instruction
stringlengths 22
321
| context
stringlengths 75
3.6k
| context_neg
stringlengths 75
3.6k
|
|---|---|---|
Do changes in aldehyde dehydrogenase-1 expression during neoadjuvant chemotherapy predict outcome in locally advanced breast cancer? | Although neoadjuvant chemotherapy (NAC) for locally advanced breast cancer can improve operability and local disease control, there is a lack of reliable biomarkers that predict response to chemotherapy or long-term survival. Since expression of aldehyde dehydrogenase-1 (ALDH1) is associated with the stem-like properties of self-renewal and innate chemoresistance in breast cancer, we asked whether expression in serial tumor samples treated with NAC could identify women more likely to benefit from this therapy. Women with locally advanced breast cancer were randomly assigned to receive four cycles of anthracycline-based chemotherapy, followed by four cycles of taxane therapy (Arm A), or the same regimen in reverse order (Arm B). Tumor specimens were collected at baseline, after four cycles, and then at surgical resection. ALDH1 expression was determined by immunohistochemistry and correlated with tumor response using Fisher's exact test while Kaplan-Meier method was used to calculate survival. A hundred and nineteen women were enrolled into the study. Fifty seven (48%) were randomized to Arm A and 62 (52%) to Arm B. Most of the women (90%) had ductal carcinoma and 10% had lobular carcinoma. Of these, 26 (22%) achieved a pathological complete response (pCR) after NAC. There was no correlation between baseline ALDH1 expression and tumor grade, stage, hormone receptor, human epidermal growth factor receptor 2 (HER2) status and Ki67 index. ALDH1 negativity at baseline was significantly associated with pCR (P = 0.004). The presence of ALDH1(+) cells in the residual tumor cells in non-responding women was strongly predictive of worse overall survival (P = 0.024). Moreover, serial analysis of specimens from non-responders showed a marked increase in tumor-specific ALDH1 expression (P = 0.028). Overall, there was no survival difference according to the chemotherapy sequence. However, poorly responding tumours from women receiving docetaxel chemotherapy showed an unexpected significant increase in ALDH1 expression. | More than 200,000 children each year are treated at emergency departments for injuries occurring on playgrounds. Empirically derived data are needed to elucidate factors associated with playground safety and reduce injury rates. Determine if neighborhood, park and playground characteristics are significantly associated with playground safety. A 24-item report card developed by the National Program for Playground Safety was used to assess playground safety at 41 public parks in a small to midsized, Midwestern city. Trained assessors evaluated the parks and playgrounds in June/July and used a standardized method to count the numbers of users. Data from the 2010 U.S. Census were used to describe the neighborhoods surrounding the parks. The average safety score for all playgrounds was 77.4% which denotes acceptable safety levels. However, 17.1% of the playgrounds were potentially hazardous and in need of corrective measures. Playgrounds were safer in neighborhoods with more youth (< 18 years of age) and educated adults and in parks with better quality features. Playgrounds with fewer amenities were relatively less safe. |
Does learning of serial digits lead to frontal activation in functional MR imaging? | Clinical studies have shown that performance on the serial digit learning test (SDLT) is dependent upon the mesial temporal lobes, which are responsible for learning and its consolidation. However, an effective SDLT performance is also dependent upon sequencing, temporal ordering, and the utilization of mnemonic strategies. All of these processes are among the functions of the frontal lobes; in spite of this, the relationship between SDLT performance and the frontal lobes has not been demonstrated with previously used mapping techniques. The aim of this study was to investigate the areas of the brain that are activated by SDLT performance. Ten healthy, right handed volunteers (mean age, 20.1 years; SD: 3.3) who had 12 years of education were studied with a 1.0 T MR imaging scanner. BOLD (blood oxygen level dependent) contrast and a modified SDLT were used. Activated loci were automatically mapped using a proportional grid. In learning, the most consistent activation was observed in B-a-7 of the right (80%) and the left hemispheres (50%). In recall, the most consistent activation was observed in B-a-7 of the right hemisphere (60%). Activations were observed in 2.5+/-0.97 Talairach volumes in learning, whereas they encompassed 1.7+/-0.95 volumes in recall. The difference between both phases (learning and recall) regarding total activated volume was significant (p < 0.05). | Icodextrin is a glucose polymer derived by hydrolysis of cornstarch. The different biocompatibility profile of icodextrin-containing peritoneal dialysis (PD) solutions may have a positive influence on peritoneal host defence. Furthermore, cases of sterile peritonitis potentially associated with icodextrin have been reported. The primary objective of this multicentre, longitudinal, observational, non-interventional, prospective cohort study, which included 722 PD patients, was to evaluate the incidence of overall peritonitis in patients treated with icodextrin-containing PD solutions (Extraneal) used during one long-dwell exchange/day compared with those treated with non-icodextrin-containing PD solutions. The secondary objective was to determine if culture-negative peritonitis rates differed between patients treated with icodextrin from two independent manufacturers. All peritonitis episodes were assessed by a Steering Committee in a blind manner. There was no significant difference between icodextrin-treated and control patients in the adjusted overall, culture-positive or culture-negative peritonitis rates. When stratified by the icodextrin supplier, there was no significant difference in the adjusted rate of culture-negative peritonitis episodes between groups. |
Is history of the diagnosis of a sexually transmitted disease linked to normal variation in personality traits? | Stable individual differences in personality traits have well-documented associations with various aspects of health. One of the health outcomes that directly depends on people's behavioral choices, and may therefore be linked to personality traits, is having a sexually transmitted disease (STD). The study examines the associations between a comprehensive set of basic personality traits and past STD history in a demographically diverse sample. Participants were 2,110 Estonians (1,175 women) between the ages of 19 and 89 (mean age 45.8 years, SD = 17.0). The five-factor model personality traits (Neuroticism, Extraversion, Openness to Experience, Agreeableness, and Conscientiousness) and their specific facets were rated by participants themselves and knowledgeable informants. Sex, age, and educational level were controlled for. History of STD diagnosis based on medical records and/or self-report. History of STD diagnosis was associated with higher Neuroticism and lower Agreeableness in both self- and informant-ratings. Among the specific personality facets, the strongest correlates of STD were high hostility and impulsiveness and low deliberation. | The nephrotoxic mechanisms of andrographolide sodium bisulfate (ASB) remain largely unknown. This study attempted to explore the mechanism of ASB-induced nephrotoxicity using human proximal tubular endothelial cells (HK-2). For this study HK-2 cells were treated with rising concentrations of ASB. Their survival rate was detected using MTT assay and ultrastructure was observed with electron microscopy. L-Lactate dehydrogenase (LDH) assay was followed by examination of mitochondrial membrane potential (MMP). Reactive oxygen species (ROS) was detected using different methods and apoptosis/autophage related proteins were detected using immunoblotting. We found that ASB inhibited HK-2 cell proliferation and decreased cell survival rate in a time and dose-dependent manner (P<0.05, P<0.01, respectively). With increasing ASB concentration, cell structure was variably damaged and evidence of apoptosis and autophagy were observed. MMP gradually decreased and ROS was induced. The expression of JNK and Beclin-1 increased and activation of the JNK signaling pathway were seen. Apoptosis was induced via the mitochondrial-dependent caspase-3 and caspase-9 pathway, and autophagy related protein Beclin-1 was enhanced by ASB. |
Do biomarkers S100B and neuron-specific enolase predict outcome in hypothermia-treated encephalopathic newborns*? | To evaluate if serum S100B protein and neuron-specific enolase measured during therapeutic hypothermia are predictive of neurodevelopmental outcome at 15 months in children with neonatal encephalopathy. Prospective longitudinal cohort study. A level IV neonatal ICU in a freestanding children's hospital. Term newborns with moderate to severe neonatal encephalopathy referred for therapeutic hypothermia during the study period. Serum neuron-specific enolase and S100B were measured at 0, 12, 24, and 72 hours of hypothermia. Of the 83 infants enrolled, 15 (18%) died in the newborn period. Survivors were evaluated by the Bayley Scales of Infant Development-II at 15 months. Outcomes were assessed in 49 of 68 survivors (72%) at a mean age of 15.2 ± 2.7 months. Neurodevelopmental outcome was classified by Bayley Scales of Infant Development-II Mental Developmental Index and Psychomotor Developmental Index scores, reflecting cognitive and motor outcomes, respectively. Four-level outcome classifications were defined a priori: normal = Mental Developmental Index/Psychomotor Developmental Index within 1 SD (> 85), mild = Mental Developmental Index/Psychomotor Developmental Index less than 1 SD (70-85), moderate/severe = Mental Developmental Index/Psychomotor Developmental Index less than 2 SD (< 70), or died. Elevated serum S100B and neuron-specific enolase levels measured during hypothermia were associated with increasing outcome severity after controlling for baseline and socioeconomic characteristics in ordinal regression models. Adjusted odds ratios for cognitive outcome were 2.5 (95% CI, 1.3-4.8) for S100B and 2.1 (95% CI, 1.2-3.6) for neuron-specific enolase, and for motor outcome, 2.6 (95% CI, 1.2-5.6) for S100B and 2.1 (95% CI, 1.2-3.6) for neuron-specific enolase. | Smoking cessation rapidly reduces cardiovascular risk. The pathophysiological mechanisms involved are still being debated. We measured structural and functional arterial wall properties of the femoral and carotid arteries after smoking cessation to investigate their possible role in cardiovascular risk reduction. Out of 127 smokers, 33 proved to stop smoking for two years. They were compared with 50 nonsmokers and 55 persistent smokers in a prospective study. Cross-sectional compliance and distensibility coefficients as well as intima-media thickness of both carotid arteries and of the right common femoral artery were measured ultrasonographically at baseline and 3, 6, 12 and 24 months after smoking cessation. The nonsmoking and persistent smokers group were measured twice at an interval of 24 months. Persistent smoking and two years of smoking cessation did not affect cross-sectional compliance and distensibility coefficients. Although at baseline intimal-medial layers were thicker in smokers, the change over time in intima-media thickness did not differ significantly between all three groups. |
Does immunotherapy prevent recurrent abortion without influencing natural killer receptor status? | We assessed the expression of natural killer (NK) receptors in recurrent aborters before and after immunotherapy using their husbands' peripheral blood mononuclear cells (PBMCs). Using stored PBMCs from recurrent aborters before and after the immunotherapy, the expression of NK receptors, CD158a, CD158b, CD159 and CD94, were analyzed using monoclonal antibodies for respective receptors. The diversity of killer activatory receptors (KARs) and killer inhibitory receptors (KIRs) was also examined using reverse transcriptase-polymerase chain reaction (RT-PCR)-single strand conformation polymorphism (SSCP) method. In recurrent aborters, no apparent changes in NK receptor expression and the balance between KARs and KIRs were found before and after the immunotherapy. | To test the hypothesis that a novel phase-contrast optical coherence tomography (OCT) system can image retinal and choroidal vessels in the living mouse. A high-speed spectral domain optical coherence tomography (SDOCT) system, which measures the reflections for the entire depth of the retina at once with each axial scan (A-scan), was developed for mouse retinal imaging. Acquiring multiple A-scans over a transverse line across the mouse retina offers a two-dimensional cross-sectional image (B-scan); several neighboring B-scans can be assembled into a three-dimensional OCT image. To visualize mobility and transverse flow in retinal vessels, the statistical variance of phase for each location was calculated from multiple B-scans acquired successively for the same retinal cross-section. Such measures of phase variance offer a direct measure of motions over a large dynamic range of flow velocities. Three-dimensional phase-contrast images of the live mouse retina were created using multiple two-dimensional cross-sectional image slices through the retina. For the data presented here, each cross-sectional phase-contrast slice resulted from five images of 100 or 200 transverse pixels, acquired over 25 ms or 50 ms, respectively. The approach offered clear identification of motion regions at different depths, including flow in the retinal microvasculature and in the choroidal vessels. |
Does catalase improve saccharification of lignocellulose by reducing lytic polysaccharide monooxygenase-associated enzyme inactivation? | Efficient enzymatic saccharification of plant cell wall material is key to industrial processing of agricultural and forestry waste such as straw and wood chips into fuels and chemicals. Saccharification assays were performed on steam-pretreated wheat straw under ambient and O2-deprived environments and in the absence and presence of a lytic polysaccharide monooxygenase (LPMO) and catalase. A kinetic model was used to calculate catalytic rate and first-order inactivation rate constants of the cellulases from reaction progress curves. The addition of a LPMO significantly (P < 0.01, Student's T test) enhanced the rate of glucose release from 2.8 to 6.9 h(-1) under ambient O2 conditions. However, this also significantly (P < 0.01, Student's T test) increased the rate of inactivation of the enzyme mixture, thereby reducing the performance half-life from 65 to 35 h. Decreasing O2 levels or, strikingly, the addition of catalase significantly reduced (P < 0.01, Student's T test) enzyme inactivation and, as a consequence, higher efficiency of the cellulolytic enzyme cocktail was achieved. | Only 2 % of the human genome code for proteins. Among the remaining 98 %, transposable elements (TEs) represent millions of sequences. TEs have an impact on genome evolution by promoting mutations. Especially, TEs possess their own regulatory sequences and can alter the expression pattern of neighboring genes. Since they can potentially be harmful, TE activity is regulated by epigenetic mechanisms. These mechanisms participate in the modulation of gene expression and can be associated with some human diseases resulting from gene expression deregulation. The fact that the TE silencing can be removed in cancer could explain a part of the changes in gene expression. Indeed, epigenetic modifications associated locally with TE sequences could impact neighboring genes since these modifications can spread to adjacent sequences. We compared the histone enrichment, TE neighborhood, and expression divergence of human genes between a normal and a cancer conditions. We show that the presence of TEs near genes is associated with greater changes in histone enrichment and that differentially expressed genes harbor larger histone enrichment variation related to the presence of particular TEs. |
Is periodontal disease associated with brachial artery endothelial dysfunction and systemic inflammation? | The purpose of this study was to determine whether periodontal disease is associated with endothelial dysfunction and systemic inflammation. Epidemiological studies suggest that severe periodontal disease is associated with increased cardiovascular disease risk, but the mechanisms remain unknown. We assessed flow-mediated dilation and nitroglycerin-mediated dilation of the brachial artery using vascular ultrasound in 26 subjects with advanced periodontal disease and 29 control subjects. The groups were matched for age and sex, and patients with hypercholesterolemia, diabetes mellitus, hypertension, and history of cigarette smoking were excluded. We also examined serum levels of C-reactive protein using an established high-sensitivity method. Subjects with advanced periodontal disease had lower flow-mediated dilation compared with control patients (7.8+/-4.6% versus 11.7+/-5.3%, P=0.005). Nitroglycerin-mediated dilation was equivalent in the two groups. Subjects with advanced periodontitis exhibited higher serum levels of high-sensitivity C-reactive protein compared with healthy controls patients (2.3+/-2.3 versus 1.0+/-1.0 mg/L, P=0.03). | Recurrent loss of part of the long arm of chromosome 11 is a well established hallmark of a subtype of aggressive neuroblastomas. Despite intensive mapping efforts to localize the culprit 11q tumour suppressor gene, this search has been unsuccessful thus far as no sufficiently small critical region could be delineated for selection of candidate genes. To refine the critical region of 11q loss, the chromosome 11 status of 100 primary neuroblastoma tumours and 29 cell lines was analyzed using a BAC array containing a chromosome 11 tiling path. For the genes mapping within our refined region of loss, meta-analysis on published neuroblastoma mRNA gene expression datasets was performed for candidate gene selection. The DNA methylation status of the resulting candidate gene was determined using re-expression experiments by treatment of neuroblastoma cells with the demethylating agent 5-aza-2'-deoxycytidine and bisulphite sequencing. Two small critical regions of loss within 11q23 at chromosomal band 11q23.1-q23.2 (1.79 Mb) and 11q23.2-q23.3 (3.72 Mb) were identified. In a first step towards further selection of candidate neuroblastoma tumour suppressor genes, we performed a meta-analysis on published expression profiles of 692 neuroblastoma tumours. Integration of the resulting candidate gene list with expression data of neuroblastoma progenitor cells pinpointed CADM1 as a compelling candidate gene. Meta-analysis indicated that CADM1 expression has prognostic significance and differential expression for the gene was noted in unfavourable neuroblastoma versus normal neuroblasts. Methylation analysis provided no evidence for a two-hit mechanism in 11q deleted cell lines. |
Does endoscopic ultrasonography-identified celiac adenopathy remain a poor prognostic factor despite preoperative chemoradiotherapy in esophageal adenocarcinoma? | We reviewed our experience with preoperative chemoradiotherapy in patients with adenocarcinoma of the distal esophagus and pretreatment endoscopic ultrasonography-identified celiac adenopathy. One hundred eighty-six patients with adenocarcinoma of the distal esophagus were staged with endoscopic ultrasonography before treatment from 1997 through 2004. All patients were treated with concurrent chemoradiotherapy (CRT group) and surgical intervention or induction chemotherapy followed by concurrent chemoradiotherapy (C-->CRT group) and surgical intervention. Survival analysis (excluding operative mortality) evaluated various pretreatment factors. Multivariable Cox regression analysis showed that pretreatment endoscopic ultrasonography-identified celiac adenopathy was a significant predictor of decreased long-term survival (P = .03). Median and 3-year survivals were 49 months and 54% in the endoscopic ultrasonography-identified cN0 M0 group (n = 65), 45 months and 56% in the endoscopic ultrasonography-identified cN1 M0 group (n = 96), and 19 months and 12% in the endoscopic ultrasonography-identified celiac adenopathy (cM1a) group (n = 18; P = .03). Increased systemic relapse was noted in the endoscopic ultrasonography-identified cM1a group (44% vs 22%, P = .07). The only factor associated with increased survival in the endoscopic ultrasonography-identified cM1a group (27 vs 15 months, P = .02) was the addition of induction chemotherapy before concurrent chemoradiotherapy and surgical intervention. | Cognitive impairment is a common feature of late-life bipolar disorder (BD). Yet, there is limited information on the biological mechanisms associated with this process. It is uncertain whether cognitively impaired patients with BD may present the Alzheimer's disease (AD) bio-signature in the cerebrospinal fluid (CSF), defined as a combination of low concentrations of the amyloid-beta peptide (Aβ1-42 ) and high concentrations of total tau (T-tau) and tau phosphorylated at threonine 181 (P-tau). In this study, we sought to determine whether cognitive impairment in elderly patients with BD is associated with the AD CSF bio-signature. Seventy-two participants were enrolled in the study. The test group comprised older adults with BD and mild cognitive impairment (BD-MCI; n = 16) and the comparison groups comprised patients with dementia due to AD (n = 17), patients with amnestic MCI (aMCI; n = 14), and cognitively healthy older adults (control group; n = 25). CSF samples were obtained by lumbar puncture and concentrations of Aβ1-42 , T-tau and P-tau were determined. CSF concentrations of all biomarkers were significantly different in the AD group compared to all other groups, but did not differentiate BD-MCI subjects from aMCI subjects and controls. BD-MCI patients had a non-significant reduction in CSF Aβ1-42 compared to controls, but this was still higher than in the AD group. Concentrations of T-tau and P-tau in BD-MCI patients were similar to those in controls, and significantly lower than those in AD. |
Do exosome-like vesicles released from lipid-induced insulin-resistant muscles modulate gene expression and proliferation of beta recipient cells in mice? | The crosstalk between skeletal muscle (SkM) and beta cells plays a role in diabetes aetiology. In this study, we have investigated whether SkM-released exosome-like vesicles (ELVs) can be taken up by pancreatic beta cells and can deliver functional cargoes. Mice were fed for 16 weeks with standard chow diet (SCD) or with standard diet enriched with 20% palmitate (HPD) and ELVs were purified from quadriceps muscle. Fluorescent ELVs from HPD or SCD quadriceps were injected i.v. or intramuscularly (i.m.) into mice to determine their biodistributions. Micro (mi)RNA quantification in ELVs was determined using quantitative real-time RT-PCR (qRT-PCR)-based TaqMan low-density arrays. Microarray analyses were performed to determine whether standard diet ELVs (SD-ELVs) and high palmitate diet ELVs (HPD-ELVs) induced specific transcriptional signatures in MIN6B1 cells. In vivo, muscle ELVs were taken up by pancreas, 24 h post-injection. In vitro, both SD-ELVs and HPD-ELVs transferred proteins and miRNAs to MIN6B1 cells and modulated gene expressions whereas only HPD-ELVs induced proliferation of MIN6B1 cells and isolated islets. Bioinformatic analyses suggested that transferred HPD-ELV miRNAs may participate in these effects. To validate this, we demonstrated that miR-16, which is overexpressed in HPD-ELVs, was transferred to MIN6B1 cells and regulated Ptch1, involved in pancreas development. In vivo, islets from HPD mice showed increased size and altered expression of genes involved in development, including Ptch1, suggesting that the effect of palm oil on islet size in vivo was reproduced in vitro by treating beta cells with HPD-ELVs. | In clinical trials, change in tumor size is used to stratify patients into response categories. The objective of the current study was to: 1) determine whether early change in the tumor size were correlated with survival in patients with advanced nonsmall cell lung cancer (NSCLC) using modified response categories from the Response Evaluation Criteria in Solid Tumors (RECIST), and 2) to determine whether there was an optimal percentage change in tumor size that could be used to define a partial response that also correlated with survival. A total of 99 consecutive patients presenting for the treatment of advanced NSCLC during the year 2003 who had computed tomography (CT) scans before and after treatment available for review were included in the study. The largest target thoracic lesion was measured on CT before treatment, and again 2 months to 3 months after the initiation of treatment. Percent change in tumor size was calculated. The relation between tumor response and patient survival was investigated. There was no definite relation noted between early tumor response and patient survival (P = .754). Patients who had any initial reduction in tumor size were not found to have a significantly different survival compared with patients with initial disease progression (P = .580). In addition, there was no particular percent reduction in tumor size that was found to optimally correlate with survival. |
Is association between frequency of chromosomal aberrations and cancer risk influenced by genetic polymorphisms in GSTM1 and GSTT1? | The frequency of chromosomal aberrations (CA) in peripheral blood lymphocytes of healthy individuals has been associated with cancer risk. It is presently unclear whether this association is influenced by individual susceptibility factors such as genetic polymorphisms of xenobiotic-metabolizing enzymes. To evaluate the role of polymorphisms in glutathione S-transferase (GST) M1 (GSTM1) and theta 1 (GSTT1) as effect modifiers of the association between CA and cancer risk. A case-control study was performed pooling data from cytogenetic studies carried out in 1974-1995 in three laboratories in Italy, Norway, and Denmark. A total of 107 cancer cases were retrieved from national registries and matched to 291 controls. The subjects were classified as low, medium, and high by tertile of CA frequency. The data were analyzed by setting up a Bayesian model that included prior information about cancer risk by CA frequency. The association between CA frequency and cancer risk was confirmed [OR(medium) (odds ratio)(medium) = 1.5, 95% credibility interval (CrI), 0.9-2.5; OR(high) = 2.8, 95% CrI, 1.6-4.6], whereas no effect of the genetic polymorphism was observed. A much stronger association was seen in the Italian subset (OR(high)= 9.4, 95% CrI, 2.6-28.0), which was characterized by a lower technical variability of the cytogenetic analysis. CA level was particularly associated with cancer of the respiratory tract (OR(high)= 6.2, 95% CrI, 1.5-20.0), the genitourinary tract (OR(high) = 4.0, 95% CrI, 1.4-10.0), and the digestive tract (OR(high) = 2.8, 95% CrI, 1.2-5.8). | Myocardial infarction (MI) induces neural remodelling of the left stellate ganglion (LSG), which may contribute to ischaemia-induced arrhythmias. The neural chemorepellent Semaphorin 3a (Sema3a) has been identified as a negative regulator of sympathetic innervation in the LSG and heart. We previously reported that overexpression of Sema3a in the border zone could reduce the arrhythmogenic effects of cardiac sympathetic hyperinnervation post-MI. This study investigated whether Sema3a overexpression within the LSG confers an antiarrhythmic effect after MI through decreasing extra- and intra-cardiac neural remodelling. Sprague-Dawley rats were subjected to MI, and randomly allocated to intra-LSG microinjection of either phosphate-buffered saline (PBS), adenovirus encoding green fluorescent protein (AdGFP), or adenovirus encoding Sema3a (AdSema3a). Sham-operated rats served as controls. Two weeks after infarction, MI-induced nerve sprouting and sympathetic hyperinnervation in the LSG and myocardium were significantly attenuated by intra-LSG injection with AdSema3a, as assessed by immunohistochemistry and western blot analysis of growth-associated protein 43 and tyrosine hydroxylase. This was also confirmed by sympathetic nerve function changes assessed by cardiac norepinephrine content. Additionally, intra-LSG injection with AdSema3a alleviated MI-induced accumulation of dephosphorylated connexin 43 in the infarct border zone. Furthermore, Sema3a overexpression in the LSG reduced the incidence of inducible ventricular tachyarrhythmia by programmed electrical stimulation post-MI, and arrhythmia scores were significantly lower in the AdSema3a group than in the PBS and AdGFP groups. |
Do smoking and unstable hinge fractures cause delayed gap filling irrespective of early weight bearing after open wedge osteotomy? | The purpose of this study was to examine the osteotomy gap filling rate with new bone after open wedge high tibial osteotomy (HTO) without bone graft and the effects of smoking, lateral hinge fracture, and early full weight bearing. A prospective series (N = 70) of open wedge HTOs with the TomoFix plate (DePuy Synthes, Umkirch, Germany) was performed. Radiologic follow-up examinations took place postoperatively, after 6 and 12 weeks, and after 6, 12, and 18 months to measure osteotomy gap filling at each follow-up. Bone healing was compared in smokers versus nonsmokers who underwent open wedge HTOs with intact lateral hinges. Fractured lateral hinges were classified according to the Takeuchi classification and separately analyzed regarding bone healing. Patients were randomly assigned to undergo early (11 days) or standard (6 weeks) full-weight-bearing rehabilitation. A delay in the osteotomy gap filling rate between smokers and nonsmokers could be observed at all follow-up periods, but differences were not significant. A fracture of the lateral hinge was found in 39% of the patients. A type I fracture was observed in 14% of patients, a type II fracture was observed in 13%, and a type III fracture was found in 6%. The highest increase in the osteotomy gap filling rate was observed between 12 weeks and 6 months after surgery in patients with intact lateral hinges. For patients with unstable type II fractures, the highest increase in the gap filling rate was delayed until 6 to 12 months. Early full weight bearing had no effect on the gap filling rate in any of the patient groups evaluated. | Grass carp reovirus (GCRV) is responsible for viral hemorrhagic disease in cultured grass carp (Ctenopharyngon idellus). GCRV is a non-enveloped, double-stranded RNA virus in the genus Aquareovirus, of the family Reoviridae, which encodes seven structural proteins (VP1-VP7) and five nonstructural proteins (NS80, NS38, NS31, NS26, and NS16). To date, the mechanism of GCRV entry into CIK Ctenopharyngon idellus kidney (CIK) cells remains poorly understood. Here, we present a study of the GCRV internalization mechanism in CIK cells. Our results indicated that GCRV infection was inhibited by chlorpromazine, the specific inhibitor for clathrin-mediated endocytosis. Colocalization of GCRV virions with endogenous clathrin was observed during early infection by confocal microscopy. Moreover, GCRV infection of CIK cells depended on acidification of the endosome. This was indicated by significant inhibition of viral infection following prophylactic treatment with the lysosomotropic drugs chloroquine or ammonium chloride. In addition, the disturbance of dynamin activity blocked GCRV entry, which confirmed the dynamin-dependent nature of clathrin-mediated endocytosis. |
Is eGFR-TKI effective regardless of treatment timing in pulmonary adenocarcinoma with EGFR mutation? | Although epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have become key therapeutic agents for non-small cell lung cancer (NSCLC) patients with EGFR mutation, little is known about the efficacy of EGFR-TKIs according to different treatment timings. A total of 1,250 patients with NSCLC were screened for EGFR mutations at a single institution between March 2006 and May 2010. The efficacy of EGFR-TKIs in terms of response rate (RR), progression-free survival (PFS), and overall survival (OS) were compared according to the treatment timing. Among the 437 patients (36.1 %) with EGFR mutation, we analyzed 222 patients who received EGFR-TKI treatment. With a median follow-up duration of 27.5 months (range 8.3-69.2), EGFR-TKI was given to 97 (43.7 %), 109 (49.1 %), and 16 (7.2 %) patients as first-line, second-line, and third-line therapy, respectively. All three groups showed similar RR (71.1, 72.5, and 75.0 %, respectively) to EGFR-TKI (p = 0.802). No significant difference was observed according to treatment timing of EGFR-TKI in terms of PFS (median 10.6, 13.0, and 10.4 months; p = 0.670) and OS (median 20.5, 26.2, and 17.1 months; p = 0.142). The treatment timing of EGFR-TKI still showed no association with PFS or OS after adjusting significant prognostic factors including performance, disease status, and EGFR mutation types. | No previous studies have investigated the psychiatric characteristics of patients with postherpetic neuralgia (PHN). Similarly, no studies have been performed on patients with different chronic somatic symptoms due to a defined medical disease to compare the characteristics of psychiatric morbidity associated with each etiology. After completing the subscales of the Symptom Checklist 90-R, a psychiatrist administered the Diagnostic Interview Schedule to all subjects. The psychiatric comorbidity in 35 patients with pain due to PHN was compared with a control group of 34 patients with the nonpainful aversive symptom of vertigo due to a peripheral vestibular disorder that caused unilateral hypofunction. PHN patients had significantly more symptoms of major depression and somatization disorder. No significant differences were found between groups for psychiatric diagnoses. Patients with PHN reported significantly less acutely distressing somatic symptoms. |
Does estrogen receptor beta protect the murine heart against left ventricular hypertrophy? | Left ventricular hypertrophy (LVH) displays significant gender-based differences. 17beta-estradiol (E2) plays an important role in this process because it can attenuate pressure overload hypertrophy via 2 distinct estrogen receptors (ERs): ERalpha and ERbeta. However, which ER is critically involved in the modulation of LVH is poorly understood. We therefore used ERalpha-deficient (ERalpha-/-) and ERbeta-deficient (ERbeta-/-) mice to analyze the respective ER-mediated effects. Respective ER-deficient female mice were ovariectomized and were given E2 or placebo subcutaneously using 60-day release pellets. After 2 weeks, they underwent transverse aortic constriction (TAC) or sham operation. In ERalpha-/- animals, TAC led to a significant increase in ventricular mass compared with sham operation. E2 treatment reduced TAC induced cardiac hypertrophy significantly in wild-type (WT) and ERalpha-/- mice but not in ERbeta-/- mice. Biochemical analysis showed that E2 blocked the increased phosphorylation of p38-mitogen-activated protein kinase observed in TAC-treated ERalpha-/- mice. Moreover, E2 led to an increase of ventricular atrial natriuretic factor expression in WT and ERalpha-/- mice. | To search for novel disease-specific markers in gastric juice by investigating the protein concentrations and components in gastric juice from patients with various gastroduodenal diseases. Protein concentrations and pH values in fasting gastric juice were examined in 120 healthy subjects and 39 gastric ulcer, 38 duodenal ulcer, and 31 gastric cancer patients. The protein components in gastric juice were studied by two-dimensional PAGE and mass spectrometric analysis. Protein concentrations in gastric juice of patients with gastric ulcers and gastric cancer were significantly higher than those in healthy subjects (1.06 and 2.61 mg/mL versus 0.48 mg/mL; P=0.001 and P<0.001, respectively), and duodenal ulcer patients had lower gastric juice protein concentrations compared with healthy subjects (0.26 versus 0.48 mg/mL; P<0.05). Gastric hypoacidity and advanced age were independent factors affecting the protein concentrations in gastric juice with odds ratios of 32.9 (95% confidence interval, 11.8-90.9) and 3.2 (95% confidence interval, 1.3-8.3), respectively. Each electrophoresis images of gastric juice could be classified into one of three patterns: basic band, specific band, or nonspecific band. The frequencies of specific band pattern in healthy subjects, gastric ulcer, duodenal ulcer, and gastric cancer patients were 6%, 42%, 6%, and 93%, respectively. Proteomic analysis revealed that alpha1-antitrypsin precursor was the principal peptide in the specific band. |
