'A total of 570 patients underwent surgery, of whom 522 were discharged within 28 days and are included for readmission analysis. The readmission rate was 24.3% (127 patients with a total of 163 episodes of hospital readmissions) within 90 days following surgery. The most frequent cause for readmission was complications related to adjuvant chemotherapy (18.4%) followed by wound-related complications (14.1%). Most patients presenting with wound-related complications were admitted within 60 days and patients with chemotherapy-related complications after 61 days; 13/127 (10.2%) patients who were readmitted underwent emergency surgery, and one patient died following readmission. Multivariate analysis demonstrated that comorbidity was the only independent risk factor.'] |
['The interactions between cancer stem cells (CSCs) and tumor-associated macrophages (TAMs) can promote tumor progression, maintain the CSCs population, and reduce therapeutic effects. The objective of this study was to investigate the coexpression of CSCs and TAMs and its clinical significance in pancreatic ductal adenocarcinoma (PDAC).', 'Ninety-six patients with PDAC were included in this study. Tissue microarrays were constructed for immunostaining of the CSCs markers CD44 and CD133 and the TAMs marker CD204. Correlations between the expression of CSCs and TAMs markers and clinicopathologic characteristics or disease progression were analyzed.', 'Expression levels of CD44/CD133 and CD204 were significantly higher in tumor tissues than in normal tissues (P\u2009<\u2009.0001). The variables associated with survival were high coexpression of CD44/CD133 (P\u2009=\u2009.000), high expression of CD204 (P\u2009=\u2009.011), and tumor grade (P\u2009=\u2009.014). There was a positive correlation between CD44/CD133 and CD204 expression (r\u2009=\u20090.294; P\u2009=\u2009.004). Survival analysis indicated that high coexpression of CD44/CD133 and CD204 was associated significantly with shorter overall survival (P\u2009=\u2009.000) and disease-free survival (P\u2009=\u2009.003). Multivariate analysis revealed that high CD44/CD133 expression was an independent prognostic factor for disease-free survival, whereas high CD204 expression was an independent predictor for both overall and disease-free survival.'] |
['Serum vascular adhesion protein-1 (VAP-1) predicts cancer-related mortality in diabetic subjects. However, whether serum VAP-1 predicts cancer incidence or cancer progression remains unclear. We conducted a cohort study to investigate whether serum VAP-1 and related clinical variables predict incident cancers in type II diabetic subjects.', 'From 1996 to 2003, we enrolled 568 type II diabetic subjects who were free of cancer at baseline. Serum VAP-1 at enrollment was measured by time-resolved immunofluorometric assay. Chronic kidney disease (CKD) was defined as estimated glomerular filtration rate <60 mL/min per 1.73 m(2). The subjects were followed until first occurrence of cancer or until December 31, 2011.', 'During a mean follow-up of 11.3 years, 71 subjects developed incident cancers. The HRs for incident cancers in subjects with highest tertile of serum VAP-1 and in subjects with CKD were 2.95 [95% confidence interval (CI), 1.31-6.63; P = 0.009] and 2.29 (95% CI, 1.18-4.44; P = 0.015), respectively, after multivariate adjustment. There was an interaction between serum VAP-1 and CKD on the risk of incident cancers (P = 0.01 for log-transformed VAP-1 × CKD). The relationship among serum VAP-1, CKD, and incident cancers was similar if death was considered in the competing risk models or if subjects with shorter follow-up period were excluded.'] |
['To compare the relative efficacies of lansoprazole 15 mg o.m. and omeprazole 10 mg o.m. in relieving heartburn and epigastric pain in patients with acid-related dyspepsia. In addition, the study compared the safety profiles of the two treatments.', 'This double-blind, parallel group, randomised, multicentre study was conducted in 52 general practices in the UK. A total of 609 patients was recruited, 562 of whom were eligible for inclusion in the intention-to-treat analysis. All of the patients had experienced at least mild heartburn or mild epigastric pain persistently on at least 4 of the previous 7 days; patients with severe symptoms were excluded. 283 patients received lansoprazole 15 mg and 279 received omeprazole 10 mg, both for 4 weeks. The main efficacy measure was relief of symptoms, based on physician assessments.', 'In the intention-to-treat population, a complete relief of overall primary symptoms of dyspepsia was achieved after 2 weeks in 53% of patients receiving lansoprazole and in 41% of patients receiving omeprazole (P = 0.007). After 4 weeks, 59% of the lansoprazole group and 51% of the omeprazole group had achieved complete symptom relief (P = 0. 078). Antacids were taken for additional relief of symptoms in fewer patients given lansoprazole compared to the omeprazole group in the third and fourth weeks (P = 0.035) and also significantly fewer antacids were taken by patients in the lansoprazole group compared with patients in the omeprazole group (P = 0.033). The proportion of patients reporting adverse events was similar in both groups.'] |
['Recently, we have reported that LIM kinase 2 (LIMK2) involves programmed necrotic neuronal deaths induced by aberrant cyclin D1 expression following status epilepticus (SE). Up-regulation of LIMK2 expression induces neuronal necrosis by impairment of dynamin-related protein 1 (DRP1)-mediated mitochondrial fission. However, we could not elucidate the upstream effecter for LIMK2-mediated neuronal death. Thus, we investigated the role of endothelin-1 (ET-1) in LIMK2-mediated neuronal necrosis, since ET-1 involves neuronal death via various pathways.', 'Following SE, ET-1 concentration and its mRNA were significantly increased in the hippocampus with up-regulation of ETB receptor expression. BQ788 (an ETB receptor antagonist) effectively attenuated SE-induced neuronal damage as well as reduction in LIMK2 mRNA/protein expression. In addition, BQ788 alleviated up-regulation of Rho kinase 1 (ROCK1) expression and impairment of DRP1-mediated mitochondrial fission in CA1 neurons following SE. BQ788 also attenuated neuronal death and up-regulation of LIMK2 expression induced by exogenous ET-1 injection.'] |
['To evaluate if complement C3 is associated with insulin secretion, as suggested by recent in\xa0vitro studies, independently of confounders including adiposity measures.', '1010 nondiabetic subjects were stratified into quartiles according to complement C3 values. Insulin secretion was assessed using indexes derived from oral glucose tolerance test (OGTT) in the whole study group and from intravenous glucose tolerance test (IVGTT) in a subgroup (n\xa0=\xa0110). Significant differences between quartiles of C3 were observed in body mass index (BMI), waist, fat mass, blood pressure, total cholesterol, high density lipoprotein (HDL), triglycerides, fasting and 2-h post-load glucose, fasting insulin, C reactive protein (hsCRP), fibrinogen, aspartate aminotransferase (AST), alanine aminotransferase (ALT), complement C4, and insulin sensitivity with C3 quartiles exhibiting graded increases in cardio-metabolic risk factors. Differences in insulin secretion indexes between C3 quartiles remained significant after adjustment for age, gender, BMI, insulin sensitivity, blood pressure, total cholesterol, HDL, triglycerides, hsCRP, fibrinogen, and complement C4 levels (P\xa0<\xa00.0001). A multivariable regression analysis revealed that complement C3 is a contributor of insulin secretion, explaining 2.4% and 1.9% of variation of the Stumvoll index for first-phase and second-phase insulin secretion, respectively, and 2.1% of variation of the InsAUC30/GluAUC30 index, independently of gender, age, BMI, waist, fat mass, blood pressure, total cholesterol, HDL, triglycerides, hsCRP, fibrinogen, AST, ALT.'] |
['The voltage-gated KCNQ1 potassium channel regulates key physiological functions in a number of tissues. In the heart, KCNQ1 alpha-subunits assemble with KCNE1 beta-subunits forming a channel complex constituting the delayed rectifier current I(Ks). In epithelia, KCNQ1 channels participate in controlling body electrolyte homeostasis. Several regulatory mechanisms of the KCNQ1 channel complexes have been reported, including protein kinase A (PKA)-phosphorylation and beta-subunit interactions. However, the mechanisms controlling the membrane density of KCNQ1 channels have attracted less attention.', 'Here we demonstrate that KCNQ1 proteins expressed in HEK293 cells are down-regulated by Nedd4/Nedd4-like ubiquitin-protein ligases. KCNQ1 and KCNQ1/KCNE1 currents were reduced upon co-expression of Nedd4-2, the isoform among the nine members of the Nedd4/Nedd4-like family displaying the highest expression level in human heart. In vivo expression of a catalytically inactive form of Nedd4-2, able to antagonize endogenous Nedd4-2 in guinea-pig cardiomyocytes, increased I(Ks) significantly, but did not modify I(K1). Concomitant with the reduction in current induced by Nedd4-2, an increased ubiquitylation as well as a decreased total level of KCNQ1 proteins were observed in HEK293 cells. Pull-down and co-immunoprecipitation experiments showed that Nedd4-2 interacts with the C-terminal part of KCNQ1. The Nedd4/Nedd4-like-mediated regulation of the KCNQ1 channel complexes is strictly dependent on a PY motif located in the distal part of the C-terminal domain. When this motif was mutated, the current and ubiquitylation levels were unaffected by Nedd4-2, and Nedd4-2 proteins were neither pulled-down nor co-immunoprecipitated.'] |
['Dendritic cells (DCs) are considered potential candidates for cancer immunotherapy due to their ability to process and present antigens to T cells and stimulate immune responses. However, DC-based vaccines have exhibited minimal effectiveness against established tumors in mice and human cancer patients. The use of appropriate adjuvants can enhance the efficacy of DC-based cancer vaccines in treating established tumors.', 'In this study we have employed alpha-tocopheryl succinate (alpha-TOS), a nontoxic esterified analogue of vitamin E, as an adjuvant to enhance the effectiveness of DC vaccines in treating established murine Lewis lung (3LL) carcinomas.', 'We demonstrate that locally or systemically administered alpha-TOS in combination with nonmatured DCs injected intratumorally (i.t.) or subcutaneously (s.c.) significantly inhibits the growth of preestablished 10-day tumors (mean tumor volume of 77.5 +/- 17.8 mm3 on day 30 post-tumor injection) as compared to alpha-TOS alone (mean tumor volume of 471 +/- 68 mm3 on day 30 post-tumor injection). Additionally, the adjuvant effect of alpha-TOS was superior to that of cyclophosphamide (CTX). The mean tumor volume on day 28 post-tumor injection in mice treated with CTX+DCs was 611 +/- 94 mm3 as compared to 105 +/- 36 mm3 in mice treated with alpha-TOS+DCs. Analysis of purified T lymphocytes from mice treated with alpha-TOS+DC revealed significantly increased secretion of IFN-gamma as compared to T cells from the various control groups.'] |
