Miracle-dz/UniFAR-FTUs huggingface dataset:
CTSH regulates β-cell function and disease progression in newly diagnosed type 1 diabetes patients

Significance In type 1 diabetes (T1D), the insulin-producing pancreatic β-cells are destroyed by the immune system. Both genetic and environmental factors contribute to T1D risk. Candidate genes for T1D identified by genome-wide association studies have been proposed to act at both the immune system and the β-cell levels. This study shows that the risk variant rs3825932 in the candidate gene cathepsin H (CTSH) predicts β-cell function in both model systems and human T1D. Collectively, our data indicate that higher CTSH expression in β-cells may protect against immune-mediated damage and preserve β-cell function, thereby representing a possible therapeutic target. Our study reinforces the concept that candidate genes for T1D may affect disease progression by modulating survival and function of the β-cells. Over 40 susceptibility loci have been identified for type 1 diabetes (T1D). Little is known about how these variants modify disease risk and progression. Here, we combined in vitro and in vivo experiments with clinical studies to determine how genetic variation of the candidate gene cathepsin H (CTSH) affects disease mechanisms and progression in T1D. The T allele of rs3825932 was associated with lower CTSH expression in human lymphoblastoid cell lines and pancreatic tissue. Proinflammatory cytokines decreased the expression of CTSH in human islets and primary rat β-cells, and overexpression of CTSH protected insulin-secreting cells against cytokine-induced apoptosis. Mechanistic studies indicated that CTSH exerts its antiapoptotic effects through decreased JNK and p38 signaling and reduced expression of the proapoptotic factors Bim, DP5, and c-Myc. CTSH overexpression also up-regulated Ins2 expression and increased insulin secretion. Additionally, islets from Ctsh−/− mice contained less insulin than islets from WT mice. Importantly, the TT genotype was associated with higher daily insulin dose and faster disease progression in newly diagnosed T1D patients, indicating agreement between the experimental and clinical data. In line with these observations, healthy human subjects carrying the T allele have lower β-cell function, which was evaluated by glucose tolerance testing. The data provide strong evidence that CTSH is an important regulator of β-cell function during progression of T1D and reinforce the concept that candidate genes for T1D may affect disease progression by modulating survival and function of pancreatic β-cells, the target cells of the autoimmune assault.
Acute regulation of aquaporin-2 phosphorylation at Ser-264 by vasopressin

By phosphoproteome analysis, we identified a phosphorylation site, serine 264 (pS264), in the COOH terminus of the vasopressin-regulated water channel, aquaporin-2 (AQP2). In this study, we examined the regulation of AQP2 phosphorylated at serine 264 (pS264–AQP2) by vasopressin, using a phospho-specific antibody (anti-pS264). Immunohistochemical analysis showed pS264–AQP2 labeling of inner medullary collecting duct (IMCD) from control mice, whereas AQP2 knockout mice showed a complete absence of labeling. In rat and mouse, pS264–AQP2 was present throughout the collecting duct system, from the connecting tubule to the terminal IMCD. Immunogold electron microscopy, combined with double-labeling confocal immunofluorescence microscopy with organelle-specific markers, determined that the majority of pS264 resides in compartments associated with the plasma membrane and early endocytic pathways. In Brattleboro rats treated with [deamino-Cys-1, d-Arg-8]vasopressin (dDAVP), the abundance of pS264–AQP2 increased 4-fold over controls. Additionally, dDAVP treatment resulted in a time-dependent change in the distribution of pS264 from predominantly intracellular vesicles, to both the basolateral and apical plasma membranes. Sixty minutes after dDAVP exposure, a proportion of pS264–AQP2 was observed in clathrin-coated vesicles, early endosomal compartments, and recycling compartments, but not lysosomes. Overall, our results are consistent with a dynamic effect of AVP on the phosphorylation and subcellular distribution of AQP2.
Levels of cerebrospinal fluid nerve‐growth factor differ in infantile autism and Rett syndrome

Autism and Rett syndrome (RS) are both developmental disorders of unknown origin. Autism is a behaviourally defined syndrome. RS, which affects girls only, is characterized by a profound learning disability following early normal development, with a consistent cluster of clinical features. Differentiation of RS from infantile autism in the very early stages of the disorders is not always easy. Both syndromes still lack discriminative laboratory markers for accurate diagnosis and differentiation. We decided to compare the CSF nerve‐growth factor (NGF) levels of children with infantile autism and children with RS using enzyme‐linked immunosorbent assay (ELISA). Our findings of mainly normal CSF NGF in autism and low to negligible values in RS are in agreement with the different morphological and neurochemical findings (brain growth, affected brain areas, neurotransmitter metabolism) in the two syndromes. CSF NGF could be used as a biochemical marker for differentiation of patients with autism from those with RS.
Anthropometric Measurements and Lipid Profiles to Detect Early Lipodystrophy in Antiretroviral Therapy Experienced HIV-Infected Children in the Chapas-3 Trial