Do iBD-associated TL1A gene ( TNFSF15 ) haplotypes determine increased expression of TL1A protein? | The recently identified member of the TNF superfamily TL1A (TNFSF15) increases IFN-gamma production by T cells in peripheral and mucosal CCR9+ T cells. TL1A and its receptor DR3 are up-regulated during chronic intestinal inflammation in ulcerative colitis and Crohn's disease (CD). TL1A gene haplotypes increase CD susceptibility in Japanese, European, and US cohorts. Here we report that the presence of TL1A gene haplotype B increases risk in Jewish CD patients with antibody titers for the E. coli outer membrane porin C (OmpC+) (Haplotype B frequency in Jewish CD patients: 24.9% for OmpC negative and 41.9% for OmpC positive patients, respectively, P< or =0.001). CD14+ monocytes isolated from Jewish OmpC+ patients homozygous for TL1A gene haplotype B express higher levels of TL1A in response to FcgammaR stimulation, a known inducing pathway of TL1A, as measured by ELISA. Furthermore, the membrane expression of TL1A is increased on peripheral monocytes from Jewish but not non-Jewish CD patients with the risk haplotype. | To assess the relationship between infarct-related artery (IRA) stenosis and capillary density and to assess its effect on scar formation in the human heart. Morphometric evaluation was performed in 51 human hearts, as follows. Group I non-cardiac death (control), Group II post-Q-wave myocardial infarction (QMI) death and Group III patients who survived QMI and who underwent aneurysmectomy. Using morphometric parameters, the relationship between left ventricle (LV) mass, infarct size, IRA stenosis, cellular hypertrophy and changes in microcirculation were analyzed within the infarcted area and free LV wall. A significant reduction in capillary density within the infarcted area was noted in group II when compared to the control group (1525.6+/-378.5/mm(2) vs. 2968.7+/-457.3/mm(2); p<0.001). Reduction in capillary density was inversely related to infarct size (r=-0.616; p=0.006) and degree of IRA stenosis (r(S)=-0.512; p=0.03). The most significant reduction in capillary density was observed in patients with total IRA occlusion (1204.6+/-156.9/mm(2) vs. 1676.6+/-245.8/mm(2); p<0.001). Similarly, a reduction in capillary density of over 60% (1030.7+/-241.8/mm(2)) was observed within aneurysms resected surgically. |
Does partial amniotic carbon dioxide insufflation ( PACI ) facilitate fetoscopic interventions in complicated monochorionic twin pregnancies? | Adequate visualization of the placenta or umbilical cord during fetoscopic procedures in complicated monochorionic twin pregnancies may be difficult because of placental position and spatial constraints, as well as stained amniotic fluid. Partial amniotic carbon dioxide insufflation (PACI) has made it possible to overcome these obstacles in other fetoscopic procedures, but its value has not yet been reported in monochorionic twins. Partial amniotic carbon dioxide insufflation was carried out in five expectant women with complicated monochorionic twin pregnancies between 19 + 6 to 29 + 4 weeks of gestation when adequate fetoscopic visualization of pathological placental surface vessels or the umbilical cord was impossible because of stained or too little amniotic fluid. In four cases, five fetoscopic laser ablations of pathological placental vessels in twin-to-twin transfusion syndrome (TTTS) were performed. In one discordant twin pregnancy with TTTS, PACI was carried out in order to achieve umbilical cord ligation in a recipient with omphalocele and cardiac malformation. Partial amniotic carbon dioxide insufflation offered superior visualization and did not result in any acute maternal or fetal complications. After fetoscopic laser coagulation, three women delivered one fetus at 27 + 5, two fetuses at 28 + 6, and two fetuses at 35 + 4 weeks of gestation, respectively. One set of twins with TTTS was lost. Following umbilical cord ligation, the surviving twin was delivered at 37 + 2 weeks of gestation. | According to reports in the literature, more than 30% of depressive patients fail to achieve remission. Therapy with the conventional antidepressant drugs may induce the serious adverse reactions. Moreover, its benefits may be seen at least 2-4 weeks after the first dose. Therefore, the alternative strategies for prevention and treatment of depression are sought. The main aim of our study was to assess the effects of ifenprodil given at a non-active dose (10mg/kg) on the activity of antidepressant agents from diverse pharmacological groups. The antidepressant-like effect was assessed by the forced swim test in mice. Ifenprodil potentiated the antidepressant-like effect of imipramine (15mg/kg) and fluoxetine (5mg/kg) while did not reduce the immobility time of animals which simultaneously received reboxetine (2.5mg/kg) or tianeptine (15mg/kg). |
Is beta-catenin involved in N-cadherin-dependent adhesion , but not in canonical Wnt signaling in E2A-PBX1-positive B acute lymphoblastic leukemia cells? | The t(1;19)(q23;13) translocation, resulting in the production of the E2A-PBX1 chimeric protein, is a common nonrandom translocation in pediatric B-lineage acute lymphoblastic leukemia (B-ALL). The E2A-PBX1 chimeric protein activates expression of several genes, including Wnt16. In the present study, we explored the role of Wnt16 and beta-catenin in t(1;19) B-ALL cells. Canonical Wnt signaling was measured by TOPflash activity. Localization of beta-catenin in the cell membrane and its involvement in leukemia-stroma interaction were studied by confocal microscopy. Adhesion to N-cadherin was analyzed by adding (3)H-thymidin-labeled cells to N-cadherin-coated wells. In contrast to previous reports, we detected no effects on cell viability or proliferation upon modulation of the Wnt16 levels. Moreover, despite high levels of Wnt16 and beta-catenin, the cells had very low levels of canonical Wnt signaling. Instead, beta-catenin was located in the cell membrane along with N-cadherin. E2A-PBX1-positive leukemia cells adhered strongly to bone marrow stroma cells, and we showed that adherence junctions stained strongly for both proteins. Moreover, knockdown of beta-catenin reduced the adhesion of E2A-PBX1-positive leukemia cells to N-cadherin, suggesting that beta-catenin and N-cadherin play a central role in homotypic cell-to-cell adhesion and in leukemia-stroma adhesion. Interestingly, knockdown of Wnt16 by small interfering RNA reduced the level of N-cadherin. | Adipose tissue of obese subjects is known to exhibit increased inflammatory activity linked to altered expression of factors involved in glucose and lipid metabolism. The surgical procedure constitutes an injury per se, evoking a systemic inflammatory response. To evaluate changes in the expression of key-genes in adipose tissue after common surgical procedures performed in obese patients. A tertiary hospital. Paired subcutaneous (SAT) and visceral (VAT) adipose tissue samples were collected at the beginning and the end of surgery in 33 obese patients that underwent laparoscopic Roux-en-Y gastric bypass (RYGB, n = 17) or laparoscopic vertical sleeve gastrectomy (SG, n = 16). The expression of genes involved in inflammation, glucose and lipid metabolism was assessed. The surgical procedure led to increased expression of interleukin 6, interleukin 8 (P<.0001 in both depots), tumor necrosis factor α (P = .001 in SAT), and lipopolysaccharide binding protein (P = .0004 in VAT). Surgery also induced concomitant decreased expression of GLUT4, IRS1 (P = .046 in VAT), and adiponectin, whereas the messenger RNA of lipogenic genes [fatty acid synthase (P = .024); sterol regulatory element binding transcription factor 1 (P = .011) and aquaporin 9 (P<.0001) in SAT; and PPARγ (P = .018) and solute carrier family 27 (fatty acid transporter), member 2 (P = .028) in VAT] increased in parallel to inflammation. Changes in gene expression during surgery were enhanced in patients following RYGB, when compared with SG. |
Does choice of xenogenic-free expansion media significantly influence the myogenic differentiation potential of human bone marrow-derived mesenchymal stromal cells? | Mesenchymal stromal cells (MSCs) have great potential for use in cell-based therapies for restoration of structure and function of many tissue types including smooth muscle. We compared proliferation, immunophenotype, differentiation capability and gene expression of bone marrow-derived MSCs expanded in different media containing human serum, plasma and platelet lysate in combination with commonly used protocols for myogenic, osteogenic, chondrogenic and adipogenic differentiation. Moreover, we developed a xenogenic-free protocol for myogenic differentiation of MSCs. Expansion of MSCs in media complemented with serum, serum + platelet lysate or plasma + platelet lysate were multipotent because they differentiated toward four mesenchymal (myogenic, osteogenic, chondrogenic, adipogenic) lineages. Addition of platelet lysate to expansion media increased the proliferation of MSCs and their expression of CD146. Incubation of MSCs in medium containing human serum or plasma plus 5% human platelet lysate in combination with smooth muscle cell (SMC)-inducing growth factors TGFβ1, PDGF and ascorbic acid induced high expression of ACTA2, TAGLN, CNN1 and/or MYH11 contractile SMC markers. Osteogenic, adipogenic and chondrogenic differentiations served as controls. | Because of the extreme genetic variability of hepatitis C virus (HCV), we analyzed whether specific HCV-genotypes are differently prone to develop resistance to linear and macrocyclic protease-inhibitors (PIs). The study includes 1568 NS3-protease sequences, isolated from PI-naive patients infected with HCV-genotypes 1a (N = 621), 1b (N = 474), 2 (N = 72), 3 (N = 268), 4 (N = 54) 5 (N = 6), and 6 (N = 73). Genetic-barrier was calculated as the sum of nucleotide-transitions (score = 1) and/or nucleotide-transversions (score = 2.5) required for drug-resistance-mutations emergence. Forty-three mutations associated with PIs-resistance were analyzed (36A/M/L/G-41R-43S/V-54A/S/V-55A-Q80K/R/L/H/G-109K-138T-155K/Q/T/I/M/S/G/L-156T/V/G/S-158I-168A/H/T/V/E/I/G/N/Y-170A/T-175L). Structural analyses on NS3-protease and on putative RNA-models have been also performed. Overall, NS3-protease was moderately conserved, with 85/181 (47.0%) amino-acids showing <1% variability. The catalytic-triad (H57-D81-S139) and 6/13 resistance-associated positions (Q41-F43-R109-R155-A156-V158) were fully conserved (variability <1%). Structural-analysis highlighted that most of the NS3-residues involved in drug-stabilization were highly conserved, while 7 PI-resistance residues, together with selected residues located in proximity of the PI-binding pocket, were highly variable among HCV-genotypes. Four resistance-mutations (80K/G-36L-175L) were found as natural polymorphisms in selected genotypes (80K present in 41.6% HCV-1a, 100% of HCV-5 and 20.6% HCV-6; 80G present in 94.4% HCV-2; 36L present in 100% HCV-3-5 and >94% HCV-2-4; 175L present in 100% HCV-1a-3-5 and >97% HCV-2-4). Furthermore, HCV-3 specifically showed non-conservative polymorphisms (R123T-D168Q) at two drug-interacting positions. Regardless of HCV-genotype, 13 PIs resistance-mutations were associated with low genetic-barrier, requiring only 1 nucleotide-substitution (41R-43S/V-54A-55A-80R-156V/T: score = 1; 54S-138T-156S/G-168E/H: score = 2.5). By contrast, by using HCV-1b as reference genotype, nucleotide-heterogeneity led to a lower genetic-barrier for the development of some drug-resistance-mutations in HCV-1a (36M-155G/I/K/M/S/T-170T), HCV-2 (36M-80K-155G/I/K/S/T-170T), HCV-3 (155G/I/K/M/S/T-170T), HCV-4-6 (155I/S/L), and HCV-5 (80G-155G/I/K/M/S/T). |
Does greater body mass independently predict less radiographic progression on X-ray and MRI over 1-2 years? | Greater body mass index (BMI) has been associated with less radiographic progression in rheumatoid arthritis (RA). We evaluated the association between BMI and joint damage progression as measured by X-ray and MRI. 1068 subjects with RA from two clinical trials of golimumab (GO-BEFORE and GO-FORWARD) had radiographs performed at weeks 0, 52 and 104 and evaluated using the van der Heijde-Sharp (vdHS) scoring system. Contrast-enhanced MRIs of the dominant wrist and hand were obtained at weeks 0, 12, 24, 52 and 104. Multivariable logistic regression evaluated the risk of radiographic progression for each BMI category (<25, 25-30, >30 kg/m(2)). Within GO-BEFORE, piecewise, robust generalised estimating equations marginal models assessed the probability of MRI erosion progression for each BMI category. Multivariable linear regression models assessed baseline associations between BMI and bone oedema (a precursor of bone erosion). Higher BMI category was associated with a lower probability of progression in vdHS score at weeks 52 and 104 independent of potential confounders. Higher BMI was also independently associated with a lower probability of progression in MRI erosion score over 2 years. Subjects with greater BMI demonstrated less bone oedema independent of differences in other disease severity measures, including MRI synovitis in the same joints. | Although previous animal studies clearly demonstrated antiarrhythmic effects of vagal stimulation during acute myocardial ischemia, highly invasive nature of vagal stimulation limited its clinical use. Recently, intravascular parasympathetic cardiac nerve stimulation (IPS) has emerged as a novel approach to the cardiac autonomic nervous system. We hypothesized that IPS might prevent ventricular arrhythmias during acute myocardial ischemia. The IPS (36 V, 10 Hz) was performed in superior vena cava using an expandable electrode-basket catheter. In 18 open-chest dogs, left anterior descending coronary artery ligation was performed without IPS (control group, n= 6), with IPS (IPS group, n= 6) and with IPS and right atrial pacing at 180/min (IPS+P group, n=6). The ECGs were monitored for 60 min. The incidence and severity of ventricular arrhythmias were analyzed. The IPS significantly decreased the frequency of premature ventricular contractions (control group: 9.1 ± 4.6/min, IPS group: 0.2 ± 0.4 /min, IPS+P group: 10.6 ± 4.2 / min; p<0.05). The frequency of ventricular tachycardia was lower in IPS group (0 ± 0 /min) than in control group (0.15 ± 0.18 /min, p<0.05) and than in IPS+P group (0.17 ± 0.12 /min, p<0.05). The incidence of ventricular fibrillation was lower in IPS group (0%) than in control group (33.3%) and than in IPS+P group (33.3%). |
Is gPRC6a required for the effects of a high-protein diet on body weight in mice? | The G-protein coupled receptor family C group 6 member A (GPRC6A) is activated by proteinogenic amino acids and may sense amino acids in the gastrointestinal tract and the brain. The study investigated whether GPRC6A was necessary for the effects of low- and high-protein diets on body weight and food intake in mice. The role of GPRC6A in mediating the effects of a low-protein diet on body weight was investigated in GPRC6a knockout (GPRC6a-KO) and wild-type (WT) mice fed a control diet (18% protein) or a low-protein diet (6% protein) for 9 days. The role of GPRC6A in mediating the effects of a high-protein diet on body weight was investigated in GPRC6a-KO and WT mice fed a control diet (18% protein) or a high-protein diet (50% protein) for 5 weeks. A high-protein diet reduced body weight gain and food intake compared with a control diet in both WT and GPRC6a-KO mice. A low-protein diet decreased body weight gain in GPRC6a-KO mice. | The biomarker suppression of tumorigenicity 2 (ST2) is a well-established clinical biomarker of cardiac strain and is frequently elevated in a variety of cardiac conditions. Here, we sought to evaluate the prognostic value of ST2 in critically ill medical intensive care unit (MICU) patients without primary cardiac illness. We measured ST2 and high-sensitivity troponin T (hsTnT) on plasma specimens collected on 441 patients following admission to a noncardiac MICU and evaluated the prognostic power of ST2 both alone and in multivariate models. Of these critically ill patients, 96% exhibited ST2 concentrations above the reference interval. ST2 concentrations were highly predictive of intensive care unit and hospital length of stay, as well as in-hospital mortality, with high concentrations predicting a poor prognosis. Rates of in-hospital mortality were more than four times higher in patients with ST2 concentrations in the highest compared with the lowest quartile. In multivariate analysis, ST2 remained an important predictor of death after adjustment for age, hsTnT, and common diagnoses. |
Do age and gender modulate the neural circuitry supporting facial emotion processing in adults with major depressive disorder? | Emotion processing, supported by frontolimbic circuitry known to be sensitive to the effects of aging, is a relatively understudied cognitive-emotional domain in geriatric depression. Some evidence suggests that the neurophysiological disruption observed in emotion processing among adults with major depressive disorder (MDD) may be modulated by both gender and age. Therefore, the present study investigated the effects of gender and age on the neural circuitry supporting emotion processing in MDD. Cross-sectional comparison of fMRI signal during performance of an emotion processing task. Outpatient university setting. One hundred adults recruited by MDD status, gender, and age. Participants underwent fMRI while completing the Facial Emotion Perception Test. They viewed photographs of faces and categorized the emotion perceived. Contrast for fMRI was of face perception minus animal identification blocks. Effects of depression were observed in precuneus and effects of age in a number of frontolimbic regions. Three-way interactions were present between MDD status, gender, and age in regions pertinent to emotion processing, including frontal, limbic, and basal ganglia. Young women with MDD and older men with MDD exhibited hyperactivation in these regions compared with their respective same-gender healthy comparison (HC) counterparts. In contrast, older women and younger men with MDD exhibited hypoactivation compared to their respective same-gender HC counterparts. | Benefits of adopting restrictive guidelines for erythrocyte transfusions are still controversial. The objective of this study was to verify if a very strict guideline could reduce erythrocyte transfusions in preterm infants without adverse outcomes. Two prospective cohorts of neonates with gestational age < 37 weeks and birth weight < 1500 g were studied. Neonates born in Period 1 were submitted to a strict guideline for erythrocyte transfusions. In Period 2, a new stricter protocol was introduced. Infants of both periods were compared regarding number of transfusions and clinical outcome. The median number of transfusions decreased from 2 (1 to 14) in Period 1 to 1 (1-9), P = 0.001, in Period 2. The linear regression multivariate analysis showed that the implementation of the stricter guideline was associated with a reduction in the number of transfusions received by patients by 0.55 (95% confidence interval: -0.08; -1.02) units/patients. Number of apnea episodes, weight at 28 days of life and days of hospital stay were similar in both periods. Intra-hospital death was lower in Period 2. |
Does dynamic contrast-enhanced MR microscopy identify regions of therapeutic response in a preclinical model of colorectal adenocarcinoma? | A typical dynamic contrast-enhanced (DCE)-MRI study often compares the derived pharmacokinetic parameters on manually selected tumor regions or over the entire tumor volume. These measurements include domains where the interpretation of the biomarkers may be unclear (such as in necrotic areas). Here, the authors describe a technique for increasing the sensitivity and specificity of DCE-MRI by identifying tumor regions with a variable response to therapy. Two cohorts (n = 8/group) of nu/nu mice with LS-174T implanted in the mammary fat pad were imaged at five time points over four weeks. The treatment/control group received bevacizumab/saline at a dose of 5 mg/kg or 5 ml/kg twice weekly; imaging experiments were performed weekly. MR images were acquired at an isotropic resolution of 156 μm(3)(2.4 nl) and with a sampling rate of 9.9 s. The histogram of the time-to-peak (TTP) was used to identify two (fast- and slow-enhancing) regions based on a threshold of TTP = 1000 s. The regions were correlated with histology, and the effect of therapy was locally examined. Tumors in the treatment group had a significantly longer doubling time. The regions defined by thresholding the TTP histogram identified two distinct domains correlating significantly with tumor permeability and microvessel density. In the fast-enhancing region, the mean permeability constant (K(trans)) was significantly lower in the treatment group at day 9; in the slow-enhancing region, K(trans) was not different between the control and treatment groups. At day 9, the relative volume of the fast-enhancing region was significantly lower in the treatment group, while that of the slow-enhancing region was significantly higher. | We performed genetic association studies using a native Japanese population to examine the reproducibility of results of lysyl oxidase-like 1 (LOXL1) genetic association studies for exfoliation glaucoma (XFG) beyond the differences of ethnicity. We also quantified LOXL1 mRNA expression in the human lens capsule to examine the possible correlation between LOXL1 expression and XFG pathogenesis. We performed a case-control study using 95 Japanese XFG patients and 190 controls. Real-time polymerase chain reaction (PCR) analysis was performed using lens capsules obtained during surgery. The TT genotype in the single nucleotide polymorphism (SNP) rs1048661 and the GG genotype in the SNP rs3825942 in exon 1 of LOXL1 were significantly associated with an increased risk of XFG under recessive models (chi(2) test, p=5.34 x 10(-34) and p=2.1 x 10(-8), respectively). Quantification of LOXL1 mRNA expression demonstrated no significant difference between XFG and senile cataract samples. |
Does n-acetylcysteine-induced vasodilation involve voltage-gated potassium channels in rat aorta? | N-acetylcysteine (NAC) has a protective effect against vascular dysfunction by decreasing the level of reactive oxygen species (ROS) in experimental and human hypertension. This study was designed to examine whether NAC would relax vascular rings in vitro via nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway, extracellular Ca2+ and/or K+ channels. Rat aortic arteries were mounted in an organ bath, contracted with 0.1, 0.5 or 1 micromol/L phenylephrine to plateau, and the vasodilatory effect of NAC was examined in the absence or presence of ROS scavengers, inhibitors of NO-cGMP pathway or K+ channels. Vascular smooth muscle cells (VSMCs) were loaded with a calcium sensitive fluorescent dye fluo-3 AM, and [Ca2+](i) was determined with laser-scanning confocal microscopy. NAC (0.1-4 mmol/L) dose-dependently relaxed rat aorta pre-contracted with phenylephrine. Endothelium removal, endothelial nitric oxide synthase inhibitor N(omega)-Nitro-l-arginine (L-NNA) (100 micromol/L) or soluble guanylyl cyclase (sGC) inhibitor (ODQ) (10 micromol/L) did not affect NAC-induced vasodilation. In contrast, NAC-induced vasodilation was blunted after extracellular calcium was removed and calcium imaging showed that 4 mmol/L NAC quickly decreased [Ca2+](i) in fluo-3 AM loaded VSMCs. NAC-induced vasodilation was significantly reduced in the presence of voltage-gated K+ channels (Kv) inhibitor 4-aminopyridine (4-AP). | Association of increased levels of CD4(+)CD25(+) regulatory T cells (Tregs) with impaired immune response and hepatitis B infection progression has been proposed. For determination of Tregs various effects among hepatitis B infected patients we performed a meta-analysis of the available literature. Current content, abstract books of congresses, and electronic databases were searched. Critical appraisal has been done. According to the result of heterogeneity tests (Q, I-squared, and Tau-squared), we used fix/random model for analysis. Twelve studies that fulfilled inclusion criteria entered to analysis. Pooled estimation of reported results showed that CD4(+)CD25(+) Tregs have higher expression of forkhead box P3 (FoxP3) versus CD4(+)CD25(-) Tregs, odd ratio (OR) was 31.49 (95% Confidence Intervals (CI): 5.09-194.94). Tregs level among chronic hepatitis B (CHB) patients was 77% (OR=1.77 95% CI: 1.43-2.19) higher than healthy controls. Patients with more than 10,000,000 HBV copies/ml have higher level of Tregs (OR: 1.24 95% CI: 1.08-1.41) comparing subjects with less than that. CHB patients have increased level of Tregs versus acute hepatitis B patients (OR=1.33 95% CI: 1.16-1.52). CD8 cells activity increased significantly after depletion of circulating Tregs (OR=1.93 CI: 1.37-2.73). Also, Tregs reduce response to treatment and non-responders to INF-α had higher level of Tregs (OR=1.60 95% CI: 1.09-2.36). In addition, Tregs increase risk of hepatocellular carcinoma (HCC) (OR=1.36 95%CI: 1.10-1.69). |
Are plasma metastin levels negatively correlated with insulin resistance and free androgens in women with polycystic ovary syndrome? | This study was designed to: [1] measure, for the first time, metastin (kisspeptin) levels in women with polycystic ovary syndrome (PCOS), a condition associated with hypersecretion of LH and hyperandrogenemia; and [2] investigate the possible correlations between metastin and PCOS-related reproductive and metabolic disturbances. Clinical study. University hospital. Twenty-eight obese and overweight (body mass index [BMI] >25 kg/m2) women with PCOS, 28 normal weight (BMI <25 kg/m2) women with the syndrome, and 13 obese and overweight controls (ovulatory women without clinical or biochemical hyperandrogenemia) were selected. Blood samples were collected between day 3 and day 6 of a spontaneous bleeding episode in the PCOS groups and a menstrual cycle of the controls, at 9:00 AM, after an overnight fast. Circulating levels of LH, FSH, PRL, T, Delta4-androstenedione (A), DHEAS, 17alpha-OH-P, sex hormone-binding globulin (SHBG), insulin, glucose, and metastin were measured. Both normal weight women with PCOS and obese controls were less insulin resistant and had significantly higher metastin levels, compared to obese and overweight women with the syndrome. Plasma kisspeptin levels were negatively correlated with BMI, free androgen index, and indices of insulin resistance. | It is known that noxious stimuli from inflamed tissue may increase the excitability of spinal dorsal horn neurons (a process known as central sensitization), which can signal back and contribute to peripheral inflammation. However, the underlying mechanisms have yet to be fully defined. A number of recent studies have indicated that spinal NF-κB/p65 is involved in central sensitization, as well as pain-related behavior. Thus, the aim of this study was to determine whether NF-κB/p65 can facilitate a peripheral inflammatory response in rat adjuvant-induced arthritis (AIA). Lentiviral vectors encoding short hairpin RNAs that target NF-κB/p65 (LV-shNF-κB/p65) were constructed for gene silencing. The spines of rats with AIA were injected with LV-shNF-κB/p65 on day 3 or day 10 after treatment with Freund's complete adjuvant (CFA). During an observation period of 20 days, pain-related behavior, paw swelling, and joint histopathologic changes were evaluated. Moreover, the expression levels of spinal tumor necrosis factor α (TNFα), interleukin-1β (IL-1β), and cyclooxygenase 2 (COX-2) were assessed on day 14 after CFA treatment. The presence of peripheral inflammation in rats with AIA induced an increase in NF-κB/p65 expression in the spinal cord, mainly in the dorsal horn neurons and astrocytes. Delivery of LV-shNF-κB/p65 to the spinal cord knocked down the expression of NF-κB/p65 and significantly attenuated hyperalgesia, paw edema, and joint destruction. In addition, spinal delivery of LV-shNF-κB/p65 reduced the overexpression of spinal TNFα, IL-1β, and COX-2. |
Is bRAF mutation status an independent prognostic factor for resected stage IIIB and IIIC melanoma : implications for melanoma staging and adjuvant therapy? | 5-year survival for melanoma metastasis to regional lymph nodes (American Joint Committee on Cancer stage III) is <50%. Knowledge of outcomes following therapeutic lymphadenectomy for stage III melanoma related to BRAF status may guide adjuvant use of BRAF/MEK inhibitors along with established and future therapies. To determine patterns of melanoma recurrence and survival following therapeutic lymph node dissection (TLND) associated with oncogenic mutations. DNA was obtained from patients who underwent TLND and had ⩾2 positive nodes, largest node >3cm or extracapsular invasion. Mutations were detected using an extended Sequenom MelaCARTA panel. Mutations were most commonly detected in BRAF (57/124 [46%] patients) and NRAS (26/124 [21%] patients). Patients with BRAF mutations had higher 3-year recurrence rate (77%) versus 54% for BRAF wild-type patients (hazard ratio (HR) 1.8, p=0.008). The only prognostically significant mutations occurred in BRAF: median recurrence-free (RFS) and disease-specific survival (DSS) for BRAF mutation patients was 7 months and 16 months, versus 19 months and not reached for BRAF wild-type patients, respectively. Multivariate analysis identified BRAF mutant status and number of positive lymph nodes as the only independent prognostic factors for RFS and DSS. | Footwear characteristics have been shown to influence balance in older people; however, the relationship between footwear and falls is unclear. To determine the relationships between footwear characteristics and the risk of indoor and outdoor falls in older people. Footwear characteristics (shoe type, heel height, heel counter height, heel width, critical tipping angle, method of fixation, heel counter stiffness, sole rigidity and flexion point, tread pattern and sole hardness) were assessed in 176 people (56 men and 120 women) aged 62-96 (mean age 80.1, SD 6.4) residing in a retirement village. Falls were recorded over a 12-month follow-up period and comparisons made between fallers and non-fallers. 50 participants (29%) fell indoors and 36 (21%) fell outdoors. After controlling for age, gender, demographic characteristics, medication use, physiological falls risk factors and foot problems, those who fell indoors were more likely to go barefoot or wear socks inside the home (OR = 13.74; 95% CI 3.88-48.61, p < 0.01). However, there were no significant differences in indoor or outdoor footwear characteristics between fallers and non-fallers. Five indoor fallers (10%) and three outdoor fallers (8%) stated that their shoes contributed to their fall. |
Does mitral annular calcification predict mortality and coronary artery disease in end stage renal disease? | We sought to determine whether mitral annular calcification (MAC) predicts mortality and cardiac disease in a group of renal transplant candidates. Hundred and forty patients were prospectively studied. All had echocardiography and coronary angiography. Significant coronary artery disease (CAD) was defined as luminal stenosis >70% by visual estimation in at least one coronary artery. There were 21 deaths over a follow-up period of 2.2+/-0.7 years. MAC occurred in 56 patients (40%) and was associated with higher mortality (p=0.04). Patients with MAC were older (p=or<0.001), had larger left ventricular (LV) end systolic (p=0.005) and LV end diastolic (p=0.04) diameter, larger left atrial diameter (p=0.001), lower LV fractional shortening (p=0.003), larger LV mass index (p=0.04) and higher mitral E/Ea ratio (p=0.03) compared to those without. Plasma calcium (p=0.002), phosphate (p=0.004), cardiac troponin T (p=0.03), N-terminal Pro-B-type natriuretic peptide (p=0.004) concentrations were higher in those with MAC but gender, total cholesterol, haemoglobin and creatinine were similar in the two groups. The proportion diabetic (p=0.03), on dialysis (p=0.05), with significant CAD (p=or<0.001), taking calcium containing phosphate binders (p=0.02) and Vitamin D3 (p=0.04) was significantly higher in those with MAC. Significant CAD (OR 12, 95% CI 3.25, p=0.001) was the only independent associate of MAC. | Substance P (SP), neurokinin-1 receptors (NK-1Rs) are expressed in mesenteric preadipocytes and SP binding activates proinflammatory signalling in these cells. We evaluated the expression levels of SP (Tac-1), NK-1R (Tacr-1), and NK-2R (Tacr-2) mRNA in preadipocytes isolated from patients with Inflammatory Bowel Disease (IBD) and examined their responsiveness to SP compared to control human mesenteric preadipocytes. The Aim of our study is to investigate the effects of the neuropeptide SP on cytokine expression in preadipocytes of IBD vs control patients and evaluate the potential effects of these cells on IBD pathophysiology via SP-NK-R interactions. Mesenteric fat was collected from control, Ulcerative colitis (UC) and Crohn's disease (CD) patients (n=10-11 per group). Preadipocytes were isolated, expanded in culture and exposed to substance P. Colon biopsies were obtained from control and IBD patients. Tacr-1 and -2 mRNA were increased in IBD preadipocytes compared to controls, while Tac-1 mRNA was increased only in UC preadipocytes. SP differentially regulated the expression of inflammatory mediators in IBD preadipocytes compared to controls. Disease-dependent responses to SP were also observed between UC and CD preadipocytes. IL-17A mRNA expression and release increased after SP treatment in both CD and UC preadipocytes, while IL-17RA mRNA increased in colon biopsies from IBD patients. |
