bluuebunny/crossref_metadata_2025_split huggingface dataset:
Glutathione deficiency down-regulates hepatic lipogenesis in rats
Authors: Brandsch Corinna , Schmidt Tobias , Behn Diana , Weiße Kristin , Mueller Andreas S , Stangl Gabriele I 
Published: May 2010

Abstract

Background
Oxidative stress is supposed to increase lipid accumulation by stimulation of hepatic lipogenesis at transcriptional level. This study was performed to investigate the role of glutathione in the regulation of this process. For that purpose, male rats were treated with buthionine sulfoximine (BSO), a specific inhibitor of γ-glutamylcysteine synthetase, for 7 days and compared with untreated control rats.

Results
BSO treatment caused a significant reduction of total glutathione in liver (-70%), which was attributable to diminished levels of reduced glutathione (GSH, -71%). Glutathione-deficient rats had lower triglyceride concentrations in their livers than the control rats (-23%), whereas the circulating triglycerides and the cholesterol concentrations in plasma and liver were not different between the two groups of rats. Livers of glutathione-deficient rats had lower mRNA abundance of sterol regulatory element-binding protein (SREBP)-1c (-47%), Spot (S)14 (-29%) and diacylglycerol acyltransferase 2 (DGAT-2, -27%) and a lower enzyme activity of fatty acid synthase (FAS, -26%) than livers of the control rats. Glutathione-deficient rats had also a lower hepatic activity of the redox-sensitive protein-tyrosine phosphatase (PTP)1B, and a higher concentration of irreversible oxidized PTP1B than control rats. No differences were observed in protein expression of total PTP1B and the mature mRNA encoding active XBP1s, a key regulator of unfolded protein and ER stress response.

Conclusion
This study shows that glutathione deficiency lowers hepatic triglyceride concentrations via influencing lipogenesis. The reduced activity of PTP1B and the higher concentration of irreversible oxidized PTP1B could be, at least in part, responsible for this effect.
Validation of the "World Health Organization Disability Assessment Schedule, WHODAS-2" in patients with chronic diseases
Authors: Garin Olatz , Ayuso-Mateos Jose Luis , Almansa Josué , Nieto Marta , Chatterji Somnath , Vilagut Gemma , Alonso Jordi , Cieza Alarcos , Svetskova Olga , Burger Helena , Racca Vittorio , Francescutti Carlo , Vieta Eduard , Kostanjsek Nenad , Raggi Alberto , Leonardi Matilde , Ferrer Montse ,   the MHADIE consortium
Published: May 2010

Abstract

Background
The WHODAS-2 is a disability assessment instrument based on the conceptual framework of the International Classification of Functioning, Disability, and Health (ICF). It provides a global measure of disability and 7 domain-specific scores. The aim of this study was to assess WHODAS-2 conceptual model and metric properties in a set of chronic and prevalent clinical conditions accounting for a wide scope of disability in Europe.

Methods
1,119 patients with one of 13 chronic conditions were recruited in 7 European centres. Participants were clinically evaluated and administered the WHODAS-2 and the SF-36 at baseline, 6 weeks and 3 months of follow-up. The latent structure was explored and confirmed by factor analysis (FA). Reliability was assessed in terms of internal consistency (Cronbach's alpha) and reproducibility (intra-class correlation coefficients, ICC). Construct validity was evaluated by correlating the WHODAS-2 and SF-36 domains, and comparing known groups based on the clinical-severity and work status. Effect size (ES) coefficient was used to assess responsiveness. To assess reproducibility and responsiveness, subsamples of stable (at 6 weeks) and improved (after 3 moths) patients were defined, respectively, according to changes in their clinical-severity.

Results
The satisfactory FA goodness of fit indexes confirmed a second order factor structure with 7 dimensions, and a global score for the WHODAS-2. Cronbach's alpha ranged from 0.77 (self care) to 0.98 (life activities: work or school), and the ICC was lower, but achieved the recommended standard of 0.7 for four domains. Correlations between global WHODAS-2 score and the different domains of the SF-36 ranged from -0.29 to -0.65. Most of the WHODAS-2 scores showed statistically significant differences among clinical-severity groups for all pathologies, and between working patients and those not working due to ill health (p < 0.001). Among the subsample of patients who had improved, responsiveness coefficients were small to moderate (ES = 0.3-0.7), but higher than those of the SF-36.