Background Few studies have investigated objective markers of lipodystrophy in African children. We compared body circumferences, skin-fold thickness (SFT) and lipids in antiretroviral therapy (ART)-naive and stavudine (d4T)-exposed children with HIV-uninfected controls. Methods In the CHAPAS-3 trial, HIV-infected children (ART-naive or on d4T for ≥2 years without clinical lipodystrophy) were randomized to d4T, abacavir or zidovudine with lamivudine (3TC) plus a non-nucleoside reverse transcriptase inhibitor. Mid-upper-arm circumference (MUAC) and calf circumference (CC), SFT (biceps, triceps, sub-scapular and supra-iliac) and fasting lipids (total cholesterol [TC], low-density lipoprotein [LDL], high-density lipoprotein [HDL] and triglycerides [TRIG]) were measured at randomization in all HIV-infected children, and in HIV-uninfected controls. Age- and sex-adjusted z-scores of MUAC, CC, SFT and the sum of SFT (SSF) using Dutch reference data were compared across groups using linear regression. Results Of 496 children, 49% were male, 299 (median age 2.5 years [IQR 1.5–4.0]) were ART-naive, 109 (median age 6 years [IQR 5.5–7.0]) were ART-experienced and 88 (median age 2.2 years [IQR 1.5–3.0]) were control children. Overall, 100% and 95% of ART-experienced children had been on d4T plus 3TC and nevirapine, respectively, for a median 3.5 years (IQR 2.6–4.2). Mean (sd) weight-for-age z-scores and MUAC z-scores were -1.51 (1.29) versus -0.90 (0.88) versus -0.33 (1.15) and -1.56 (1.25) versus -1.24 (0.97) versus -0.65 (1.06) in ART-naive versus -experienced versus controls, respectively (all P<0.02). The mean (sd) of SSF was lower in the ART-experienced (-0.78 [1.28]) than in the ART-naive (-0.32 [1.09]; P<0.0001) children and controls (-0.29 [0.88]; P<0.002). ART-experienced children had higher mean fasting TC, LDL and HDL but lower TRIG compared to ART-naive children (P-values <0.0001), and higher TC and HDL but lower TRIG compared to controls (P-values <0.01). Conclusions In ART-experienced children on d4T-containing regimens, we observed lower SFT and higher TC and LDL values compared to ART-naive children and HIV-uninfected controls.
Diversification,Firm's Value and Earnings Fluctuation Empirical Research Based on Chinese Listed Firms

The paper point out that the premise of Marris Model about the negative relation between firm's profit and growth might not exist in Chinese listed firms which are in a transition economy,and there may be a new relation between the two.We prove that diversification is positively related to firm's value,and firms operating in the style of diversification have higher value.There is a negative relation between diversification and earnings fluctuation,that is,diversification decreases the degree of earnings fluctuation.The research dose not find that turn point of the relation between diversification and performance occurs.We think the paper explains why the mode of diversification have been widely adopted in Chinese listed firms.
Comparison of job satisfaction and stress among male and female doctors in teaching hospitals of Karachi.

BACKGROUND Job dissatisfaction and stress among doctors affect the quality of health care. We assessed the levels of satisfaction for workplace characteristics and job stress among doctors of three teaching hospitals in Karachi. METHODS A postal-survey was conducted between May to June 2002. Satisfaction for workplace characteristics and stress were inquired and graded by Likert scale (1 = very low to 5 = very high). Questions were also asked about its affect on their lives. In order to calculate the differences in means of job satisfaction and stress score by sex of doctors, chi-square and t-test with 95% confidence interval (CI) were used. Out of 270 doctors approached conveniently, 189 (70%) responded and 182 questionnaires were found complete for analysis. RESULTS Majority (68%) of the doctors was not satisfied with their jobs. Overall, the mean scores for satisfaction were low for workplace characteristics. Lowest scores were found for pay and benefits 2.12 (SE 0.8), safety and security 2.15 (SE 0.8) and workload 2.69 (SE 0.9). Female doctors had significantly lower satisfaction about workload (mean job satisfaction score difference = 0.60; 95%CI, 0.24-0.97), relation with colleagues (mean job satisfaction score difference = 0.49: 95%CI, 0.11-0.87) and autonomy (mean job satisfaction score difference = 0.45; 95%CI, 0.07-0.82) as compared to their male counterparts. Overall, 48% of doctors graded job stress from high to very high levels. CONCLUSION Majority of doctors working at these teaching hospitals of Karachi had poor satisfaction level for workplace characteristics and higher levels of job stress. This suggests that immediate steps should be taken for their control and management. This study invites further research to explore, implement and evaluate intervention strategies for prevention of stress and improvement in job satisfaction.
The Clinical Effect of a Rotator Cuff Retear: A Meta-analysis of Arthroscopic Single-Row and Double-Row Repairs