Does antisense inhibition of Entamoeba histolytica cysteine proteases inhibit colonic mucus degradation? | The exact role Entamoeba histolytica cysteine proteases play in overcoming the colonic mucus barrier, as a prerequisite to epithelial cell disruption, is not known. Herein, we determined whether E histolytica trophozoites expressing the antisense transcript to cysteine protease 5 (EhCP5) could degrade colonic mucin and destroy epithelial cells. Cysteine protease-deficient amoebae were generated by antisense inhibition of EhCP5, and assayed for proteolytic activity against [(35)S]cysteine-labeled mucin from LS 174T, and HT-29F Cl.16E cells. Recombinant EhCP5 mucinase activity was also assessed. Disruption of an intact mucus barrier and epithelial cell invasion by amoebae were measured using high mucin producing LS 174T and HT-29 Cl.16E monolayers or Chinese hamster ovary (CHO) cells devoid of a mucus barrier. Trophozoites with reduced cysteine protease activity were ineffective at degrading [(35)S]cysteine-labeled colonic mucin compared to wild-type amoebae by >60%. However, bioactive recombinant EhCP5 degraded >45% of purified native mucin, which was specifically inhibited by the cysteine proteinase (CP) inhibitor, E-64. Cysteine protease-deficient trophozoites could not overcome a protective intact mucus barrier and disrupt LS 174T or HT-29F Cl.16 cell monolayers; however, they readily adhere to and disrupt CHO monolayers devoid of a mucus barrier. | The aim of this study was to investigate whether renal sympathetic denervation (RSD) improves ventricular heart rate (HR) control in patients with persistent atrial fibrillation (AF). Twenty-one patients (aged 57.5 ± 10.2 years, 76.2% male) with persistent AF and hypertension underwent RSD and completed 7-days follow-up evaluations, including 24-hour Holter monitoring (Holter), blood pressure (BP), 24-hour ambulatory BP monitoring (ABPM). Patients were grouped into tertiles of average HR at baseline Holter recording for evaluation of RSD effects on atrioventricular (AV) node (group 1: HR ≧ 90 bpm; group 2: 80 bpm ≦ HR < 90 bpm; group 3: HR < 80 bpm). All patients successfully underwent RSD without any complications. The clinical and procedural characteristics were similar in all groups of patients. No significant changes in BP were observed in the three groups before and after RSD. Compared with baseline, the average HR (Holter) of patients in group 1, 2 and 3 had a reduction of 22.6 ± 13.2 bpm (83.3 ± 4.9 vs 106.0 ± 14.6, P = 0.004), 9.7 ± 7.8 bpm (75.7 ± 7.6 vs 85.4 ± 3.7, P = 0.017) and 2.3 ± 2.9 bpm (71.4 ± 4.0 vs 73.7 ± 4.7, P = 0.089) at 7 days after RSD, respectively. |
Does catechol-O-methyltransferase valine ( 158 ) methionine polymorphism modulate brain networks underlying working memory across adulthood? | Cognitive abilities decline with age with large individual variability. Genetic variations have been suggested to be an important source for some of this heterogeneity. Among these variations, those related to the dopaminergic system, particularly the valine(158)methionine polymorphism in catechol-O-methyltransferase (COMTval(158)met), have been implicated in modulating age-related changes in executive function. We studied 75 subjects (age 21-90 years) using functional neuroimaging while they performed a low-level working memory (WM) task to explore the effects of aging, of the COMTval(158)met polymorphism, and their interactions on the physiological patterns of interconnected cortical activity engaged by WM. Our results show that val homozygotes and older subjects showed increased activity in dorsolateral prefrontal cortex (DLPFC) and decreased activity in ventrolateral prefrontal cortex (VLPFC) relative to met homozygotes and younger subjects, respectively. Interestingly, there were also independent effects of the COMTval(158)met polymorphism and age on the strength of connectivity between brain regions within the left prefrontal-parietal network; val homozygotes and older subjects showed greater connectivity between the DLPFC and other brain regions within the network and met homozygotes showed greater connectivity between the VLPFC and other brain regions within the network. Furthermore, the greater functional connectivity strength of DLPFC in val homozygotes relative to met homozygotes was much more pronounced in older adults | Topical haemostatic agents are used to help achieve haemostasis during surgery when standard surgical techniques are insufficient. The objective of this study was to confirm the safety profile of an equine collagen patch coated with human fibrinogen and human thrombin with particular focus on the occurrence of thromboembolic events (TEEs), major bleeding and immunological events. This was a non-interventional, multicentre, prospective, surveillance study in which a collagen fleece-bound fibrin sealant was prescribed in accordance with its marketing authorisation. The decision to use the sealant was based solely on current surgical practice. All patients that received the sealant and provided informed consent were included. TEEs (any coagula-based occlusion in a vessel or the heart identified by symptomatic clinical signs and/or verified by paraclinical examination), major bleeding (any bleeding that required intervention), and immunological events (hypersensitivity including anaphylaxis) that occurred during surgery, post-operative hospital stay or 6 months of follow-up were reported as adverse events. The primary endpoint was the proportion of patients experiencing a confirmed TEE. A total of 3098 patients were recruited at 227 centres in 12 European countries. The most frequent types of surgery were hepatic (33%), gastrointestinal (16%) and urological (14%) and the main indication for surgery was for primary (35%) or secondary (20%) malignancy. Forty-six patients (1.5%, 95% CI 1.1-2.0%) had at least one TEE during the study. The most commonly reported TEEs were pulmonary embolism or post-procedural pulmonary embolism (n = 18) and deep vein thrombosis (n = 9). There were 64 major bleedings in 62 patients and 9 immunological events in 8 patients. |
Does peplomycin induce G1-phase specific apoptosis in liver carcinoma cell line Bel-7402 involving G2-phase arrest? | To investigate the mechanism of peplomycin (PEP)-induced apoptosis in liver carcinoma cell line (Bel-7402). Growth inhibition by PEP was analyzed using 3- 4,5-Dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptotic cells were detected using Hoechest 33258 staining, and confirmed by flow cytometric analysis and DNA fragmentation analysis. The expression of cyclin A and B1 were determined by flow cytometry and Western blot. Annexin V assay was measured by flow cytometric analysis. PEP induced apoptosis and then inhibited cell proliferation in liver carcinoma cell line Bel-7402. Cells treated with PEP 50 mumol/L for 15 h were arrested in G2-phase with dramatical expression of cyclin A and a little change in cyclin B1. Almost all the apoptosis occurred in cells undergoing the G1-phase after treatment for 24 h. | The aim of this study was to evaluate the associations between vasomotor symptoms ([VMS] hot flushes or flashes and night sweats) and markers of cardiovascular risk. Healthy postmenopausal women in a randomized controlled trial of progesterone for VMS recorded VMS frequency in the Daily Menopause Diary for 28 days at baseline. Accepted risks for cardiovascular disease were measured: body mass index (BMI), waist circumference (WC), waist-to-height ratio (WHtR), blood pressure (BP), endothelial function by venous occlusion plethysmography, fasting lipids, glucose, high-sensitivity C-reactive protein, albumin, and D-dimer. Relationships between risk variables and VMS frequency (24 h, day and night) were assessed by univariate and multivariate robust regressions with adjustment for age and WHtR. Data were available for 145 healthy, nonsmoking women without heart disease, hypertension, or diabetes who were 1 to 11 years past their final menstruation and were aged 43 to 65 years, with a mean (SD) BMI of 25.0 (2.9) kg/m and WC of 79.1 (7.1) cm. Anthropometric variables (BMI, WC, and WHtR) were significantly negatively associated with total (24-h day) VMS frequency and with day VMS but not with night VMS frequency. Systolic BP decreased with greater 24-hour VMS frequency, and both systolic and diastolic BPs were inversely related to day but not night VMS frequency. Albumin was positively associated with night VMS frequency but not with day or 24-hour VMS frequency. Other variables showed little association with VMS frequency. |
Does azithromycin cure pityriasis rosea? | Pityriasis rosea (PR) is a common skin disorder in children. Its cause is unknown. A recent publication reported a 73% cure rate in patients with PR after treatment with erythromycin. To duplicate this result using a drug with fewer adverse effects and greater biological half-life, we set out to study the effect of azithromycin on PR. Azithromycin is an azalide antibiotic with a spectrum of antimicrobial activity very similar to that of erythromycin. We randomly assigned 49 children with PR to receive either azithromycin (12 mg/kg per day, up to a maximum of 500 mg/day) for 5 days or a similar-appearing placebo. Study physicians were blinded to patients' treatment type. Two pediatricians had to agree on the diagnosis of PR before patients could be enrolled. Subjects were seen at follow-up visits 1, 2, and 4 weeks after starting treatment. We measured the appearance of new lesions and resolution of lesions. Rates of cure and of partial resolution were similar in the azithromycin and placebo groups. | Relations of the 25 mammalian selenoprotein genes with obesity and the associated inflammation remain unclear. This study explored impacts of high-fat diet-induced obesity on inflammation and expressions of selenoprotein and obesity-related genes in 10 tissues of pigs. Plasma and 10 tissues were collected from pigs (n = 10) fed a corn-soy-based control diet or that diet containing 3-7% lard from weanling to finishing (180 d). Plasma concentrations (n = 8) of cytokines and thyroid hormones and tissue mRNA abundance (n = 4) of 25 selenoprotein genes and 16 obesity-related genes were compared between the pigs fed the control and high-fat diets. Stepwise regression was applied to analyze correlations among all these measures, including the previously reported body physical and plasma biochemical variables. The high-fat diet elevated (P < 0.05) plasma concentrations of tumor necrosis factor α, interleukin-6, leptin, and leptin receptor by 29-42% and affected (P < 0.05-0.1) tissue mRNA levels of the selenoprotein and obesity-related genes in 3 patterns. Specifically, the high-fat diet up-regulated 12 selenoprotein genes in 6 tissues, down-regulated 13 selenoprotein genes in 7 tissues, and exerted no effect on 5 genes in any tissue. Body weights and plasma triglyceride concentrations of pigs showed the strongest regressions to tissue mRNA abundances of selenoprotein and obesity-related genes. Among the selenoprotein genes, selenoprotein V and I were ranked as the strongest independent variables for the regression of phenotypic and plasma measures. Meanwhile, agouti signaling protein, adiponectin, and resistin genes represented the strongest independent variables of the obesity-related genes for the regression of tissue selenoprotein mRNA. |
Is reduced CD151 expression related to advanced tumour stage in urothelial bladder cancer? | CD151 belongs to the group of tetraspanins and is aberrantly expressed in different tumours and differential expression has been associated with prognosis. The aim of this study was to clarify the relationship of CD151 expression with tumour phenotype and clinical outcome in bladder cancer. A bladder cancer tissue microarray containing samples from 686 urothelial bladder cancers was analysed by immunohistochemistry. Membranous CD151 immunostaining was recorded in 409 (66.0%) of 620 analysable cases. High CD151 expression was seen in normal urothelium and in most non-invasive tumours. Low CD151 expression levels were associated with a more unfavourable tumour phenotype. CD151 staining was seen in 71.5% of 284 pTa, 62.1% of 145 pT1 and 60.4% of 187 pT2-4 cancers (p = 0.0033). CD151 staining was detectable in 77.3% of 75 grade 1, 71.1% of 273 grade 2 and 57.7% of 272 grade 3 cancers (p < 0.0001). CD151 expression status was not associated with overall or tumour-specific survival in muscle-invasive cancers (pT2-4), tumour progression in pT1 and recurrences in pTa tumours. | The effects of prenatal cigarette smoke (CS) exposure and hypoxemia on cardiorespiratory control have been investigated in full-term infants. However, few data are available in preterm infants, who form a particularly vulnerable population, with developmentally immature cardiorespiratory control. To investigate the effects of prenatal CS exposure on the duration and recovery of breathing pauses and oxygen saturation levels under baseline and hypoxemic conditions in preterm infants. The study was performed on 22 (12 born to smoking and 10 to nonsmoking mothers) spontaneously breathing preterm infants between 28 and 36 weeks' gestation. Cardiorespiratory variables were recorded under baseline normoxemic and hypoxemic conditions. Breathing pauses, pause indices, time to recovery, percent pause recovery, oxygen saturation (Sp(O2)), periods of wakefulness, and cardiorespiratory rates were compared between the two groups. Spontaneous recovery of breathing pauses (P = 0.03) and Sp(O(2)) levels (P = 0.017) were attenuated in CS-exposed infants as compared with the control group during the hypoxemic and posthypoxemic periods, respectively. The episodes of wakefulness during the hypoxemic challenge were similar between the two groups. Furthermore, CS-exposed infants showed a greater increase in heart rate (P < 0.001) during the hypoxemic challenge when compared with control infants. |
Does hematuria duration predict kidney function at 1 year in ANCA-associated glomerulonephritis? | Hematuria is considered a marker of active renal disease in ANCA-associated glomerulonephritis (ANCA-GN) with induction immunosuppression often continued until hematuria has resolved. We aim to determine whether longer hematuria duration is associated with lower estimated glomerular filtration rate (eGFR) at 1 year. We conducted a retrospective study of 55 patients with biopsy-proven ANCA-GN. Linear regression models were constructed to determine predictors of eGFR at 1 year. The primary exposure was hematuria (>5 rbc/hpf) duration, defined as <90 days vs. ≥ 90 days following renal biopsy. Covariates included age, gender, ANCA type, baseline eGFR, and baseline proteinuria. Mean age at diagnosis was 58 years (53% male, 80% Caucasian, 38% PR3-ANCA, and 45% MPO-ANCA). At baseline, all patients had hematuria, 95% had proteinuria, and mean serum creatinine was 3.1 [standard deviation (SD) = 2.3]mg/dL. Overall, 93% were treated with steroids in combination with either cyclophosphamide or rituximab. Mean hematuria duration was 92 (SD = 77) days with 34 (62%) patients having hematuria resolution within 90 days. Older age and lower baseline eGFR were associated with lower eGFR at 1 year (p = 0.03 and p < 0.001, respectively). Hematuria resolution (<90 days vs. ≥ 90 days) was not predictive of eGFR at 1 year (p = 0.93). | Tachygastria is known to be associated with gastric hypomotility. This study investigated the effect of tachygastrial electrical stimulation (TES) on food intake and its effects on gastric motility. Five experiments were performed to study the effects of TES on gastric slow waves, gastric tone, accommodation, and antral contractions, gastric emptying, acute food intake, and chronic food intake in dogs. TES at tachygastrial frequencies induced tachygastria and reduced normal slow waves. TES significantly reduced gastric tone or induced gastric distention, impaired gastric accommodation, and inhibited antral contractions. TES significantly delayed gastric emptying. Acute TES reduced food intake but did not induce any noticeable symptoms. Chronic TES resulted in a 20% reduction in food intake, and the effect of TES was found to be related to specific parameters. |
Does static stretch induce active morphological remodeling and functional impairment of alveolar epithelial cells? | Static stretch is frequently observed in the lung. Both static stretch and cyclic stretch can induce cell death and Na(+)/K(+)-ATPase trafficking, but stretch-induced alveolar epithelial cell (AEC) functions are much less responsive to static than to cyclic stretch. AEC remodeling under static stretch may be partly explained. The aim of this study was to explore the AEC remodeling and functional changes under static stretch conditions. We used A549 cells as a model of AEC type II cells. We assessed F-actin content and cell viability by fluorescence staining at various static-stretch magnitudes and time points. Specifically, we used scanning electron microscopy to explore the possible biological mechanisms used by A549 cells to 'escape' static-stretch-induced injury. Finally, we measured choline cytidylyltransferase-alpha (CCT alpha) mRNA and protein by real-time PCR and Western blot to evaluate cellular secretory function. The results showed that the magnitude of static stretch was the primary determinant of static-stretch-induced cell death and cytoskeleton organization, but an extended duration of high static deformation/stretch (37% change in surface area) had no cumulative effects on cell death and cytoskeleton organization. AEC remodeling (expansion-contraction-reexpansion) under static stretch conditions may explain this interesting phenomenon partly. After cell remodeling, CCT alpha expression in A549 cells was influenced not only by stretch magnitude but also by stretch time. | To investigate the relationship between gestational diabetes mellitus (GDM) and the usual intake of fatty acids and indices of dietary fat quality [the atherogenicity (AI) and thrombogenicity indices (TI), and the ratios of hypo-and hypercholesterolemic (hH), ∑n-3/∑n-6, and polyunsaturated/saturated fatty acids (P:S)], during mid-pregnancy. 799 adult pregnant women living in Ribeirão Preto, SP, Brazil were screened and accepted for this cross-sectional GDM study. The Multiple Source Method was used to estimate participants' usual diet, using two 24-hour dietary recalls during mid-pregnancy. Diagnosis of GDM was defined by the American Diabetes Association criteria of 2015. Logistic regression analysis were used to assess the association between GDM and dietary fat, adjusted for age, education, parity, gestational age at the time of the interview, pre-pregnancy and current BMI, prior GDM, family history of diabetes, smoking, physical activity, energy, fiber, and fatty acids. The mean (standard deviation) age of the women was 28 (5) years, and 19% had GDM. After multiple adjustments, inverse associations between the highest tertile of ∑n-3 fatty acids intake [0.21 (0.08-0.56)], α-linolenic intake [0.15 (0.05-0.42)], and GDM were found. A positive association between GDM and the highest tertile of TI [2.66 (1.34-5.29)], and a negative association with the highest tertile of hH ratio [0.41 (0.22-0.77)], were observed. No association between GDM and other indices of dietary fat quality were found. |
Is inflammation the cause of an elevated serum ferritin in non-alcoholic fatty liver disease? | In non-alcoholic fatty liver disease (NALFD), it has often been assumed that an elevation in serum ferritin is likely related to inflammation rather than iron overload. Patients referred with NAFLD were entered into a clinical study of phlebotomy therapy. A liver biopsy with liver iron concentration was done at entry and 6 months after phlebotomy (n = 56) until the patient had a low serum ferritin or developed anemia. Serum ferritin was compared to liver iron concentration, ESR, CRP, BMI and grade of inflammation on liver biopsy. Iron removed by phlebotomy in NAFLD correlated with the decrease in serum ferritin (r = 0.57, p = 0.0014) and liver iron concentration (r = 0.57, p = 0.0013). There was no significant correlations between serum ferritin and ESR, CRP or grade of liver inflammation. | Pandemic strains of HIV-1 (group M) encode a total of nine structural (gag, pol, env), regulatory (rev, tat) and accessory (vif, vpr, vpu, nef) genes. However, some subtype A and C viruses exhibit an unusual gene arrangement in which the first exon of rev (rev1) and the vpu gene are placed in the same open reading frame. Although this rev1-vpu gene fusion is present in a considerable fraction of HIV-1 strains, its functional significance is unknown. Examining infectious molecular clones (IMCs) of HIV-1 that encode the rev1-vpu polymorphism, we show that a fusion protein is expressed in infected cells. Due to the splicing pattern of viral mRNA, however, these same IMCs also express a regular Vpu protein, which is produced at much higher levels. To investigate the function of the fusion gene, we characterized isogenic IMC pairs differing only in their ability to express a Rev1-Vpu protein. Analysis in transfected HEK293T and infected CD4+ T cells showed that all of these viruses were equally active in known Vpu functions, such as down-modulation of CD4 or counteraction of tetherin. Furthermore, the polymorphism did not affect Vpu-mediated inhibition of NF-кB activation or Rev-dependent nuclear export of incompletely spliced viral mRNAs. There was also no evidence for enhanced replication of Rev1-Vpu expressing viruses in primary PBMCs or ex vivo infected human lymphoid tissues. Finally, the frequency of HIV-1 quasispecies members that encoded a rev1-vpu fusion gene did not change in HIV-1 infected individuals over time. |
Does type of preexisting lipid therapy predict LDL-C response to ezetimibe? | Ezetimibe as monotherapy or in combination with statins effectively lowers low-density lipoprotein cholesterol (LDL-C). However, there are few reports of ezetimibe's effect when added to ongoing non-statin lipid-lowering drugs or combination lipid-lowering therapy. To evaluate the impact of preexisting lipid therapy on LDL-C response to ezetimibe. We performed a retrospective review of all patients started on ezetimibe therapy at the Veterans Affairs Long Beach Healthcare System between March 1, 2003, and March 1, 2005. We calculated the ezetimibe-induced percent change in LDL-C in patients without concomitant changes in other lipid-lowering medications. We then stratified the population according to the type and number of preexisting lipid therapies and compared the LDL-C-lowering efficacy of ezetimibe among these groups. Overall, ezetimibe was associated with a 23.0% reduction in LDL-C. Patients with preexisting statin monotherapy had significantly greater LDL-C reduction with ezetimibe than did those with preexisting non-statin drugs (-26.1% vs -9.3%; p = 0.0138). In patients with no preexisting lipid therapy (n = 58), monotherapy (n = 115), double therapy (n = 36), or triple therapy (n = 9), ezetimibe decreased LDL-C by 17.3%, 21.4%, 33.5%, and 38.1%, respectively. This stepwise trend in increased ezetimibe efficacy was statistically significant, even with adjustments for baseline LDL-C. | To determine whether burn-induced peroxynitrite production and expression of lung inducible nitric oxide synthase (iNOS), intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, CXCR2, macrophage inflammatory protein (MIP)-2, and neutrophil chemokine (KC) are mediated by the c-Jun NH2-terminal kinase (JNK). Prospective, experimental study. Research laboratory at a university hospital. Thermal injury models in the mice. In experiment 1, specific pathogen-free C57/BL6 mice were subjected to 30% total body surface area third-degree burn over shaved back. At 0 hr, 2 hrs, 4 hrs, and 6 hrs after burn, lung tissues of those mice were harvested for JNK activity assay, AP-1 DNA-binding activity, and pJNK immunohistochemistry. In experiment 2, a specific JNK inhibitor, SP600125, was given (30 mg/kg intraperitoneally) to mice immediately postburn to suppress the JNK activity. At 8 hrs after burn, blood was assayed for the peroxynitrite-mediated dihydrorhodamine (DHR) 123 oxidation. Lung tissues were harvested for myeloperoxidase (MPO) determination, ICAM-1, VCAM-1, CXCR2, KC, MIP-2, interleukin-1beta, and interleukin-6 messenger RNA expression; iNOS immunohistochemical staining; and histologic studies. Pulmonary microvascular dysfunction was quantified by measuring the extravasations of Evans blue dye. The JNK activity and AP-1 DNA-binding activity of lung tissue significantly increased to a peak at 2 hrs and 4 hrs, respectively, after thermal injury. Immunohistochemical study demonstrated that the increase of the pJNK was mostly from the bronchiole epithelial cells. This increase of MPO activity in lung, blood DHR 123 oxidation level, and lung permeability increased six-fold, nine-fold, and four-fold after burn. SP600125 administration obliterated the thermal injury-induced JNK activity, AP-1 DNA-binding activity, and iNOS expression in lung tissue. SP600125 treatment also significantly decreased MPO activity, blood DHR 123 oxidation, and lung permeability by 54%, 8%, and 47%, respectively, and markedly decreased the thermal injury-induced perivascular and interstitial inflammatory cell infiltration and septum edema. Furthermore, SP600125 abolished thermal injury-induced ICAM-1, VCAM-1, CXCR2, MIP-2, and KC but not interleukin-1beta and interleukin-6 messenger RNA levels of lung tissues. |
Do microenvironmental effects limit efficacy of thymoquinone treatment in a mouse model of ovarian cancer? | Ovarian cancer is the most lethal gynecologic malignancy, with limited treatment options for chemoresistant disease. An important link between inflammation and peritoneal spread of ovarian cancer is NF-κB signaling. Thymoquinone (TQ) exerts multiple anti-tumorigenic cellular effects, including NF-κB inhibition. We aimed to investigate the therapeutic potential of TQ in an established murine syngeneic model of ovarian cancer. ID8-NGL mouse ovarian cancer cells stably expressing an NF-κB reporter transgene were injected intra-peritoneally into C57BL/6 mice, and mice were treated with TQ or vehicle for 10 or 30 days. TQ was combined with the macrophage depleting drug, liposomal clodronate, in selected experiments. Effects on peritoneal tumor burden were measured by volume of ascites, number of peritoneal implants and mesenteric tumor mass. NF-κB reporter activity and markers of proliferation and apoptosis were measured in tumors and in confirmatory in vitro experiments. Protein or mRNA expression of M1 (anti-tumor) and M2 (pro-tumor) macrophage markers, and soluble cytokine profiles, were examined from harvested ascites fluid, peritoneal lavages and/or tumor sections. 2-tailed Mann-Whitney tests were used for measuring differences between groups in in vivo experiments. Consistent with its effects in vitro, TQ reduced proliferation and increased apoptosis in ID8-NGL tumors after 10 and 30 day treatment. Prolonged TQ treatment did not significantly alter tumor number or mass compared to vehicle, but rather exerted an overall deleterious effect by stimulating ascites formation. Increased ascites was accompanied by elevated NF-κB activity in tumors and macrophages, increased pro-tumor M2 macrophages and expression of pro-tumorigenic soluble factors such as VEGF in ascites fluid, and increased tumor infiltration of M2 macrophages. In contrast, a 10 day exposure to TQ produced no ascites, and reduced tumor NF-κB activity, M2 macrophages and soluble VEGF levels. Peritoneal macrophage depletion by clodronate significantly reduced tumor burden. However, TQ-stimulated ascites was further enhanced by co-treatment with clodronate, with macrophages present overwhelmingly of the M2 phenotype. | Anxiety and depression frequently co-occur in the elderly and in patients with dementia. Prior research has shown that depression is related to the risk of dementia, but the effect of anxiety on dementia remains unclear. We studied whether anxiety symptoms and anxiety disorders are associated with the risk of dementia and cognition. We studied 2,708 nondemented participants from the prospective, population-based Rotterdam Study who underwent the Hospital Anxiety and Depression Scale (HADS) (sample I, baseline 1993-1995) and 3,069 nondemented participants who underwent screening for anxiety disorders (sample II, baseline 2002-2004). In 1993-1995, anxiety symptoms were assessed using the HADS. In 2002-2004, anxiety disorders were assessed using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. In both study samples, participants were continuously monitored for dementia until January 1, 2011. Cognition was tested in 2002-2004 and at a follow-up visit in 2009-2011 in sample II only. In sample I, 358 persons developed dementia, and in sample II, 248 persons developed dementia. We did not find an association with the risk of dementia for anxiety symptoms (hazard ratio 1.05, 95% confidence interval: 0.77-1.43, Wald statistic 0.08, p = 0.77, df = 1) or for anxiety disorders (hazard ratio 0.92, 95% confidence interval: 0.58-1.45, Wald statistic 0.14, p = 0.71, df = 1). We could demonstrate an association of anxiety disorders with poor cognition cross-sectionally, but this attenuated after additional adjustments. |
Does high expression of Cullin1 indicate poor prognosis for NSCLC patients? | Cullin1 is a scaffold protein of the ubiquitin E3 ligase Skp1/Cullin1/Rbx1/F-box protein complex which ubiquitinates a broad range of proteins participating in biochemical events like cell-cycle progression, signal transduction, and transcription. Cullin1 is involved in the progression of several cancers, such as melanoma, breast cancer, and gastric cancer. To investigate the role of Cullin1 in the development of non-small-cell lung cancer (NSCLC), we examined the expression of Cullin1 in 8-paired fresh NSCLC tissues. We then constructed immunohistochemistry (IHC) on 114 paraffin-embedded slices and evaluated the correlation between Cullin1 expression and clinicopathologic variables, as well as patients' overall survival. We found that Cullin1 was highly expressed in NSCLC tissues and significantly associated with NSCLC's histological differentiation (P=0.002), clinical stage (P=0.010) and Ki-67 (P=0.021). Furthermore, we showed a strong correlation between high Cullin1 expression and worse overall survival rates in NSCLC patients (P<0.001). Cox regression analysis revealed that Cullin1 expression was an independent prognostic factor to predict 5-year patient outcome in NSCLC cancer (P=0.033). | In prior studies of exercise done before or after breakfast and lunch, postprandial activity generally reduces glycemia more than pre-meal. This study sought to examine the effects of exercise before or after an evening meal. Examined the differing effects of a single bout of pre- or postprandial moderate exercise or no exercise on the glycemic response to an evening (dinner) meal in individuals with type 2 diabetes. Community-dwelling participants tested at a research university in Virginia. Twelve men and women subjects (mean age of 61.4+/-2.7 years) with type 2 diabetes treated with diet and/or oral medications. Three trials conducted on separate days consisting of a rest day when subjects consumed a standardized dinner with a moderate glycemic effect and 2 exercise days when they undertook 20 minutes of self-paced treadmill walking immediately before or 15 to 20 minutes after eating. Blood samples taken every 30 minutes over a 4-hour period and later assayed for plasma glucose; from these data both absolute and relative changes in glucose levels were determined, as well as the total glucose area under the curve (AUC) of the 4-hour testing period. Initial samples were additionally assayed for glycated hemoglobin and lipid levels. Twenty minutes of self-paced walking done shortly after meal consumption resulted in lower plasma glucose levels at the end of exercise compared to values at the same time point when subjects had walked pre-dinner. Total glucose AUC over 4-hours was not significantly different among trials. |
Does adalimumab significantly reduce the recurrence rate of anterior uveitis in patients with ankylosing spondylitis? | To investigate whether use of adalimumab decreases the frequency of attacks of anterior uveitis (AU) in patients with ankylosing spondylitis (AS). Consecutive patients with AS, visiting an outpatient clinic and treated for at least 12 weeks with adalimumab, were enrolled. The number of attacks of AU in the year before start and during treatment were assessed by patient history and ophthalmological controls. In the 77 patients a total of 52 AU attacks occurred in the year before baseline (68 attacks per 100 patient-yrs), whereas during adalimumab treatment 19 attacks were seen (14 per 100 patient-yrs; reduction rate 80%). Twenty-six patients with AU in the year before start of adalimumab treatment had recurrent attacks, with a median number of 2.0 AU attacks per year [interquartile range (IQR) 1.00-3.00], whereas during treatment this decreased to 10 patients with a median number of 0.56 attacks per year (IQR 0.30-0.75). Hence, the number of attacks per year decreased by 72% (p = 0.000). | Isotopic turnover quantifies the metabolic renewal process of elements in organs and excreta. Knowledge of the isotopic turnover of animal organs and excreta is necessary for diet reconstruction via stable isotope analysis, as used in animal ecology, palaeontology and food authentication. Effects of dietary protein content on the isotopic carbon and nitrogen turnover (i.e. delay, representing the time between ingestion and start of renewal, and half-life) are unknown for most mammalian organs and excreta. To examine the effect of dietary protein content on turnover (delay and turnover rate), we fed 18 rats either a diet at protein maintenance or above protein maintenance, and quantified their isotopic carbon and nitrogen turnover in ten organs and excreta. These included the excreta faeces and urine, the visceral organs blood plasma, liver, kidney, lung and spleen, the cerebral tissue brain, and the muscular tissues heart and muscle. For data analysis, we used piecewise linear/non-linear exponential modelling that allows quantifying delay and turnover rate simultaneously. Delays were ~0.5 days for carbon and nitrogen turnover and were not affected by dietary protein content. Half-lives during the following reaction progress were in the range of 1 to 45 days, increasing from excreta to visceral organs to muscular and cerebral organs. Rats fed the higher protein amount had 30% shorter nitrogen half-lives, and 20% shorter carbon half-lives. |
Does the specificity of tests for anti-beta-lactam IgE antibodies decline progressively with increase of total serum IgE? | Immediate allergic reactions to beta-lactam antibiotics are mediated by specific IgE antibodies. The Phadia CAP System FEIA is a commercial method for quantification of specific IgE. We wished to determine anti-beta-lactam IgE antibodies in patients without penicillin allergy but with high levels of total IgE. Sera from 41 patients (31 with high total IgE, 10 with low total IgE) were analyzed for IgE antibodies specific to penicilloyl G, penicilloyl V, amoxicilloyl and ampicilloyl using the CAP FEIA((R)) method that was available up to 2006. Seven sera that tested positive were rechecked in a new improved system available after 2006. In patients without a history of penicillin allergy, the specificities of commercial tests for anti-beta-lactam IgE antibodies were 100%, 60%, 27% and 20% at total IgE levels of 8-263 kU/l, 500-664 kU/l, 1000-2000 kU/l and > 2000 kU/l, respectively. In seven retested sera, only 2 (28%) were still positive for penicillin-specific IgE antibody. | Emerging evidence suggests that light physical activity (LPA), besides moderate-to-vigorous physical activity (MVPA), may beneficially influence physical functioning of colorectal cancer survivors, but its relation with other health-related outcomes is unknown. We applied a biopsychosocial approach to investigate independent associations between self-reported LPA, MVPA, and multiple health-related quality of life (HRQoL) outcomes in 2- to 10-yr postdiagnosis colorectal cancer survivors. Stage I-III colorectal cancer survivors diagnosed between 2002 and 2010 at Maastricht University Medical Center+, the Netherlands, were included in a cross-sectional study (n = 151). Time spent in LPA and MVPA (h·wk⁻¹), and HRQoL outcome scores (0-100 points) were assessed by validated questionnaires. Median time spent in LPA and MVPA was 10.0 (interquartile range, 2.0-22.0) and 8.7 h·wk⁻¹ (4.5-15.0), respectively. In multivariable linear regression models, both LPA and MVPA were significantly and independently associated with higher physical functioning (mean difference [MD] between highest and lowest quartile, 10.2; 95% confidence interval [CI], 0.2-20.3; and 14.5; 5.1-23.9, respectively; both P-trend < 0.05). In addition, LPA was significantly associated with higher role functioning (MD, 19.5; 95% CI, 6.9-32.1; P-trend < 0.01) and lower disability (MD, -9.9; 95% CI, -17.8 to -1.9; P-trend = 0.02), independent from MVPA. Subgroup analyses showed that beneficial associations between LPA and HRQoL were mainly observed in women and participants with multiple comorbidities. |