Conclusions
The latent structure originally designed by WHODAS-2 developers has been confirmed for the first time, and it has shown good metric properties in clinic and rehabilitation samples. Therefore, considerable support is provided to the WHODAS-2 utilization as an international instrument to measure disability based on the ICF model.
The conformation change of Bcl-2 is involved in arsenic trioxide-induced apoptosis and inhibition of proliferation in SGC7901 human gastric cancer cells
Authors: Zheng Yihu , Zhou Mengtao , Ye Aifang , Li Qiu , Bai Yongheng , Zhang Qiyu 
Published: May 2010

Abstract

Background
Arsenic trioxide has been established as a first-line agent for treating acute promyelocytic leukemia. Experimental data suggest that arsenic trioxide also can have a potential use as chemotherapeutic agent for other malignancies. The precise mechanisms of action of arsenic trioxide have though not been elucidated. As the role of Bcl-2 in arsenic trioxide-mediated cell apoptosis and conformation change of Bcl-2 in response to arsenic trioxide treatment has not been studied. The aim of the present study was to determine whether conformation change of Bcl-2 is involved in the action of arsenic trioxide.

Methods
Human gastric cancer SGC7901 cells were exposed to different concentrations of arsenic trioxide. Proliferation was measured by using the Kit-8 cell counting assay. Analysis of nuclear morphology was observed by DAPI staining. The apoptosis rates of cells treated with arsenic trioxide were analyzed by flow cytometry using Annexin V-FITC staining. The conformation change of Bcl-2 and Bax activation were detected by immunostaining and Western blot analysis. Total expression of Bcl-2 and Bax were examined by Western blot analysis.

Results
Arsenic trioxide inhibited the growth of human gastric cancer SGC7901 cells and induced apoptosis. There were two Bcl-2 phenotypes coexisting in SGC7901 cells and the Bcl-2 cytoprotective phenotype could change into a cytodestructive phenotype following conformational change of Bcl-2, triggered by arsenic trioxide exposure. Bax activation might also be involved in arsenic trioxide-induced Bcl-2 conformational change. Arsenic trioxide did not change levels of total Bcl-2 expression, but up-regulated total Bax expression for the treatment time ranging from 3 to 24 hours.

Conclusion
Arsenic trioxide induces apoptosis through induction of Bcl-2 conformational change, Bax activation and up-regulation of total Bax expression rather than affecting total Bcl-2 expression in human gastric cancer SGC7901 cells. The conformational change of Bcl-2 may be a novel described mechanism of arsenic trioxide-induced apoptosis in cancer cells.
Undetectable plasma viral load predicts normal survival in HIV-2-infected people in a West African village
Authors: van der Loeff Maarten F Schim , Larke Natasha , Kaye Steve , Berry Neil , Ariyoshi Koya , Alabi Abraham , van Tienen Carla , Leligdowicz Aleksandra , Sarge-Njie Ramu , da Silva Zacharias , Jaye Assan , Ricard Dominique , Vincent Tim , Jones Sarah Rowland , Aaby Peter , Jaffar Shabbar , Whittle Hilton 
Published: May 2010

Abstract

Background
There have been no previous studies of the long-term survival and temporal changes in plasma viral load among HIV-2 infected subjects.

Methods
133 HIV-2 infected and 158 HIV-uninfected subjects from a rural area in North-west Guinea-Bissau, West Africa were enrolled into a prospective cohort study in 1991 and followed-up to mid-2009. Data were collected on four occasions during that period on HIV antibodies, CD4% and HIV-2 plasma viral load.

Results
Median age (interquartile range [IQR]) of HIV-2 infected subjects at time of enrollment was 47 (36, 60) years, similar to that of HIV-uninfected control subjects, 49 (38, 62) (p = 0.4). Median (IQR) plasma viral load and CD4 percentage were 347 (50, 4,300) copies/ml and 29 (22, 35) respectively.
Overall loss to follow-up to assess vital status was small, at 6.7% and 6.3% for HIV-2 infected and uninfected subjects respectively. An additional 17 (12.8%) and 16 (10.1%) of HIV-2 infected and uninfected subjects respectively were censored during follow-up due to infection with HIV-1. The mortality rate per 100 person-years (95% CI) was 4.5 (3.6, 5.8) among HIV-2 infected subjects compared to 2.1 (1.6, 2.9) among HIV-uninfected (age-sex adjusted rate ratio 1.9 (1.3, 2.8, p < 0.001) representing a 2-fold excess mortality rate associated with HIV-2 infection.
Viral load measurements were available for 98%, 78%, 77% and 61% HIV-2 infected subjects who were alive and had not become super-infected with HIV-1, in 1991, 1996, 2003 and 2006 respectively. Median plasma viral load (RNA copies per ml) (IQR) did not change significantly over time, being 150 (50, 1,554; n = 77) in 1996, 203 (50, 2,837; n = 47) in 2003 and 171 (50, 497; n = 31) in 2006. Thirty seven percent of HIV-2 subjects had undetectable viraemia (<100 copies/ml) at baseline: strikingly, mortality in this group was similar to that of the general population.