Background: The clinical effect of a retear after rotator cuff repair remains unclear. While some studies have indicated clinical deficits due to a retear, others have stated that a retear does not detrimentally affect outcomes. Purpose: To conduct a meta-analysis comparing clinical outcomes between intact and retorn rotator cuffs after arthroscopic repair. Study Design: Meta-analysis. Methods: A literature search using the terms “arthroscopic,” “rotator cuff,” “repair,” “retear,” “re-tear,” “defect,” “single-row,” “double-row,” “clinical outcomes,” and “functional outcomes” was conducted. Article inclusion criteria were an adequate description of the surgical technique, stratification of outcomes by intact rotator cuff versus retear with a minimum of 1 year of follow-up, and documentation of the presence/absence of a full-thickness retear using imaging. Exclusion criteria were isolated subscapularis tears/repairs, labral repairs, infections, postoperative fractures, insufficient data or statistical indications, and postoperative data not stratified by retear versus intact rotator cuff. A meta-analysis was performed using a random-effects model on variables that had comparisons from at least 3 studies. Single-row (SR) and double-row (DR) studies were analyzed both separately and together in an “all arthroscopic repairs” (AAR) comparison. The calculated effect was considered significant at a P value <. 05. Results: Within the SR group, patients with a rotator cuff retear had a significantly lower Constant score (mean difference [95% CI], −6.79 [–8.94 to −4.65]; P < .001) and lower University of California, Los Angeles (UCLA) score (−3.21 [–5.27 to −1.15]; P = .002) but not higher pain (0.071 [–0.34 to 0.49]; P = .739). Within the DR group, patients with a rotator cuff retear had a significantly lower Constant score (mean difference [95% CI], −9.35 [–12.2 to −6.50]; P < .001), lower American Shoulder and Elbow Surgeons (ASES) score (−12.1 [–17.1 to −7.26]; P < .001), lower UCLA score (−3.07 [–4.85 to −1.29]; P < .001), higher pain (0.622 [0.19 to 1.05]; P = .005), and lower abduction strength (P < .001). In the AAR comparison, patients with a retear had a significantly lower Constant score (mean difference [95% CI], −7.56 [–9.55 to −5.57]; P < .001), lower ASES score (−10.1 [–15.5 to −4.64]; P < .001), lower UCLA score (−3.00 [–4.47 to −1.53]; P < .001), and lower abduction strength (in kg·f) (−3.32 [–4.53 to −2.12]; P < .001) but not higher pain (0.332 [–0.014 to 0.680]; P = .060). Conclusion: Patients with a full-thickness rotator cuff retear exhibited significantly lower clinical outcome scores and strength compared with patients with an intact or partially torn rotator cuff.
Multicenter case-control study of the risk factors for ulcerative colitis in China.