['Lymphoedema is a common complication after cancer treatment. We have reported that low-energy extracorporeal shock wave (SW) therapy up-regulates vascular endothelial growth factor (VEGF) in ischaemic myocardium. As VEGF plays an important role in lymphangiogenesis, we investigated whether our low-energy SW therapy enhances lymphangiogenesis in rats.', 'We created a tail model of lymphoedema in rats. The tail was treated with or without low-energy SW therapy (0.25 mJ mm(-2), 500 impulses) four times (days 3, 5, 7, and 9). The tail volume and the fluorescence intensity of indocyanine green (ICG) were measured. The expression of VEGF-C and basic fibroblast growth factor (bFGF) were evaluated by RT-PCR, and the lymphatic vessel density was assessed histochemically.', 'The tail volume increased significantly in the control group and was significantly improved in the SW group. The lymphatic system function (evaluated with fluorescence intensity of ICG), the lymphatic vessel density, and the expression of VEGF-C and bFGF were all enhanced by the SW therapy (all P < 0.05).'] |
['Post-traumatic stress disorder (PTSD) is an anxiety disorder that develops after exposure to a life-threatening traumatic experience. Meta-analyses of the brainstem showed that midsagittal area of the pons was significantly reduced in patients with PTSD, suggesting a potential apoptosis in dorsal raphe nucleus after single-prolonged stress (SPS). The aim of this study is to investigate whether SPS induces apoptosis in dorsal raphe nucleus in PTSD rats, which may be a possible mechanism of reduced volume of pons and density of gray matter.', 'In this study, rats were randomly divided into 1d, 7d and 14d groups after SPS along with the control group. The apoptosis rate was determined using annexin V-FITC/PI double-labeled flow cytometry (FCM). Levels of Cytochrome c (Cyt-C) was examined by Western blotting. Expression of Cyt-C on mitochondria in the dorsal raphe nucleus neuron was determined by enzymohistochemistry under transmission electron microscopy (TEM). The change of thiamine monophosphatase (TMP) levels was assessed by enzymohistochemistry under light microscope and TEM. Morphological changes of the ultrastructure of the dorsal raphe nucleus neuron were determined by TEM.', 'Apoptotic morphological alterations were observed in dorsal raphe nucleus neuron for all SPS-stimulate groups of rats. The apoptosis rates were significantly increased in dorsal raphe nucleus neuron of SPS rats, along with increased release of cytochrome c from the mitochondria into the cytoplasm, increased expression of Cyt-C and TMP levels in the cytoplasm, which reached to the peak of increase 7 days of SPS.'] |
['In spite of insufficient evidence to guide the use of lipid-lowering drugs (LLDs) among the dialysis population, these drugs are frequently used to treat dyslipidemia. Several studies have found that long-term use of LLDs is associated with an increased risk of gallstone disease (GSD) in the general population. However, the lithogenic risk of LLDs in patients undergoing hemodialysis (HD) has not been studied.', 'It is to assess the influence of long-term use of LLDs on the prevalence of GSD among patients undergoing HD.', "This cross-sectional study included 108 eligible patients receiving maintenance HD: 35 receiving lovastatin; 34 fenofibrate; and 39 no LLD. GSD was defined as the presence of gallstones or the performance of cholecystectomy while taking LLD. Abdominal ultrasonography, demographic parameters, and laboratory data were obtained for all enrolled subjects. ANOVA with Bonferroni's test and chi-square test were used to compare differences among the three groups.", 'The three groups had similar clinical characteristics with regard to age, gender, duration of HD, body mass index, and total cholesterol values. However, a significantly higher prevalence of GSD and higher triglyceride levels were found in patients receiving fenofibrate, compared with those in other groups (p < 0.05). Among dialysis patients on fenofibrate, increased age, female gender, larger daily dose, and longer duration of treatment were associated with increased risks for GSD.'] |
['Imported fire ant (IFA) stings are an important cause of stinging insect hypersensitivity in endemic areas. IFA stings are difficult to avoid, and many studies have shown high field sting rates. No studies report the natural IFA sting rate that patients experience while receiving IFA immunotherapy.', 'To determine the frequency of IFA stings in patients receiving IFA immunotherapy compared with an aeroallergen immunotherapy control group.', 'Patients were surveyed by telephone to characterize the frequency of stings, reactions, and attitudes toward IFA avoidance.', 'A total of 23 of 28 patients reported IFA stings during their IFA immunotherapy compared with 16 of 28 patients during their aeroallergen immunotherapy. More of the IFA immunotherapy-treated patients were stung than the aeroallergen immunotherapy patients, which is inconsistent with our hypothesis (chi2 = 4.139, P < .042). The annualized sting rates between the IFA immunotherapy and aeroallergen immunotherapy groups were similar (1.82 vs 1.72 stings per year, P < .55). The IFA immunotherapy patients were more likely to report any kind of reaction (chi2 = 9.124, P < .003) compared with the control group. Most patients reported feeling careful to avoid stings.'] |
['Abnormalities in the serotonergic (5-HT) system have been implicated in the pathogenesis of suicidal behavior. Studies on peripheral serotonergic parameters as a measure for central serotonergic function in suicidal patients appear to be promising, yet failed to show a clear association with suicidality. The objective of this study was to elucidate the role of serotonergic blood parameters in depressed suicidal patients and to examine their usefulness as a potential biological marker for suicidality. A number of personality traits were assessed in order to provide a basis for a psychobiological model of suicidal behavior.', 'Depressed patients with a recent suicide attempt (SA; n = 59) were compared to those without history of suicide attempts (NSA; n = 28). 5-HT2A receptor binding in platelets and tryptophan/amino acid ratio in plasma were measured. Acute psychopathology and personality traits as well as characteristics of suicide attempts were assessed.', 'There was no significant difference between SA and NSA in terms of peripheral serotonergic parameters as well as personality traits. However, the whole sample showed associations between certain personality traits and serotonergic platelet parameters. Furthermore, we observed a relation between suicidal ideation, lethality of suicide attempts and peripheral serotonergic markers.'] |
['In humans and rats, pregnancy-associated maternal plasma volume expansion and plasma hypotonicity may facilitate maternal-to-fetal water transfer. Although reduced amniotic fluid volume occurs commonly in postterm pregnancy, the mechanisms are unknown. We previously demonstrated a reversal of pregnancy-induced maternal plasma hypotonicity that occurs in the near term (20 days) pregnant rats. We sought to determine whether the relative maternal plasma hypertonicity continues in the postterm period.', 'Rat gestation (normal, 21 days) was prolonged with subcutaneous progesterone injection. Pregnant rats at gestation, 18 days, 21 days, and 24 days and nonpregnant rats were studied. Maternal and fetal hematocrit levels, plasma osmolality, electrolyte levels, and amniotic fluid volume were determined. In addition, maternal and fetal tissues were analyzed for water and electrolyte content.', 'Compared with term (21days), postterm pregnant rats (24 days) had a significant increase in maternal and fetal plasma osmolality (293.7+/-1.4 mOsm/kg vs 302.8+/-3.7 mOsm/kg and 301.0+/-2.0 mOsm/kg vs 310.3+/-3.2 mOsm/kg, respectively; P<.01) and sodium and chloride concentrations. Conversely, both maternal and fetal hematocrit levels decreased significantly in the postterm period. Postterm rats demonstrated an increased fetal mortality rate (24%) and a significantly reduced amniotic fluid volume (4.2+/-0.6 mL vs 6.6+/-0.6 mL, P<.01).'] |
['Arterial stiffness is an important feature of diabetic macrovascular complications. Activin receptor-like kinase 7 (ALK7), a member of type I transforming growth factor-β (TGF-β) receptors, is correlated with pathogenic risks of type 2 diabetes mellitus and cardiovascular diseases and may be involved in cardiovascular remodeling. We aimed to investigate whether ALK7 is implicated in diabetes-induced aortic stiffness.', 'Type 2 diabetes was induced by high-fat diet and low-dose streptozotocin (STZ; 27.5 mg/kg). Forty rats were separated into four groups: control, diabetes, diabetes with empty virus and diabetes treated with ALK7-shRNA. The metabolic index, ALK 7 expression and aortic stiffness were evaluated. We used gene silencing method to investigate the role of ALK7 in the pathological development.', 'Diabetic rats showed increased blood glucose, cholesterol, triglyceride levels, severe insulin resistance and ALK7 overexpression. Diabetes enhanced aortic stiffness, as demonstrated by the loss and disruption of elastic fibers as well as by an increase in collagen fibers in the aortic media. ALK7 gene silencing ameliorated metabolic hyperlipidemia and insulin resistance. With ALK7 gene silencing, collagen content, elastin to collagen ratio, as well as collagen I-to-collagen III content ratio in diabetic rats were significantly decreased. Moreover, the phosphorylation level of Smad2/3 was markedly decreased after ALK7 gene silencing.'] |
['Obesity adversely inhibits antibody response to vaccination. Three doses of HPV4 may or may not provide adequate long term protection against HPV 16/18 in obese females. The aim of this study was to determine whether adherence to HPV4 vaccination in a safety net population was reduced with increasing body mass index (BMI).', 'We designed a historical prospective study evaluating the number and dates of HPV4 dosing that occurred from July 1, 2006 through October 1, 2009 by the demographic characteristics of the 10-26 year old recipient females. The defined dosing intervals were adapted from the literature and obesity categories were defined by the WHO.', '1240 females with BMI measurements received at least one dose of HPV4; 38% were obese (class I, II and III) and 25% were overweight. Females with normal BMI received on-time triplet dosing significantly more often than did the obese class II and III females (30% vs. 18%, p<0.001). Obese class II/III females have a significant 45% less chance of completing the on-time triplet HPV4 series than normal women (OR\u200a=\u200a0.55, 95% CI: 0.37, 0.83). Pregnancy history has a significant influence on BMI and HPV4 dosing compliance in this safety net population where 71% had been gravid. Hispanic females were less likely to complete HPV4 dosing regardless of BMI (aOR\u200a=\u200a0.39, 95% CI: 0.16, 0.95).'] |