Conclusions
A substantial proportion of HIV-2 infected subjects in this cohort have stable plasma viral load, and those with an undetectable viral load (37%) at study entry had a normal survival rate. However, the sequential laboratory findings need to be interpreted with caution given the number of individuals who could not be re-examined.
Severe hepatic encephalopathy in a patient with liver cirrhosis after administration of angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker combination therapy: a case report
Authors: Oertelt-Prigione Sabine , Crosignani Andrea , Gallieni Maurizio , Vassallo Emanuela , Podda Mauro , Zuin Massimo 
Published: May 2010

Abstract

Introduction
A combination therapy of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers has been used to control proteinuria, following initial demonstration of its efficacy. However, recently concerns about the safety of this therapy have emerged, prompting several authors to urge for caution in its use. In the following case report, we describe the occurrence of a serious and unexpected adverse drug reaction after administration of a combination of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers to a patient with nephrotic syndrome and liver cirrhosis with severe portal hypertension.

Case presentation
We administered this combination therapy to a 40-year-old Caucasian man with liver cirrhosis in our Hepatology Clinic, given the concomitant presence of glomerulopathy associated with severe proteinuria. While the administration of one single drug appeared to be well-tolerated, our patient developed severe acute encephalopathy after the addition of the second one. Discontinuation of the therapy led to the disappearance of the side-effect. A tentative rechallenge with the same drug combination led to a second episode of acute severe encephalopathy.

Conclusion
We speculate that this adverse reaction may be directly related to the effect of angiotensin II on the excretion of blood ammonia. Therefore, we suggest that patients with liver cirrhosis and portal hypertension are at risk of developing clinically relevant encephalopathy when angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker combination therapy is administered, thus indicating the need for a careful clinical follow-up. In addition, the incidence of this serious side-effect should be rigorously evaluated in all patients with liver cirrhosis administered with this common treatment combination.
Guillain-Barré Syndrome Following H1N1 Immunization in a Pediatric Patient
Authors: Tremblay Marie-Eve , Closon Aurélie , D'Anjou Guy , Bussières Jean-François 
Published: May 2010

Objective: To report a case of Guillain-Barré syndrome (GBS) following a dose of influenza A (H1N1) vaccine (Arepanrix). Case Summary: An 11-year-old boy was admitted to the hospital after presenting with facial diplegia; abdominal, forehead, and thigh pain; and acute cervical pain. He had received the Arepanrix H1N1 subcutaneous vaccine 13 days before symptom onset. The neurologic examination also revealed a symmetric bilateral paralysis of the VIIth cranial nerve and intense pain, proximal weakness of the shoulder girdles and pelvis, and preserved deep tendon reflexes. Cerebrospinal fluid analysis revealed an albuminocytologic dissociation. Therefore, a diagnosis of atypical GBS following vaccination against H1N1 influenza was made. Discussion: Based on the clinical evaluation, laboratory test results, neurologic features, and the exclusion of alternative diagnoses, the Naranjo probability scale revealed a probable relationship between the clinical manifestations of GBS and the vaccine against influenza A (H1N1) received by the patient. This is the first published case for the 2009 influenza pandemic in children. Conclusions: While recent studies have found inconclusive results on the association between influenza vaccine and GBS, all suspected cases should be published for further evaluation.
Deletion of cathepsin H perturbs angiogenic switching, vascularization and growth of tumors in a mouse model of pancreatic islet cell cancer
Authors: Gocheva Vasilena , Chen Xiaoping , Peters Christoph , Reinheckel Thomas , Joyce Johanna A. 
Published: May 2010