Does a Human Open Field Test reveal Thigmotaxis Related to Agoraphobic Fear? | Thigmotaxis refers to a specific behavior of animals (i.e., to stay close to walls when exploring an open space). Such behavior can be assessed with the open field test (OFT), which is a well-established indicator of animal fear. The detection of similar open field behavior in humans may verify the translational validity of this paradigm. Enhanced thigmotaxis related to anxiety may suggest the relevance of such behavior for anxiety disorders, especially agoraphobia. A global positioning system was used to analyze the behavior of 16 patients with agoraphobia and 18 healthy individuals with a risk for agoraphobia (i.e., high anxiety sensitivity) during a human OFT and compare it with appropriate control groups (n = 16 and n = 19). We also tracked 17 patients with agoraphobia and 17 control participants during a city walk that involved walking through an open market square. Our human OFT triggered thigmotaxis in participants; patients with agoraphobia and participants with high anxiety sensitivity exhibited enhanced thigmotaxis. This behavior was evident in increased movement lengths along the wall of the natural open field and fewer entries into the center of the field despite normal movement speed and length. Furthermore, participants avoided passing through the market square during the city walk, indicating again that thigmotaxis is related to agoraphobia. | To establish the benefits of immature reticulocyte fraction (IRF) measurement using an automated hematology cells analyzer over absolute neutrophil count (ANC) in predicting bone marrow recovery post induction chemotherapy. A prospective observational study was carried out in the Departments of Pathology, Medicine, and Pediatrics, Universiti Kebangsaan Malaysia, Medical Center (UKMMC), Kuala Lumpur, Malaysia during a period of 19 months from April 2009 to December 2010 to assess the bone marrow recovery in patients with acute leukemia. A total of 22 patients in remission induction phases were enrolled in this study. The blood specimens were collected from day zero after chemotherapy, and every 3 days until patients recovered hematologically. All blood samples were measured for ANC and IRF using an automated hematology analyzer (Beckman-Coulter LH750). The percentage of patients showing IRF recovery earlier than ANC recovery was 63.6% (14 out of 22 patients). There was a significant difference in the mean number of days for IRF recovery as compared with ANC recovery (14.05 and 17.18 days), p=0.005. |
Is [ Acute scrotum a condition requiring surgical intervention ]? | Acute scrotum (AS) is a clinical syndrome, in which authors indicate a surgical exploration of the scrotum. We retrospectively analyzed the group of 354 patients in 10 years (1997-2006) to compare the preoperative findings with the diagnosis of surgical exploration. The aim was to actualize diagnostics and therapeutic management. We focused on the age of patients, incidence of nosological units of AS and preoperative and surgical diagnosis. 334 boys were operated on from the whole group - 354 patients. Most frequent incidence of AS was in the age group 8-12 (55%). Torsion of testicular appendix or epididymis is the most frequent cause of AS in our group - 204, 59%. In this group of patients ultrasound confirmed the diagnosis only in 120 patients, 65%. Testicular torsion was managed in 74 boys (30 neonates), in 40 of them we decided, mostly at the second look operation after 48-72 hours, for testicle ablation caused by the organ avitality. In all patients with testicular torsion ultrasound confirmed the diagnosis, 100%. In 10 boys we found testicular tumor. In the group of 334 patients operated on, there were no serious complications. | To investigate for the first time whether the plasma CXCL16 concentration is altered in coronary artery disease (CAD) patients. Accumulating evidence suggests that the novel chemokine/scavenger receptor CXCL16/SR-PSOX is involved in the development of atherosclerosis and CAD. Using ELISA we assessed the plasma CXCL16 concentration in 40 stable angina pectoris (SAP) patients, 17 unstable angina pectoris/non-ST-elevation myocardial infarction (UAP/non-STEMI) patients, 387 survivors of a first myocardial infarction (MI) and healthy control subjects (44 controls for SAP and UAP/non-STEMI patient groups and 387 controls for post-MI patients). SAP patients exhibited significantly lower median CXCL16 levels (2111 pg/ml) than the corresponding control subjects (2678 pg/ml) (P=0.0012). UAP/non-STEMI patients also appeared to have lower CXCL16 levels (2192 pg/ml) compared with controls (NS). Patients investigated 3 months after MI tended (P=0.07) to have lower CXCL16 levels (2529 pg/ml) than the corresponding controls (2638 pg/ml). There were no significant correlations between CXCL16 levels and different measures of CAD severity determined by quantitative coronary angiography in post-MI patients. Neither patients nor controls exhibited significant correlations between CXCL16 levels and plasma lipoprotein fractions, inflammatory cytokines, C-reactive protein or numbers of inflammatory cells in peripheral blood. |
Does high serum level of the soluble CD30 identify Chinese kidney transplant recipients at high risk of unfavorable outcome? | We sought to investigate the relationship between serum level of sCD30 and recipient/graft survival rates, rejection types, as well as other prognostic factors among Chinese kidney transplant patients. We performed enzyme-linked immunosorbent assays of serum sCD30 levels in duplicate among retrospective cohort of 707 renal transplant patients. The incidences of rejection increased in relation to the pretransplant sCD30 level. The reversal rates of rejection were 100%, 90.6%, and 78.6% for the low, intermediate, and high sCD30 groups. This observation suggested that high levels of sCD30 and pretransplant panel-reactive antibody (PRA)-positive patients are risk factors for acute rejection with odds ratios of 6.862 and 1.756. High sCD30 was an independent risk factor for functional graft survival. The 5-year graft survival rates were 99.39% +/- 6.1%, 93.11% +/- 1.93%, and 82.07% +/- 3.97% among the low, intermediate, and high sCD30 groups, while the 5-year recipient survival rates were 89.25% +/- 2.41%, 91.82% +/- 1.64%, and 88.85% +/- 2.36%, respectively. Increased sCD30 levels were observed among patients who were PRA-positive, cytomegalovirus antigens or antibodies positive, on long-term dialysis, and <or= 20 years old. | We investigated whether glucose fluctuations aggravate cardiac fibrosis and increase the occurrence of atrial fibrillation (AF) in rats with diabetes mellitus (DM). Streptozotocin-induced diabetic rats were randomly divided into three groups: uncontrolled DM (U-STZ) group, controlled DM (C-STZ) group, and DM with glucose fluctuations (STZ-GF) group. Glucose fluctuations were induced by fasting for 24 h and additional regular insulin injections (0.5 IU/kg) administered three times per week for three consecutive weeks. C-STZ rats were administered long acting insulin (20 IU/kg) twice a day to control blood glucose levels. Cardiac fibrosis evaluated by Masson trichrome staining and the expressions of collagen type 1, collagen type 3, and α-smooth muscle actin were increased in U-STZ rats compared with C-STZ rats, which were more pronounced in STZ-GF rats. The inducibility of AF was significantly larger in U-STZ rats than C-STZ rats and was greatest in STZ-GF rats. To explore the mechanism of cardiac fibrosis, we investigated the levels of reactive oxygen species (ROS) and apoptosis. The expression of malondialdehyde, an indicator of ROS levels, was significantly upregulated in STZ-GF rats compared with U-STZ rats, along with increased thioredoxin-interacting protein (Txnip) expression in STZ-GF rats. Furthermore, caspase-3 expression and the number of TUNEL-positive cells were significantly increased in STZ-GF rats compared with U-STZ and C-STZ rats. |
Does ocular Fluid Analysis in Children reveal Interleukin-29/Interferon-λ1 as a Biomarker for Juvenile Idiopathic Arthritis-Associated Uveitis? | Childhood uveitis is a vision-threatening inflammatory eye disease commonly attributed to juvenile idiopathic arthritis (JIA). The pathogenesis is poorly understood, which makes clinical management challenging. We analyzed soluble mediators in ocular fluid (aqueous humor [AqH]) and serum from children with JIA-associated uveitis and common childhood uveitis to identify potential biomarkers and investigate the ocular microenvironment of this sight-threatening eye disease. AqH (n = 73) and paired serum (n = 66) samples were analyzed for 51 soluble mediators of inflammation by multiplex immunoassay. Twenty-one children with JIA-associated uveitis were compared to 15 children with chronic anterior uveitis without arthritis, 29 children with noninfectious idiopathic uveitis, and 8 children with noninflammatory conditions (controls). For visualization of the joint effect of multiple mediators, we used the radial coordinate visualization (Radviz) method. Optimal biomarker level cutoffs were also determined. The levels of interleukin-29 (IL-29)/interferon-λ1 (IFNλ1) were decreased (P < 0.001) and the levels of latency-associated peptide and osteoprotegerin were increased (P = 0.002 and P = 0.001, respectively) in samples of AqH, but not serum, from patients with JIA-associated uveitis. Multivariate analysis correcting for disease activity and treatment revealed that intraocular levels of IL-29/IFNλ1 were specifically decreased in patients with JIA-associated uveitis as compared to those with idiopathic uveitis. Indeed, JIA-associated uveitis patients and idiopathic uveitis patients showed distinct profiles of intraocular soluble mediators. IL-29/IFNλ1 showed a high area under the curve value (0.954), with 23.5 pg/ml as the optimal cutoff value. | Routine intra-abdominal drainage has been recommended for detecting surgical complications, such as anastomotic leaks or intra-abdominal hemorrhage, after laparoscopic gastric bypass for morbid obesity. The aim of this study was to determine whether routine drainage after laparoscopic gastric bypass is indeed necessary. Patients undergoing laparoscopic gastric bypass with intra-abdominal drainage (D-group) were compared with those without drainage (N-group) in a retrospective study. The main outcome measures were postoperative course and complications. No differences were observed in the postoperative complications. Both groups had one major complication of leakage (1/90, 1.1%). Minor complications occurred in six D-group patients (6/90, 6.7%) and eight N-group patients (8/90, 8.9%) (P=0.578). No difference was observed in postoperative analgesic dose usage (mean ± SD: 63 ± 37 mg vs 60 ± 31 mg; P=0.963) or length of stay hospital (5.2 ± 2.6 d vs 4.7 ± 1.8 d; P=0.135). However, the N-group had a shorter time to flatus passage compared to the D-group (1.6 ± 0.7 d vs 1.2 ± 0.5 d; P=0.006). |
Do serum levels of preoperative α-fetoprotein and CA19-9 predict survival of hepatic carcinoma patients after liver transplantation? | The aim of this study was to assess serum levels of presurgical α-fetoprotein (AFP) and carbohydrate antigen 19-9 (CA19-9) as prognostic markers in patients with hepatic carcinoma after liver transplantation (LT). A total of 226 patients were recruited for the analysis of serum AFP and CA19-9 levels, on the basis of which the tumor marker type (TMT) was defined and evaluated for prognostic prediction. Overall survival (OS) and relapse-free survival (RFS) were analyzed using Kaplan-Meier curves, and univariate and multivariate Cox models. One-year and 5-year OS were 79.0 and 58.0%, respectively, whereas RFS were 70.3 and 62.2%, respectively, in this cohort of patients. There were six variables predicting both OS and RFS, including TMT, tumor size, number of tumor lesions, extrahepatic or vascular invasion, and histopathological grade. Among these, TMT, tumor size, and extrahepatic invasion were all independent predictors of OS and RFS among these patients. Further, on the basis of TMT, novel LT selection criteria for patients with hepatic carcinoma, which supplemented the Milan criteria, were adopted, because the patients within the Milan criteria (n=107) and those exceeding Milan but fulfilling the proposed criteria (n=30) had similar 5-year OS (77.8 vs. 79.3%, P=0.862) and RFS (85.5 vs. 75.1%, P=0.210) rates. | Oxytocin is believed to be involved in ejaculation by increasing sperm number and contracting ejaculatory tissues. However, oxytocin may mediate these effects via oxytocin or vasopressin (AVP) receptors. The aim of this study was to determine the effect of oxytocin and AVP on peripheral tissues involved in ejaculation and to identify the receptor subtype(s) involved. Standard tissue bath techniques were used to measure isometric tension from tissues involved in ejaculation and erection. Oxytocin and AVP failed to elicit a tonic contractile response in rat and rabbit testes, vas deferens, epididymis, seminal vesicles and prostate. In contrast, oxytocin and AVP elicited large tonic contractions in erectile (corpus spongiosum and corpus cavernosum) and ejaculatory (prostatic urethra, bladder neck and ejaculatory duct) tissues in a concentration-dependent manner. The selective oxytocin agonist, [Thr4,Gly7]-oxytocin and the V2 agonist, [deamino-Cys1,Val4,D-Arg8]-vasopressin (dDAVP), failed to contract tissues. Oxytocin and AVP-induced contractions were weakly antagonized by the selective oxytocin antagonist, L-368899 but potently antagonized by the V1A antagonist, SR49059. The V1B antagonist SSR149415 failed to antagonize AVP contractions except in rabbit bladder neck. Neither L-368899 nor SR49059 antagonized endothelin-1-induced contractions. |
Is kleihauer-betke testing important in all cases of maternal trauma? | In maternal trauma, the Kleihauer-Betke (KB) test has traditionally been used to detect transplacental hemorrhage (TPH), so that Rh-negative women could receive appropriate Rh immune prophylaxis. Reasoning that the magnitude of TPH would reflect uterine injury, we evaluated Kleihauer-Betke testing as an independent predictor of preterm labor (PTL) after maternal trauma. Admissions to the Shock Trauma Center, University of Maryland, from January 1996 to January 2002, were reviewed. Of 30,362 trauma patients admitted, 166 were pregnant, and 93 of these underwent electronic fetal monitoring. Their records were abstracted for demographics, injury type, three separate trauma scores, documented uterine contractions, PTL (contractions with progressive cervical change), and serious perinatal complications. In 71 cases, transplacental hemorrhage was assessed by maternal KB test. TPH, defined as KB-positive for greater than 0.01 mL of fetal blood in the maternal circulation, occurred in 46 women. Forty-four had documented contractions (25 had overt PTL) and 2 had no contractions. In 25 women with a negative KB test, none had uterine contractions. All patients with contractions or PTL had positive KB tests. By logistic regression, KB test result was the single risk factor associated with PTL (p < 0.001; likelihood ratio, 20.8 for positive KB test). Compared with other sites, abdominal trauma was associated more often with uterine contractions (p < 0.001), PTL (p = 0.001), and a positive KB test (p < 0.001, chi). None of the trauma scoring systems predicted PTL. | Previous results have shown that mice lacking in the group 1B phospholipase A(2) (Pla2g1b) are resistant to obesity and diabetes induced by feeding a diabetogenic high-fat/high-carbohydrate diet. This study examined the potential of using the Pla2g1b inhibitor methyl indoxam as therapy to suppress diet-induced obesity and diabetes. Male C57BL/6 mice were fed the diabetogenic diet with or without methyl indoxam supplementation. Body weight gain, fasting plasma glucose levels, glucose tolerance and postprandial lysophospholipid absorption were compared. Wild-type C57BL/6 mice fed the diabetogenic diet without Pla2g1b inhibitor showed 31 and 69% body weight gain after 4 and 10 weeks respectively. These animals also showed elevated plasma glucose levels and were glucose intolerant. In contrast, C57BL/6 mice fed the diabetogenic diet with 90 mg.kg(-1) of methyl indoxam gained only 5% body weight after 10 weeks. These animals were also euglycaemic and displayed normal glucose excursion rates in glucose tolerance test. Methyl indoxam suppression of diet-induced body weight gain and glucose intolerance was correlated with the inhibition of Pla2g1b-mediated postprandial lysophospholipid absorption. |
Does economic influence on GPs ' decisions to provide out-of-hours care? | Introduction of the new general medical services contract offered UK general practices the option to discontinue providing out-of-hours (OOH) care. This aimed to improve GP recruitment and retention by offering a better work-life balance, but put primary care organisations under pressure to ensure sustainable delivery of these services. Many organisations arranged this by re-purchasing provision from individual GPs. To analyse which factors influence an individual GP's decision to re-provide OOH care when their practice has opted out. Cross-sectional questionnaire survey. Rural and urban general practices in Scotland, UK. A postal survey was sent to all GPs working in Scotland in 2006, with analyses weighted for differential response rates. Analysis included logistic regression of individuals' decisions to re-provide OOH care based on personal characteristics, work and non-work time commitments, income from other sources, and contracting primary care organisation. Of the 1707 GPs in Scotland whose practice had opted out, 40.6% participated in OOH provision. Participation rates of GPs within primary care organisations varied from 16.7% to 74.7%. Males with young children were substantially more likely to participate than males without children (odds ratio [OR] 2.44, 95% confidence interval [CI] = 1.36 to 4.40). GPs with higher-earning spouses were less likely to participate. This effect was reinforced if GPs had spouses who were also GPs (OR 0.52, 95% CI = 0.37 to 0.74). GPs with training responsibilities (OR 1.36, 95% CI = 1.09 to 1.71) and other medical posts (OR 1.38, 95% CI = 1.09 to 1.75) were more likely to re-provide OOH services. | Physiological roles of apelin and its specific receptor APJ signaling were investigated in vascular smooth muscle cells (VSMCs). The present study determined whether apelin activates myosin light chain (MLC), a major regulatory event in initiating smooth muscle contraction. To assess MLC activation, we performed Western blot and immunohistochemical studies using an antibody against the phospho-MLC. In VSMCs, apelin induces the phosphorylation of MLC in a concentration-dependent manner with a peak at 2 minutes. Pretreatment of VSMCs with pertussis toxin abolishes the apelin-induced phosphorylation of MLC. Inhibition of protein kinase C (PKC) with GF-109203X markedly attenuated the apelin-induced MLC phosphorylation. In addition, methylisobutyl amiloride, a specific inhibitor of the Na+/H+ exchanger (NHE), and KB-R7943, a potent inhibitor for the reverse mode of the Na+/Ca2+ exchanger (NCX), significantly suppressed the action of apelin. In wild-type mice, apelin phosphorylates MLC in vascular tissue, whereas it had no response in APJ-deficient mice by Western blot and immunohistochemistry. Apelin-induced phosphorylation of MLC was accompanied with myosin phosphatase target subunit phosphorylation. |
Are anticipatory and consummatory effects of ( hedonic ) chocolate intake associated with increased circulating levels of the orexigenic peptide ghrelin and endocannabinoids in obese adults? | Hedonic hunger refers to consumption of food just for pleasure and not to maintain energy homeostasis. Recently, consumption of food for pleasure was reported to be associated with increased circulating levels of both the orexigenic peptide ghrelin and the endocannabinoid 2-arachidonoyl-glycerol (2-AG) in normal-weight subjects. To date, the effects of hedonic hunger, and in particular of chocolate craving, on these mediators in obese subjects are still unknown. To explore the role of some gastrointestinal orexigenic and anorexigenic peptides and endocannabinoids (and some related congeners) in chocolate consumption, we measured changes in circulating levels of ghrelin, glucagon-like peptide 1 (GLP-1), peptide YY (PYY), anandamide (AEA), 2-AG, palmitoylethanolamide (PEA), and oleoylethanolamide (OEA) in 10 satiated severely obese subjects after consumption of chocolate and, on a separate day, of a non-palatable isocaloric food with the same bromatologic composition. Evaluation of hunger and satiety was also performed by visual analogic scale. The anticipatory phase and the consumption of food for pleasure were associated with increased circulating levels of ghrelin, AEA, 2-AG, and OEA. In contrast, the levels of GLP-1, PYY, and PEA did not differ before and after the exposure/ingestion of either chocolate or non-palatable foods. Hunger and satiety were higher and lower, respectively, in the hedonic session than in the non-palatable one. | Multidrug resistant (MDR) uropathogens are increasing in prevalence and may contribute to significant morbidity after percutaneous nephrolithotomy (PCNL). We investigate the presence of MDR bacteriuria and occurrence of postoperative infectious complications in patients who underwent PCNL at our institution. Retrospective review was performed of 81 patients undergoing PCNL by a single surgeon (RLS) between 2009 and 2013. Patient demographics, comorbidities, stone parameters on imaging, and microbial data were compiled. MDR organisms were defined as resistant to three or more of the American Urological Association Best Practice Statement antimicrobial classes for PCNL. Postoperative complications were graded by Clavien score and European Association of Urology infection grade. Univariate comparisons were analyzed between patients with and without a postoperative infectious complication. Multivariate logistic regression was performed to determine significant predictor variables for postoperative infectious complications. Of the 81 patients undergoing PCNL, 41/81 (51%) had positive preoperative urine culture, 24/81 (30%) had positive MDR urine culture, and 16/81 (19%) had a postoperative infectious complication. Multivariate analysis revealed a positive preoperative MDR urine culture significantly increased the risk of postoperative infectious complication (odds ratio [OR]=4.89, 95% confidence interval [CI] 1.134-17.8, P=0.016). The presence of more than one access tract during PCNL also predicted for infectious complications (OR=7.5, 95% CI 2.13-26.4, P=0.003) Of the 16 patients with a postoperative infection 3 (18%) had postoperative urine cultures discordant with the preoperative urine cultures. |
Is sperm-derived SPANX-B a clinically relevant tumor antigen that is expressed in human tumors and readily recognized by human CD4+ and CD8+ T cells? | The sperm-derived SPANX family proteins can be found expressed in human tumors. Here, we aimed to perform a comprehensive study to evaluate immunotherapeutic relevance of one of its members, SPANX-B. We wanted to test its expression pattern in human tumors and to evaluate CD4(+) and CD8(+) T-cell responses in healthy humans after in vitro immunizations. Expression of SPANX-B in human malignancies, including a multitumor tissue array of 145 primary tumors, was assessed using reverse transcription-PCR, Western blotting, and immunohistochemical analysis. T-cell immunogenicity and immunodominant epitopes of SPANX-B were studied using in vitro immunizations of healthy human donor-derived leukocytes. SPANX-B was abundantly expressed in melanoma and carcinomas of lung, ovary, colon, and breast. In melanoma, tissue array data indicated that it was expressed in advanced and metastatic disease. Unlike most tumor-associated antigens, SPANX-B was an immunogenic antigen that was recognized by circulating T-cell precursors in healthy humans. Importantly, these T cells were readily expanded to generate SPANX-B-specific helper CD4(+) and cytolytic CD8(+) T cells that recognized unique immunodominant epitopes: at least one HLA-DR-restricted Pep-9 epitope (SPANX-B(12-23)) and two HLA-A2-restricted Pep-2 and Pep-4 epitopes (SPANX-B(23-31) and SPANX-B(57-65), respectively). CD8(+) T cells were fully functional to recognize and lyse HLA-A2-expressing tumors, including primary human melanomas. | Serum ghrelin levels are elevated in uremic patients. However, no data are available on the relationship between metabolic syndrome and serum ghrelin levels in peritoneal dialysis (PD) patients. Metabolic syndrome and its components were defined using diagnostic criteria recommended by the International Diabetes Federation. Fasting serum samples were taken from 30 PD patients. Serum ghrelin levels were measured by using a commercial enzyme-linked immunosorbent assay kit. Of the 30 PD patients, 53.3% (16/30) had metabolic syndrome. Fasting serum ghrelin corrected inversely with metabolic syndrome among these PDs patients (p = 0.002). By odds ratio (OR) analysis of metabolic syndrome and metabolic syndrome diagnostic criteria, the predictors for metabolic syndrome are fasting glucose [OR: 39.00; 95% confidence interval (CI): 3.80 to 399.85; p < 0.001], triglycerides (OR: 37.50; 95% CI: 3.64 to 386.51; p < 0.001), and waist circumference (OR: 4.20; 95% CI: 1.95 to 9.03; p < 0.001). Univariate linear regression analysis showed that body weight (r = -0.461, p = 0.010), waist circumference (r = -0.390, p = 0.033), and body mass index (r = -0.438, p = 0.016) were negatively correlated with serum ghrelin, and serum high density lipoprotein [HDL (r = 0.626, p < 0.001)] was positively correlated with serum ghrelin. Multivariate forward stepwise linear regression analysis of the significant variables showed that HDL (R(2) change = 0.392; p < 0.001) was the independent predictor of serum ghrelin in PD patients and explained 39.2% of the variance. |
Does hepatitis C virus viremia increase the incidence of chronic kidney disease in HIV-infected patients? | Several studies have reported on an association between hepatitis C virus (HCV) antibody status and the development of chronic kidney disease (CKD), but the role of HCV viremia and genotype are not well defined. Patients with at least three serum creatinine measurements after 1 January 2004 and known HCV antibody status were included. Baseline was defined as the first eligible estimated glomerular filtration rate (eGFR) (Cockcroft-Gault equation), and CKD was either a confirmed (>3 months apart) eGFR of 60 ml/min per 1.73 m or less for patients with a baseline eGFR more than 60 ml/min per 1.73 m or a confirmed 25% decline in eGFR for patients with a baseline eGFR of 60 ml/min per 1.73 m or less. Incidence rates of CKD were compared between HCV groups (anti-HCV-negative, anti-HCV-positive with or without viremia) using Poisson regression. Of 8235 patients with known anti-HCV status, 2052 (24.9%) were anti-HCV-positive of whom 983 (47.9%) were HCV-RNA-positive, 193 (9.4%) HCV-RNA-negative and 876 (42.7%) had unknown HCV-RNA. At baseline, the median eGFR was 97.6 (interquartile range 83.8-113.0) ml/min per 1.73 m. During 36123 person-years of follow-up (PYFU), 495 patients progressed to CKD (6.0%) with an incidence rate of 14.5 per 1000 PYFU (95% confidence interval 12.5-14.9). In a multivariate Poisson model, patients who were anti-HCV-positive with HCV viremia had a higher incidence rate of CKD, whereas patients with cleared HCV infection had a similar incidence rate of CKD compared with anti-HCV-negative patients. There was no association between CKD and HCV genotype. | Neuropathic pain, characterized by spontaneous pain, hyperalgesia and allodynia, is a devastating neurological disease that seriously affects patients' quality of life. We have previously shown that tanshinone IIA (TIIA), an important lipophilic component of Danshen, had significant anti-nociceptive effect in somatic and visceral pain, it is surprisingly noted that few pharmacological studies have been carried out to explore the possible analgesic action of TIIA on neuropathic pain and the underlying mechanisms. Therefore, in the present study, by using spinal nerve ligation (SNL) pain model, the antinociceptive and antihyperalgesic effects of TIIA on neuropathic pain were evaluated by intraperitoneal administration in rats. The results indicated that TIIA dose-dependently inhibited SNL-induced mechanical hyperalgesia. As revealed by OX42 levels, TIIA effectively repressed the activation of spinal microglial activation in SNL-induced neuropathic pain. Meanwhile, TIIA also decreased the expressions of inflammatory cytokines TNF-α and IL-1β in the spinal cord. Furthermore, TIIA inhibited oxidative stress by significantly rescuing the superoxide dismutase (SOD) activity and decreasing the malondialdehyde (MDA). Moreover, TIIA depressed SNL-induced MAPKs activation in spinal cord. |
Do mouse neutrophils lacking lamin B-receptor expression exhibit aberrant development and lack critical functional responses? | The capacity of neutrophils to eradicate bacterial infections is dependent on normal development and activation of functional responses, which include chemotaxis and generation of oxygen radicals during the respiratory burst. A unique feature of the neutrophil is its highly lobulated nucleus, which is thought to facilitate chemotaxis, but may also play a role in other critical neutrophil functions. Nuclear lobulation is dependent on expression of the inner nuclear envelope protein, the lamin B receptor (LBR), mutations of which cause hypolobulated neutrophil nuclei in human Pelger-Huët anomaly and the "ichthyosis" (ic) phenotype in mice. In this study, we have investigated roles for LBR in mediating neutrophil development and activation of multiple neutrophil functions, including chemotaxis and the respiratory burst. A progenitor EML cell line was generated from an ic/ic mouse, and derived cells that lacked LBR expression were induced to mature neutrophils and then examined for abnormal morphology and functional responses. Neutrophils derived from EML-ic/ic cells exhibited nuclear hypolobulation identical to that observed in ichthyosis mice. The ic/ic neutrophils also displayed abnormal chemotaxis, supporting the notion that nuclear segmentation augments neutrophil extravasation. Furthermore, promyelocytic forms of ic/ic cells displayed decreased proliferative responses and produced a deficient respiratory burst upon terminal maturation. | The objective is the evaluation of treatment outcome difference between men and women through measuring quality of life persons who experienced war torture in Bosnia and Herzegovina. The research is analytical-descriptive and retrospective. It was conducted at two samples which were homogeneous according to gender. All persons included in the research regarding torture consequences have received comprehensive psychosocial rehabilitation at the Association for Rehabilitation of Torture Victims-Centre for Torture Victims in Sarajevo, Bosnia and Herzegovina. MANSA (Manchester Short Assessment of Quality of Life) questionnaire have been applied as instrument of research. The results indicates that women who experienced war torture, after completition of psychosocial rehabilitation, have bit better quality of life in post war conditions comparing to men. |
Does pentobarbital have curare-like effects on adult-type nicotinic acetylcholine receptor channel currents? | Pentobarbital (PB) is widely used as a short-term sedative and anticonvulsive drug with a side-effect of relaxing muscle tone. We investigated block of nicotinic acetylcholine receptor (nAChR) channel currents by PB using the patch-clamp technique in combination with an ultrafast system for solution exchange. As a preparation, recombinant rat adult-type nAChR channels transiently expressed in HEK293 cells were used. Appli-cation of 1 mM acetylcholine to small cells or outside-out patches showed a transient current with fast activation and desensitization kinetics. Adding PB to the acetylcholine-containing solution resulted in a decrease of the time constant of current decay and of the peak current amplitude starting at concentrations >0.01 mM PB. Preincubation of nAChR channels with PB led to a decrease of the peak current amplitude without alteration of activation and desensitization kinetics caused by competitive block of nAChR channels. In conclusion, similar to the effect of d-Tubocurarine, block of nAChR channel currents by PB can be explained by a combination of open-channel and competitive block. | Bone marrow plays a key role in bone formation and healing. Although a subset of marrow explants ossifies in vitro without excipient osteoinductive factors, some explants do not undergo ossification. The disparity of outcome suggests a significant heterogeneity in marrow tissue in terms of its capacity to undergo osteogenesis. We sought to identify: (1) proteins and signaling pathways associated with osteogenesis by contrasting the proteomes of ossified and poorly ossified marrow explants; and (2) temporal changes in proteome and signaling pathways of marrow ossification in the early and late phases of bone formation. Explants of marrow were cultured. Media conditioned by ossified (n = 4) and poorly ossified (n = 4) subsets were collected and proteins unique to each group were identified by proteomic analysis. Proteomic data were processed to assess proteins specific to the early phase (Days 1-14) and late phase (Days 15-28) of the culture period. Pathways involved in bone marrow ossification were identified through bioinformatics. Twenty-eight proteins were unique to ossified samples and eight were unique to poorly ossified ones. Twelve proteins were expressed during the early phase and 15 proteins were specific to the late phase. Several identified pathways corroborated those reported for bone formation in the literature. Immune and inflammatory pathways were specific to ossified samples. |