AIM To evaluate potential risk factors in the development of ulcerative colitis (UC) in China. METHODS A total of 1308 patients with UC and 1308 age-matched and sex-matched controls were prospectively studied in China. The UC cases were collected from 17 hospitals in China from April 2007 to April 2010. Uniform questionnaires were designed to investigate risk factors including smoking, appendectomy, stress, socio-economic conditions, nonsteroidal anti-inflammatory drugs (NSAIDs), oral contraceptives, diet, breastfeeding, infections and family sanitary conditions. Group comparisons by each factor were done using simple logistic regression analysis. Conditional logistic regression was used for multivariate analysis. RESULTS By univariate analysis, the variables predictive of UC included feeling stress, light and heavy alcoholic drinking, spicy food, sugar consumption and infectious diarrhea, while heavy tea intake and tap water consumption were protective against UC. On multivariate analysis, the protective factor for UC was tap water consumption [odds ratios (OR) = 0.424, 95%CI: 0.302-0.594, P < 0.001]; while the potential risk factors for UC were heavy sugar consumption (OR = 1.632, 95%CI: 1.156-2.305, P < 0.001), spicy food (light intake: OR = 3.329, 95%CI: 2.282-4.857, P < 0.001; heavy intake: OR = 3.979, 95%CI: 2.700-5.863, P < 0.001), and often feeling stress (OR = 1.981, 95%CI: 1.447-2.711, P < 0.001). Other factors, such as smoking habit, appendectomy, breastfeeding, a history of measles, rural or urban residence, education, oral contraceptives, and NSAID use have not been found to have a significant association with the development of UC in the present study. CONCLUSION Our study showed tap water consumption was a protective factor for UC, while spicy food, heavy sugar consumption and often feeling stress were risk factors for UC in this Chinese population.
PROTEIN TYROSINE KINASE ACTIVITY AND THE INFLUENCE OF GENDER IN PHAGOCYTOSIS AND TUMOR NECROSIS FACTOR SECRETION IN ALVEOLAR MACROPHAGES AND LUNG‐RECRUITED NEUTROPHILS

The role of tyrosine phosphorylation in endotoxin-induced phagocytic and tumor necrosis factor secretory responses was studied in rat alveolar macrophages and lung-recruited neutrophils. Exploration of sexual dimorphism in some aspects of these functions was also a specific aim. Male and female rats were injected intratracheally with endotoxin or saline. Two and a half hours later the animals were subjected to bronchoalveolar lavage, and alveolar macrophages and lung-recruited neutrophils were isolated. Circulating neutrophils of endotoxin-treated rats were also isolated at this time. Phagocytosis and CD11b/c and CD18 expression were measured by flow cytometry; tumor necrosis factor was measured with a cytotoxicity assay. Using the protein tyrosine kinase inhibitor AG126 and phosphotyrosine immunoblotting, we demonstrated that tyrosine phosphorylation is an important signaling pathway in the activation of these cells by endotoxin and that it is coupled to phagocytosis and tumor necrosis factor secretion, but not to β2 integrin expression. Conditioned medium of alveolar macrophages of endotoxininjected rats upregulates phagocytosis by blood neutrophils of naive rats and this upregulating activity is tyrosine phosphorylation dependent. The substrates for tyrosine phosphorylation are different in alveolar macrophages and lung neutrophils, as are their sensitivities to AG126. Significant gender differences exist in the modulation of phagocytosis by inhibition of tyrosine phosphorylation and in tumor necrosis factor secretion by endotoxin-stimulated alveolar macrophages.
Changes in the T cell receptor macromolecular signaling complex and membrane microdomains during T cell development and activation.

Initiation and propagation of T cell receptor signaling pathways involves the mobilization and aggregation of a variety of signaling intermediates with the T cell receptor and associated molecules into specialized signaling complexes. Accumulating evidence suggests that differential regulation of the formation and composition of the T cell receptor macromolecular signaling complex may affect the different biological consequences of T cell activation. The regulatory mechanisms involved in the assembly of these complexes remains poorly understood, but in part is affected by the avidity of the T cell receptor ligand, co-stimulatory signals, and by the differentiation state of the T cell.
High Expression of Somatostatin Receptor Subtype 2 (sst2) in Medulloblastoma: Implications for Diagnosis and Therapy

Medulloblastoma is a pediatric malignancy, which arises in cerebellum. The neuropeptide somatostatin (SS-14) is a neuromodulator and growth regulator in the developing cerebellum. SS-14 has previously been demonstrated in medulloblastomas with immunohistochemical techniques, but somatostatin receptor (sst) expression is less well understood. We analyzed somatostatin and sst subtype expression (sst1-5) in central primitive neuroectodermal tumors (cPNET), including 23 medulloblastomas, 6 supratentorial PNET, and 10 cPNET cell lines. The expression of SS-14 and sst genes in cPNET was compared with expression of these genes in 17 tumors of the Ewing's sarcoma family of tumors using reverse transcriptase-PCR, Southern hybridization, quantitative in vitro receptor autoradiography, and competitive membrane binding assays. The sst1 subtype was expressed in similar frequency in cPNET (83%) and Ewing's sarcoma family of tumors (71%). Nine of the 10 cell lines and 76% of the cPNET expressed mRNA for sst2 compared with 35% of the Ewing's sarcoma family of tumors. High-affinity binding of SS-14 was demonstrated in cPNET by quantitative autoradiography as well as by competitive binding assays. The cPNET cell line D283 Med bound SS-14 and octreotide with high affinity; SS-14 inhibited proliferation of D283 Med cells as measured by a decrease in [3H]thymidine uptake. We conclude that both sst1 and sst2 are highly expressed in cPNET and suggest that somatostatin may regulate proliferation and differentiation in these developmental tumors.
Interleukin‐10 gene –627 allele variants, not interleukin‐I beta gene and receptor antagonist gene polymorphisms, are associated with atopic bronchial asthma