Abstract
Proteases can regulate many aspects of tumor development as their actions, which include degradation of the extracellular matrix, proteolytic processing of chemokines and activation of other enzymes, influence several key tumorigenic processes. Members of one protease class, the cysteine cathepsins, have received increasing recognition for their involvement in cancer development, and numerous clinical studies have reported correlations between elevated cathepsin levels and malignant progression. This is also the case for cathepsin H, a member of the cysteine cathepsin family, and its utility as a prognostic marker has been analyzed extensively. However, there is limited information available on its specific functions in tumor development and progression. To gain further insight into the role of this protease in cancer, we crossed cathepsin H-deficient mice with the RIP1-Tag2 model of pancreatic islet carcinogenesis. Deletion of cathepsin H significantly impaired angiogenic switching of the pre-malignant hyperplastic islets and resulted in a reduction in the subsequent number of tumors that formed. Moreover, the tumor burden in cathepsin H null RT2 mice was significantly reduced, in association with defects in the blood vasculature and increased apoptosis. Thus, we demonstrate here for the first time important tumor-promoting roles for cathepsin H in vivo using a mouse model of human cancer.
Structure, mechanism and inhibition of γ-secretase and presenilin-like proteases
Authors: Wolfe Michael S. 
Published: May 2010

AbstractPresenilin is the catalytic component of γ-secretase, a complex aspartyl protease and a founding member of intramembrane-cleaving proteases. γ-Secretase is involved in the pathogenesis of Alzheimer's disease and a top target for therapeutic intervention. However, the protease complex processes a variety of transmembrane substrates, including the Notch receptor, raising concerns about toxicity. Nevertheless, γ-secretase inhibitors and modulators have been identified that allow Notch processing and signaling to continue, and promising compounds are entering clinical trials. Molecular and biochemical studies offer a model for how this protease hydrolyzes transmembrane domains in the confines of the lipid bilayer. Progress has also been made toward structure elucidation of presenilin and the γ-secretase complex by electron microscopy as well as by studying cysteine-mutant presenilins. The signal peptide peptidase (SPP) family of proteases are distantly related to presenilins. However, the SPPs work as single polypeptides without the need for cofactors and otherwise appear to be simple model systems for presenilin in the γ-secretase complex. SPP biology, structure, and inhibition will also be discussed.
Is BACE1 a suitable therapeutic target for the treatment of Alzheimer's disease? Current strategies and future directions
Authors: Klaver David W. , Wilce Matthew C.J. , Cui Hao , Hung Amos C. , Gasperini Robert , Foa Lisa , Small David H. 
Published: May 2010

AbstractAlzheimer's disease (AD) is characterized by the extracellular deposition of the β-amyloid protein (Aβ). Aβ is a fragment of a much larger precursor protein, the amyloid precursor protein (APP). Sequential proteolytic cleavage of APP by β-secretase and γ-secretase liberates Aβ from APP. The aspartyl protease BACE1 (β-siteAPP-cleavingenzyme 1) catalyses the rate-limiting step in the production of Aβ, and as such it is considered to be a major target for drug development in Alzheimer's disease. However, the development of a BACE1 inhibitor therapy is problematic for two reasons. First, BACE1 has been found to have important physiological roles. Therefore, inhibition of the enzyme could have toxic consequences. Second, the active site of BACE1 is relatively large, and many of the bulky compounds that are needed to inhibit BACE1 activity are unlikely to cross the blood-brain barrier. This review focuses on the structure BACE1, current therapeutic strategies based on developing active-site inhibitors, and new approaches to therapy involving targeting the expression or post-translational regulation of BACE1.
Molecular diagnosis of congenital adrenal hyperplasia due to 21-hydroxylase deficiency: an update of new CYP21A2 mutations
Authors: Concolino Paola , Mello Enrica , Zuppi Cecilia , Capoluongo Ettore 
Published: May 2010