Do periodontal ligament mesenchymal stromal cells increase proliferation and glycosaminoglycans formation of temporomandibular joint derived fibrochondrocytes? | Temporomandibular joint (TMJ) disorders are common disease in maxillofacial surgery. The aim of this study is to regenerate fibrocartilage with a mixture of TMJ fibrochondrocytes and periodontal ligament derived mesenchymal stem cells (PD-MSCs). Fibrochondrocytes and PD-MSC were cocultured (ratio 1 : 1) for 3 weeks. Histology and glycosaminoglycans (GAGs) assay were performed to examine the deposition of GAG. Green florescent protein (GFP) was used to track PD-MSC. Conditioned medium of PD-MSCs was collected to study the soluble factors. Gene expression of fibrochondrocytes cultured in conditioned medium was tested by quantitative PCR (qPCR). Increased proliferation of TMJ-CH was observed in coculture pellets when compared to monoculture. Enhanced GAG production in cocultures was shown by histology and GAG quantification. Tracing of GFP revealed the fact that PD-MSC disappears after coculture with TMJ-CH for 3 weeks. In addition, conditioned medium of PD-MSC was also shown to increase the proliferation and GAG deposition of TMJ-CH. Meanwhile, results of qPCR demonstrated that conditioned medium enhanced the expression levels of matrix-related genes in TMJ-CH. | This is a prospective study of psychiatric patients presenting to the emergency department (ED) to determine the value of routine laboratory studies used to attempt to exclude concomitant medical illness. Physical exams and laboratory tests were performed on 375 psychiatric patients presenting for "medical clearance" in the ED. Upon completion of these tests, the percentage and impact of abnormal physical exams and laboratory results were assessed. Fifty-six of 375 patients (14.9%) had a non-substance-induced laboratory abnormality. Forty-two of these 56 patients (75.0%) also had abnormal history or physical exam findings indicating laboratory screening. Ten had normal history and physical exams with insignificant laboratory abnormalities. The four (1.1% [95% CI 0.3-2.7%]) remaining patients with normal history and physical exams had abnormal urinalyses which did not affect final disposition or contribute to altered behavior. |
Does propofol increase phosphorylation of troponin I and myosin light chain 2 via protein kinase C activation in cardiomyocytes? | Troponin I (TnI) and myosin light chain 2 (MLC2) are important myofibrillar proteins involved in the regulation of myofilament calcium (Ca2+) sensitivity and cardiac inotropy. The objectives of this study were to determine the role of protein kinase C (PKC) in mediating propofol-induced changes in actomyosin adenosine triphosphatase activity in cardiac myofibrils and to examine the extent to which propofol alters the phosphorylation of TnI and MLC2 in cardiomyocytes. Freshly isolated adult rat ventricular myocytes were used for the study. Cardiac myofibrils were extracted for assessment of actomyosin adenosine triphosphatase activity and phosphorylation of TnI and MLC2. Western blot analysis for PKC-alpha was performed on cardiomyocyte subcellular fractions. Simultaneous measurement of intracellular free Ca2+ concentration ([Ca2+](i)) and myocyte shortening was assessed using fura-2 and video edge detection, respectively. Propofol (30 microM) reduced the Ca2+ concentration required for activation of actomyosin adenosine triphosphatase activity, and this effect was abolished by bisindolylmaleimide I. In addition, propofol stimulated dose-dependent phosphorylation of TnI and MLC2. PKC activation with phorbol myristic acetate also stimulated an increase in phosphorylation of TnI and MLC2. The actions of propofol and phorbol myristic acetate together on phosphorylation of TnI and MLC2 were not additive. PKC inhibition with bisindolylmaleimide I attenuated phorbol myristic acetate- and propofol-induced phosphorylation of TnI and MLC2. Propofol stimulated translocation of PKC-alpha from cytosolic to membrane fraction. Propofol caused a shift in the extracellular Ca2+-shortening relationship, and this effect was abolished by bisindolylmaleimide I. | Whether low socioeconomic status (SES) is associated with worse rheumatoid arthritis (RA) outcomes in countries with general tax-financed healthcare systems (such as Sweden) remains to be elucidated. Our aim was to investigate the influence of educational background (achieving university/college degree (high) or not (low)) on the outcomes of early RA, in terms of disease activity (DAS28), pain (VAS-pain), and functional impairment (HAQ). We evaluated DMARD-naïve RA patients recruited in the Epidemiological Investigation of RA (EIRA) study with outcomes followed in the Swedish Rheumatology Quality (SRQ) register (N = 3021). Outcomes were categorized in three ways: (1) scores equal to/above median vs. below median; (2) DAS28-based low disease activity, good response, remission; (3) scores decreased over the median vs. less than median. Associations between educational background and outcomes were calculated by modified Poisson regressions, at diagnosis and at each of the three standard (3, 6, 12 months) follow-up visits. Patients with different educational background had similar symptom durations (195 days) and anti-rheumatic therapies at baseline, and comparable treatment patterns during follow-up. Patients with a high education level had significantly less pain and less functional disability at baseline and throughout the whole follow-up period (VAS-pain: baseline: 49 (28-67) vs. 53 (33-71), p <0.0001; 1-year visit: RR = 0.81 (95% CI 0.73-0.90). HAQ: baseline: 0.88 (0.50-1.38) vs. 1.00 (0.63-1.50), p = 0.001; 1-year visit: 0.84 (0.77-0.92)). They also had greater chances to achieve pain remission (VAS-pain ≤20) after one year (1.17 (1.07-1.28)). Adjustments for smoking and BMI altered the results only marginally. Educational background did not influence DAS28-based outcomes. |
Do histones induce phosphatidylserine exposure and a procoagulant phenotype in human red blood cells? | Extracellular histones exert part of their prothrombotic activity through the stimulation of blood cells. Besides platelets, histones can bind to red blood cells (RBCs), which are important contributors to thrombogenesis, but little is known about the functional consequences of this interaction. To evaluate the effect of histones on the procoagulant potential of human RBCs with particular regard to the expression of surface phosphatidylserine (PS). PS exposure on human RBCs treated with a natural mixture of histones or recombinant individual histones was evaluated with fluorescein isothiocyanate-annexin-V binding and measured with flow cytometry. Calcium influx in RBCs loaded with the calcium-sensitive fluorophore Fluo-4 AM was assessed with flow cytometry. The procoagulant potential of histone-treated RBCs was evaluated with a purified prothrombinase assay and a one-stage plasma recalcification clotting test. Natural histones induced PS exposure on RBCs in a dose-dependent manner, and neutralization or cleavage of histones by heparin or activated protein C, respectively, abolished PS externalization. H4 was mainly responsible for the stimulating activity of histones, whereas the other subtypes were almost ineffective. Similarly, natural histones and H4 induced influx of calcium into RBCs, whereas the other individual histones did not. Histone-induced exposure of PS on RBCs translated into increased prothrombinase complex-mediated prothrombin activation and accelerated fibrin formation in plasma. | To establish which symptoms of major depressive episode (MDE) predict postremission suicide attempts in complicated single-episode cases. Using the nationally representative two-wave National Epidemiologic Survey on Alcohol and Related Conditions data set, we identified wave 1 lifetime single-episode MDE cases in which the episode remitted by the beginning of the wave 2 three-year follow-up period (N = 2791). The analytic sample was further limited to 'complicated' cases (N = 1872) known to have elevated suicide attempt rates, defined as having two or more of the following: suicidal ideation, marked role impairment, feeling worthless, psychomotor retardation, and prolonged (>6 months) duration. Logistic regression analyses showed that, after controlling for wave 1 suicide attempt which significantly predicted postremission suicide attempt (OR = 10.0), the additional complicated symptom 'feelings of worthlessness' during the wave 1 index episode significantly and very substantially predicted postremission suicide attempt (OR = 6.96). Neither wave 1 psychomotor retardation nor wave 1 suicidal ideation nor any of the other wave 1 depressive symptoms were significant predictors of wave 2 suicide attempt. |
Does interferon α-2b gain high sustained response therapy for advanced essential thrombocythemia and polycythemia vera with JAK2V617F positive mutation? | This open-label, prospective, observational study aimed to evaluate treatment response, efficacy therapy and safety to IFN α-2b for the essential thrombocythemia (ET) and polycythemia vera (PV) with JAK2V617F positive mutation. A total of 123 ET patients received IFNα-2b therapy with JAK2V617F positive or negative mutation; and 136 PV patients with JAK2V617F(+) received IFNα-2b or hydroxyurea (HU) therapy according to random number assignment (ages 18-65 years old). ET patients receiving IFN α-2b with JAK2V617F(+) had a greater advantage in overall hematologic response (OHR) than JAK2V617F(-) (83.3% versus 61.4%, P<0.01). For PV patients with JAK2V617F(+), IFN had no OHR superiority to HU (70.3% versus 70.8%, P>0.05), but which gained a greater satisfactory molecular response than HU (54.7% versus 19.4%, P<0.01). IFN significantly decreased the phlebotomy rate, which was better than HU for MPDs patients with OHR than HU (3.6% versus 65.7%, P<0.01). Furthermore, ET patients with JAK2V617F(+) demonstrated a definite advantage over JAK2V617F(-) in five-year PFS (75.9% versus 47.6%, P<0.05). For PV patients with JAK2V617F(+), IFN α-2b was superior to HU in five-year PFS (66.3% versus 46.7%, P<0.01). Moreover, IFN α-2b also contributed to improved vasomotor symptoms in MPDs, and especially significantly decreased the incidence of distal paresthesias (14.1% versus 37.5%) and erythromelalgia (9.4% versus 29.2%) better than HU (P<0.01). Meanwhile, IFN did not observe the severe hematological adverse events in patients with PV or ET. | Perchlorate is an environmental contaminant that blocks iodine uptake into the thyroid gland and reduces thyroid hormones. This action of perchlorate raises significant concern over its effects on brain development. The purpose of this study was to evaluate neurologic function in rats after developmental exposure to perchlorate. Pregnant rats were exposed to 0, 30, 300, or 1,000 ppm perchlorate in drinking water from gestational day 6 until weaning. Adult male offspring were evaluated on a series of behavioral tasks and neurophysiologic measures of synaptic function in the hippocampus. At the highest perchlorate dose, triiodothyronine (T(3)) and thyroxine (T(4)) were reduced in pups on postnatal day 21. T(4) in dams was reduced relative to controls by 16%, 28%, and 60% in the 30-, 300-, and 1,000-ppm dose groups, respectively. Reductions in T(4) were associated with increases in thyroid-stimulating hormone in the high-dose group. No changes were seen in serum T(3). Perchlorate did not impair motor activity, spatial learning, or fear conditioning. However, significant reductions in baseline synaptic transmission were observed in hippocampal field potentials at all dose levels. Reductions in inhibitory function were evident at 300 and 1,000 ppm, and augmentations in long-term potentiation were observed in the population spike measure at the highest dose. |
Does [ Expression of human telomerase reverse transcriptase gene in HCC depend on proliferating cell nuclear antigen and P53 ]? | To investigate the expression of human telomerase reverse transcriptase(hTERT) gene and its relationship with proliferating cell nuclear antigen and P53. Immunohistochemical staining was used to detect the expressions of hTERT, PCNA and P53 in 42 hepatocellular carcinoma(HCC) tissues. The relationship between hTERT expression, pathological characters of HCC and PCNA and P53 expression was analyzed. The expression rates of hTERT, PCNA and P53 in HCC tissues were 71.4%(30/42),76.2%(32/42) and 73.8%(31/42), respectively. hTERT was not expressed in normal liver tissues. The expression rates of hTERT gene in HCC tissues of different pathological grades (I, II and III)were 40.0%(4/10), 70.0%(14/20) and 100%(12/12), respectively. The expression of hTERT was correlated with HCC recurrence. | To compare the postoperative analgesic effects of 50 mg diclofenac p.o. before surgery and intra-articular ropivacaine injected after diagnostic day-case knee arthroscopy performed under spinal anesthesia. In a randomized, double-blind investigation, 200 ASA physical status 1-2 outpatients, age 18-60 yr, received either 50 mg diclofenac p.o. or placebo one hour before operation (100 patients per group), and intraarticular injections of either 20 ml of ropivacaine 0.5% or 20 ml of saline 0.9% (50 patients in each premedication groups). Patients received 50 mg diclofenac p.o. prn and, if needed, 0.1 mg x kg(-1) oxycodone im for postoperative pain relief. Patients were discharged home with a supply of 50 mg diclofenac tablets and were given a sheet of paper with knee pain VAS scales and a questionnaire of analgesics taken. Patients rated their VAS scores eight hours after surgery and in the moming and at the end of the first and the second postoperative days, respectively. The only statistically significant difference was found when the diclofenac groups were combined and compared with the combined placebo premedication groups. The VAS scores of knee pain at eight hours after the operation were 19+/-22 in the two diclofenac premedication groups and 32+/-28 in the two placebo groups (P = 0.001). |
Is the metabolic syndrome amplified in hypothyroid rheumatoid arthritis patients : a cross-sectional study? | Rheumatoid arthritis (RA) patients are at increased risk of cardiovascular disease (CVD), which is even more pronounced in hypothyroid RA patients. An unfavourable cardiovascular risk profile conferred by a higher prevalence of the metabolic syndrome (MetS) and a higher Framingham risk score might explain this amplified cardiovascular morbidity. This study compared first, MetS (features) and second, the Framingham 10-year CVD risk in RA patients with hypothyroidism compared with euthyroid RA patients. RA patients participating in the CARRE investigation were divided into two groups: hypothyroid and euthyroid RA patients. MetS according to the National Cholesterol Education Program Third Adult Treatment Panel criteria and the Framingham risk score was compared between hypothyroid and non-hypothyroid CVD event-free RA patients. In total, 257 RA patients were included: 236 with RA (91.8%) and 21 with hypothyroid RA (8.2%), respectively. The prevalence of the MetS was significantly higher in hypothyroid RA patients (43%) compared with RA patients (20%). Moreover, female hypothyroid RA patients had a higher Framingham risk score compared with euthyroid RA patients. With RA patients as the reference category, the age and gender-adjusted prevalence odds ratio for the MetS was 3.5 (95% CI 1.3 to 9.1) in hypothyroid RA. | To evaluate intestinal inflammatory and apoptotic processes after intestinal ischemia/reperfusion injury, modulated by pentoxifylline and hypertonic saline. It was allocated into four groups (n=6), 24 male Wistar rats (200 to 250 g) and submitted to intestinal ischemia for 40 min and reperfusion for 80 min: IR (did not receive any treatment); HS group (Hypertonic Saline, 4 ml/kg-IV); PTX group (Pentoxifylline, 30 mg/kg-IV); HS+PTX group (Hypertonic Saline and Pentoxifylline). All animals were heparinized (100 U/kg). At the end of reperfusion, ileal fragments were removed and stained on hematoxylin-eosin and histochemical studies for COX-2, Bcl-2 and cleaved caspase-3. The values of sO2 were higher on treated groups at 40 minutes of reperfusion (p=0.0081) and 80 minutes of reperfusion (p=0.0072). Serum lactate values were lower on treated groups after 40 minutes of reperfusion (p=0.0003) and 80 minutes of reperfusion (p=0.0098). Morphologic tissue injuries showed higher grades on IR group versus other groups: HS (p=0.0006), PTX (p=0.0433) and HS+PTX (p=0.0040). The histochemical study showed lesser expression of COX-2 (p=0.0015) and Bcl-2 (p=0.0012) on HS+PTX group. A lower expression of cleaved caspase-3 was demonstrated in PTX (p=0.0090; PTXvsIR). |
Are structural abnormalities similar in familial and nonfamilial mesial temporal lobe epilepsy? | Diffuse temporal lobe abnormalities can be observed on MRI of patients with mesial temporal lobe epilepsy (MTLE). Our objective was to perform qualitative and quantitative analyses of temporal lobe structures in patients with familial MTLE (FMTLE) and nonfamilial MTLE. Two groups of patients were ascertained: 67 FMTLE patients (14 with refractory seizures) and 30 patients with nonfamilial refractory MTLE. We performed qualitative analyses of MRI (with multiplanar reconstruction) and volumes of hippocampi and anterior temporal lobes in all patients, and in a normal control group of 23 individuals. We used the Chi-square test and ANOVA for statistical analyses. We identified anterior temporal lobe abnormalities by visual analysis in only 4% of FMTLE patients and atrophy of the anterior temporal lobe by volumetric analysis in 19%. In the group of nonfamilial MTLE patients we found anterior temporal lobe abnormalities by visual analysis in 17% of patients and anterior temporal lobe atrophy in 13%. Hippocampal atrophy was present in 90% of FMTLE and in 83% of nonfamilial MTLE. No signs of cortical dysplasia were observed. | Cardiac surgery with cardiopulmonary bypass (CPB) induces an acute phase reaction that is implicated in the pathogenesis of several postoperative complications. Studies have shown that proinflammatory cytokines are increased by acute hyperglycemia. Recent evidence suggests that insulin has antiinflammatory properties. Therefore, we hypothesized that high-dose insulin therapy would attenuate the systemic inflammatory response to cardiopulmonary bypass and surgery in coronary artery bypass patients while maintaining normoglycemia. A total of 52 patients who presented for elective coronary artery bypass were randomized to receive intraoperative intravenous insulin infusion, titrated to maintain blood glucose concentrations less than 180 mg/dL (group I, n = 25), or receive intraoperative fixed high dose of intravenous insulin infusion (5 mU/kg/min) with dextrose 20% infused separately to maintain a blood glucose level between 70 and 110 mg/dL (group II, n = 27). Blood samples were collected at different time points to determine tumor necrosis factor alpha (TNFalpha), interleukin 6 and 8 (IL6 and IL8), and complement factor 3 and 4 (C3 and C4). Patients in both groups had similar preoperative characteristics. Patients in the high-dose insulin group had higher blood insulin concentrations and tighter blood glucose control. There were lower levels of IL6 (150 pg/dL vs 245 pg/dL, p = 0.03), IL-8 (49 pg/dL vs 74 pg/dL, p = 0.05), and TNFalpha (2.2 pg/dL vs 3.0 pg/dL, p = 0.04) in group II in the early postoperative period. |
Does valsartan attenuate cardiac and renal hypertrophy in rats with experimental cardiorenal syndrome possibly through down-regulating galectin-3 signaling? | Aortocaval fistula (AV) induced chronic volume overload in rats with preexisting mild renal dysfunction (right kidney remove: UNX) could mimic the type 4 cardiorenal syndrome (CRS): chronic renocardiac syndrome. Galectin-3, a β-galactoside binding lectin, is an emerging biomarker in cardiovascular as well as renal diseases. We observed the impact of valsartan on cardiac and renal hypertrophy and galectin-3 changes in this model. Adult male Sprague-Dawley (SD) rats (200-250 g) were divided into S (Sham, n = 7), M (UNX+AV, n = 7) and M+V (UNX+AV+valsartan, n = 7) groups. Eight weeks later, cardiac function was measured by echocardiography. Renal outcome was measured by glomerular filtration rate, effective renal plasma flow, renal blood flow and 24 hours albuminuria. Immunohistochemistry and real-time PCR were used to evaluate the expressions of galectin-3 in heart and renal. Cardiac hypertrophy and renal hypertrophy as well as cardiac enlargement were evidenced in this AV shunt induced chronic volume overload rat model with preexisting mild renal dysfunction. Cardiac and renal hypertrophy were significantly attenuated but cardiac enlargement was unaffected by valsartan independent of its blood pressure lowering effect. 24 hours urine albumin was significantly increased, which was significantly reduced by valsartan in this model. Immunohistochemistry and real-time PCR evidenced significantly up-regulated galectin-3 expression in heart and kidney and borderline increased myocardial collagen I expression, which tended to be lower post valsartan treatment. | The aim of this study was to investigate the effect of season of diagnosis on the outcome of patients with diffuse large B-cell lymphoma (DLBCL) and Hodgkin lymphoma (HL). In this study, we included curatively treated DLBCL (n = 5875) and HL (n = 1693) patients, diagnosed between 2000 and 2011, based on data from the Swedish Lymphoma Register. Overall survival was significantly better for patients diagnosed with DLBCL during the summer months, but not for patients diagnosed with HL. The difference remained in a multivariable analysis adjusted for age, stage, performance status, number of extra nodal sites and year of diagnosis (HR 1.08; 95% CI 1.02-1.14, P = 0.0069). When analyzing the DLBCL patients according to gender in the multivariable model, the effect of season was shown to be restricted to male patients (HR = 1.09, 95% CI 1.01-1.17, P = 0.0269. |
Does microRNA-361-5p inhibit Cancer Cell Growth by Targeting CXCR6 in Hepatocellular Carcinoma? | A growing body of evidence supports the notion that MicroRNAs (miRNAs) function as key regulators of tumorigenesis. In the present study, the expression and roles of miRNA-361-5p were explored in hepatocellular carcinoma (HCC). Quantitative real-time PCR was used to detect the expression miR-361-5p in HCC tissues and pair-matched adjacent normal tissues. MTT and BrdU assays were used to identify the role of miR-361-5p in the regulation of proliferation and invasion of HCC cells. Using bioinformatics analysis, luciferase reporter assays and Western blots were used to identify the molecular target of miR-361-5p. nude mice were used to detect the anti-tumor role of miR-361-5p in vivo. miR-361-5p was down-regulated in HCC tissues in comparison to adjacent normal tissues, due to hypermethylation at its promoter region. Overexpression of miR-361-5p suppressed proliferation and invasion of HCC cells. Chemokine (C-X-C Motif) receptor 6 (CXCR6) was identified as a target of miR-361-5p. Indeed, knockdown of CXCR6 photocopied, while overexpression of CXCR6 largely attenuated the anti-proliferative effect of miR-361-5p. More importantly, in vivo studies demonstrated that forced expression of miR-361-5p significantly inhibited tumor growth in the nude mice. | The relative contribution of nitric oxide (NO) to the killing of Mycobacterium tuberculosis in human tuberculosis (TB) is controversial, although this has been firmly established in rodents. Studies have demonstrated that clinical strains of M. tuberculosis differ in susceptibility to NO, but how this correlates to drug susceptibility and clinical outcome is not known. In this study, 50 sputum smear- and culture-positive patients with pulmonary TB in Gondar, Ethiopia were included. Clinical parameters were recorded and drug susceptibility profile and spoligotyping patterns were investigated. NO susceptibility was studied by exposing the strains to the NO donor DETA/NO. Clinical isolates of M. tuberculosis showed a dose- and time-dependent response when exposed to NO. The most frequent spoligotypes found were CAS1-Delhi and T3_ETH in a total of nine known spoligotypes and four orphan patterns. There was a significant association between reduced susceptibility to NO (>10% survival after exposure to 1 mM DETA/NO) and resistance against first-line anti-TB drugs, in particular isoniazid (INH). Patients infected with strains of M. tuberculosis with reduced susceptibility to NO showed no difference in cure rate or other clinical parameters but a tendency towards lower rate of weight gain after two months of treatment, independent of antibiotic resistance. |
Is strengthening of mass drug administration implementation required to eliminate lymphatic filariasis from India : an evaluation study? | The mass drug administration (MDA) is one of the strategies to eliminate lymphatic filariasis in India. Eleven districts are endemic for the disease in Madhya Pradesh state of India, which conduct MDA activities annually. A mid-term evaluation was conducted with the objectives to review the progress of the single dose of di-ethyl-carbamazine (DEC) administration, and to understand the functioning of the programme to recommend mid-term amendments. A qualitative cross-sectional study was conducted in three endemic districts of Madhya Pradesh between July and October 2007. The teams of faculty members from medical college visited the study districts and collected data by desk review, indepth interviews, on site observations, and from the community. The filaria units in these districts were understaffed. There were no night clinics in two out of the three districts. The sufficient number of trainings for MDA were conducted without any mechanism for quality assurance. There was erratic and inadequate supply of DEC tablets, leading to the postponement of MDA activity, twice. The evaluated coverage with DEC tablets was much lower than that reported by the district officials. The tablet intake was not ensured by the distributors and the compliance rate was in the range of 60-70%. The IEC activities were conducted in limited areas, and there were prevailing myths and misconceptions, contributing to low compliance rate. There was no proper recording of the data on filariasis with gross mismatch at district headquarters and peripheral health facilities. A proportion of community members developed side effects following DEC tablet intake and had to visit private health facilities for treatment. | We and others have shown that swimming exercise training performed before irreversible coronary occlusion improves the outcome of the heart injury and alters gene expression at the remodeling phase. The purpose of the current study was to identify temporal changes in the molecular response to myocardial infraction of prior exercise trained rats during the acute, the subacute, and the chronic phases postinfarction. Rats underwent a 7-wk swimming or sedentary protocol and were subjected to surgical induction of acute myocardial infarction (MI). Hearts were removed before and at 4 h, 2 d, and 4 wk after surgery. RNA extracted from the surviving myocardium of the MI hearts or from corresponding tissues in the non-MI hearts was subjected to multitranscript profiling. Results for representative transcripts were validated by reverse transcription and quantitative polymerase chain reaction amplification. Global analysis of the 3686 detected transcripts generated a two-branch dendrogram that distinguished the pre-MI and the 4-h groups from the 2-d and the 4-wk groups and indicated that early after MI, the impact of infarction on the genes expressed overrides the training effect, whereas at 4 wk, the exercised hearts differ markedly from the nonexercised. Clustering the 1500 genes that showed the highest variance over time indicated differential expression of transcription regulators and proapoptotic genes 4 h and 2 d after MI and of stress-related and profibrotic genes 4 wk later in the exercised compared with sedentary hearts. |
Does noladin ether act on trabecular meshwork cannabinoid ( CB1 ) receptors to enhance aqueous humor outflow facility? | To study the effects of 2-arachidonyl glyceryl ether (noladin ether), an endocannabinoid ligand selective for cannabinoid (CB)1 receptor, on aqueous humor outflow facility, to investigate the involvement of trabecular meshwork CB1 receptors and the p42/44 MAP kinase signaling pathway and to explore the cellular mechanisms of noladin ether-induced changes of outflow facility. The effects of noladin ether on aqueous humor outflow facility were measured in a porcine anterior-segment-perfused organ culture model. The expression of CB1 receptors on cultured porcine trabecular meshwork cells and the coupling of these receptors to p42/44 MAP kinase was determined by immunofluorescence microscopy and Western blot analysis. Both Western blot and zymography were used to monitor the effects of noladin ether on matrix metalloproteinase (MMP)-2. In morphologic studies, AlexaFluor 488-labeled phalloidin staining was used to examine actin filament, and immunohistochemistry with anti-paxillin antibodies was used to detect focal adhesions. Within 1 hour after adding 3, 30, or 300 nM of noladin ether, the aqueous humor outflow facility increased concentration dependently. The effect of 30 nM of noladin ether was completely blocked by SR141716A, a selective CB1 antagonist. Positive signals were detected on cultured porcine trabecular meshwork cells with an anti-CB1 antibody in immunofluorescence microscopy and Western blot studies. Treatment of trabecular meshwork cells with 30 nM of noladin ether activated p42/44 MAP kinase, whereas pretreatment with SR141716A blocked the p42/44 MAP kinase-activating effects of noladin ether. In addition, the enhancement of outflow facility induced by noladin ether was blocked by pretreatment of porcine anterior segments with PD98059, an inhibitor of p42/44 MAP kinase pathway. Furthermore, noladin ether treatment caused rounding of trabecular meshwork cells, and there was a decrease of actin stress fibers, as well as a decrease in focal adhesions. These noladin ether-induced morphologic changes were also blocked by SR141716A and PD98059. | Serum ferritin concentration >100 ng/mL was associated with a higher risk of death in hemodialysis patients in Japan, whereas such an association was less clear in hemodialysis patients in Western countries. Since Japanese dialysis patients are generally less inflamed than those in Western countries, inflammation may modify the association between serum ferritin and the adverse outcomes. We performed an observational cohort study using data from 2606 Japanese hemodialysis patients who participated in the Dialysis Outcomes and Practice Patterns Study (DOPPS) III (2005-2008) or DOPPS IV (2009-2012). The predictor was serum ferritin category (<50, 50-99.9, 100-199.9, and ≥200 ng/mL), and the primary and secondary outcomes were all-cause mortality and cardiovascular hospitalization, respectively. C-reactive protein (CRP, cut-off by 0.3 mg/dL) and serum albumin (cut-off by 3.8 g/dL) were stratification factors related to systemic inflammation. After adjustment for relevant confounding factors, a U-shaped association was observed between serum ferritin and all-cause mortality in the group with low CRP levels, whereas such relationship was not significant in the high CRP counterparts. In contrast, we found a linear association between serum ferritin and cardiovascular hospitalization in the low CRP and high CRP groups commonly. Similar results were obtained when the total cohort was stratified by serum albumin. |
Are decreased plasma levels of select very long chain ceramide species associated with the development of nephropathy in type 1 diabetes? | Sphingolipid metabolism is altered in diabetes and we analyzed the plasma concentrations of sphingolipid species to investigate their association with the development of albuminuria in type 1 patients with diabetes. Samples were collected from 497 type 1 diabetic patients during their enrollment into the Diabetes Control and Complications Trial (DCCT). We determined plasma concentrations of multiple ceramide species and individual sphingoid bases and their phosphates using high performance liquid chromatography-tandem mass spectrometry and investigated their association with the development of albuminuria during 14-20 years of follow-up. Patients exhibited normal albumin excretion rates (AER <40 mg/24h) at the time of plasma sampling. Although the majority of patients (N = 291; 59%) exhibited normal levels of albuminuria throughout follow-up, 141 patients (28%) progressed to microalbuminuria (40 mg/24h ≤ AER<300 mg/24h), while 65 (13%) progressed to macroalbuminuria (AER ≥ 300 mg/24h). To test the association of log transformed plasma sphingolipid level with the development of albuminuria, generalized logistic regression models were used where normal, micro- and macroalbuminuria were the outcomes of interest. Models were adjusted for DCCT treatment group, baseline retinopathy, gender, baseline HbA1c %, age, AER, lipid levels, diabetes duration, and the use of ACE/ARB drugs. Increased plasma levels of very long, but not long chain ceramide species measured at DCCT baseline were associated with decreased odds to develop macroalbuminuria during the subsequent nineteen years (DCCT Baseline to EDIC year 8). | Accurate tumour bed localisation is a key requirement for adjuvant radiotherapy. A new procedure is described for head and neck cancer treatment that improves tumour bed localisation using titanium clips. Following complete local excision of the primary tumour, the tumour bed was marked with titanium clips. Preoperative gross target volume (GTV) and postoperative tumour bed were examined and the distances between the centres of gravity were evaluated. 49 patients with squamous cell carcinoma of the oral cavity were prospectively enrolled in this study. All patients underwent tumour resection, neck lymph node dissection and defect reconstruction in one stage. During surgery, 7-49 clips were placed in the resection cavity. Surgical clip insertion was successful in 88% (n=43). Clip identification and tumour bed delineation was successful in all 43 patients. The overall distance between the centres of gravity of the preoperative tumour extension to the tumour bed was 0.9cm. A significant relationship between the preoperative tumour extension and the postoperative tumour bed volume could be demonstrated. |