['We created a novel continuous infusion system to evaluate the efficacy of juxta-aortic doxycycline delivery as a transitional step toward developing hybrid drug/device treatment strategies for abdominal aortic aneurysm (AAA) disease.', 'Controlled comparison of treatment outcomes was studied in animal models with molecular and morphologic tissue analysis in a collaboration between university and corporate research laboratories. Rat AAAs were created via porcine pancreatic elastase (PPE) infusion and grouped and analyzed by subsequent treatment status (either doxycycline in vehicle or vehicle alone) and drug delivery method (continuous infusion via periaortic delivery system [PDS] or twice-daily subcutaneous injection). The main outcome measures were AAA diameter via direct measurement, medial elastin lamellar preservation via light microscopy, mural smooth muscle cell (SMC) proliferation and SMC and macrophage density via immunostaining and counting, expression of matrix metalloproteinases 2, 9, and 14 and tissue inhibitors of metalloproteinases 1 and 2 via real-time reverse transcriptase-polymerase chain reaction, and enzymatic activity via substrate zymography. Serum drug levels were analyzed via liquid chromatography/mass spectroscopy.', 'PDS (1.5 mg/kg/day) and subcutaneous (60 mg/kg/day) delivery methods caused comparable reductions in AAA diameter during the period of 14 days after PPE infusion. PDS rats gained more weight during the postoperative period (P <.001), possibly as a result of reduced serum drug levels and systemic toxicity. Doxycycline treatment reduced AAA macrophage infiltration and SMC proliferation significantly. Despite reduced diameter, circumferential elastic lamellar preservation was not apparent in doxycycline-treated AAAs.'] |
['The mechanisms by which monocyte/macrophage cells migrate to the joint involve a series of integrated adhesion and signaling events in which chemokines and their receptors are strongly implicated. This study was undertaken to investigate the hypothesis that stromal cell-derived factor 1 (SDF-1), a CXC chemokine (CXCL12), plays a critical role in monocyte/macrophage localization to synovium.', 'SDF-1 and CXC receptor 4 (CXCR4) expression in rheumatoid arthritis (RA) and osteoarthritis synovium and graft SDF-1, tumor necrosis factor alpha (TNF alpha), and human and murine vascular markers were examined by immunohistochemistry and double-immunofluorescence. The functional capacity of SDF-1 to modulate monocyte migration into joints was investigated by examining the localization of pro-myelomonocytic U937 cells into synovial tissue transplanted into SCID mice. SDF-1, TNF alpha, or saline was injected into graft sites and response determined by the number of fluorescently labeled U937 cells (injected intravenously) detected in grafts by ultraviolet microscopy.', 'SDF-1 and CXCR4 were highly expressed in CD68+ cells in the RA synovium. SDF-1 induced U937 cell migration in vitro and in vivo in a dose-dependent manner and, in vivo, SDF-1 was more effective than TNF alpha. In contrast to TNF alpha, SDF-1 did not induce intracellular adhesion molecule 1 in transplant microvasculature. Furthermore, intragraft injection of SDF-1 did not up-regulate TNF alpha, or vice versa.'] |
['Frequent chronic obstructive pulmonary disease (COPD) exacerbations are a major cause of hospital admission and mortality and are associated with increased airway inflammation. Macrolides have airway antiinflammatory actions and may reduce the incidence of COPD exacerbations.', 'To determine whether regular therapy with macrolides reduces exacerbation frequency.', 'We performed a randomized, double-blind, placebo-controlled study of erythromycin administered at 250 mg twice daily to patients with COPD over 12 months, with primary outcome variable being the number of moderate and/or severe exacerbations (treated with systemic steroids, treated with antibiotics, or hospitalized).', 'We randomized 109 outpatients: 69 (63%) males, 52 (48%) current smokers, mean (SD) age 67.2 (8.6) years, FEV1 1.32 (0.53) L, FEV1% predicted 50 (18)%. Thirty-eight (35%) of the patients had three or more exacerbations in the year before recruitment, with no differences between treatment groups. There were a total of 206 moderate to severe exacerbations: 125 occurred in the placebo arm. Ten in the placebo group and nine in the macrolide group withdrew. Generalized linear modeling showed that the rate ratio for exacerbations for the macrolide-treated patients compared with placebo-treated patients was 0.648 (95% confidence interval: 0.489, 0.859; P = 0.003) and that these patients had shorter duration exacerbations compared with placebo. There were no differences between the macrolide and placebo arms in terms of stable FEV1, sputum IL-6, IL-8, myeloperoxidase, bacterial flora, serum C-reactive protein, or serum IL-6 or in changes in these parameters from baseline to first exacerbation over the 1-year study period.'] |
['Atherosclerosis is believed to be an independent predictor of cardiovascular diseases. A growing body of evidence suggests that quercetin is a potent antioxidant and anti-inflammatory compound. The molecular mechanisms underlying its protective effects against oxidative stress in human endothelial cells remain unclear. This study was designed to confirm the hypothesis that quercetin inhibits oxidized LDL (oxLDL) induced endothelial oxidative damage by activating sirtuin 1 (SIRT1) and to explore the role of adenosine monophosphate activated protein kinase (AMPK), which is a negative regulator of Nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase) and free radicals.', 'Human umbilical vein endothelial cells were treated with oxLDL with or without quercetin pretreatment. We found that quercetin pretreatment increased SIRT1 mRNA expression. In fact, quercetin protected against oxLDL-impaired SIRT1 and AMPK activities and reduced oxLDL-activated NOX2 and NOX4. However, silencing SIRT1 and AMPK diminished the protective function of quercetin against oxidative injuries. The results also indicated that oxLDL suppressed AKT/endothelial NO synthase, impaired mitochondrial dysfunction, and enhanced reactive oxygen species formation, activating the Nuclear Factor Kappa B (NF-κB) pathway.'] |
['Little is known about the asthma candidate gene neuropeptide S receptor 1 (NPSR1) in relation to environmental exposures, but recent evidences suggest its role as an effect modifier.', 'To explore the interaction between NPSR1 polymorphisms and environmental exposures related to farming lifestyle and to study the in vitro effects of lipopolysaccharide (LPS) stimulation on NPSR1 expression levels.', 'We studied 3113 children from PARSIFAL, a European cross-sectional study on environmental/lifestyle factors and childhood allergy, partly focused on children brought up on a farm. Information on exposures and outcomes was primarily obtained from parental questionnaires. Seven tagging polymorphisms were analysed in a conserved haplotype block of NPSR1. Multivariate logistic regression was used to evaluate a multiplicative model of interaction. NPSR1 protein and messenger RNA (mRNA) levels in monocytes were measured after LPS stimulation by fluorescence activated cell sorting (FACS) and quantitative real-time polymerase chain reaction (PCR).', 'A strong interaction was seen between current regular contact to farm animals and several NPSR1 polymorphisms, particularly rs323922 and rs324377 (p<0.005), with respect to allergic symptoms. Considering the timing of initiation of such current regular farm animal contact, significant interactions with these and two additional polymorphisms (SNP546333, rs740347) were revealed. In response to LPS, NPSR1-A protein levels in monocytes were upregulated (p = 0.002), as were NPSR1-A mRNA levels (p = 0.02).'] |
['Prealbumin levels have been proven to correlate with hospital length of stay, wound healing, infection rates, and mortality in adults hospitalized for medical or surgical purposes, or those who have chronic illnesses. Little is known about the utility of prealbumin evaluation in adults with severe anorexia nervosa (AN).', 'We retrospectively evaluated prealbumin levels, along with numerous other clinical parameters relevant to illness acuity and early refeeding outcomes, in 132 adults with AN admitted for definitive inpatient medical stabilization from October 1, 2008 to December 31, 2012. Per clinical protocol, prealbumin was checked on admission and approximately weekly thereafter until discharge.', 'Patients had a median age of 28 years old, a mean admission body mass index (BMI) of 12.9 kg/m(2) (S.D. 6.1), and 89% of patients were women. A total of 47% of patients had a low prealbumin at the time of admission. By discharge, 77% of patients had normalized their prealbumin levels. Patients with low admission prealbumin levels had a threefold increased risk of refeeding hypophosphatemia and a twofold increase in hypoglycemia compared with patients who had a normal admission prealbumin, independent of admission BMI.'] |
['The effect of red palm oil (RPO) supplementation on infarct size after ischaemia/reperfusion in a cholesterol enriched diet-induced hyperlipidemic animal model has not been reported. Previous studies reported results on the effect of RPO in a normal diet, whilst evidence of protection has been linked to improved functional recovery, prosurvival kinase, anti-apoptosis and NO-cGMP. Therefore, we aimed to investigate the effects of dietary RPO supplementation in a cholesterol-enriched diet-induced hyperlipidemic rat model and to investigate the involvement of matrix metalloproteinase 2 (MMP2) inhibition as a possible mechanism of protection.', 'Male Wistar rats were fed either a standard rat chow diet (Norm) or a 2% cholesterol-enriched diet (Chol) for nine weeks. Additionally, two more groups received the same treatment, however, at the week 4, diet was supplemented with RPO for the last five weeks (Norm+RPO and Chol+RPO), respectively. After the feeding period hearts were isolated, perfused according to Langendorff and subjected to 30 minutes of normothermic global ischaemia followed by two hours of reperfusion. Infarct size was measured by 2,3,5-triphenyltetrazolium chloride staining at the end of reperfusion.', 'Cholesterol-enriched diet increased myocardial infarct size from 23.5±3.0% to 37.2±3.6% (p<0.05) when compared to normal diet. RPO supplementation significantly reduced infarct size either in Norm+RPO or in Chol+RPO (to 9.2±1.0% and 26.9±3.0%), respectively. Infarct size in Chol+RPO was comparable to the Norm group. MMP2 activity before ischaemia was significantly reduced in the Chol+RPO group when compared to the Chol group. However, the MMP2 activity of the hearts of the RPO fed rats was significantly increased when compared to the normal diet group after ischaemia.'] |