Asthma is an airway hyperresponsive disease characterized by the expression of multiple inflammatory genes, including cytokines. Interleukin‐I and interleukin‐10 (IL‐1 and IL‐10) are cytokines that might play a role in the process of inflammation and are therefore considered to be involved in the pathogenesis of bronchial asthma. The aim of this study was to test whether the polymorphisms of the promoter region and exon 5 of the IL‐1 gene, intron 2 of the IL‐1Ra gene, and –627 nucleotide (C/A) of the IL‐10 gene could be genetic markers for the susceptibility of bronchial asthma. A normal control group made up of 47 healthy volunteers and 117 patients with bronchial asthma were examined in this study. We analyzed the variable number of tandem repeats at intron 2 of the IL‐1Ra gene for the polymorphisms by polymerase chain reaction (PCR). PCR‐based restriction analysis of the IL‐1 gene polymorphisms of the promoter region and exon 5 was carried out by the endonucleases Ava I and Taq I, respectively. The IL‐10 gene –627 C/A polymorphisms were investigated by PCR‐based restriction analysis. The distribution of CC homozygotes in the IL‐10 gene was significantly lower in asthma patients than in controls (P=0.013, OR=3.599, 95% CI=1.240∼10.441). The polymorphisms studied in the IL‐1 genes did not reveal any significant association with bronchial asthma when compared with the control group (promoter region by chi‐square test, P=0.627; exon 5 region by Fisher's exact test, P=0.403). Only two alleles of the IL‐1Ra gene corresponding to one and two copies of an 86‐base pair sequence repeat were identified by PCR in the control group. There were three alleles found in the asthmatic patient group. The results revealed no significant differences between normal individuals and asthma patients (P=0.454, Fisher's exact test). The IL‐10 gene –627 “A” allele is an associated risk factor of developing atopic asthma. J. Clin. Lab. Anal. 17:168–173, 2003. © 2003 Wiley‐Liss, Inc.
Cholera stool bacteria repress chemotaxis to increase infectivity

Factors that enhance the transmission of pathogens are poorly understood. We show that Vibrio cholerae shed in human ‘rice‐water’ stools have a 10‐fold lower oral infectious dose in an animal model than in vitro grown V. cholerae, which may aid in transmission during outbreaks. Furthermore, we identify a bacterial factor contributing to this enhanced infectivity: The achievement of a transient motile but chemotaxis‐defective state upon shedding from humans. Rice‐water stool V. cholerae have reduced levels of CheW‐1, which is essential for chemotaxis, and were consequently shown to have a chemotaxis defect when tested in capillary assays. Through mutational analyses, such a state is known to enhance the infectivity of V. cholerae. This is the first report of a pathogen altering its chemotactic state in response to human infection in order to enhance its transmission.
Liver alcohol dehydrogenase and aldehyde dehydrogenase in the Japanese: isozyme variation and its possible role in alcohol intoxication.

Forty autopsy livers from Japanese individuals were studied concerning alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) isozymes using electrophoretic and enzyme assay methods. A remarkably high frequency (85%) was found for the atypical ADH phenotype. The gene frequencies of ADH22 and ADH32 were . 625 and . 05, respectively. The usual ALDH phenotype showed two major isozyme bands, a faster migrating (low Km for acetaldehyde) and a slower migrating isozyme (high Km for acetaldehyde). Fifty-two percent of the specimens had an unusual phenotype of ALDH, which showed only the slower migrating isozyme. The usual phenotype was inhibited about 20%--30% by disulfiram and the unusual type up to 90%. Such a high incidence in the Japanese of the unusual phenotype, which lacks in the low Km isozyme, suggests that the initial intoxicating symptoms after alcohol drinking in these subjects might be due to delayed oxidation of acetaldehyde rather than its higher-than-normal production by typical or atypical ADH.