Abstract
Steroid 21-hydroxylase deficiency is present in more than 90% of patients with congenital adrenal hyperplasia, an inherited metabolic disorder of adrenal steroidogenesis. Impaired enzymatic activity leads to the accumulation of metabolic intermediates (progesterone and 17-hydroxyprogesterone), which results in excessive androgen production and varied signs of virilisation. CYP21A2 is an active gene and encodes for the steroid 21-hydroxylase enzyme, whereas CYP21A1P is an inactive pseudogene that contains a series of deleterious mutations. The major part of disease-causing mutations in CYP21A2 alleles are CYP21A1P-derived sequence transferred to the active gene by macro or microconversion events. Approximately 5% of all disease-causing CYP21A2 alleles harbour rare mutations that do not originate from the pseudogene. A list of all reported CYP21A2 mutations can be found in the CYP21A2 database created by the Human Cytochrome P450 (CYP) Allele Nomenclature Committee (http:www.imm.Ki.se/CYPalleles/cyp21.htm). Unfortunately, the last update of this database was in 2006. However, over the last 4 years many other novel CYP21A2 mutations have been reported in PubMed. The aim of this review is to provide a focus on the molecular and genetic aspects of the diagnosis of 21-hydroxylase deficiency. In addition, an updated list of the last new CYP21A2 mutations is included.
Clin Chem Lab Med 2010;48:1057–62.
Evaluation of the BacT/ALERT® 3D system for the implementation of in-house quality control sterility testing at Canadian Blood Services
Authors: Mastronardi Cherie , Perkins Heather , Derksen Paul , denAdmirant Michael , Ramírez-Arcos Sandra 
Published: May 2010

Abstract

Background: Until recently, Canadian Blood Services (CBS) was performing quality control sterility testing of blood components using three different processes. This study was conducted in order to standardize sterility testing at all CBS centers in a cost-effective manner using the BacT/ALERT® 3D system.

Methods: Blood components including fresh frozen plasma, platelet concentrates, and red blood cells were inoculated with eight bacterial species at target concentrations of 1 and 10 CFU/mL. Pre- and post-spiked samples were inoculated into BacT/ALERT® aerobic and anaerobic culture bottles and incubated for a maximum of 10 days. Specificity of the positive culture bottles was verified by Gram staining. Positive results obtained pre- and post-implementation of the in-house sterility testing program at CBS were collected and analyzed.

Results: The BacT/ALERT®3D system detected all bacteria in all blood components tested in this validation. Positive cultures were obtained within 28 h of incubation with the exception of Propionibacterium acnes which was detected within 134 h. The percentage of positive cultures ranged from 0.01% to 0.2%. All contaminants isolated were either normal skin flora or environmental microorganisms.

Conclusions: This study demonstrates the capability of the BacT/ALERT®3D system to detect aerobic and anaerobic bacterial contamination in all tested blood components, thereby supporting its use for quality control sterility testing and not only bacterial screening. A standardized process will allow CBS to evaluate and compare blood collection and manufacturing practices across the country.
Clin Chem Lab Med 2010;48:1179–87.
Acute effects of hydrocortisone on the metabolic response to a glucose load: increase in the first-phase insulin secretion
Authors: Vila Greisa , Krebs Michael , Riedl Michaela , Baumgartner-Parzer Sabina M , Clodi Martin , Maier Christina , Pacini Giovanni , Luger Anton 
Published: May 2010

Background and aimSeveral basic science studies support the existence of non-genomic glucocorticoid signaling in pancreas, liver, and adipocytes, but its clinical relevance has not yet been elucidated. This study aimed at investigating the rapid effects of hydrocortisone on the human metabolic response to glucose.Subjects and methodsIn a randomized placebo-controlled crossover study, ten healthy men received an i.v. bolus of 0.6 mg/kg hydrocortisone once and placebo once 4 min before the administration of 330 mg/kg glucose. Cortisol, glucose, insulin, C-peptide, ghrelin, and peptide YY (PYY) levels were measured during the following 3 h. Minimal model analysis was performed for evaluating the metabolic response.ResultsHydrocortisone attenuated the rise in plasma glucose during the initial 15 min following glucose administration (P=0.039), and it led to lower glucose levels during the first 2 h (P=0.017). This was accompanied by enhanced circulating insulin (P=0.02) and C-peptide (P=0.03) levels during the initial 15 min, and a 35% increase in the first-phase β-cell function (P=0.003). Hydrocortisone decreased PYY concentrations during the initial 30 min (P=0.014), but it did not affect the ghrelin response to glucose.ConclusionOne i.v. bolus of hydrocortisone induces rapid effects on carbohydrate metabolism increasing the first-phase β-cell function. The modulation of PYY plasma levels suggests the possible non-genomic effects of glucocorticoids on appetite-regulatory hormones.