Does maze surgery normalize left ventricular function in patients with persistent lone atrial fibrillation? | The aim of this study is to evaluate the mid-term clinical and functional outcomes of maze surgery in symptomatic refractory lone atrial fibrillation (AF) patients. Between March 2008 and January 2013, 39 highly symptomatic patients [mean age 51 ± 10 (mean ± standard deviation); 95% CI, European Heart Rhythm Association class III-IV] underwent maze surgery for lone AF. Biatrial ablations were performed with bipolar radiofrequency and cryoenergy, according to a maze III lesion set (modified by omitting the intercaval line in 5 of 39 patients). Mean ejection fraction was 51 ± 9% (range 17-60), <45% in 10 patients (26%). Seventeen of 39 patients (44%) had persistent, 22 of 39 patients (56%) long-standing persistent AF, and 35 of 39 patients (90%) had previous transvenous ablations (median = 2; range 0-8). No patient had concomitant structural heart disease. A minimally invasive approach was adopted in 22 patients (56%). Major complications were 1 mediastinitis, 1 re-exploration for bleeding and 2 pacemaker (5%) implantation. At a mean follow-up of 29.4 ± 14.2 months, freedom from arrhythmias was 92 and 93% at 24 and 36 months, respectively. Freedom without antiarrhythmic drugs was 75 and 85% at 24 and 36 months, respectively. Ejection fraction normalized in all cases, from 51.3 ± 9% to 61.1 ± 3% (P < 0.001) overall, and from 37.0 ± 10% to 60.3 ± 3% (P < 0.001) when ≤ 45% preoperatively. AF-related symptoms score decreased to class I in 36 patients (93%). No early or late stroke occurred. | A growing body of evidence indicates a positive correlation between expression of human antimicrobial peptide leucin leucin 37 (LL-37) and progression of epithelial cancers, including prostate cancer (PCa). Although the molecular mechanisms for this correlation has not yet been elucidated, the primary function of LL-37 as a chemotactic molecule for innate immune effector cells suggests its possible association in coordinating protumorigenic mechanisms, mediated by tumor-infiltrating immune cells. To investigate protumorigenic role(s) of cathelicidin-related antimicrobial peptide (CRAMP), a murine orthologue of LL-37, the present study compared tumor growth kinetics between mouse PCa cell lines with and without CRAMP expression (TRAMP-C1 and TRAMP-C1(CRAMP-sh) , respectively) in immunocompetent mice. CRAMP-mediated chemotaxis of different innate immune cell types to the tumor microenvironment (TME) was observed in vivo and confirmed by in vitro chemotaxis assay. The role of CRAMP in differentiation and polarization of immature myeloid progenitors (IMPs) to protumorigenic type 2 macrophages (M2) in TME was determined by adoptive transfer of IMPs into mice bearing CRAMP(+) and CRAMP(-) tumors. To differentiate protumorigenic events mediated by tumor-derived CRAMP from host immune cell-derived CRAMP, tumor challenge study was performed in CRAMP-deficient mice. To identify mechanisms of CRAMP function, macrophage colony stimulating factor (M-CSF) and monocyte chemoattractant protein 1 (MCP-1) gene expression was analyzed by QRT-PCR and STAT3 signaling was determined by immunoblotting. Significantly delayed tumor growth was observed in wild-type (WT) mice implanted with TRAMP-C1(CRAMP-sh) cells compared to mice implanted with TRAMP-C1 cells. CRAMP(+) TME induced increased number of IMP differentiation into protumorigenic M2 macrophages compared to CRAMP(-) TME, indicating tumor-derived CRAMP facilitates differentiation and polarization of IMPs toward M2. Tumor challenge study in CRAMP deficient mice showed comparable tumor growth kinetics with WT mice, suggesting tumor-derived CRAMP plays a crucial role in PCa progression. In vitro study demonstrated that overexpressed M-CSF and MCP-1 in TRAMP-C1 cells through CRAMP-mediated autocrine signaling, involving p65, regulates IMP-to-M2 differentiation/polarization through STAT3 activation. |
Is obesity associated with increased postoperative complications after operative management of proximal humerus fractures? | Obesity has become a significant public health concern in the United States. The goal of this study was to assess the effect of obesity on postoperative complications after operative management of proximal humerus fractures by use of a national database. Patients who underwent operative management of a proximal humerus fracture were identified in a national database by Current Procedural Terminology codes for procedures in patients with International Classification of Diseases, Ninth Revision (ICD-9) codes for proximal humerus fracture, including (1) open reduction and internal fixation, (2) intramedullary nailing, (3) hemiarthroplasty, and (4) total shoulder arthroplasty. These groups were then divided into obese and nonobese cohorts by use of ICD-9 codes for obesity, morbid obesity, or body mass index >30. Each cohort was then assessed for local and systemic complications within 90 days and mortality within 2 years postoperatively. Odds ratios and 95% confidence intervals were calculated. From 2005 to 2011, 20,319 patients who underwent operative management of proximal humerus fractures were identified, including 14,833 (73.0%) open reduction and internal fixation, 1368 (9.2%) intramedullary nail, 3391 (16.7%) hemiarthroplasty, and 727 (3.6%) shoulder arthroplasty. Overall, 3794 patients (18.7%) were coded as obese, morbidly obese, or body mass index >30. In each operative group, obesity was associated with a substantial increase in local and systemic complications. | Cell proliferation, vector titer and accessibility of target cells represent hurdles for efficient gene transfer to lung epithelia in vivo using recombinant murine leukemia (MuLV)-based retroviruses. We tested the hypothesis that the pulmonary epithelium is susceptible to retroviral-mediated gene transfer when stimulated to proliferate by a mitogen, keratinocyte growth factor (KGF). Rats received keratinocyte growth factor (KGF, 2.5 micrograms/g x 4 doses, two consecutive days) intratracheally followed by high titer amphotropic retrovirus expressing beta-galactosidase. Gene transfer was assessed five days later. KGF stimulated transient proliferation in the bronchiolar and alveolar epithelia (30-40% PCNA positive cells at peak) which decreased to background levels seven days after administration. Gene transfer to epithelia (X-Gal positive cells) occurred more frequently in KGF treated rats, but proliferation exceeded the level of gene transfer. X-gal positive cells were noted in the alveolar epithelium and occasionally in the bronchiolar epithelium. In order to understand the discrepancy between the number of proliferating and transduced cells, primary rat tracheal epithelium cultured at the air-liquid interface was infected from either the apical or basolateral side. Gene transfer was achieved only through basolateral application of vector, suggesting that epithelial polarity represents a barrier to MuLV-based lung gene transfer in vivo. |
Is calnexin essential for mammalian rod opsin biogenesis? | Misfolding mutations in rod opsin are a major cause of the inherited blindness retinitis pigmentosa. Therefore, understanding the role of molecular chaperones in facilitating rod opsin biogenesis and the response to mutant rod opsin is important for retinal disease and fundamental retinal cell biology. A recent report has shown that Drosophila rhodopsin Rh1 requires calnexin (Cnx) for its maturation and correct localization to R1-6 rhabdomeres. In this report, we investigate the role of Cnx in the processing of wild-type and mutant mammalian rod opsin. Mouse embryonic fibroblasts (MEFs) from control mice (WT) and mice that express a truncated dysfunctional version of Cnx (sCnx) were used to assess the role of Cnx in the biogenesis, maturation, degradation, and aggregation of mutant and wild-type rod opsin. The mutant P23H rod opsin was used as a prototypical class II misfolding mutant as it is retained in the endoplasmic reticulum (ER) and is either degraded by ER associated degradation (ERAD) or forms aggregates that coalesce to form intracellular inclusions. Wild-type rod opsin protein translocated normally to the plasma membrane in both cell lines. In contrast, P23H rod opsin was retained in the ER in both cell lines. The only difference observed in rod opsin processing between the WT and sCnx MEFs was a small increase in the incidence of P23H intracellular inclusions in the sCnx cells. This did not appear to be specific for rod opsin, however, as non-rod opsin-expressing sCnx cells also had an increased incidence of ubiquitylated inclusions. | The onset of insulin resistance is an important metabolic event in the development of type 2 diabetes. For patients with type 2 diabetes, we recently showed that peripheral insulin sensitivity was increased during hyperbaric oxygen treatment (HBOT). This study aims to investigate whether this occurs in a non-patient population with and without type 2 diabetes, along with the mechanism of this effect. Overweight and obese male participants were recruited from the community, 11 without and eight with type 2 diabetes. Insulin sensitivity was measured by the glucose infusion rate (GIR) during a hyperinsulinaemic euglycaemic clamp (80 mU·m⁻²·min⁻¹) at baseline and during the third HBOT session. Monocyte chemo-attractant protein-1 (MCP-1), tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6) were measured in fasting serum and adipose tissue samples taken for their gene expression at baseline and immediately following four HBOT sessions. Additional fasting serum samples were collected during the first HBOT at 0, 60 and 120 minutes, and 24-hours after the last HBOT. In response to HBOT, GIR was increased by 29±32% in those without (n=10, P=0.01), and by 57±66% in those with type 2 diabetes (n=7, P=0.04). This increase was maintained for 30 minutes post HBOT. Reduced MCP-1 and TNF-α were observed after HBOT, whereas IL-6 was increased only in individuals without diabetes and this correlated with the increase in insulin sensitivity (r²=0.72, P=0.004). |
Do cognitive complaints correlate with depression rather than concurrent objective cognitive impairment in the successful aging evaluation baseline sample? | Whether subjective cognitive complaints are suggestive of depression or concurrent cognitive impairment in older adults without dementia remains unclear. The current study examined this question in a large (N = 1000), randomly selected, community-based sample of adults aged 51 to 99 years without a formal diagnosis of dementia (Successful AGing Evaluation [SAGE] study). The modified Telephone Interview for Cognitive Status (TICS-m) measured objective cognitive function, the Cognitive Failures Questionnaire (CFQ) measured subjective cognitive complaints, and the 9-item Patient Health Questionnaire (PHQ-9) measured depression. Spearman ρ correlations and linear regression models were conducted to examine the relationship among variables in the baseline SAGE sample. There was a weak association between TICS-m and CFQ scores (ρ = -.12); however, a moderate to large association was observed for CFQ and PHQ-9 (ρ = .44). Scores on the CFQ were not associated with TICS-m scores (β = -.03, P = .42) after controlling for PHQ-9 and variables of interest, such as age, gender, ethnicity, and physical functioning, while PHQ-9 was significantly associated with CFQ scores (β = .46, P < .001) after controlling for variables of interest. | To study the efficacy of an oxygen-carrying solution in early resuscitation of hemorrhagic shock induced by penetrating vascular injury. Experimental study with anesthetized rats. Severe hemorrhagic shock was induced by a 25-gauge needle puncture to the infrarenal aorta. Forty animals were resuscitated 10 minutes after injury with either lactated Ringer's solution (LR; 60 mL/kg), 7.5% hypertonic saline (HTS; 5 mL/kg), or modified diaspirin cross-linked hemoglobin (PolyDCLHb; 5 or 20 mL/kg) or were not resuscitated (NR) and followed for 6 hours. Total blood loss was similar in all treatment groups. Mean arterial pressure was restored to baseline values, base deficit was corrected to base excess, and venous oxygen saturation improved with PolyDCLHb and more slowly with LR but persisted below baseline values with HTS and NR. The 6-hour mortality rates were zero of eight (low-dose PolyDCLHb), three of eight (high-dose PolyDCLHb), two of eight (LR), six of eight (HTS), and six of eight (NR). |
Is brachial artery ligation with total graft excision a safe and effective approach to prosthetic arteriovenous graft infections? | While autogenous arteriovenous access is preferred, prosthetic arteriovenous grafts (AVG) are still required in a large number of patients. Infection of AVGs occurs frequently and may cause life-threatening bleeding or sepsis. Multiple treatment strategies have been advocated (ranging from graft preservation to excision with complex concomitant reconstructions), indicating a lack of consensus on appropriate management of infected AVGs. We undertook this study to evaluate if, in the setting of anastomotic involvement, brachial artery ligation distal to the origin of the deep brachial artery accompanied by total graft excision (BAL) is safe and effective. All prosthetic arteriovenous graft infections managed by a single surgeon between 1995 and 2006 were reviewed retrospectively. Patients were identified from a computerized vascular registry, and data were obtained via patient charts and the electronic medical record. We identified 45 AVG infections in 43 patients. Twenty-one patients (49%) demonstrated arterial anastomotic involvement and were treated with BAL; these form the cohort for this analysis. Mean patient age was 53.2 (SD 9.5) years. The primary etiologies for end stage renal disease (ESRD) were hypertension (29%), HIV (24%), and diabetes (19%). An upper arm AVG was present in 95% of patients; one (5%) had a forearm AVG. The majority of grafts were polytetrafluoroethylene (PTFE) (90%). Follow-up was 100% at 1 month, 86% at 3 months, and 67% at 6 months. No ischemic or septic complications occurred in the 21 patients who underwent BAL. | Sialic acid, a key component of both human milk oligosaccharides and neural tissues, may be a conditional nutrient during periods of rapid brain growth. We tested the hypothesis that variations in the sialic acid content of a formula milk would influence early learning behavior and gene expression of enzymes involved in sialic acid metabolism in piglets. Piglets (n = 54) were allocated to 1 of 4 groups fed sow milk replacer supplemented with increasing amounts of sialic acid as casein glycomacropeptide for 35 d. Learning performance and memory were assessed with the use of easy and difficult visual cues in an 8-arm radial maze. Brain ganglioside and sialoprotein concentrations and mRNA expression of 2 learning-associated genes (ST8SIA4 and GNE) were measured. In both tests, the supplemented groups learned in significantly fewer trials than did the control group, with a dose-response relation for the difficult task (P = 0.018) but not the easy task. In the hippocampus, significant dose-response relations were observed between amount of sialic acid supplementation and mRNA levels of ST8SIA4 (P = 0.002) and GNE (P = 0.004), corresponding with proportionate increases in protein-bound sialic acid concentrations in the frontal cortex. |
Are physical distance , genetic relationship , age , and leprosy classification independent risk factors for leprosy in contacts of patients with leprosy? | Close contacts of patients with leprosy have a higher risk of developing leprosy. Several risk factors have been identified, including genetic relationship and physical distance. Their independent contributions to the risk of developing leprosy, however, have never been sufficiently quantified. Logistic-regression analysis was performed on intake data from a prospective cohort study of 1037 patients newly diagnosed as having leprosy and their 21,870 contacts. Higher age showed an increased risk, with a bimodal distribution. Contacts of patients with paucibacillary (PB) leprosy with 2-5 lesions (PB2-5) and those with multibacillary (MB) leprosy had a higher risk than did contacts of patients with single-lesion PB leprosy. The core household group had a higher risk than other contacts living under the same roof and next-door neighbors, who again had a higher risk than neighbors of neighbors. A close genetic relationship indicated an increased risk when blood-related children, parents, and siblings were pooled together. | Malignant astrocytic gliomas are the most common and lethal brain malignancies due to their refractory to the current therapies. Nowadays, molecular targeted therapy has attracted great attention in treatment of glioma. Connexin 43 (Cx43) and micro ribonucleic acid-21(miR-21) are among molecules that are involved in glioma development and progression. These molecules showed potential to be as target molecules with regard to glioma. Some studies have reported that cyclic adenosine monophosphate (cAMP) signaling could be effective on Cx43 and miR-21 in tissues other than in brain. We investigate possible relationship between β-adrenergic receptor and its newly described downstream, exchange protein directly activated by cAMP (Epac) signaling pathway and expression of Cx43 and miR-21 in low (1321N1) and high grade (U87MG) glioma cell lines. We treated cells with β-adrenergic agonist and Epac activator with and without adenyl cyclase inhibitor. Cx43 and miR-21 expression were measured with real-time PCR. Our data showed that in 1321N1 cells, β-adrenergic-Epac pathway stimulation up and down-regulated Cx43 and miR-21 expression respectively. Whereas, in U87MG cells these interventions had no effect on Cx43 and miR-21 expression. |
Does human epidermal growth factor enhance healing of diabetic foot ulcers? | To study the healing effect of recombinant human epidermal growth factor (hEGF) on diabetic foot ulcers. A total of 127 consecutive patients were screened and 61 diabetic subjects were recruited into this double-blind randomized controlled study. Predetermined criteria were used for diagnosis and classification of the diabetic wound. The patients were randomized into three groups. All patients attended our Diabetes Ambulatory Care Center every other week for joint consultation with the diabetologist and the podiatrist. Group 1 (control) was treated with Actovegin 5% cream (Actovegin), group 2 with Actovegin plus 0.02% (wt/wt) hEGF, and group 3 with Actovegin plus 0.04% (wt/wt) hEGF. The study end point was the complete closure of the wound. Failure to heal was arbitrarily defined as incomplete healing after 12 weeks. Final data were obtained from 61 patients randomly assigned into three groups. The mean ages of the patients, wound sizes, wound duration, metabolic measurements, and comorbidities were comparable within groups, except that group 3 had more female patients. Mean follow-up for the patients was 24 weeks. Data were cutoff at 12 weeks, and results were analyzed by intention to treat. After 12 weeks, in group 1 (control) eight patients had complete healing, two patients underwent toe amputation, and nine had nonhealing ulcers. In group 2 (0.02% [wt/wt] hEGF) 12 patients experienced wound healing, 2 had toe amputations, and 7 had nonhealing ulcers. Some 20 of 21 patients in group 3 (0.04% [wt/wt] hEGF) showed complete wound healing. Healing rates were 42.10, 57.14, and 95% for the control, 0.02% (wt/wt) hEGF, and 0.04% (wt/wt) hEGF groups, respectively. Kaplan-Meier survival analysis suggested that application of cream with 0.04% (wt/wt) hEGF caused more ulcers to heal by 12 weeks and increased the rate of healing compared with the other treatments (log-rank test, P = 0.0003). | Our main objective was to determine the neuropathological correlates of dementia in patients with Lewy body disease (LBD). Furthermore, we used data derived from clinical, neuropathological and genetic studies to investigate boundary issues between Dementia with Lewy bodies (DLB) and Parkinson's disease with (PDD) and without (PDND) dementia. One hundred and twenty-one cases with a neuropathological diagnosis of LBD and clinical information on dementia status were included in the analysis (55 PDD, 17 DLB and 49 PDND). We carried out topographical and semi-quantitative assessment of Lewy bodies (LB), Aβ plaques and tau-positive neuropil threads (NT). The APOE genotype and MAPT haplotype status were also determined. The cortical LB (CLB) burden was the only independent predictor of dementia (OR: 4.12, P < 0.001). The total cortical Aβ plaque burden was an independent predictor of a shorter latency to dementia from onset of motor signs (P = 0.001). DLB cases had a higher LB burden in the parietal and temporal cortex, compared to PDD. Carrying at least one APOE ϵ4 allele was associated with a higher cortical LB burden (P = 0.02), particularly in the neocortical frontal, parietal and temporal regions. |
Does pluronic L-81 ameliorate diabetic symptoms in db/db mice through transcriptional regulation of microsomal triglyceride transfer protein? | To test whether oral L-81 treatment could improve the condition of mice with diabetes and to investigate how L-81 regulates microsomal triglyceride transfer protein (MTP) activity in the liver. Genetically diabetic (db/db) mice were fed on chow supplemented with or without L-81 for 4 wk. The body weight, plasma glucose level, plasma lipid profile, and adipocyte volume of the db/db mice were assessed after treatment. Toxicity of L-81 was also evaluated. To understand the molecular mechanism, HepG2 cells were treated with L-81 and the effects on apolipoprotein B (apoB) secretion and mRNA level of the MTP gene were assessed. Treatment of db/db mice with L-81 significantly reduced and nearly normalized their body weight, hyperphagia and polydipsia. L-81 also markedly decreased the fasting plasma glucose level, improved glucose tolerance, and attenuated the elevated levels of plasma cholesterol and triglyceride. At the effective dosage, little toxicity was observed. Treatment of HepG2 cells with L-81 not only inhibited apoB secretion, but also significantly decreased the mRNA level of the MTP gene. Similar to the action of insulin, L-81 exerted its effect on the MTP promoter. | The 2011 American Academy of Pediatrics clinical practice guideline for childhood febrile urinary tract infection recommends voiding cystourethrography if renal and bladder ultrasound reveals hydronephrosis, scarring or "other findings" that suggest high grade vesicoureteral reflux. We sought to determine if the finding of uroepithelial thickening indicates greater risk of high grade vesicoureteral reflux and whether uroepithelial thickening improves the screening value of renal and bladder ultrasound. We retrospectively analyzed renal and bladder ultrasound and voiding cystourethrogram findings in children 2 to 24 months old with first febrile urinary tract infection during an 11-year period. Patients with uroepithelial thickening were compared to an age and gender matched sample without uroepithelial thickening. Logistic regression was used to identify factors associated with high grade vesicoureteral reflux. Test characteristics of renal and bladder ultrasound for high grade reflux were compared based on different criteria to define an abnormal renal and bladder ultrasound. Of 226 patients 143 (63%) had vesicoureteral reflux, of whom 37 (26%) had high grade reflux. On multivariable analysis uroepithelial thickening was a significant independent predictor of high grade vesicoureteral reflux (OR 5.41, 95% CI 1.74-16.79, p = 0.004). When hydronephrosis and hydroureter were considered the only abnormal renal and bladder ultrasound findings warranting voiding cystourethrography, sensitivity of renal and bladder ultrasound for high grade reflux was 84%, and 6 children with high grade and 82 with low grade reflux would have been missed. When uroepithelial thickening was also considered an abnormal finding, the sensitivity increased to 97%, and only 1 child with high grade and 57 with low grade reflux would have been missed. |
Does a high carbohydrate diet induce insulin resistance through decreased glucose utilization in ovariectomized rats? | Recent research has reported that high sugar diets increase insulin resistance, without abdominal obesity, in male, but not female Wistar rats. Whether a high sucrose (SU) diet increased insulin resistance in ovariectomized (OVX) rats was determined. Female Sprague Dawley rats, weighing 273 +/- 20 g, had either an ovariectomy or a sham operation (sham). OVX and sham rats were divided into two groups: one group had a 68 En% SU diet and the other a 68 En% starch (ST) diet for 8 weeks. The body weight was higher in the OVX than the sham rats, regardless of dietary carbohydrate subtype. The fasting serum glucose levels did not differ according to diet and ovariectomy. However, the fasting serum insulin levels were higher in the OVX than the sham rats, and in the OVX rats, a high SU diet increased the serum insulin levels more than a high ST diet. The whole body glucose disposal rates, which referred to the state of insulin sensitivity, were lower in the OVX rats fed both the high SU and ST diets, compared to sham rats. Glycogen deposits in the soleus and quadriceps muscles were lower in the OVX rats fed high SU and ST diets than in sham rats. The glucose transporter 4 content and fraction velocity of glycogen synthase in muscles showed similar glucose disposal rates. However, the triacylglycerol content in the muscles were higher in the OVX rats with a high SU diet than those with a high ST diet. | Extranodal natural killer/T-cell lymphoma, nasal type (ENKTL), is an aggressive type of lymphoma whose standard treatment and validated prognostic model have not yet been defined. CD30 expression was detected using immunohistochemistry in 96 ENKTL patients, and the data were used to evaluate its relationship with clinical features, treatment response and prognosis. Expression of CD30 was detected in 31.2% of ENKTL patients, which was significantly correlated with B symptoms and elevated serum lactate dehydrogenase. The complete remission rate was not significantly different between CD30-positive and negative groups. After a median follow-up time of 31 months, 5-year overall survival (OS) and 5-year progression-free survival (PFS) rates in the CD30-positive group were both significantly lower than those in the CD30-negative group (34.1% vs. 64.4%, P=0.002, for 5 year-OS; 26.0% vs. 66.7%, P<0.001, for 5 year-PFS). In patients with an International Prognostic Index (IPI) or Korean Prognostic Index (KPI) score of 0-1, CD30 positivity was associated with shorter 5-year OS and PFS (IPI: P=0.001 and 0.002, respectively; KPI: P=0.018 and 0.023, respectively). In a multivariate Cox regression model, CD30 expression and stage were independent prognostic factors for OS (p=0.004 and p=0.012, respectively) and PFS (p=0.001 and p=0.022, respectively). |
Is immediate post-traumatic pulmonary embolism associated with right ventricular dysfunction? | Post-traumatic pulmonary embolic events are associated with significant morbidity. Computed tomographic (CT) measurements can be predictive of right ventricular (RV) dysfunction after pulmonary embolus. However, it remains unclear whether these physiologic effects or clinical outcomes differ between early (<48 hours) vs late (≥48 hours) post-traumatic pulmonary embolism (PE). All patients with traumatic injury and CT evidence of PE between 2008 and 2013 were identified. The study population was divided into 2 groups based on the time of diagnosis of the PE. The primary outcome was PE-related mortality. Fifty patients were identified (14 early PE and 36 late PE). Patients sustaining a late PE had a higher PE-related mortality rate (16.7% vs 0%), larger RV diameters, RV/left ventricular diameter ratios, RV volumes, and RV/left ventricular volume ratios (all P < .05). | In coeliac disease, wheat, barley and rye are traditionally excluded in the gluten-free diet. However, few studies have examined the small intestinal immune response to barley and rye. To investigate the immunogenicity of barley and rye prolamins (hordein and secalin respectively) in comparison with wheat gliadin. Duodenal biopsies from 22 coeliac patients and 23 disease controls were cultured for 4 h with gliadin, hordein or secalin and compared with culture medium alone. Proinflammatory cytokines, interferon-gamma and interleukin-2, were quantified by TaqMan polymerase chain reaction and enzyme-linked immunosorbent assay. Hordein caused the greatest increase in interferon-gamma mRNA in coeliac patients (median: 3.3-fold) in comparison with control subjects (median: 0.28-fold, P < 0.085). Secalin and gliadin induced similar levels of interferon-gamma mRNA with median fold-changes of 3.4 and 2.8, respectively, in coeliac patients in comparison with 1.6- and 1.1-fold increases in control subjects (P < 0.294 and P < 0.105, respectively). The median fold-changes for interleukin-2 mRNA did not differ between coeliac patients and controls. Cytokine protein was not upregulated. |
Is decline in functional capacity unaffected by diet quality alone or in combination with physical activity among generally healthy older adults with T2D from the NuAge cohort? | Both diet quality (DQ) and physical activity (PA) have been shown to play a role in the prevention of functional capacity (FC) decline. Because older adults (OA) with T2D are at a higher risk of FC decline compared to their non-diabetic counterparts, our aim was to determine if DQ alone, or combined with PA is associated with FC decline in OA with T2D over a 3-year follow-up in a secondary analysis of the NuAge cohort. In 159 OA with T2D (mean age=75 years), FC change was calculated as the difference in FC scores at T1 and T4 measured by the SMAF (Système de Mesure de l'Autonomie Fonctionnelle). Baseline DQ was calculated from three non-consecutive 24-h dietary recalls collected at T1 using the validated Canadian Healthy Eating Index (C-HEI). PA change was calculated from Physical Activity Scale for the Elderly (PASE) as T4-T1. Associations were evaluated between FC decline and four combinations of variables: C-HEI score < or ≥70 with PASE change < or > median and analyzed by GLM while controlling for covariates. Neither DQ alone nor DQ combined with PA change were associated with FC decline over follow-up. | The present study was designed to give possible answers to some of the discrepancies regarding the presence or not of intact fetal cells in maternal plasma during pregnancy. 12-mL peripheral blood was collected from 33 pregnant women in the second trimester: 6 mL was harvested by 3-step Percoll gradient centrifugation and plasma cells were analyzed by FISH with X/Y chromosome specific probes. From the remaining 6 mL, plasma-derived cells were isolated with three different gradient centrifugation protocols and apoptosis was determined following EthBr staining. The number of cells recovered ranged from 900 to 3000. At least one Y positive signal was seen in 12 out of 17 cases with male fetuses at a frequency of 0.12% (range 0.05-0.27%). No XY cells were detected in the plasma of women carrying female fetuses. Hybridization efficiency was <60%. EthBr staining demonstrated that the majority of these cells were in their late apoptosis. |
Does the receptor-binding region of human apolipoprotein E have direct anti-infective activity? | The APOE genotype has a uniquely strong influence on the outcome of viral infection. The mechanism is unknown, although one possibility is direct inhibition of viral entry into cells. We have examined the direct anti-infective activity of a peptide analogue of the receptor-binding region of apolipoprotein E (apoE) that is known as "apoE dimer tandem repeat peptide" (apoEdp) and has previously been shown to mimic some of the biological effects of apoE and that recently was shown to bind low-density lipoprotein receptor-related protein. apoEdp has activity against herpes simplex virus types 1 and 2, human immunodeficiency virus, Pseudomonas aeruginosa, and Staphylococcus aureus; concentrations in the range of 1-20 micromol/L inhibit infection by 50%. These biological actions depend on adoption of an alpha -helical structure, as has been found for other biological effects of apoE peptides. The peptide interferes with the earliest stages of viral infection, preventing viral attachment and exerting a mild virucidal action. In addition, an N-terminal fragment of apoE that also contains this binding domain has antiviral activity. | Sternal dehiscence and mediastinitis are rare but serious complications following cardiac surgery. The aim of this study was to investigate the influence of the number of sternal wires used for chest closure on sternal complications. From May 2003 to April 2007, 4714 adult patients received cardiac surgery in our institute. X-ray images of all patients were reviewed and the used wires were counted. Patients who received another material or longitudinal wiring technique according to Robicsek for chest closure were excluded from this analysis; thus 4466 patients were included into the final analysis. Figure-of-eight wiring was counted as two wires. Sternal complications occurred in 2.4%, and hospital mortality with or without sternal complications were 2.8 and 2.7%, respectively (P = 0.60). Mean numbers of sternal wires were 7.8 in both patient groups with or without sternal complications (P = 0.79). Multivariate analysis revealed diabetes mellitus [odds ratio (OR) 1.54, 95% CI 1.01-2.34, P = 0.04], chronic obstructive pulmonary disease (OR 1.85, 95% CI 1.12-2.79, P = 0.01) and renal insufficiency (OR 1.70, 95% CI 1.11-2.59, P = 0.001) as significant risk factors for sternal complications. In high-risk patients, the use of less than eight wires was significantly associated with postoperative sternal complications. |
Do [ Evaluation of efficacy and safety on steroid withdraw at the seventh day after liver transplantation ]? | To evaluate efficacy and safety on steroid withdrawal at the seventh day after liver transplantation. Seventy-six adult patients undergoing first cadaveric liver transplantation from October 2005 to October 2007 were randomly divided into 7 day (n = 40) and 3 month (n = 36) steroid withdrawal groups. All patients received FK506 3 mg and intravenous methylprednisolone 1000 mg during intra-operation and FK506 thereafter was adjusted to predefined 8 - 12 microg/L from day 1 to month 6. Patients in 7 day steroid withdrawal group received 500, 240, 200, 160, 80, 40 and 20 mg intravenous methylprednisolone tapered daily from postoperative day 1 to day 7. In 3 month steroid withdrawal group, patients received the same protocol as 7 day steroid withdrawal group for intravenous methylprednisolone tapered daily from postoperative day 1 to day 7 and thereafter received oral prednisone 48, 40, 32, 24, 16, 8, 4 mg tapered every 3 days and maintained 4 mg to the 3(rd) month. All patients were followed up for 6 months. The incidence of treated acute rejection and side effects were evaluated between two groups. A total of 69 cases were fully followed up, and 7 cases were discontinued including death (n = 2), server infection (n = 2), protocol violation (n = 2) and retransplantation (n = 1). There were no statistical difference between 2 groups concerning the incidence of acute rejection, hypertension, hyperlipemia and other adverse events (P > 0.05), but significant difference in incidence of diabetes (17.5% vs. 38.9%, P = 0.047). | To detect whether muscovite exerts its protective role in the progression of atrophic gastritis (AG) and evaluate the possible mechanism. AG rats were established and then randomly divided into groups administrated with different doses of muscovite for 8 weeks. Histological changes in gastric antrum and the number of parietal cells, chief cells, and G/D cells were observed. Serum gastrin and prostaglandin E2 (PGE2) were evaluated by enzyme-linked immunosorbent assay (ELISA). The expression of proliferating cell nuclear antigen (PCNA), epidermal growth factor receptor (EGFR), C-erbB-2, p21, p53, p16 and bcl-2 in gastric tissue were detected by immunohistochemistry. The concentrations of TNF-alpha and IL-1beta secreted by THP-1 cells were detected when incubated with different doses of muscovite. The grade of inflammation in muscovite groups was lower (p < 0.05), while the thickness and number of gastric glands were significantly elevated in muscovite groups (p < 0.01). The expression height of PCNA in the muscovite group was higher than in the AG group (p < 0.01). Immunohistochemistry results showed a positive expression rate of EGFR; p16 in muscovite-treated AG rats was increased (p < 0.05), while C-erbB-2 and p21 were decreased (p < 0.05). Serum gastrin and PGE2 were significantly elevated in the high-dose muscovite-treated rats (p < 0.05). In vitro studies showed that muscovite had a dose-dependent adsorption of TNF-alpha and IL-1beta. |