['To investigate the expression of Th22 cells and related cytokines in colorectal cancer (CRC) tissues, and the probably mechanism.', 'CRC tumor and paratumor tissues were collected to detect the expression levels of Th22 cells and of related cytokines by immunohistochemistry, flow cytometry and real-time quantitative polymerase chain reaction (RT-qPCR). Interleukin (IL)-22 alone or with a STAT3 inhibitor was co-cultured with RKO cells in vitro to study the effects of IL-22 on colon cancer cells. IL-22 alone or with a STAT3 inhibitor was injected into a BALB/c nude mouse model with subcutaneously transplanted RKO cells to study the effects of IL-22 on colon cancer growth.', 'The percentage of Th22 cells in the CD4(+) T subset was significantly higher in tumor tissues compared with that in paratumor tissues (1.47% ± 0.083% vs 1.23% ± 0.077%, P < 0.05) as determined by flow cytometry. RT-qPCR analysis revealed that the mRNA expression levels of IL-22, aryl hydrocarbon receptor, CCL20 and CCL22 were significantly higher in tumor tissues compared with those in paratumor tissues. CCL27 mRNA also displayed a higher expression level in tumor tissues compared with that in paratumor tissues; however, these levels were not significantly different (2.58 ± 0.93 vs 2.30 ± 0.78, P > 0.05). IL-22 enhanced colon cancer cell proliferation in vitro and displayed anti-apoptotic effects; these effects were blocked by adding a STAT3 inhibitor. IL-22 promoted tumor growth in BALB/c nude mice; however, this effect was reversed by adding a STAT3 inhibitor.'] |
Continuous periaortic infusion lowers the effective doxycycline dose for experimental AAA limitation. Alternative biologic inhibition strategies might also be amenable to direct intra-aortic or juxta-aortic delivery. Periaortic infusion might improve the clinical outcome of minimally invasive AAA treatment strategies. Clinical relevance Aneurysm remodeling may continue after successful endovascular AAA exclusion. Continued proteolytic activity within the aneurysm wall potentiates late graft migration and failure. The doxycycline infusion system developed in these experiments may serve as a prototype for adjuvant treatment modalities that complement endovascular AAA exclusion. Local delivery of doxycycline or other agents active in AAA disease, either continuously or at selected intervals after graft implantation, may stabilize the wall and aid in maintaining aneurysm exclusion. Alternative delivery methods could include passive diffusion from either the graft material itself or treatment reservoirs incorporated into endografts. Given the recognized limitations of current technologies, adjuvant biologic therapies have the potential to improve long-term patient outcome significantly after endovascular exclusion. |
['Despite the effective use of antibiotics, occurrences of mortality and neurological sequelae following Streptococcus pneumoniae meningitis remain high.', "We investigated the neurogenesis of endogenous neural stem cells (NSCs) after inoculation with exogenous brain-derived neurotrophic factor (BDNF) in the hippocampus dentate gyrus following experimental S. pneumoniae meningitis using a double-labeling immunofluorescence analysis with 5-bromo-2'-deoxyuridine (BrdU), Nestin, DCX and NeuN.", 'Our results showed that 7days after inoculation, the number of BrdU & Nestin co-labeled cells increased in the hippocampus in meningitis rats compared with control rats (p<0.05). But the number of DCX-positive cells decreased in the dentate gyrus of infected rats treated with saline (p<0.05). However, these cell numbers returned to close to normal-control levels in infected rats treated with BDNF (p>0.05). After treatment with exogenous BDNF, the number of BrdU & Nestin co-labeled cells increased in the hippocampus in both the meningitis rats and normal control rats (p<0.05), but this increase was more significant in the former (p<0.05). We found that the percentage of BrdU & DCX/BrdU co-labeled cells increased in infected rats treated with BDNF both 7days and 14days after inoculation in a greater proportion compared to other groups (p<0.05). No significant differences were found in the percentage of BrdU & NeuN/BrdU 28days after inoculation among all of the groups (p>0.05).'] |
['The incidence of colorectal cancer increases with vitamin D deficiency as shown in recently published studies. In addition, prospective investigations have indicated that low vitamin D levels may be associated with increased mortality of colorectal cancer, especially in stage III and IV cases. However, the exact incidence of vitamin D deficiency and the relation between vitamin D deficiency and osteopenia/osteporosis is still not known. The aim of this study is to identify severity of vitamin D deficiency and absolute risk factors of osteopenia/osteoporosis in colorectal cancer survivors.', 'A total of 113 colorectal cancer survivors treated with surgery and/or chemotherapy ± radiotherapy were recruited from medical oncology outpatient clinics during routine follow-up visits in 2012-2013. Bone mineral densitometry (BMD) was performed, and serum 25-OH vitamin D levels were also checked on the same day of the questionnaire. The patients was divided into 2 groups, group A with normal BMD and group B with osteopenia/osteoporosis.', 'The median age of the study population was 58 (40-76). Thirty (30.0%) were female, whereas 79 (70.0%) were male. The median follow-up was 48 months (14-120 months). Vitamin D deficiency was found in 109 (96.5%); mild deficiency (20-30 ng/ml) in 19 (16.8%), moderate deficiency (10-20 ng/ml) in 54 (47.8%) and severe deficiency (<10 ng/ml) in 36 (31.9%). Osteopenia was evident in 58 (51.4%) patients whereas osteoporosis was noted in 17 (15.0%) . Normal BMD was observed in 38 (33.6%). No apparent effects of type of surgery, presence of stoma, chemotherapy, radiotherapy and TNM stage were found regarding the risk of osteopenia and osteoporosis. Also, the severity of the vitamin D deficiency had no effect in the risk of osteopenia and osteporosis (p=0.93). In female patients, osteopenia/osteoporosis were observed in 79.5% patients as compared to 60.7% of male patients (p=0.04).'] |
['Acute hypotension may be implicated in cognitive dysfunction. L-type calcium channel blockers in the setting of hypoxia are protective of learning and memory. We tested the hypothesis that hypotension induced by nimodipine (NIMO) and nicardipine (NICA) would be protective of long- and short-term memory compared to hypotension induced by nitroglycerin (NTG).', 'Forty Swiss-Webster mice (30 to 35 g, 6 to 8 weeks) were randomized into 4 groups for i.p. injection immediately after passive avoidance (PA) learning on day 0: (1) NTG (30 mg/kg); (2) NICA (40 mg/kg); (3) NIMO (40 mg/kg); and (4) saline. PA training latencies (seconds) were recorded for entry from a suspended platform into a Plexiglas tube where a shock (0.3 mA; 2-second duration) was automatically delivered. On day 2 latencies were recorded during a testing trial during which no shock was delivered. Latencies >900 seconds were assigned this value. Lower testing latency is indicative of an impairment of long-term associative memory. Forty-nine additional mice were randomized into similar groups for object recognition testing (ORT) and given i.p. injections on day 0. ORT measures short-term memory by exploiting the tendency of mice to prefer novel objects where a familiar object is present. On day 5 during training, 2 identical objects were placed in a circular arena and mice explored both for 15 minutes. A testing trial was conducted 1 hour later for 3 minutes after a novel object replaced a familiar one. Mice with intact memory spend about 65% of the time exploring the novel object. Mice with impaired memory devote equal time to each object. Recognition index (RI) is defined as the ratio of time spent exploring the novel object to time spent exploring both objects was the measure of memory. Mean arterial blood pressure (MAP), cerebral bloodflow, and body and brain oxygenation (PO(2)) studies were done in separate groups of mice to determine the dosages for matched degrees of hypotension and the physiological profile of each treatment.', 'The median PA latencies for the different conditions were as follows: NTG (219.5 ± 93.5 second semi-interquartile range [SIQR]), NICA (372.5 ± 75.5 second SIQR), NIMO (540 ± 200 second SIQR) and saline (804 ± 257.5 second SIQR). Rank methods were used to analyze the PA latencies for significant differences. NTG latency was significantly shorter than NIMO latency (P = 0.012) and saline latency (P = 0.006), but not NICA latency (P = 0.126). ORT RI values showed a similar pattern. We found that NTG RI (47.2 ± 5.9% SEM) was different from NIMO RI (60.2 ± 4.6% SEM, P = 0.031) and different from saline RI (66.9 + 3.7% SEM, P = 0.006). Physiological experiments showed that MAP decreased to 45 to 50 mm Hg in all animals who became minimally responsive to external stimuli within 10 to 15 minutes of injection. Intergroup differences for MAP, body and brain oxygenation, and cerebral bloodflow were not statistically significant.'] |
['We have developed a transgenic mouse with cardiac-restricted overexpression of tumor necrosis factor-alpha (TNF-alpha). These mice develop a heart failure phenotype characterized by left ventricular dysfunction and remodeling, pulmonary edema, and elevated levels of TNF-alpha in the peripheral circulation from cardiac spillover. Given that TNF-alpha causes atrophy and loss of function in respiratory muscle, we asked whether transgenic mice developed diaphragm dysfunction and whether contractile losses were caused by oxidative stress or tissue remodeling.', "muscles excised from transgenic mice and littermate controls were studied in vitro with direct electrical stimulation. Cytosolic oxidant levels were measured with 2', 7'-dichlorofluorescin diacetate; emissions of the oxidized product were detected by fluorescence microscopy. Force generation by the diaphragm of transgenic animals was 47% less than control (13.2+/-0. 8 [+/-SEM] versus 25.1+/-0.6 N/cm(2); P:<0.001); this weakness was associated with greater intracellular oxidant levels (P:<0.025) and was partially reversed by 30-minute incubation with the antioxidant N:-acetylcysteine 10 mmol/L (P:<0.01). Exogenous TNF-alpha 500 micromol/L increased oxidant production in diaphragm of wild-type mice and caused weakness that was inhibited by N:-acetylcysteine, suggesting that changes observed in the diaphragm of transgenic animals were mediated by TNF-alpha. There were no differences in body or diaphragm weights between transgenic and control animals, nor was there evidence of muscle injury or apoptosis."] |