Does probucol protect against smooth muscle cell proliferation by upregulating heme oxygenase-1? | Evidence suggests that induction of heme oxygenase-1 (HO-1) inhibits proliferation of vascular smooth muscle cells and intimal thickening after arterial injury, and therapeutic molecules induce HO-1. Probucol is the only oral drug that inhibits restenosis in humans and intimal thickening in animals, although its underlying mechanism remains unclear. Aortas were harvested from New Zealand White rabbits fed normal or 0.75% (wt/wt) probucol-fortified chow, with or without endothelial denudation of the abdominal aorta on day 21, and analyzed for heme oxygenase and apoptosis. Uninjured aortas were harvested on day 21 and balloon-injured aortas on days 22 and 25. Probucol significantly increased mRNA of HO-1 assessed by real-time PCR and HO activity in aortas at all time points. Probucol also enhanced apoptosis of medial cells in the injured aorta, as evidenced by the TUNEL assay. Furthermore, probucol (100 micromol/L) increased HO-1 mRNA and HO activity when added to rabbit aortic smooth muscle cells (RASMCs) cultured in serum-free medium for 24 hours. Induction of HO-1 mRNA was inhibited by actinomycin D and was associated with inhibition of RASMC proliferation. This probucol-induced increase in HO-1 mRNA and inhibition of RASMC proliferation was prevented by the HO inhibitor Sn(IV) protoporphyrin or transfection with small interference RNA (siRNA) to knockdown HO-1, but not by inactive Cu(II) protoporphyrin or scrambled siRNA. | To test the following hypotheses: (1) eyes from individuals with human immunodeficiency virus (HIV) have electrophysiologic abnormalities that manifest as multifocal electroretinogram (mfERG) abnormalities; (2) the retinal effects of HIV in immune-competent HIV individuals differ from the effects in immune-incompetent HIV individuals; (3) strong machine learning classifiers (MLCs), like support vector machine (SVM), can learn to use mfERG abnormalities in the second-order kernel (SOK) to distinguish HIV from normal eyes; and (4) the mfERG abnormalities fall into patterns that can be discerned by MLCs. We applied a supervised MLC, SVM, to determine if mfERGs in eyes from patients with HIV differ from mfERGs in HIV-negative controls. Ninety-nine HIV-positive patients without visible retinopathy were divided into 2 groups: (1) 59 high-CD4 individuals (H, 104 eyes), 48.5 +/- 7.7 years, whose CD4 counts were never observed below 100, and (2) 40 low-CD4 individuals (L, 61 eyes), 46.2 +/- 5.6 years, whose CD4 counts were below 100 for at least 6 months. The normal group (N, 82 eyes) had 41 age-matched HIV-negative individuals, 46.8 +/- 6.2 years. The amplitude and latency of the first positive curve (P1, hereafter referred to as a) and the first negative curve (N1, referred to as b) in the SOK of 103 hexagon patterns of the central 28 degrees of the retina were recorded from the eyes in each group. SVM was trained and tested with cross-validation to distinguish H from N and L from N. SOK was chosen as a presumed detector of inner retinal abnormalities. Classifier performance was measured with the area under the receiver operating characteristic (AUROC) curve to permit comparison of MLCs. Improvement in performance and identification of subsets of the most important features were sought with feature selection by backward elimination. In general, the SOK b-parameters separated L from N and H from N better than a-parameters, and latency separated L from N and H from N better than amplitude. In the HIV groups, on average, amplitude was diminished and latency was extended. The parameter that most consistently separated L from N and H from N was b-latency. With b-latency, SVM learned to distinguish L from N (AUROC = 0.7.30 +/- 0.044, P = .001 against chance [0.500 +/- 0.051]) and H from N (0.732 +/- 0.038, P = .0001 against chance) equally well. With best-performing subsets (21 out of 103 hexagons) derived by backward elimination, SVM distinguished L from N (0.869 +/- 0.030, P < .00005 against chance) and H from N (0.859 +/- 0.029, P <.00005 against chance) better than SVM with the full set of hexagons. Mapping the top 10 hexagon locations for L vs N and H vs N produced no apparent pattern. |
Does ski diminish TGF-β1-induced myofibroblast phenotype via up-regulating Meox2 expression? | The aim of the present work was to investigate the mechanism of transforming growth factor (TGF)-β1 and Sloan-Kettering Institute (Ski) in the pathogenesis of hypertrophic scars (HS). Wound healing is an inherent process, but the aberrant wound healing of skin injury may lead to HS. There has been growing evidence suggesting a role for TGF-β1 and Ski in the pathogenesis of fibrosis. The MTT assay was used to detect the cell proliferation induced by TGF-β1. The Ski gene was transduced into cells with an adenovirus, and then the function of Ski in cell proliferation and differentiation was observed. Ski mRNA levels were measured by RT-PCR. Western blotting was used to detect the protein expression of α-SMA, E-cadherin, Meox1, Meox2, Zeb1 and Zeb2. TGF-β1 can promote human skin fibroblast (HSF) cell proliferation in a time-dependent manner, but the promoting effect could be suppressed by Ski. TGF-β1 also induces the formation of the myofibroblast phenotype and the effect of TGF-β1 could be diminished by Ski. Also, Ski modulates the cardiac myofibroblast phenotype and function through suppression of Zeb2 by up-regulating the expression of Meox2. | Dopamine and dopamine transporters (DAT, which regulate extracellular dopamine in the brain) are implicated in the modulation of attention but their specific roles are not well understood. Here we hypothesized that dopamine modulates attention by facilitation of brain deactivation in the default mode network (DMN). Thus, higher striatal DAT levels, which would result in an enhanced clearance of dopamine and hence weaker dopamine signals, would be associated to lower deactivation in the DMN during an attention task. For this purpose we assessed the relationship between DAT in striatum (measured with positron emission tomography and [(11)C]cocaine used as DAT radiotracer) and brain activation and deactivation during a parametric visual attention task (measured with blood oxygenation level dependent functional magnetic resonance imaging) in healthy controls. We show that DAT availability in caudate and putamen had a negative correlation with deactivation in ventral parietal regions of the DMN (precuneus, BA 7) and a positive correlation with deactivation in a small region in the ventral anterior cingulate gyrus (BA 24/32). With increasing attentional load, DAT in caudate showed a negative correlation with load-related deactivation increases in precuneus. |
Are bRAF ( L597 ) mutations in melanoma associated with sensitivity to MEK inhibitors? | Kinase inhibitors are accepted treatment for metastatic melanomas that harbor specific driver mutations in BRAF or KIT, but only 40% to 50% of cases are positive. To uncover other potential targetable mutations, we conducted whole-genome sequencing of a highly aggressive BRAF (V600) and KIT (W557, V559, L576, K642, and D816) wild-type melanoma. Surprisingly, we found a somatic BRAF(L597R) mutation in exon 15. Analysis of BRAF exon 15 in 49 tumors negative for BRAF(V600) mutations as well as driver mutations in KIT, NRAS, GNAQ, and GNA11, showed that two (4%) harbored L597 mutations and another two involved BRAF D594 and K601 mutations. In vitro signaling induced by L597R/S/Q mutants was suppressed by mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibition. A patient with BRAF(L597S) mutant metastatic melanoma responded significantly to treatment with the MEK inhibitor, TAK-733. Collectively, these data show clinical significance to BRAF(L597) mutations in melanoma. | Results of many studies show that apolipoprotein B (apo B) is a better marker of risk of vascular disease than other lipid markers including LDL and HDL-cholesterol and triglycerides. We investigated the association between two infectious agents: C. pneumoniae and H. pylori, known to have an atherogenic effect, and apo B, to evaluate the effects of chronic infections on apo B levels. The study group consisted of 257 patients in whom diagnostic coronary angiography was performed. C. pneumoniae IgG and IgM and H. pylori IgG and IgA antibodies were measured by enzyme-linked immunosorbent assay and apo B levels were measured by the nephelometry method. Established risk factors of atherosclerosis were recorded. Of 257 patients recruited, 104 had normal vessels, 88 had 3 or more vessels obstructed and 65 had ectatic vessels without atherosclerosis. Mean apo B concentration was significantly higher in C. pneumoniae IgG and IgM positive healthy subjects compared with C. pneumoniae negatives (0.954 vs. 0.722 and 0.973 vs. 0.851, p < 0.001 and p = 0.007, respectively). Apo B levels were significantly higher in severe atherosclerotic patients (0.985 +/- 0.234 g/l) compared with control subjects (0.892 +/- 0.244 g/l) (p = 0.008), but the difference was not significant in ectatic subjects (0.946 +/- 0.272 g/l) when compared with controls (p = 0.18). Apo B levels were higher but not statistically significant in H. pylori antibody positive cases when compared with negatives. |
Do saphenous vein conduits harvested by endoscopic technique exhibit structural and functional damage? | Injury to the saphenous vein endothelium during harvest impacts patency after coronary artery bypass graft surgery. Many centers are adopting endoscopic saphenous vein harvest (ESVH) instead of using the traditional open saphenous vein harvest (OSVH) technique. Our objective was to compare the effects of ESVH and OSVH on the structural and functional viability of saphenous vein endothelium using multiphoton imaging, immunofluorescence, and biochemical techniques. Ten patients scheduled for coronary artery bypass graft surgery were prospectively identified. Each underwent ESVH for one portion and OSVH for another portion of the saphenous vein. A 1-cm segment from each portion was immediately transported to the laboratory for processing. The vessel segments were labeled with fluorescent markers to quantify cell viability (esterase activity), calcium mobilization, and generation of nitric oxide. Samples were also labeled with immunofluorescent antibodies to visualize caveolin, endothelial nitric oxide synthase, von Willebrand factor, and cadherin, and extracted to identify these proteins using Western blot techniques. All labeling, imaging, and image analysis was done in a blinded fashion. Esterase activity was significantly higher in the OSVH group (p < 0.0001). Similarly, calcium mobilization and nitric oxide production were significantly greater in the OSVH group (p = 0.0209, p < 0.0001, respectively). Immunofluoresence and Western blot techniques demonstrated an abnormal alteration in distribution of caveolin and endothelial nitric oxide synthase in the ESVH group. | To determine interrelationships between the expression of long intergenic (noncoding) RNA-p21 (lincRNA-p21), NF-κB activity, and responses to methotrexate (MTX) in rheumatoid arthritis (RA) by analyzing patient blood samples and cell culture models. Expression levels of long noncoding RNA and messenger RNA (mRNA) were determined by quantitative reverse transcription-polymerase chain reaction. Western blotting and flow cytometry were used to quantify levels of intracellular proteins. Intracellular NF-κB activity was determined using an NF-κB luciferase reporter plasmid. Patients with RA expressed reduced basal levels of lincRNA-p21 and increased basal levels of phosphorylated p65 (RelA), a marker of NF-κB activation. Patients with RA who were not treated with MTX expressed lower levels of lincRNA-p21 and higher levels of phosphorylated p65 compared with RA patients treated with low-dose MTX. In cell culture using primary cells and transformed cell lines, MTX induced lincRNA-p21 through a DNA-dependent protein kinase catalytic subunit (DNA PKcs)-dependent mechanism. Deficiencies in the levels of PRKDC mRNA in patients with RA were also corrected by MTX in vivo. Furthermore, MTX reduced NF-κB activity in tumor necrosis factor α-treated cells through a DNA PKcs-dependent mechanism via induction of lincRNA-p21. Finally, we observed that depressed levels of TP53 and lincRNA-p21 increased NF-κB activity in cell lines. Decreased levels of lincRNA-p21 did not alter NFKB1 or RELA transcripts; rather, lincRNA-p21 physically bound to RELA mRNA. |
Does ambulatory monitoring predict development of drug-treated hypertension in subjects with high normal blood pressure? | High normal blood pressure (HNBP), i.e. blood pressure (BP) > or = 130/85 mmHg and <140/90 mmHg, is an important predictor of progression to established hypertension. The purpose of this retrospective study was the evaluation of the predictive value of ambulatory blood pressure monitoring (ABPM) for the development of drug-treated hypertension in subjects with HNBP and other risk factors. We studied 127 subjects (69 M, 58 F, age 50 +/- 14 years): 59 subjects had normal BP (NBP: < 130/85 mmHg), 68 subjects had systolic and/or diastolic HNBP. All the subjects underwent ABPM. There were 21/68 (30.9%) subjects in the HNBP group vs. 1/59 (1.7%) in the NBP group with an elevated (>135/85 mmHg) daytime ambulatory blood pressure (ABP) (p < 0.01). After an average follow-up of 103 +/- 28 months, 27 subjects (39.7%) in the HNBP group and 4 subjects (6.8%) in the NBP group developed drug-treated hypertension (p < 0.01). An elevated daytime ABP correctly predicted development of drug-treated hypertension in 17/21 subjects (81%) of the HNBP group and in the only subject of the NBP group. Development of drug-treated hypertension was associated with higher office and ambulatory BP (p < 0.01) and pulse pressures (p < 0.05), longer follow-up (p < 0.05) and higher prevalence of hypercholesterolaemia and smoking (p < 0.01). | We evaluated whether CK19, one of the main cytoskeleton proteins of epithelial cells, is released as full-length protein from viable tumor cells and whether this property is relevant for metastatic progression in breast cancer patients. EPISPOT (EPithelial ImmunoSPOT) assays were performed to analyze the release of full-length CK19 by carcinoma cells of various origins, and the sequence of CK19 was analyzed with mass spectrometry. Additional functional experiments with cycloheximide, Brefeldin A, or vincristine were done to analyze the biology of the CK19-release. CK19-EPISPOT was used to detect disseminated tumor cells in bone marrow (BM) of 45 breast cancer patients who were then followed up over a median of 6 years. CK19 was expressed and released by colorectal (HT-29, HCT116, Caco-2) and breast (MCF-7, SKBR3, and MDA-MB-231) cancer cell lines. The CK19-EPISPOT was more sensitive than the CK19-ELISA. Dual fluorescent EPISPOT with antibodies against different CK19 epitopes showed the release of the full-length CK19, which was confirmed by mass spectrometry. Functional experiments indicated that CK19 release was an active process and not simply the consequence of cell death. CK19-releasing cells (RCs) were detectable in BM of 44% to 70% of breast cancer patients. This incidence and the number of CK19-RCs were correlated to the presence of overt metastases, and patients with CK19-RCs had a reduced survival as compared with patients without these cells (P = 0.025, log-rank test; P = 0.0019, hazard ratio, 4.7; multivariate analysis). |
Does age-dependent disease expression determine remodeling of the retinal mosaic in carriers of RPGR exon ORF15 mutations? | To characterize the retinal histopathology in carriers of X-linked progressive retinal atrophy (XLPRA1 and XLPRA2), two canine models of X-linked retinitis pigmentosa caused, respectively, by a stop and a frameshift mutation in RPGRORF15. Retinas of XLPRA2 and XLPRA1 carriers of different ages were processed for morphologic evaluation, TUNEL assay, and immunohistochemistry. Cell-specific markers were used to examine retinal remodeling events. A mosaic pattern composed of patches of diseased and normal retina was first detected in XLPRA2 carriers at 4.9 weeks of age. A peak of photoreceptor cell death led to focal rod loss; however, in these patches an increased density of cones was found to persist over time. Patches of disease gradually disappeared so that by 39 weeks of age the overall retinal morphology, albeit thinner, had improved lamination. In older XLPRA2 carriers (>or=8.8 years), extended regions of severe degeneration occurred in the peripheral/mid-peripheral retina. In XLPRA1 carriers, opsin mislocalization and rare events of rod death were detected by TUNEL assay at 20 weeks of age; however, only patchy degeneration was seen by 1.4 years and was still apparent at 7.8 years. | This study examines the physiologic effects of theraputic plasma exchange (TPE) in the setting of refractory burn shock and attempts to identify variables that correlate with the eventual need for TPE. A retrospective analysis was conducted of 40 patients over 24 months with >20% TBSA burns who experienced complicated resuscitations. TPE was utilized in 21 patients when the patients' total resuscitation volumes exceeded 1.2 times the amount predicted by the modified Baxter formula (3 cm(3) LR/kg/%TBSA). Nineteen matched, contemporaneous patients served as controls. Demographic, injury severity, and acute clinical variables were abstracted for comparison between the two groups. Additionally, the TPE group was analyzed for blood lactate levels, mean arterial pressure (MAP) and urine output (UOP) before and after TPE. Univariate and multivariate statistical analyses were used for comparisons, where appropriate. In response to TPE, MAP increased by 24% (p<0.0001), UOP increased by >400% (p=<0.0001), IVF rates were reduced by 25% (p=0.01), and lactate levels decreased by almost 50% (p=0.0006). On univariate analysis, admission lactate (p=0.0006) and %TBSA (p=0.01) were found to be significantly increased in the TPE group compared to controls, while there was no difference in age, gender, weight, admission HCT, incidence of acute renal failure, or mortality between the groups. However, on multivariate logistic regression analysis, only elevated admission lactate was independently associated with the eventual need for TPE (OR 2.23, 95% CI=1.30-3.84, p=0.004). |
Does intracultural variation of knowledge about wild plant used in the Biosphere Reserve Grosses Walsertal ( Austria )? | Leading scholars in ethnobiology and ethnomedicine continuously stress the need for moving beyond the bare description of local knowledge and to additionally analyse and theorise about the characteristics and dynamics of human interactions with plants and related local knowledge. Analyses of the variation of local knowledge are thereby perceived as minimal standard. In this study we investigate the distribution and variation of wild plant knowledge in five domains: food, drinks, human medicine, veterinary medicine and customs. We assess relations between the wild plant knowledge of informants and their socio-demographic as well as geographic background. Research was conducted in the Biosphere Reserve Grosses Walsertal, Austria. Structured questionnaires were used to inquire wild plant knowledge from 433 informants with varying socio-demographic and geographic background. Children assisted in the data collection. Data was analysed using descriptive statistics and generalized linear models. | GM-CSF has broad clinical applicability as a potent myelopoietic stimulator. However, its function is not restricted to the myelopoietic system and several observations suggest that GM-CSF may interfere with the hemostatic balance. In order to assess whether GM-CSF has any influence on hemostasis, we evaluated some coagulative and fibrinolytic parameters in patients treated with GM-CSF following chemotherapy. Fibrinolytic activity (FA), fibrinogen and D-dimer were evaluated before and after high-dose cyclophosphamide in 6 patients additionally treated with GM-CSF and in 5 control patients; moreover, tissue plasminogen activator (tPA) was assayed in those treated with GM-CSF. Comparative in vitro analysis was performed on cultured endothelial cells before and after exposure to GM-CSF. Control patients showed a significant decrease in plasma FA after chemotherapy compared to basal values (FA/mm2: 15.6 +/- 2.1 at day + 2 and 20.8 +/- 19 at day + 4 vs. 103.8 +/- 64.2 at day 0; p < 0.005); conversely, no FA reduction was observed in GM-CSF-treated subjects. In this latter group a marked increase in tPA antigen was seen, consistent with enhanced FA. No significant changes in plasma D-dimer and fibrinogen values were detected in the two groups. tPA, urokinase-type plasminogen activator, PAI-1 and procoagulant activity were evaluated in vitro on cultured human endothelial cells and found to be unchanged following GM-CSF addition. |
Do plasma protein biomarkers enhance the clinical prediction of kidney injury recovery in patients undergoing liver transplantation? | Biomarkers predictive of recovery from acute kidney injury (AKI) after liver transplantation (LT) could enhance decision algorithms regarding the need for liver-kidney transplantation or renal sparing regimens. Multianalyte plasma/urine kidney injury protein panels were performed immediately before and 1 month post-LT in an initial test group divided by reversible pre-LT AKI (rAKI = post-LT renal recovery) versus no AKI (nAKI). This was followed by a larger validation set that included an additional group: irreversible pre-LT AKI (iAKI = no post-LT renal recovery). In the test group (n = 16), six pre-LT plasma (not urine) kidney injury proteins (osteopontin [OPN], neutrophil gelatinase-associated lipocalin, cystatin C, trefoil factor 3, tissue inhibitor of metalloproteinase [TIMP]-1, and β-2-microglobulin) were higher in rAKI versus nAKI (P < 0.05) and returned to normal values with renal recovery post-LT. In the validation set (n = 46), a number of proteins were significantly higher in both rAKI and iAKI versus nAKI. However, only pre-LT plasma OPN (P = 0.009) and TIMP-1 (P = 0.019) levels were significantly higher in rAKI versus iAKI. Logistic regression modeling was used to correlate the probability of post-LT rAKI, factoring in both pre-LT protein markers and clinical variables. A combined model including elevated OPN and TIMP-1 levels, age <57, and absence of diabetes had the highest area under the curve of 0.82, compared to protein-only and clinical variable-only models. | Insecticide resistance in Trialeurodes vaporariorum W. is unknown in the species' northern distribution range where it inhabits mainly commercial greenhouses. Resistance development in whiteflies feeding on year-round crops in greenhouses is possible owing to the use of chemical treatments to back up biocontrol. The authors tested the response levels to spiromesifen, pymetrozine and imidacloprid in whiteflies collected from seven greenhouses within a 35 km radius in western Finland. All except one (PR) population had LC50 values below the recommended concentrations for the tested compounds. However, some populations showed reduced susceptibility to pymetrozine in comparison with the reference susceptible population. Resistance ratios to pymetrozine were highly variable (resistance ratio 0.5-39.7), even among closely located greenhouses, and higher than those for imidacloprid (resistance ratio 1.05-10.5) and spiromesifen (resistance ratio 0.8-11.5). LC50 values and application frequencies of pymetrozine correlated positively among the sampled populations. |
Do essiac and Flor-Essence herbal tonics stimulate the in vitro growth of human breast cancer cells? | People diagnosed with cancer often self-administer complementary and alternative medicines (CAMs) to supplement their conventional treatments, improve health, or prevent recurrence. Flor-Essence and Essiac Herbal Tonics are commercially available complex mixtures of herbal extracts sold as dietary supplements and used by cancer patients based on anecdotal evidence that they can treat or prevent disease. In this study, we evaluated Flor-Essence and Essiac for their effects on the growth of human tumor cells in culture. The effect of Flor-Essence and Essiac((R)) herbal tonics on cell proliferation was tested in MCF-7, MDA-MB-436, MDA-MB-231, and T47D cancer cells isolated from human breast tumors. Estrogen receptor (ER) dependent activation of a luciferase reporter construct was tested in MCF-7 cells. Specific binding to the ER was tested using an ICI 182,780 competition assay. Flor-Essence and Essiac herbal tonics at 1%, 2%, 4% and 8% stimulated cell proliferation relative to untreated controls in both estrogen receptor positive (MCF-7 and T47D) and estrogen receptor negative (MDA-MB-231 and MDA-MB-436) cell lines. Exposure to the tonics also produced a dose-dependent increase in ER dependent luciferase activity in MCF-7 cells. A 10(-7) M concentration of ICI 182,780 inhibited the induction of ER dependent luciferase activity by Flor-Essence and Essiac, but did not affect cell proliferation. | The variable-pitch pulse oximeter is an important intraoperative patient monitor. Our ability to hear its auditory signal depends on its acoustical properties and our hearing. This study quantitatively describes the audio spectrum and sound pressure levels of the monitoring tones produced by five variable-pitch pulse oximeters. We compared the Datex-Ohmeda Capnomac Ultima, Hewlett-Packard M1166A, Datex-Engstrom AS/3, Ohmeda Biox 3700, and Datex-Ohmeda 3800 oximeters. Three machines of each of the five models were assessed for sound pressure levels (using a precision sound level meter) and audio spectrum (using a hanning windowed fast Fourier trans-form of three beats at saturations of 99%, 90%, and 85%). The widest range of sound pressure levels was produced by the Hewlett-Packard M1166A (46.5 +/- 1.74 dB to 76.9 +/- 2.77 dB). The loudest model was the Datex-Engstrom AS/3 (89.2 +/- 5.36 dB). Three oximeters, when set to the lower ranges of their volume settings, were indistinguishable from background operating room noise. Each model produced sounds with different audio spectra. Although each model produced a fundamental tone with multiple harmonic overtones, the number of harmonics varied with each model; from three harmonic tones on the Hewlett-Packard M1166A, to 12 on the Ohmeda Biox 3700. There were variations between models, and individual machines of the same model with respect to the fundamental tone associated with a given saturation. |
Are genetic polymorphisms associated with serum levels of sex hormone binding globulin in postmenopausal women? | Estrogen activity plays a critical role in bone homeostasis. The serum levels of sex hormone binding globulin (SHBG) influence free estrogen levels and activity on target tissues. The objective of this study was to analyze the influence of common polymorphisms of the SHBG gene on serum SHBG, bone mineral density (BMD), and osteoporotic fractures. Four biallelic polymorphisms of the SHBG gene were studied by means of Taqman assays in 753 postmenopausal women. BMD was measured by DXA and serum SHBG was measured by ELISA. Age, body weight, and two polymorphisms of the SHBG gene (rs6257 and rs1799941 [A/G]) were significantly associated with serum SHBG in unadjusted and age- and weight-adjusted models. Alleles at the rs1799941 locus showed the strongest association with serum SHBG (p=0.0004). The difference in SHBG levels between women with AA and GG genotypes at the rs1799941 locus was 39%. There were no significant differences in BMD across SHBG genotypes. The genotypes showed similar frequency distributions in control women and women with vertebral or hip fractures. | Congestion-reperfusion injury (CRI) is a common complication after living donor liver transplantation, which has not been fully understood. It causes more severe inflammatory response as compared with ischemia-reperfusion injury (IRI). Ischemic preconditioning (IPC) has been endowed with powerful protective properties toward IRI. This study aimed to investigate whether IPC also has a protective effect against CRI and potential underlying mechanisms. Mice were randomly divided into sham operation, CRI, IPC-CRI, and congestion precondition (CPC-CRI) group. The hepatic vein of the left anterior hepatic lobe was occluded for 75 min followed by reperfusion in the CRI group. The blood inflow was previously clamped for 10 min followed by 10 min of reperfusion just before occluding the hepatic vein in the IPC-CRI group. To imitating IPC in the CPC-CRI group, 10 min of congestion followed by 10 min of reperfusion just before CRI was performed. The animals were sacrificed at 2, 6, 24, 48 h, and 7 d after reperfusion. The blood and liver samples were collected for hepatic function assay, histology, terminal deoxynucleotidyl transferase dUTP nick end labeling, myeloperoxidase, and real-time polymerase chain reaction analysis. Mice in the CRI, IPC-CRI, and CPC-CRI group demonstrated elevated liver enzymes, histologic damage, cellular apoptosis, and inflammatory response compared with those in the sham operation group. Compared with the CRI group, mice in the IPC-CRI group expressed lower alanine transaminase activities (2 h: 839.2 ± 132.5 versus 384.2 ± 94.8, P < 0.01; and 6 h: 680 ± 142.4 versus 342.3 ± 99.7, P < 0.01) and lower myeloperoxidase levels (2 h: 7.1 ± 4.0 U/g versus 3.8 ± 1.6 U/g, P < 0.05; and 6 h: 8.1 ± 1.3 U/g versus 5.2 ± 3.0 U/g, P < 0.05). However, the alanine transaminase level in the CPC-CRI group was notably higher at 2 h (839.2 ± 132.5 versus 1087.5 ± 192.5, P < 0.05). Livers from mice in the IPC-CRI group showed better tissue integrity, diminished hepatocellular injury, and apoptosis at 2 and 6 h. The messenger RNA transcriptions of interleukin 1 and interleukin 6 were significantly lower after 2-24 h of reperfusion, whereas tumor necrosis factor α and monocyte chemoattractant protein 1 were significantly lower after 24 h of reperfusion in the IPC-CRI group. |
Does comparison between stabilometry with and without head tilt in a roll plane? | We examined the influence of head-tilting on stabilometry, which is similar to positional nystagmus in a sitting position. The subjects were 35 healthy individuals and 11 patients with unilateral vestibular disorder. We compared parameters measured in an upright position and those with left head-tilt or right head-tilt. We used Wilcoxon's signed ranks test for statistical analysis. In the group of healthy adults, the Enveloped area with left head-tilt and right head-tilt increased significantly compared to that in the upright position (P=0.0111). The parameters that decreased significantly were Locus length per unit area (P=0.0007). The center of gravity on the Y-axis shifted backward significantly (P<0.0001). In the group of unilateral vestibular disorder, there were no parameters that showed significant difference | This study determined the mechanism used by neutrophils (PMNs) to induce hepatocellular injury. Neutrophils have been shown to be potent mediators of cell and tissue injury and have been hypothesized to contribute to the hepatic injury that occurs after trauma and infection. Oxygen radical scavengers protect the liver in vivo from inflammatory injury and it has been suggested that PMNs are the source of these toxic oxygen radicals. The specific mechanism used by PMNs to produce hepatocellular damage, however, has not been determined. Neutrophils were cultured in vitro with hepatocytes (HCs) and stimulated with phorbol 12-myristate 13-acetate (PMA) to induce HC injury in the presence of oxygen radical scavengers and protease inhibitors. PMA induced a PMN-mediated HC injury that was dependent on the number of PMNs present and the concentration of PMA. Protease inhibitors reduced the extent of HC injury, while oxygen radical scavengers had no effect. Hydrogen peroxide, directly applied, was able to injure HCs, but only at concentrations greater than those that could be produced by PMA-stimulated PMNs. |
Does intravitreal inhibition of complement C5a reduce choroidal neovascularization in mice? | To investigate the influence of complement component C5a inhibition on laser-induced choroidal neovascularization (CNV) in mice using a C5a specific L-aptamer. In C57BL/6 J mice CNV was induced by argon-laser, C5a-inhibitor (NOX-D20) was intravitreally injected in three concentrations: 0.3, 3.0, and 30 mg/ml. The unPEGylated derivate (NOX-D20001) was applied at 3.0 mg/ml; the vehicle (5 % glucose) was injected in controls. Vascular leakage was evaluated using fluorescence angiography, CNV area was examined immunohistochemically. Activated immune cells surrounding the CNV lesion and potential cytotoxicity were analyzed. Compared to controls, CNV areas were significantly reduced after NOX-D20 injection at a concentration of 0.3 and 3.0 mg/ml (p = 0.042; p = 0.016). NOX-D20001 significantly decreased CNV leakage but not the area (p = 0.007; p = 0.276). At a concentration of 30 mg/ml, NOX-D20 did not reveal significant effects on vascular leakage or CNV area (p = 0.624; p = 0.121). The amount of CD11b positive cells was significantly reduced after treatment with 0.3 and 3.0 mg/ml NOX-D20 (p = 0.027; p = 0.002). No adverse glial cell proliferation or increased apoptosis were observed at effective dosages. | Type 2 diabetes and associated co-morbidities run epidemic waves worldwide. Since pathophysiological constellations are individual and display a wide spread of dysmetabolic profiles personalized health care assessments start to emerge. Therefore, we established a specific in silico assessment tool targeting metabolic characterizations individually. Values obtained from oral glucose and intraperitoneal insulin tolerance tests performed on pkbα(-/-) mice (KO) as well as age- and gender-matched controls (WT) were analysed using our established in silico model. Generally, male pkbα(-/-) mice (KO) presented significantly increased insulin sensitivity at an age of 6 months compared with age-matched WTs (p = 0.036). Female KO and WT groups displayed improved glucose sensitivities compared with age-matched males (for WT p ≤ 0.011). |
Are in sickness and in health : classmates highly motivated to provide in-hospital support during childhood cancer therapy? | Extended hospitalization for school-aged cancer patients increases their risk of social marginalization. School-aged children mature through peer-interaction, but healthcare providers fail to incorporate this in rehabilitation efforts. The RESPECT study offers classmates to cancer patients to become ambassadors during hospital stays. This study explores classmate decision-making patterns about ambassadorship. An open-ended question was prospectively and consecutively provided to classmates (N = 221) (and parents) of 10 children diagnosed with cancer in 2014 and enrolled in the RESPECT study. Statements were analysed using thematic content analysis. Of 221 classmates, 140 responded (63%). Of these, 81 applied for ambassadorship (median 8/patient), 58 declined, one was undecided. Nine forms were incomplete; leaving 131 in total that revealed 303 statements for analysis. Five major themes emerged: existing friendship (132/303 statements), personal resources (academic, emotional and social) (107/303), attitudes towards the ambassadorship (34/303), hospital environment (18/303) and logistics (12/303). Of the classmates with pre-existing friendships, 77% applied for ambassadorship and 80% with a surplus of personal resources applied. These were predominant predictors for ambassadorship application. Classmate motives were condensed into four archetypes: pre-existing friendship with a surplus of resources (100% applied), non-friend classmates with a surplus of resources (63% applied), pre-existing friendship with limited resources (22% applied) and non-friend classmates with limited resources (0% applied). | Fatty Acid Binding Protein-4 (FABP4) is a member of a family of FABP proteins that regulate intracellular lipid trafficking in diverse tissues. We recently showed that FABP4 regulates triglyceride accumulation in primary human trophoblasts. To assess the function of placental FABP4 in vivo, we tested the hypothesis that FABP4 is expressed in the murine placenta, and regulates placenta triglyceride accumulation. C57Bl/6 wild type or Fabp4-null mice were time-bred, and fetuses and placentas harvested at different time points during pregnancy. Placental FABP4 expression was assessed at different gestational ages, using quantitative PCR, immunohistochemistry, immunofluorescence and western immunoblotting. FABPs expression was examined by RT-qPCR. Placental lipids were extracted using the Folch method and triglyceride levels determined using a colorimetric quantification kit. Using immunohistochemistry, we found that FABP4 was expressed in the placental labyrinthine layer, predominantly in endothelial cells in association with CD31 positive fetal capillaries. The level of placental FABP4 mRNA and protein increased from E12.5 to E16.5 and slightly decreased at E18.5. Breeding of Fabp4 heterozygous mice resulted in embryonic genotypes that followed a Mendelian distribution and exhibited normal weight and morphology, triglyceride content, and expression of other FABP family members. Exposure to hypoxia (O2 = 12%) between E12.5-E18.5 did not uncover a difference between wild type and Fabp4-null mice. |
Is cardiomyocyte troponin T immunoreactivity modified by cross-linking resulting from intracellular calcium overload? | During myocardial ischemia, the increase in cytosolic Ca2+ promotes the activation of neutral proteases such as calpains. Since the troponin T subunit is a substrate for calpains, we investigated the effects of irreversible myocyte damage on troponin T immunoreactivity. Hearts from adult guinea pigs (n=32) were perfused under conditions of normoxia, ischemia, postischemic reperfusion, or Ca2+ paradox. Hearts were frozen and processed for immunohistochemistry and Western blot with three anti-troponin T monoclonal antibodies. Two of these antibodies are unreactive on cryosections of freshly isolated and normoxic hearts and of hearts exposed to 30 minutes of no-flow ischemia. In contrast, reactivity is detected in rare myocytes after 60 minutes of ischemia, in a large population of myocytes after 60 minutes of ischemia followed by 30 minutes of reperfusion, and in every myocyte exposed to Ca2+ paradox. In Western blots, samples from ischemia-reperfusion and Ca2+ overloaded hearts show reactive polypeptides of about 240 to 260 kD and 65 to 66 kD in addition to troponin T. A similar pattern of immunoreactivity is observed with an anti-troponin I antibody. Histochemical troponin T immunoreactivity and reactivity on high-molecular-weight polypeptides are detectable in normal heart samples after preincubation with 10 mmol/L Ca2+ or with transglutaminase, whereas they are not if either transglutaminase or calpain is inhibited. | Reabsorption of bile acids from the intestine by ileal bile acid transporter is pivotal for the enterohepatic circulation of BAs and sterol homoeostasis. To assess tolerability and study, bile acid metabolism in a phase 1 trial with the selective ileal bile acid transporter inhibitor A4250. A randomised double-blind, single-ascending dose (SAD) and multiple-ascending-dose study consisting of five cohorts comprising 40 individuals with a single administration of A4250 (0.1, 0.3, 1, 3, or 10 mg) or placebo and three cohorts comprising 24 individuals with a 1-week administration of A4250 (1 or 3 mg once daily or 1.5 mg twice daily) or placebo. For the multiple-ascending-dose study, bile acids were measured by HPLC-MS in plasma and faeces, and fibroblast growth factor 19 (FGF19) and 7α-hydroxy-4-cholesten-3-one (C4) were measured in plasma. No serious adverse events occurred and all participants finished the trial per protocol. At the end of the multiple-ascending-dose study, plasma total bile acids and FGF19 decreased by 47% and 76%, respectively, at 3 mg/day (P < 0.01), and by 15% and 16%, respectively, at 1.5 mg twice daily (P < 0.05). Plasma C4 and faecal bile acids increased at all dose regimens, by 555%, 664%, 292% and 338%, 421%, 420%, respectively (P < 0.01-0.05). The primary bile acids cholic and chenodeoxycholic acids constituted the majority of faecal bile acids in the A4250-treated groups. |
Is postgastrectomy polyneuropathy with thiamine deficiency identical to beriberi neuropathy? | We assessed whether postgastrectomy polyneuropathy associated with thiamine deficiency is clinicopathologically identical to beriberi neuropathy, including a biochemical determination of thiamine status. Clinicopathologic features of 17 patients who had postgastrectomy polyneuropathy with thiamine deficiency were compared with those of 11 patients who had thiamine-deficiency neuropathy caused by dietary imbalance. The typical presentation for the two etiologies was as a symmetric sensorimotor polyneuropathy predominantly involving the lower limbs. A variety of clinical features, including neuropathic symptoms, progression, and coexistence of heart failure or Wernicke's encephalopathy, was seen similarly in both conditions. In both groups, the main electrophysiologic findings were those of axonal neuropathy, most prominently in the lower limbs. Sural nerve biopsy specimens also indicated axonal degeneration in both groups. Subperineurial edema was commonly observed. | Respiratory syncytial virus (RSV) causes severe bronchiolitis and is a risk factor for asthma. Since there is no commercially available vaccine against RSV, a short interfering RNA against the RSV-NS1gene (siNS1) was developed and its potential for decreasing RSV infection and infection-associated inflammation in rats was tested. Plasmids encoding siNS1 or an unrelated siRNA were complexed with a chitosan nanoparticle delivery agent and administered intranasally. Control animals received a plasmid for a non-specific siRNA. After expression of the plasmid in lung cells for 24 hours, the rats were intranasally infected with RSV. Prophylaxis with siNS1 significantly reduced lung RSV titers and airway hyperreactivity to methacholine challenge compared to the control group. Lung sections from siNS1-treated rats showed a sizable reduction in goblet cell hyperplasia and in lung infiltration by inflammatory cells, both characteristics of asthma. Also, bronchoalveolar lavage samples from siNS1-treated animals had fewer eosinophils. Treatment of rats with siNS1 prior to RSV exposure was effective in reducing virus titers in the lung and in preventing the inflammation and airway hyperresponsiveness associated with the infection that has been linked to development of asthma. |
Does eNOS T-786C polymorphism affect atorvastatin-induced changes in erythrocyte membrane fluidity? | Statins have pleiotropic effects, including endothelial nitric oxide synthase (eNOS) upregulation and increased nitric oxide formation, which can be modulated by a genetic polymorphism in the promoter region of the eNOS gene (T-786C). Here, we report our investigation of whether this polymorphism modulates the effects of atorvastatin on the fluidity of erythrocyte membranes. We genotyped 200 healthy subjects (males, 18-60 years of age) and then randomly selected 15 of these with the TT genotype and 15 with the CC genotype to receive placebo or atorvastatin (10 mg/day oral administration) for 14 days. Cell membrane fluidity was evaluated by electron paramagnetic resonance (EPR) and spin-labeling method. The EPR spectra were registered on a VARIAN-E4 spectrometer. Thiobarbituric acid-reactive species (TBA-RS) and plasma membrane cholesterol were determined in the erythrocytes. Atorvastatin reduced membrane fluidity in CC subjects (P < 0.05) but not in those with the TT genotype (P > 0.05). While no significant differences were found in plasma membrane cholesterol concentrations, higher TBA-RS concentrations were found in the CC subjects than in the TT subjects (P < 0.05). | To determine the involvement of the transforming growth factor (TGF)-β with the development of experimental subretinal fibrosis in a mouse model. Subretinal fibrosis was induced by subretinal injection of macrophage-rich peritoneal exudate cells (PECs) and the local expression of TGF-β isoforms was assessed by quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) and enzyme-linked immunosorbent assay (ELISA) at various time points. In addition, we investigated the effect of TFG-β-neutralizing antibodies (TGF-β NAb) on subretinal fibrosis development. TGF-β1 and TGF-β2 mRNA level was significantly elevated at day 2 after subretinal fibrosis induction and increased further to 5 and 6.5-fold respectively at day 5, reaching the peak. TGF-β3 mRNA was not detected in the present study. The result of ELSIA showed that active TGF-β1 and TGF-β2 levels were upregulated to 10-fold approximately, while total TGF-β1 and TGF-β2 levels were even upregulated more than 10-fold and more than 20-fold respectively in subretinal fibrosis mice in comparison with naïve mice at day 5. TGF-β NAb resulted in a reduced subretinal fibrosis areas by 65% compared to animals from control group at day 7. |
Are fatigue , pain and muscle weakness frequent after Guillain-Barré syndrome and poliomyelitis? | Guillain- Barré syndrome (GBS) and poliomyelitis may cause life-long health problems. We studied fatigue, pain and muscular weakness in both conditions to define possible interactions between these symptoms and their influence on residual disability and daily functioning. We studied 50 patients with previous GBS, 89 patients with a history of poliomyelitis and a reference group of 81 people with similar sex and age and no history of poliomyelitis or GBS using the Fatigue Severity Scale, self-reported pain and muscular weakness Disability Rating Index, and Positive and Negative Affect Schedule (PANAS-X). We assessed the quality of life using the SF-36 Health Survey. The mean score on the Fatigue Severity Scale was significantly higher in the GBS and poliomyelitis patients than in the reference group. This was true also in the subgroups of mild disease, i. e., nonparalytic polio and initial Hughes score less than 3 in the GBS group. Thirty-four percent of GBS patients and 63 % of poliomyelitis patients reported pain; 13 % of GBS and 36 % of poliomyelitis patients reported residual muscle weakness. Fatigue, pain, and muscle weakness interacted in both diseases. Perceived health problems influenced all aspects of the quality of life except mental health in both diseases. | Endothelial progenitor cells (EPCs) are key elements in vascular homeostasis. Their function is regulated by estrogens and estrogen receptors (ERs), but the effect of estrogenic compounds such as bisphenol A (BPA; an agonist of ER-β and agonist and antagonist of ER-α) and (R,R)-5,11-diethyl-5,6,11,12-tetrahydro-2,8-chrysenediol (THC; an agonist of ER-α and antagonist of ER-β) on human EPCs is unknown. We analyzed whether BPA and THC influence the migration of human EPCs, an essential process in endothelial regeneration, in both male and female EPCs. EPCs isolated from healthy adult men and women were assayed for ER expression by Western blotting and chemotaxis assay. Male and female EPCs similarly expressed ERs and did not differ in basal migration. Interestingly, 17-β-estradiol (10(-9) and 10(-10) M) significantly inhibited migration in female EPCs but not in males. Moreover, both 10(-5) M THC and 10(-8) M BPA blocked migration in female EPCs, allowing us to hypothesize that the effect is mediated by ER-α. |
Do external nasal dilator strips affect treadmill performance in subjects wearing mouthguards? | To determine the effect of the Breathe Right (BR) external nasal dilator strip on treadmill exercise performed while wearing an upper maxillary mouthguard. Two-way repeated-measures design with subjects acting as their own controls. Subjects performed 2 randomly assigned bouts of incremental treadmill exercise (with and without the BR strip) while wearing upper maxillary mouthguards. Nineteen young, healthy, recreationally active men. we assessed subjective nasal patency levels at rest. We also recorded heart rate, dyspnea rating, and treadmill speed at 2 submaximal exercise levels and at volitional fatigue. Subjective nasal patency was significantly increased with the strip. Repeated-measures analyses of variance revealed a significant main effect of the BR strip on dyspnea ratings during exercise, but there was no effect of the strip on test duration, heart rate, or running speed during the tests. | Metastasis associated gene-1 (MTA1), was initially discovered in aggressive human cancer cell lines and has been subsequently associated with the invasiveness and metastatic potential of cancer cells. In the present study, we evaluated the expression levels of MTA1 in a cohort of human pituitary tumors (n=95) and examined the relationship between MTA1 expression and the pathological, clinical and aggressiveness of these tumors. MTA1 was expressed at significantly higher levels in large tumors and in those with higher tumor grade. It was also observed that tumors that had invaded the suprasellar bones and tumors that destructed the sella had significantly higher levels than those without bone involvement (p<005). Although there did not appear to exist any relationship between MTA1 and cystic lesions in the tumors, endocrine-active tumors, namely those secreting prolactin, growth hormone, Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) had significantly lower MTA1 transcript levels than inactive tumors. |
Does repetitive gastric aspiration lead to augmented indirect allorecognition after lung transplantation in miniature swine? | Lung transplant recipients with documented gastroesophageal reflux disease (GERD) are at increased risk for graft dysfunction. Here, we present the first large-animal model of gastric aspiration after allogeneic lung transplantation and some preliminary data demonstrating the effect of chronic aspiration on the direct and indirect pathways of allorecognition. Left orthotopic lung transplants (n=3) were performed in miniature swine across a major histocompatibility complex class I disparity, followed by 12 days of high-dose cyclosporine A. At the time of transplantation, a transtracheal catheter was placed at the carina, above the bronchial anastomosis. A gastrostomy tube was placed for daily aspiration of gastric contents. Subsequently, graft lungs were instilled with gastric aspirate daily (3 mL/hrX8 hr/day) for 50 days. Recipients were followed up with daily complete blood count, scheduled chest radiographs, and biopsies. In vitro studies, including cell-mediated lympholysis, mixed lymphocyte reactions, and peptide proliferation assays, were performed. Results from these three recipients were compared with those of historical controls (n=6) who were treated identically, except for the tracheal cannulation and simulated gastric aspiration. Two of the experimental animals were euthanized with nonviable lungs soon after the postoperative day 50 biopsy. In both cases the native lung was normal. The third animal survived over 180 days without the evidence of chronic rejection. After immunosuppressive treatment, all animals demonstrated donor-specific hyporesponsiveness by assays of direct alloresponse (cell-mediated lympholysis, mixed lymphocyte reaction). A significant response to synthetic donor-derived class I peptide, however, was seen in all animals. A more pronounced and diffuse response was seen in the animals rejecting their grafts. The historical controls showed medium-term graft survival with evidence of chronic rejection in the majority of animals, as previously reported. | Semaphorins are guidance proteins implicated in several processes such as angiogenesis, organogenesis, cell migration, and cytokine release. Experimental studies showed that semaphorin-3a (SEMA3A) administration induces transient massive proteinuria, podocyte foot process effacement and endothelial cell damage in healthy animals. While SEMA3A signaling has been demonstrated to be mechanistically involved in experimental diabetic glomerulopathy and in acute kidney injury, to date its role in human chronic kidney disease (CKD) has not been investigated. To test the hypothesis that SEMA3A may play a role in human CKD, we performed a cross-sectional, nested, case-control study on 151 matched hypertensive patients with and without CKD. SEMA3A was quantified in the urine (USEMA) by ELISA. Glomerular filtration rate was estimated (eGFR) by the CKD-EPI formula and albuminuria was measured as albumin-to-creatinine ratio (ACR). USEMA levels were positively correlated with urine ACR (p = 0.001) and serum creatinine (p < 0.001). USEMA was higher in patients with both components of renal damage as compared to those with only one and those with normal renal function (p < 0.007 and <0.001, respectively). The presence of increased USEMA levels (i.e. top quartile) entailed a fourfold higher risk of combined renal damage (p < 0.001) and an almost twofold higher risk of macroalbuminuria (p = 0.005) or of reduced eGFR, even adjusting for confounding factors (p = 0.002). |
Does deep subcutaneous adipose tissue lipid unsaturation associate with intramyocellular lipid content? | Obese twins have lower saturated and higher long-chain polyunsaturated fatty acids (FA) in subcutaneous adipose tissue (SAT) compared to their lean monozygotic (MZ) co-twin. Whether this holds for metabolically distinct deep (DSAT) and superficial (SSAT) depots is unknown. Here we use non-invasive magnetic resonance spectroscopy (MRS) to measure the FA unsaturation in body mass index (BMI) discordant MZ twins in DSAT and SSAT and their relationship to ectopic fat content and body fat distribution. The main finding is further confirmed in an independent cohort using standardized measurement times. MRS and magnetic resonance imaging were used to measure DSAT and SSAT unsaturation and their relationship to intramyocellular lipids (IMCL), hepatocellular lipids (HCL) and the amount of subcutaneous (SAT) and visceral adipose tissue (VAT) in 16 pairs of healthy monozygotic twins (MZ) discordant for BMI. A second independent cohort of 12 healthy volunteers was used to measure DSAT unsaturation and IMCL with standardized measurement time. One volunteer also underwent repeated random measurements of DSAT unsaturation and IMCL. In accordance with biopsy studies SSAT unsaturation was higher in the heavier twins (15.2±1.0% vs. 14.4±1.5%, P=0.024) and associated with SAT volume (R=0.672, P=0.001). DSAT unsaturation did not differ between twins (11.4±0.8 vs. 11.0±1.0, P=0.267) and associated inversely with IMCL content (R=-0.462, P=0.001). The inverse association between DSAT unsaturation and IMCL was also present in the participants of the second cohort (R=-0.641, P=0.025) and for the repeated sampling at random of one person (R=-0.765, P=0.027). | To study the incidence and characteristics of intraoperative sclerotomy-related retinal breaks encountered during 23-gauge pars plana vitrectomy. A retrospective consecutive case series was assembled from the surgical logs and charts of patients who underwent 23-gauge pars plana vitrectomy. Demographic data and preoperative, intraoperative, and postoperative records were examined. A total 548 eyes met the inclusion criteria. Of them, 145 eyes underwent pars plana vitrectomy for repair of a rhegmatogenous retinal detachment (RRD) and 403 eyes for other indications. Sclerotomy-related retinal breaks were found in 8 of 548 (1.45%) eyes. No breaks were found in the 145 RRD eyes. In non-RRD cases, 8 of 403 (1.98%) eyes had sclerotomy-related breaks. All breaks were adjacent to the superior sclerotomies. The incidence of postoperative retinal detachment was 0% (0 of 403) in the non-RRD group. In eyes with breaks, the primary surgical indication was vitreomacular traction in six of eight eyes and epiretinal membrane in two of eight eyes. Posterior vitreous detachment was absent in six of eight eyes, and six of eight eyes were phakic. Eyes with vitreomacular traction had a significantly higher incidence of breaks (P < 0.0001). Eyes with a surgical indication other than RRD had a higher incidence of breaks, but this was not statistically significant when compared with eyes with RRD (P = 0.087). |
Does rush immunotherapy for wasp venom allergy seem safe and effective in patients with mastocytosis? | Patients with mastocytosis and wasp venom allergy (WA) may benefit from venom immunotherapy (VIT). However, fatal insect sting reactions have been described in mastocytosis patients despite previous immunotherapy. We investigated the safety and efficacy of (rush) VIT in patients with mastocytosis and WA. To investigate the safety and efficacy of (rush) VIT in patients with mastocytosis and WA. We describe nine patients with cutaneous mastocytosis and WA who received VIT. Cutaneous mastocytosis was confirmed by histopathology and systemic mastocytosis was diagnosed according to World Health Organization criteria. VIT was given according to a rush protocol. Given the difference in safety and efficacy of VIT in patients with WA and honeybee venom allergy, we reviewed the literature for VIT with the focus on WA patients with mastocytosis and addressed the difference between patients with cutaneous versus systemic mastocytosis. Nine patients had WA and mastocytosis, of whom six had cutaneous mastocytosis, two combined cutaneous and systemic mastocytosis and one systemic mastocytosis. All patients received rush IT with wasp venom. Most patients had only mild local side effects, with no systemic side effects during the course of VIT. One patient had a systemic reaction upon injection on one occasion, during the updosing phase, with dyspnoea and hypotension, but responded well to treatment. Immunotherapy was continued after temporary dose adjustment without problems. Two patients with a previous anaphylactic reaction were re-stung, without any systemic effects. | The objective of this study was to evaluate prognostic risk factors for survival in women with low-grade serous epithelial ovarian cancer (LGSC). A multicenter retrospective analysis of patients with LGSC was conducted. Potential epidemiologic risk factors evaluated included obesity, age, parity, race, smoking, oral contraceptive pill and/or hormonal replacement therapy use, and previous hysterectomy or surgery on fallopian tubes and/or ovaries. Additional factors included stage, extent of debulking, residual disease, and disease status. Eighty-one patients were identified, and pathologic diagnosis was independently confirmed. Median age at diagnosis was 56 years (range, 21-86 years). Thirty-four percent were obese, and 80% had optimally debulked disease. Forty-six percent were alive, 14% with disease, whereas 25% were dead of disease, 2% died of intercurrent disease, and 27% had an unknown status. In a univariate analysis, optimal surgical debulking was associated with improved progression-free survival (P = 0.01), disease-specific survival (P = 0.03), and overall survival (OS) (P < 0.001) and body mass index with worse OS (P = 0.05). On multivariate analysis, obesity (hazard ratio, 2.8; 95% confidence interval, 1.05-7.3; P = 0.04) and optimal tumor debulking (hazard ratio, 0.05; 95% confidence interval, 0.008-0.29; P = 0.001) were a significant predictor of OS. |
Do virologically suppressed patients with asymptomatic and symptomatic HIV-associated neurocognitive disorders display the same pattern of immune activation? | Inversion of the CD4:CD8 ratio is a marker of immune activation and age-associated disease. We measured the CD4:CD8 ratio as a marker of cognitive impairment in HIV-infected patients and explored differences according to clinical severity. Post hoc analysis of data from two prospective cohorts of HIV-infected patients randomly selected to undergo neuropsychological tests was performed. Test scores were adjusted for age, gender and education. Inclusion criteria were undetectable viral load and stable treatment for at least 6 months. Subjects with HIV-associated dementia were excluded. Patients were divided into an unimpaired group, a group with asymptomatic neurocognitive disorder (ANI) and a group with symptomatic HIV-associated neurocognitive disorder (sHAND), represented by mild neurocognitive disorder (MND). Demographic and background parameters, immune activation markers and the CD4:CD8 ratio were recorded. Two hundred patients were included in the study. The mean age was 52 years, 78% were male, the mean CD4 count was 624 cells/μL, the mean nadir CD4 count was 240 cells/μL, 27% were hepatitis C virus (HCV)-coinfected, the mean duration of HIV infection was 16 years, and the mean time on current combination antiretroviral therapy (cART) was 2.9 years. Twenty-nine per cent of subjects had HAND (21% had ANI and 8% had MND). In multivariate analysis, a CD4:CD8 ratio < 1 was associated with a nadir CD4 count < 200 cells/μL [odds ratio (OR) 3.68] and with the presence of CD4(+) CD38(+) HLA(+) cells (OR 1.23). Multinominal logistic regression showed that, in comparison with the unimpaired group, diagnosis of sHAND was associated with a CD4:CD8 ratio < 1 (OR 10.62), longer HIV infection (OR 1.15) and longer current cART (OR 1.34), while the ANI group differed from the unimpaired group only for education level. | Recent studies have shown cardiac protection effects of erythropoietin (EPO). The present experiment was designed to investigate the effects of EPO on TGF-beta1, nitric oxide synthase (NOS), collagen contents induced by angiotensin II (Ang II) in rat cardiac fibroblasts (CFs) and explore the roles of PI3-K/Akt signaling pathway on related effects. Neonatal rat CFs was isolated by collagenase and trypsinase digestion methods. PBS, EPO, Ang II in the absence or presence of LY294002, an inhibitor of PI3-K, or L-NAME, an inhibitor of NOS, were added to CFs and cultured for 24 hours. The concentration of collagen I and collagen III in culture medium were quantitated by ELISA. The levels of nitric oxide (NO) and the activities of NOS as well as NOS isoforms were measured by chemical enzymic method. Western blot was applied to detecting the protein expressions of Akt, p-Akt, eNOS, iNOS, and TGF-beta1. The concentrations of collagen I and collagen III in CFs culture medium were significantly increased while the level of NO was significantly decreased by Ang II and these changes were significantly suppressed by EPO in a dose dependent manner. The effects of EPO on eNOS and NO could be blocked by LY294002. L-NAME could block EPO's effect on NO but not on the eNOS expression. The suppression effects on expressions of TGF-beta1 and collagen by Ang II in CFs were blocked by both LY294002 and L-NAME. |
Is remote postconditioning more potent than classic postconditioning in reducing the infarct size in anesthetized rabbits? | Postconditioning confers protection to the heart after a potentially lethal episode of prolonged ischemia. There is evidence that it may also be protective when applied at a distal artery. In the present study, we sought to determine whether remote postconditioning within the heart (local) or outside the heart (distal) is effective in salvaging the ischemic heart in vivo and to compare its effect with that of the classic postconditioning. Twenty seven open chest New Zealand white anesthetized male rabbits were divided into four groups and were exposed to 30 min regional myocardial ischemia (isc), after ligation of a prominent coronary artery, followed by 3 h reperfusion (rep) after releasing the snare. Control group (n = 7) was subjected to no additional interventions, postC group (n = 6) was subjected to four cycles of 1 min isc/1 min rep of the same coronary artery at the beginning of reperfusion, remote local postC group (n = 7) to four cycles of 1 min isc/1 min rep of another coronary artery 30 s before the end of index isc and remote distal postC group (n = 7) to four cycles of 1 min isc/1 min rep of another (carotid) artery again 30 s before the end of index isc. Infarct size (I) and area at risk (R) were delineated with the aid of TTC staining and green fluorescent microspheres respectively and their ratio was expressed in percent (%I/R). Remote local and remote distal postC reduced the % I/R ratio (17.7 +/- 1.7% and 18.4 +/- 1.6%, respectively vs 47.0 +/- 2.5% in the control group, P < 0.01). Classic PostC had an intermediate protective effect (33.1 +/- 1.7%, P < 0.05 vs all the other groups). | Serum vitamin D levels are associated with bone complications in patients with primary biliary cirrhosis (PBC). Increasing evidence suggests a nonskeletal role of vitamin D in various autoimmune and liver diseases. To investigate the clinical relevance of vitamin D levels in PBC, especially their association with the therapeutic effects of ursodeoxycholic acid (UDCA). Consecutive PBC patients were retrospectively reviewed. 25-hydroxyvitamin D [25(OH)D] levels were determined in frozen serum samples collected before initiation of UDCA treatment. Response to UDCA was evaluated by Paris-I and Barcelona criteria. Logistic regressions were performed to identify the treatment response-associated parameters. Among 98 patients, the mean serum 25(OH)D concentration was 17.9 ± 7.6 ng/mL. 25(OH)D levels decreased with increasing histological stage (P = 0.029) and were negatively correlated with bilirubin and alkaline phosphatase levels. After 1 year of UDCA therapy, 31 patients failed to achieve complete response according to Paris-I criteria. The baseline 25(OH)D level was significantly lower in nonresponders (14.8 ± 6.4 vs. 19.3 ± 7.6 ng/mL, P = 0.005). Vitamin D deficiency at baseline was associated with an increased risk of incomplete response independent of advanced stages (OR = 3.93, 95% CI = 1.02-15.19, P = 0.047). Similar results were obtained when biochemical response was evaluated by Barcelona criteria. Furthermore, 25(OH)D levels were lower in patients who subsequently suffered death or liver transplantation (12.1 ± 4.6 vs. 18.4 ± 7.6 ng/mL, P = 0.023). |
Are pro-atherogenic mediators and subclinical atherogenesis related to epicardial adipose tissue thickness in patients with cardiovascular risk? | To evaluate the relationship between pro-atherogenic biomarkers and epicardial adipose tissue (EAT) thickness in patients with cardiovascular risk factors. Plasma nitric oxide (NO), soluble intercellular adhesion molecule-1 and malondialdehyde (MDA) levels, EAT thickness, flow-mediated dilation (FMD) and carotid intima media thickness (CIMT) were determined in patients aged >18 years who were referred for echocardiography for heart ischemia or non-ischemic diseases. Cardiovascular risk factors (Framingham score [FS] ≥ 20) were weighted. Hypertension, dyslipidaemia and type 2 diabetes mellitus were prevalent (≥55% of 40 patients). Patients with FS ≥ 20 (n = 21) showed significantly higher EAT and CIMT values. Globally, MDA, CIMT, age, waist circumference, high-density lipoprotein cholesterol (HDL-C) and FS were associated with EAT thickness. EAT was significantly associated with NO in patients with FS ≥ 20. Significant differences in EAT thickness were found between patients stratified by NO value, FMD, age, smoking status, dyslipidaemia, type 2 diabetes mellitus and FS. An EAT-associated atherogenic risk (CIMT ≥ 1 mm) model was statistically significant when MDA and type 2 diabetes mellitus were included. | Brivaracetam (BRV) is an antiepileptic drug in Phase III clinical development. BRV binds to synaptic vesicle 2A (SV2A) protein and is also suggested to inhibit voltage-gated sodium channels (VGSCs). To evaluate whether the effect of BRV on VGSCs represents a relevant mechanism participating in its antiepileptic properties, we explored the pharmacology of BRV on VGSCs in different cell systems and tested its efficacy at reducing the sustained repetitive firing (SRF). Brivaracetam investigations on the voltage-gated sodium current (I(Na)) were performed in N1E-155 neuroblastoma cells, cultured rat cortical neurons, and adult mouse CA1 neurons. SRF was measured in cultured cortical neurons and in CA1 neurons. All BRV (100-300 μM) experiments were performed in comparison with 100 μM carbamazepine (CBZ). Brivaracetam and CBZ reduced IN a in N1E-115 cells (30% and 40%, respectively) and primary cortical neurons (21% and 47%, respectively) by modulating the fast-inactivated state of VGSCs. BRV, in contrast to CBZ, did not affect I(Na) in CA1 neurons and SRF in cortical and CA1 neurons. CBZ consistently inhibited neuronal SRF by 75-93%. |
Does rapamycin inhibit growth of premalignant and malignant mammary lesions in a mouse model of ductal carcinoma in situ? | Rapamycin has been shown to have antitumor effects in various tumor models. To study the effect of rapamycin at different stages of breast cancer development, we used two unique mouse models of breast cancer with activated phosphatidylinositol 3-kinase (PI3K) pathway. Met-1 tumors are highly invasive and metastatic, and mammary intraepithelial neoplasia-outgrowths (MIN-O), a model for human ductal carcinoma in situ, are transplantable premalignant mammary lesions that develop invasive carcinoma with predictable latencies. Both of these models were derived from mammary lesions in Tg(MMTV-PyV-mT) mice. Met-1 tumors were used to study the effect of rapamycin treatment on invasive disease. Transplanted MIN-O model was used to study the effect of rapamycin on premalignant mammary lesions. Animals were in vivo micro-positron emission tomography imaged to follow the lesion growth and transformation to tumor during the treatment. Cell proliferation, angiogenesis, and apoptosis was assayed by immunohistochemistry. Rapamycin inhibited in vitro tumor cell proliferation and in vivo Met-1 tumor growth. The growth inhibition was correlated with dephosphorylation of mammalian target of rapamycin (mTOR) targets. Rapamycin treatment significantly reduced the growth of the premalignant MIN-O lesion, as well as tumor incidence and tumor burden. Growth inhibition was associated with reduced cell proliferation and angiogenesis and increased apoptosis. | Increased oxidative stress is associated with coronary heart disease (CHD). We examined the association between plasma markers of oxidative stress and CHD in a cross-sectional sample of patients with diabetes and prospective CHD risk in a sample of men predominantly without diabetes. Plasma total antioxidant status (TAOS) and the ratio of oxidized LDL (Ox-LDL) to LDL-cholesterol (LDL-C) were determined in a cross-section of 761 Caucasian individuals with diabetes (UDACS study). Plasma TAOS was also determined in 310 baseline samples from a 10-year prospective cohort of 3012 healthy males (NPHSII). Within UDACS, males with CHD had lower mean (SD) plasma TAOS [no CHD, 43.4 (13.2)%; CHD, 40.3 (13.8)%; P = 0.04]. The prevalence of CHD was higher in the lowest compared with the upper quartiles (32.7% vs 19.7%; P = 0.004). We observed a significant association between plasma Ox-LDL:LDL-C and CHD status [no CHD vs CHD, 16.9 (3.1) vs 19.3 (5.0) units/mmol; P = 0.04], with the prevalence of CHD being higher among men in the upper compared with lower quartiles (18.4% vs 35.1%; P = 0.003). No association was observed in females. In NPHSII, TAOS was lower in those who developed CHD [35.1 (8.0)% vs 37.1 (7.9)%; P = 0.04]. The odds ratio for CHD in the lowest compared with the upper quartile was 1.91 (95% confidence interval, 0.99-3.70; P = 0.04). This remained unchanged after adjustment for classic risk factors. |
Subsets and Splits
No community queries yet
The top public SQL queries from the community will appear here once available.