['The etiology and pathogenesis of angiogenesis in idiopathic pulmonary fibrosis (IPF) is poorly understood. Inter-alpha-trypsin inhibitor (IaI) is a serum protein that can bind to hyaluronan (HA) and may contribute to the angiogenic response to tissue injury.', 'To determine whether IaI promotes HA-mediated angiogenesis in tissue injury.', 'An examination was undertaken of angiogenesis in IaI-sufficient and -deficient mice in the bleomycin model of pulmonary fibrosis and in angiogenesis assays in vivo and in vitro. IaI and HA in patients with IPF were examined.', 'IaI significantly enhances the angiogenic response to short-fragment HA in vivo and in vitro. lal deficiency Ieads to decreased angiogenesis in the matrigel model, and decreases lung angiogenesis after bleomycin exposure in mice. IaI is found in fibroblastic foci in IPF, where it colocalizes with HA. The colocalization is particularly strong in vascular areas around fibroblastic foci. Serum levels of IaI and HA are significantly elevated in patients with IPF compared with control subjects. High serum IaI and HA levels are associated with decreased lung diffusing capacity, but not FVC.'] |
['Allergen-specific TH2 responses contribute to the development of allergic asthma. Their increase may be due to a reduced early exposure to environmental pathogens, which induces a TH1 response, and thereby suppresses the allergic TH2 response. QbG10 (bacteriophage Qbeta-derived virus-like particle with CpG-motif G10 inside), a novel Toll-like receptor 9 agonist packaged into virus-like particles, was designed to stimulate the immune system toward a TH1-mediated protective response.', 'We examined clinical efficacy, safety, and tolerability of QbG10 with patient-reported and objective clinical outcome parameters in patients with mild-to-moderate persistent allergic asthma.', 'In this proof-of-concept parallel-group, double-blind, randomized trial, 63 asthmatic patients followed conversion to a standardized inhaled steroid and were treated with 7 injections of either QbG10 or placebo. Incorporating a controlled steroid withdrawal, the effects on patient-reported (day- and nighttime asthma symptoms, salbutamol usage, and 7-item-Asthma Control Questionnaire scores) and objective clinical outcome measures (FEV1, fraction of exhaled nitric oxide, and blood eosinophils) were assessed over 12 weeks (ClinicalTrials.gov number, NCT00890734).', 'All patient-reported parameters improved overall between week 0 and 12 in QbG10-treated patients (n\xa0= 33) despite steroid withdrawal, compared with deteriorations observed under placebo (n\xa0= 30, P\xa0< .05). At week 12, two thirds of the QbG10-treated patients had their asthma "well controlled" (Asthma Control Questionnaire score ≤0.75) compared with one third under placebo. FEV1 had worsened to a clinically significant extent in patients on placebo, while it remained stable in QbG10 patients. Adverse events were mostly injection site reactions occurring after QbG10 administration.'] |
['Fusarium head blight (FHB) caused by Fusarium graminearum not only causes severe losses in yield, but also reduces quality of wheat grain by accumulating mycotoxins. Breeding for host plant resistance is considered as the best strategy to manage FHB. Resistance in wheat to FHB is quantitative in nature, involving cumulative effects of many genes governing resistance. The poor understanding of genetics and lack of precise phenotyping has hindered the development of FHB resistant cultivars. Though more than 100 QTLs imparting FHB resistance have been reported, none discovered the specific genes localized within the QTL region, nor the underlying mechanisms of resistance.', 'In our study recombinant inbred lines (RILs) carrying resistant (R-RIL) and susceptible (S-RIL) alleles of QTL-Fhb2 were subjected to metabolome and transcriptome profiling to discover the candidate genes. Metabolome profiling detected a higher abundance of metabolites belonging to phenylpropanoid, lignin, glycerophospholipid, flavonoid, fatty acid, and terpenoid biosynthetic pathways in R-RIL than in S-RIL. Transcriptome analysis revealed up-regulation of several receptor kinases, transcription factors, signaling, mycotoxin detoxification and resistance related genes. The dissection of QTL-Fhb2 using flanking marker sequences, integrating metabolomic and transcriptomic datasets, identified 4-Coumarate: CoA ligase (4CL), callose synthase (CS), basic Helix Loop Helix (bHLH041) transcription factor, glutathione S-transferase (GST), ABC transporter-4 (ABC4) and cinnamyl alcohol dehydrogenase (CAD) as putative resistance genes localized within the QTL-Fhb2 region.'] |
['Association between lymphocyte-sensitivity to immunosuppressants in transplant recipients in vitro and clinical outcomes has been demonstrated. In general, renal transplant recipients are treated with a combination of immunosuppressants such as either glucocorticoid/cyclosporin A (CsA) or glucocorticoid/tacrolimus (FK506) but the pharmacological complementarity of these drugs is still controversial. We examined relationships between the lymphocyte-sensitivities to these immunosuppressants.', 'We examined lymphocyte-sensitivities to prednisolone (PSL), CsA, and FK506 in vitro in a total of 190 chronic renal failure (CRF) patients and 140 healthy subjects. The lymphocyte-sensitivity was evaluated from the IC50 value against mitogen-stimulated lymphocyte-blastogenesis in vitro.', 'Statistically significant correlations of the IC50 values in CRF patients between the following pairs of drugs were observed: PSL and CsA (P<0.0001; n=129, r=0.419), PSL and FK506 (P<0.001; n=54, r=0. 441), and CsA and FK506 (P<0.0001; n=45, r=0.608). Similar correlations were also observed in lymphocytes from healthy subjects. The population of CRF patients who exhibited high IC50 values (low sensitivities) to PSL and FK506 was significantly larger than that of healthy subjects (P<0.05).'] |
['In liver regeneration, quiescent hepatocytes need to be primed before they can fully respond to growth factors such as hepatocyte growth factor (HGF). Recently, interleukin-6 (IL-6) has been shown to play an important role in initiating liver regeneration via activating signal transducer and activator of transcription 3 (STAT3). We therefore investigated the effect of IL-6 on liver regeneration and examined STAT3 activation following IL-6 and/or HGF treatment in rats.', "The animals underwent portal branch ligation (PBL) of the left lateral and median branches. They were intravenously treated with either IL-6 (500 microg/kg), HGF (50 microg/kg), both, or vehicle alone on and every 12 h after PBL. The degree of compensatory hypertrophy in unoccluded lobes was examined by measuring the wet weight ratios of the unoccluded lobes to the whole liver and the 5-bromo-2'-deoxyuridine labeling index of hepatocytes in each group. STAT3 expression in regenerating liver was examined by Western blotting and immunohistochemistry.", 'Coadministration of IL-6 and HGF most effectively increased both the wet weight of the unoccluded lobes and the hepatocellular DNA synthesis. HGF as well as IL-6-treated animals showed moderate STAT3 activation in hepatocytes throughout the experiment.'] |
['Women with signs and symptoms of ischemia and no obstructive coronary artery disease often have coronary microvascular dysfunction (CMD), diagnosed by invasive coronary reactivity testing (CRT). Although traditional noninvasive stress imaging is often normal in CMD, cardiac MRI may be able to detect CMD in this population.', 'Vasodilator stress cardiac MRI was performed in 118 women with suspected CMD who had undergone CRT and 21 asymptomatic reference subjects. Semi-quantitative evaluation of the first-pass perfusion images was completed to determine myocardial perfusion reserve index (MPRI). The relationship between CRT findings and MPRI was examined by Pearson correlations, logistic regression, and sensitivity/specificity. Symptomatic women had lower mean pharmacological stress MPRI compared with reference subjects (1.71±0.43 versus 2.23±0.37; P<0.0001). Lower MPRI was predictive of ≥1 abnormal CRT variables (odds ratio =0.78 [0.70, 0.88], P<0.0001, c-statistic 0.78 [0.68, 0.88]). An MPRI threshold of 1.84 predicted CRT abnormality with sensitivity 73% and specificity 74%.'] |
['To study the adaptive potential of the right ventricular myocardium after 30 days of mechanical-induced overload in rats from two different age groups.', 'We banded the pulmonary trunk, so as to increase the systolic work load of the right ventricle, in 19 adult Sprague-Dawley rats at the age of 10 weeks, and 16 weanlings when they were 3 weeks-old, using 10 adults and 10 weanlings as controls. We analysed the functional adaptation and structural changes of the right ventricular myocardium, blood vessels and interstitial tissue after 30 days of increased afterload.', 'The increased workload induced an increase of the right ventricular weight and free wall thickness in animals from both age groups when compared to controls. These changes were mostly related to cardiomyocytic hypertrophy, as confirmed by the expression of myocardial hypertrophic markers, without any apparent increase of their number, a "reactive" fibrosis especially evident in the adult rats, with p-value less than 0.0001, and a more extensive neocapillary network in the weanlings compared to the adults aubsequent to banding, the p-value being less than 0.0001.'] |
['Glutamine (GLN) treatment prior to gut ischemia-reperfusion (I/R) reportedly preserves gut glutathione levels and gut barrier function. We hypothesized that intraluminal GLN during ischemia would also protect against gut I/R.', 'After randomization to control and GLN groups, mice were exposed to 75 min (Exp 1) or 50 min (Exp 2 and 3) gut I/R. One mL of 2% GLN solution was injected into the duodenal lumen at the onset of ischemia in the GLN group, whereas controls were given normal saline. In experiment 1, survival was monitored for 120 h (n = 38). In experiment 2, blood, small intestine, and liver samples were collected at 4 h after reperfusion (n = 13). Expressions of CD11a and CD11b on myeloid cells were measured. Reactive oxygen intermediate production by myeloid cells was determined with or without phorbol myristate acetate stimulation. Glutathione levels in the small intestine and liver were also evaluated. In experiment 3, hemodynamic parameters were measured before and after I/R (n = 6).', 'In experiment 1, survival time in the GLN group was reduced compared with the control group. In experiment 2, GLN increased expression of CD11b and reactive oxygen intermediate with phorbol myristate acetate, compared with controls. There were no significant differences in gut or liver glutathione levels between the two groups. In experiment 3, the GLN group showed a transient but significant reduction in systolic blood pressure after reperfusion compared with the control group.'] |
['The decline of proteasomal activity is known to be associated with the age-related disorders but the early events involved in this process are not apparent. To address this, we investigated the early-age-related (pediatric vs. adult) mechanisms that augment immunopathogenesis of sepsis and acute lung injury.', 'The 3-weeks (pediatric) and 6-months (adult) old C57BL/6 mice were selected as the study groups. Mice were subjected to 1×20 cecal ligation and puncture (CLP) mediated sepsis or intratracheal Psuedomonas aeruginosa (Pa)-LPS induced acute lung injury (ALI).We observed a significant increase in basal levels of pro-inflammatory cytokine, IL-6 and neutrophil activity marker, myeloperoxidase (MPO) in the adult mice compared to the pediatric indicating the age-related constitutive increase in inflammatory response. Next, we found that age-related decrease in PSMB6 (proteasomal subunit) expression in adult mice results in accumulation of ubiquitinated proteins that triggers the unfolded protein response (UPR). We identified that Pa-LPS induced activation of UPR modifier, p97/VCP (valosin-containing protein) in the adult mice lungs correlates with increase in Pa-LPS induced NFκB levels. Moreover, we observed a constitutive increase in p-eIF2α indicating a protective ER stress response to accumulation of ubiquitinated-proteins. We used MG-132 treatment of HBE cells as an in vitro model to standardize the efficacy of salubrinal (inhibitor of eIF2α de-phosphorylation) in controlling the accumulation of ubiquitinated proteins and the NFκB levels. Finally, we evaluated the therapeutic efficacy of salubrinal to correct proteostasis-imbalance in the adult mice based on its ability to control CLP induced IL-6 secretion or recruitment of pro-inflammatory cells.'] |
['Low-power helium-neon (He-Ne) lasers have been increasingly widely applied in the treatment of cardiovascular diseases, and its vasodilation effect has been proven. The aim of this study was to determine the effects of low-power He-Ne laser irradiation directed at the precardial region of Wistar rats on capillary permeability in the myocardium and the expression of myocardial vascular endothelial growth factor (VEGF).', 'Sixteen rats were divided randomly into control and irradiated groups (n = 8, each). A He-Ne laser (632.8 nm) was applied to the irradiated group with a dose of 60.5 J/cm(2). Ferritin was perfused into the left femoral vein and capillary permeability was examined under an electron microscope. VEGF expression in the myocardium was investigated by immunohistochemical methods, RT-PCR, and image analysis.', 'The ultrastructures of the myocardial capillaries were examined. Compared to the control group, more high-density granules (ferritin), which were present within the capillary endothelium and the mitochondrions of myocardial cells in the internal layer of the myocardium, were observed in the irradiated group. VEGF staining of the myocardium was stronger in the irradiated group than that in the control group. The optic density of the irradiated group (0.246 +/- 0.015) was significantly higher than that of the control group (0.218 +/- 0.012, P < 0.05). Finally, the levels of RT-PCR products of VEGF165 mRNA were 2.79 times higher in irradiated rats than in the control rats.'] |
["Fluid resuscitation can contribute to postshock inflammation and the development of end organ injury. We have previously observed an attenuation in pulmonary and ileal inflammation when hypertonic saline and pentoxifylline (HSPTX) were concomitantly administered after hemorrhage. We hypothesized that the attenuation in hepatic injury observed with HSPTX is associated with the reduction of transcription factor activation and proinflammatory mediator production when compared with Ringer's lactate (RL).", 'Male Sprague-Dawley rats were resuscitated with racemic RL (32 mL/kg) or HSPTX (4 mL/kg 7.5% NaCl + PTX 25 mg/kg) and killed at 4 hours and 24 hours after resuscitation. Liver injury was determined by histology and serum aminotransferases. Nitrite, tumor necrosis factor-alpha, interleukin (IL)-1beta, and IL-6 were measured with enzyme-linked immunosorbent assay. High mobility group box 1, inducible nitric oxide synthase, nuclear factor (NF)-kappaB phosphorylation, and signal transducers and activators of transcription-3 phosphorylation were determined by Western blot. Transcription factor activation was verified with Electrophoretic Mobility Shift Assay.', 'RL resuscitation led to significant increases all measured parameters when compared with control. In contrast, HSPTX did not induce elevations in histologic liver injury or alanine aminotransferase levels. HSPTX attenuated inducible nitric oxide synthase by 23% (p < 0.01), nitrite by 25% (p < 0.05), tumor necrosis factor-alpha by 25% (p < 0.05), IL-1 by 63% (p < 0.01), IL-6 by 35% (p < 0.05), and high mobility group box 1 by 39% (p < 0.05) when compared with RL. HSPTX reduced IkappaB-alpha phosphorylation by 34% (p < 0.05), NF-kappaB p65 phosphorylation by 75% (p < 0.01), and signal transducers and activators of transcription-3 phosphorylation by 52% (p < 0.01).'] |
['Neonatal hypoxia-ischemia (HI) is a major cause of perinatal brain injury and is associated with a spectrum of neuropsychiatric disorders. Although very few treatment options are currently available, doxycycline (DOXY) has been reported to be neuroprotective in neontatal HI. Our objective was to investigate the effects of DOXY on neonatal brain development in normal and HI rat pups. We hypothesized that DOXY would inhibit microglial activation but that developmentally important processes, including cytogenesis and trophic responses, would not be impaired.', 'To investigate the putative neurodevelopmental consequences of DOXY administration in a clinically relevant animal model of HI, we performed a time-course analysis such that postnatal rat pups received DOXY (10mg/kg) or vehicle immediately before HI (n >or= 6). We then assessed cytogenesis, proinflammatory cytokines, brain-derived neurotrophic factor (BDNF) and matrix metalloproteinases regionally and longitudinally.', 'We found that DOXY significantly inhibits neuroinflammation in the frontal cortex, striatum and hippocampus; decreases interleukin-1Beta (IL-1Beta) and tumour necrosis factor-alpha (TNF-alpha); and augments BDNF following HI. In addition, DOXY-treated pups have significantly fewer 2-bromo-5-deoxyuridine (BrdU)-positive cells in the subventricular zone 6 hours post-HI. However, DOXY does not persistently affect cytogenesis in the subventricular zone or dentate gyrus up to 7 days post-HI. The BrdU-positive cells not expressing markers for mature neurons colabel with nestin, an intermediate filament protein typical of neuronal precursors.'] |
['Individuals with ulcerative colitis (UC) are at increased risk for colorectal cancer. The standard method of surveillance for neoplasia in UC by colonoscopy is invasive and can miss flat lesions. We sought to identify a gene expression signature in nondysplastic mucosa without active inflammation that could serve as a marker for remote neoplastic lesions.', 'Gene expression was analyzed by complementary DNA microarray in 5 normal controls, 4 UC patients without dysplasia, and 11 UC patients harboring remote neoplasia. Common gene ontology pathways of significantly differentially expressed genes were identified. Expression of genes which were progressively and significantly upregulated from controls to UC without neoplasia, to UC with remote neoplasia were evaluated by real-time polymerase chain reaction. Several gene products were also examined by immunohistochemistry.', 'Four hundred and sixty-eight genes were significantly upregulated, and 541 genes were significantly downregulated in UC patients with neoplasia compared with UC patients without neoplasia. Nine genes (ACSL1, BIRC3, CLC, CREM, ELTD1, FGG, S100A9, THBD, and TPD52L1) were progressively and significantly upregulated from controls to nondysplastic UC to UC with neoplasia. Immunostaining of proteins revealed increased expression of S100A9 and REG1α in UC-associated cancer and in nondysplastic tissue from UC patients harboring remote neoplasia compared with UC patients without neoplasia and controls.'] |
['To evaluate the combined contribution of UCP3-55CT and PPARγ2 Pro12Ala polymorphisms as correlates of BMI, energy expenditure (REE) and substrate oxidation in people with type 2 diabetes.', 'Two independent population with type 2 diabetes were studied: population A, n\xa0=\xa0272; population B, n\xa0=\xa0269. Based on both UCP3 and PPARγ2 genotypes three groups were created. Carriers of the PPARγ2 Pro12Ala in combination with the CC genotype of UCP3 (ProAla/CC, group 1); carriers of only one of these genotypes (either CC/ProPro or CT-TT/ProAla, group 2); people with neither variants (CT-TT/ProPro, group 3). In both populations BMI (kg/m(2)) was highest in group 1, intermediate in group 2 and lowest in group 3, independent of energy intake (i.e 35.3\xa0±\xa06.7 vs 33.4\xa0±\xa05.4 vs 31.8\xa0±\xa03, p\xa0<\xa00.02, population A; 32.4\xa0±\xa04.2 vs 31.7\xa0±\xa03.8 vs 30.1\xa0±\xa02.7; p\xa0<\xa00.03, population B). People with the ProAla/CC genotype (group 1) showed similar REE, but lower lipid oxidation (10.9 vs 13.9\xa0g/kg fat free mass/day; p\xa0=\xa00.04) and higher carbohydrate oxidation (23.6 vs 15.6\xa0g/kg fat free mass/day; p\xa0=\xa00.02) than carriers of other genotypes.'] |
['Graft survival in transplant recipients depends on pharmacokinetics and on individual susceptibility towards immunosuppressive drugs. Nevertheless, pharmacodynamic changes in T-cell functionality in response to drugs and in relation to pharmacokinetics are poorly characterized. We therefore investigated the immunosuppressive effect of calcineurin inhibitors and steroids on general T-cell functionality after polyclonal stimulation of whole blood samples.', 'General T-cell functionality in the absence or presence of immunosuppressive drugs was determined in vitro directly from whole blood based on cytokine induction after stimulation with the polyclonal stimulus Staphylococcus aureus enterotoxin B. In addition, diurnal changes in leukocyte and lymphocyte subsets, and on T-cell function after intake of immunosuppressive drugs were analyzed in 19 patients during one day and compared to respective kinetics in six immunocompetent controls. Statistical analysis was performed using non-parametric and parametric tests.', 'Susceptibility towards calcineurin inhibitors showed interindividual differences. When combined with steroids, tacrolimus led to more pronounced increase in the inhibitory activity as compared to cyclosporine A. While circadian alterations in leukocyte subpopulations and T-cell function in controls were related to endogenous cortisol levels, T-cell functionality in transplant recipients decreased after intake of the morning medication, which was more pronounced in patients with higher drug-dosages. Interestingly, calcineurin inhibitors differentially affected circadian rhythm of T-cell function, as patients on cyclosporine A showed a biphasic decrease in T-cell reactivity after drug-intake in the morning and evening, whereas T-cell reactivity in patients on tacrolimus remained rather stable.'] |
['Extrinsic innervation mediates a proabsorptive effect in small intestine. Our aim was to determine whether extrinsic neural input modulates similar effects in the proximal colon in vivo.', 'Ten adult dogs underwent enteric isolation of a 50-cm proximal colon loop; five each were randomized to undergo extrinsic denervation (Ext Den) of the isolated colonic segment or to serve as neurally innervated controls. After recovery, a 38 degrees C electrolyte solution (Na(+) 125 meq/L, K(+) 9 meq/L, Cl(-) 75 meq/L, HC03(-) 65 meq/L) was infused at 4 ml/min into the segment. Effluent was collected in 30-min intervals for 2 h after achieving steady state (determined by 14C nonabsorbable marker recovery); four studies were conducted at 1 and 12 weeks postoperatively. Net flux of H20, Na(+), K(+), and Cl(-) was determined. Colon morphometry was evaluated at 0 and 14 weeks. Data are presented as mean +/- SEM. Unpaired t test was applied for comparisons.', 'Net absorptive flux of H20 (microL/min/cm) was decreased in Ext Den vs controls at 1 week (4.40 +/- 0.63 vs 7.92 +/- 0.92, P = 0.03) but was not different at 12 weeks (4.70 +/- 1.20 vs 5.97 +/- 0.69; P > 0.05). Na(+) and Cl(-) followed the trends in H20 absorption (P < or = 0.05). Crypt depth (microm) decreased in controls at 14 weeks vs 0 week (915 +/- 20 vs 740 +/- 07, P = 0.01) but remained unchanged in Ext Den.'] |
['Serotonin is a platelet agonist and potent vasoconstrictor that has recently received attention concerning its potential role in acute coronary artery thrombosis. Selective serotonin-reuptake inhibitors, such as paroxetine, are widely used antidepressant agents. We sought to characterize the potential inhibitory effect of paroxetine on platelet function.', 'Healthy male volunteers received 20 mg/d paroxetine for 2 weeks in a randomized, double-blind, placebo-controlled, two-way cross-over trial.', 'Paroxetine decreased intraplatelet serotonin concentrations by -83% (P < .01). This inhibited platelet plug formation as reflected by a 31% prolongation of closure time measured with the platelet function analyzer-100 (P < .05). Furthermore, paroxetine lowered expression of the platelet activation marker CD63 in response to two different concentrations of thrombin receptor-activating peptide (P < .01). Plasma concentrations of prothrombin fragment, von Willebrand factor antigen, and circulating P-selectin remained unchanged in either period, indicating that paroxetine does not increase activation of coagulation, endothelium, or platelets in vivo, underlining a favorable safety profile.'] |
['The Fat family of atypical cadherins, originally identified in Drosophila, play diverse roles during embryogenesis and adult tissue maintenance. Among four mammalian members, Fat1 is essential for kidney and muscle organization, and is also essential for eye development; Fat1 knockout causes partial penetrant microphthalmia or anophthalmia. To account for the partial penetrance of the Fat1 phenotype, involvement of Fat4 in eye development was assessed. Lens phenotypes in Fat1 and 4 knockouts were also examined.', 'Fat1 and Fat4 mRNA expression was examined by in situ hybridization. Knockout phenotypes of Fat1 and Fat4 were analyzed by hematoxylin and eosin (H&E) and immunofluorescent staining.', 'We found Fat4 knockout did not affect eye induction or enhance severity of Fat1 eye defects. Although Fat1 and Fat4 mRNAs are similarly expressed in the lens epithelial cells, only Fat1 knockout caused a fully penetrant lens epithelial cell defect, which was apparent at embryonic day 14.5 (E14.5). The columnar structure of the lens epithelial cells was disrupted and in some regions cell aggregates were formed. In these multilayered regions, apical cell junctions were fragmented and the apical-basal polarity was lost. EdU incorporation assay also showed enhanced proliferation in the lens epithelial cells. Interestingly, these defects were found mainly in the central zone of the epithelial layer. The lens epithelial cells of the germinative zone maintained their normal morphology and fiber differentiation occurred normally at the equator.'] |
['To test the efficacy of maternal skin-to-skin contact, or kangaroo care (KC), on diminishing the pain response of preterm neonates to heel lancing.', "A crossover design was used, in which the neonates served as their own controls. Subjects Preterm neonates (n = 74), between 32 and 36 weeks' postmenstrual age and within 10 days of birth, who were breathing without assistance and who were not receiving sedatives or analgesics in 3 level II to III neonatal intensive care units in Canada.", 'In the experimental condition, the neonate was held in KC for 30 minutes before the heel-lancing procedure and remained in KC for the duration of the procedure. In the control condition, the neonate was in the prone position in the isolette. The ordering of conditions was random.', "The primary outcome was the Premature Infant Pain Profile, which is composed of 3 facial actions, maximum heart rate, and minimum oxygen saturation changes from baseline in 30-second blocks. Videotapes, taken with the camera positioned on the neonate's face so that an observer could not tell whether the neonate was being held or was in the isolette, were coded by research assistants who were naïve to the purpose of the study. Heart rate and oxygen levels were continuously monitored into a computer for later analysis. A repeated-measures analysis of covariance was used, with order of condition and site as factors and severity of illness as a covariate.", 'Premature Infant Pain Profile scores across the first 90 seconds from the heel-lancing procedure were significantly (.002<P<.04) lower by 2 points in the KC condition.'] |
['Patients with persistently active hepatitis B virus (HBV) replication are at high risk for progression to liver cirrhosis and hepatocellular carcinoma (HCC). The influence of the viral load of HBV on intrahepatic recurrence after local ablation therapy in patients with HBV-related HCC has not been elucidated. We aimed to evaluate predictors of intrahepatic recurrence and clarify the correlation between viral load and intrahepatic recurrence after percutaneous ablation.', 'Patients with HBV-related, solitary HCC undergoing radiofrequency ablation (RFA) or percutaneous ethanol injection (PEI), between October 2004 and December 2008 were prospectively enrolled. Statistical analyses were performed using the Kaplan-Meier method and Cox regression model to identify risk factors for intrahepatic recurrence.', 'A total of 145 patients (male, 81.4%; mean age, 55.3 years) were included. Ninety patients (62.1%) had serum HBV DNA ≥2000 IU/mL. The median follow-up duration was 28.9 months (range, 12.0-57.0) and 63 patients (43.4%) experienced intrahepatic tumor recurrence. Multivariate analysis indicated that seropositivity for hepatitis B envelope antigen (HBeAg) was an independent negative predictor of intrahepatic recurrence (hazard ratio, 0.473; P=0.026) and late (≥1 year) recurrence (HR, 0.288; P=0.012). The serum alpha fetoprotein (AFP) level also significantly predicted late recurrence (HR, 1.001; P=0.005). However, neither the ablation method nor serum HBV DNA titers were correlated with intrahepatic recurrence.'] |
['A small decrease in the serum albumin from the normal level is a common condition in preoperative laboratory tests of colorectal surgery patients; however, there is limited data examining these patients. We sought to identify outcomes of such patients.', 'The National Surgical Quality Improvement Program database was used to evaluate all patients who had modest levels of hypoalbuminemia (3 ≤ serum albumin < 3.5\xa0g/dL) before colorectal resection from 2005 to 2012. Multivariate analysis using logistic regression was performed to quantify complications associated with modest hypoalbuminemia.', 'A total of 108,898 patients undergoing colorectal resection were identified, of which 16,962 (15.6%) had modest levels of preoperative hypoalbuminemia. Postsurgical complications significantly associated (P < .05) with modest hypoalbuminemia were as follows: hospitalization more than 30\xa0days (adjusted odds ratio [AOR], 1.77), deep vein thrombosis (AOR, 1.64), unplanned intubation (AOR, 1.42), ventilator dependency for more than 48\xa0hours (AOR, 1.30), and wound disruption (AOR, 1.22).'] |
['QT dispersion has been used in stratifying risk for sudden death in adults with dilated cardiomyopathy, but its role in the pediatric population has not been delineated.', 'We reviewed electrocardiograms in pediatric patients with dilated cardiomyopathy referred for heart transplantation, to evaluate the role of QT dispersion in predicting malignant arrhythmias in these patients. Three groups were defined: Group I (n = 13) had dilated cardiomyopathy and malignant ventricular arrhythmias, Group II (n = 13) had dilated cardiomyopathy with no ventricular arrhythmias and Group III (n = 30) consisted of normals. QT dispersion was defined as the duration of the shortest QT subtracted from that of the longest. In addition, the standard deviation of the QT intervals was calculated for each ECG, using 12 leads.', 'QT dispersion was significantly prolonged in Group I (97 +/- 33 msec) compared to Group II (74 +/- 19 msec) and Group III (42 +/- 17 msec). QT standard deviation was also prolonged in Group I (30 +/- 11 msec) vs Group II (22 +/- 5 msec) and Group III (13 +/- 4 msec). Using a threshold value of 90 msec for QT dispersion or 25 msec for QT standard deviation, a sensitivity of 78% and a specificity of 70% was obtained for identifying patients who would subsequently develop ventricular arrhythmias.'] |
['To investigate the 30-day and 12-month mortality risks among hospitalized stroke patients according to compliance with guideline-based process indicators.', 'We used data from the Second Stroke Audit and the Mortality Register of Catalonia (Spain). The audit retrospectively explored quality of stroke care based on compliance with indicators among patients discharged from all public hospitals in Catalonia in 2007; they were identified and selected through a pre-established sampling method. The magnitude of the independent association of each indicator with 30-day and 12-month mortality was assessed using logistic regression with generalized estimating equations to account for clustering of patients within hospitals. Generalized estimating equations modeling was initially restricted to patients alive >72 hours poststroke to control for confounding by severity. Analyses were also run in 3 other samples (all patients, patients alive >7 days, and patients alive >14 days).', 'Of 1767 stroke admissions in the Second Stroke Audit, 1697 patients survived >72 hours poststroke. Within this sample, the adjusted 30-day mortality risk was negatively associated with nonadherence to different indicators, of which only antithrombotics at discharge (OR, 4.3; 95% CI, 1.72-10.78) remained significant in all data sets. At 12 months, the adjusted mortality risk was negatively associated with management of hypertension (OR, 1.87; 95% CI, 1.22-2.86) and antithrombotics at discharge (OR, 2.79; 95% CI, 1.41-5.54). Both remained unchanged across different samples.'] |
['Statin therapy reduces coronary heart disease (CHD) and mortality in individuals with elevated C-reactive protein (CRP) but low-density lipoprotein cholesterol below the threshold at which statin therapy is recommended. We determined the proportion of individuals with elevated CRP in whom statin therapy was not indicated, and examined predictors for elevated CRP in a multi-ethnic Asian population.', 'We studied 3404 participants (Chinese, Malays and Asian-Indians) without a history of hypercholesterolemia living in Singapore (mean age±s.d.: 48.9±11.2 years). Eligibility for statin therapy was determined based on the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III (ATPIII)) guideline. CRP was measured by high-sensitivity enzyme-linked immunosorbent assay method. CRP level greater than 2\u2009mg\u2009l(-1) was considered as elevated.', 'Elevated CRP was found in 29.3% participants who were not eligible for statin therapy (n=2974). Elevated CRP was more common in females and amongst those of Malay or Asian-Indian ethnicity. Compared with participants with low CRP, those with elevated CRP were shown to have higher levels of obesity, blood pressure, triglyceride and insulin resistance (IR), but lower high-density lipoprotein cholesterol levels (all Ps<0.001). After multivariate analysis, gender (odds ratio (OR) 3.34 for females), ethnicity (Malay OR 1.57, 95% confidence interval (CI) 1.25-1.96; Asian-Indian OR 1.97, 95% CI 1.55-2.50), waist circumference (OR 1.06, 95% CI 1.05-1.07), smoking (OR 1.49, 95% CI 1.08-2.05) and IR (OR 1.14, 95% CI 1.07-1.22) were significant predictors of CRP (all Ps--values<0.05).'] |
['Insulin is proposed as a therapy for suppressing muscle wasting after burn trauma although the long-term effects of this therapy on wound healing are not yet known. The present study was designed to investigate the effect of systemically administered insulin therapy on burn wound healing.', 'Young rats weighing 80-150 g were subjected to 15-20% total body surface area burn injury on their shaved dorsum. The insulin dosage was increased over the first 3 days in each rat from 0.25 U (Day 1), 0.5 U (Day 2), and 1.0 U (Day 3) per 100 g body wt. The rats were euthanized at the fourth or fifteenth day postinjury. Skin sections were analyzed by histochemistry and quantitative polarization microscopy.', 'Histology showed a decreased number of inflammatory cells and increased vasodilation in the insulin-treated animals at Day 4 relative to untreated rats; at Day 15 there was increased reepithelialization. Quantitative analysis using polarization microscopy and picrosirius red staining showed an increased collagen deposition in wounds by Day 4 in insulin-treated rats relative to untreated burn controls.'] |
['At one time, it was expected that if an individual reached young adulthood without smoking, his/her risk for initiation was minimal. However, recent data suggest that smoking initiation among young adults may be increasing. One particularly vulnerable population of young adults for smoking initiation is military recruits. This study examined whether a modified version of the Pierce Susceptibility Questionnaire (PSQ) might be useful for identifying military recruits who are vulnerable for the initiation of tobacco use.', 'Active duty recruits entering the U.S. Air Force over a 1-year period (n=31,107) were assessed upon entry into basic military training (BMT), and a subsample was also assessed at 12 months following training.', 'The modified PSQ predicted initiation of cigarette use for all categories of baseline smokers (never, experimenters, former smokers, and regular users). The likelihood of initiating smoking after BMT was substantially higher among those identified as susceptible than among those identified as not susceptible.'] |
['The survival rate of lung cancer is low, thus new methods for treating this form of cancer must be explored. This study applies immune therapy with metronomic chemotherapy to observe the effect of combined therapy on suppressing tumor.', 'Mice were inoculated with Lewis lung carcinoma cells. Different treatments, namely, saline, metronomic chemotherapy, dendritic cell (DC) vaccine, and metronomic chemotherapy with DC vaccine were administered to corresponding mice groups. Basic fibroblast growth factor and vascular endothelial growth factor (VEGF) were detected via microdialysis and Luminex.', 'The median survival time of mice in the metronomic chemotherapy with DC vaccine group was (27.6±3.2) days, whereas that in the saline group was (13.5±2.7) days (P=0.008), that in the DC) vaccine group was (13.1±2.3) days (P=0.01), and that in the metronomic chemotherapy group was (11.8±3.0) days (P=0.01). The mice in the metronomic chemotherapy with DC vaccine group exhibited longer survival time than the mice in the other groups. This result could be related to the downregulation of VEGF secretion in the tumor-bearing mice groups within 48 h to 72 h.'] |
['Small duct primary sclerosing cholangitis (PSC) is phenotypically a mild version of large duct PSC, but it is unknown whether these phenotypes share aetiology. We aimed to characterize their relationship by investigating genetic associations in the human leucocyte antigen (HLA) complex, which represent the strongest genetic risk factors in large duct PSC.', 'Four classical HLA loci (HLA-A, HLA-B, HLA-C and HLA-DRB1) were genotyped in 87 small duct PSC patients, 485 large duct PSC patients and 1117 controls across three geographical regions.', 'HLA-DRB1*13:01 (OR = 2.0, 95% CI 1.2-3.4, P = 0.01) and HLA-B*08 (OR = 1.6, 95% CI 1.1-2.4, P = 0.02) were significantly associated with small duct PSC compared with healthy controls. Based on the observed frequency of HLA-B*08 in small duct PSC, the strongest risk factor in large duct PSC, an estimated 32% (95% CI 4-65%) of this population can be hypothesized to represent early stages or mild variants of large duct PSC. This subgroup may be constituted by small duct PSC patients with inflammatory bowel disease (IBD), which greatly resembled large duct PSC in its HLA association. In contrast, small duct PSC without IBD was only associated with HLA-DRB1*13:01(P = 0.03) and was otherwise distinctly dissimilar from large duct PSC.'] |
['The role of inflammation in mood disorders has received increased attention. There is substantial evidence that cytokine therapies, such as interferon alpha (IFN-alpha), can induce depressive symptoms. Indeed, proinflammatory cytokines change brain function in several ways, such as altering neurotransmitters, the glucocorticoid axis, and apoptotic mechanisms. This study aimed to evaluate the impact on mood of initiating IFN-alpha and ribavirin treatment in a cohort of patients with chronic hepatitis C. We investigated clinical, personality, and functional genetic variants associated with cytokine-induced depression.', 'We recruited 344 Caucasian outpatients with chronic hepatitis C, initiating IFN-alpha and ribavirin therapy. All patients were euthymic at baseline according to DSM-IV-R criteria. Patients were assessed at baseline and 4, 12, 24, and 48 weeks after treatment initiation using the Patient Health Questionnaire (PHQ), the Hospital Anxiety and Depression Scale (HADS), and the Temperament and Character Inventory (TCI). We genotyped several functional polymorphisms of interleukin-28 (IL28B), indoleamine 2,3-dioxygenase (IDO-1), serotonin receptor-1A (HTR1A), catechol-O-methyl transferase (COMT), glucocorticoid receptors (GCR1 and GCR2), brain-derived neurotrophic factor (BDNF), and FK506 binding protein 5 (FKBP5) genes. A survival analysis was performed, and the Cox proportional hazards model was used for the multivariate analysis.', 'The cumulative incidence of depression was 0.35 at week 24 and 0.46 at week 48. The genotypic distributions were in Hardy-Weinberg equilibrium. Older age (p = 0.018, hazard ratio [HR] per 5 years = 1.21), presence of depression history (p = 0.0001, HR = 2.38), and subthreshold depressive symptoms at baseline (p = 0.005, HR = 1.13) increased the risk of IFN-induced depression. So too did TCI personality traits, with high scores on fatigability (p = 0.0037, HR = 1.17), impulsiveness (p = 0.0200 HR = 1.14), disorderliness (p = 0.0339, HR = 1.11), and low scores on extravagance (p = 0.0040, HR = 0.85). An interaction between HTR1A and COMT genes was found. Patients carrying the G allele of HTR1A plus the Met substitution of the COMT polymorphism had a greater risk for depression during antiviral treatment (HR = 3.83) than patients with the CC (HTR1A) and Met allele (COMT) genotypes. Patients carrying the HTR1A CC genotype and the COMT Val/Val genotype (HR = 3.25) had a higher risk of depression than patients with the G allele (HTR1A) and the Val/Val genotype. Moreover, functional variants of the GCR1 (GG genotype: p = 0.0436, HR = 1.88) and BDNF genes (Val/Val genotype: p = 0.0453, HR = 0.55) were associated with depression.'] |
['Cryoablation is an effective treatment for children with supraventricular tachycardias (SVT). The present study documents the effect of two different cryoablation protocols on acute and chronic success rates.', 'Fifty-three consecutive patients (age range, 5-20 years) were treated; patients 1 to 17 were treated by a standard ablation protocol and patients 18 to 53 were treated by a modified ablation protocol that required lengthier cryoablations plus delivery of a bonus cryoapplication to consolidate the acutely successful irreversible lesion created at intervention. Electrophysiological study (EPS) was performed with diagnostic catheters and cryoablations were performed with a 7FR 4 mm tip catheter (CryoCath Technologies). Acute endpoints for non-inducibility of atrioventricular nodal re-entrant tachycardia (AVNRT) by programmed atrial stimulation at baseline or during isoproterenol performed 30 min post procedure, as well as non-inducibility and conduction block over the accessory pathway (AP). The chronic endpoint was arrhythmia recurrence post intervention. No permanent cryo-related complications or adverse outcomes were reported. Acute success rates for patients 1 to 17 and 18 to 53 were 88 and 100%, respectively. The cumulative percentage of patients without arrhythmia recurrence at 12 month follow-up was significantly different at 73 and 90%, respectively.'] |
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