bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mutations in Cytoplasmic Loops of the KCNQ1 Channel and the Risk of Life-Threatening Events
Authors: Barsheshet Alon , Goldenberg Ilan , O-Uchi Jin , Moss Arthur J. , Jons Christian , Shimizu Wataru , Wilde Arthur A. , McNitt Scott , Peterson Derick R. , Zareba Wojciech , Robinson Jennifer L. , Ackerman Michael J. , Cypress Michael , Gray Daniel A. , Hofman Nynke , Kanters Jorgen K. , Kaufman Elizabeth S. , Platonov Pyotr G. , Qi Ming , Towbin Jeffrey A. , Vincent G. Michael , Lopes Coeli M. 
Published: March 2012

Background—
β-Adrenergic stimulation is the main trigger for cardiac events in type 1 long-QT syndrome (LQT1). We evaluated a possible association between ion channel response to β-adrenergic stimulation and clinical response to β-blocker therapy according to mutation location.

Methods and Results—

The study sample comprised 860 patients with genetically confirmed mutations in the
KCNQ1
channel. Patients were categorized into carriers of missense mutations located in the cytoplasmic loops (C loops), membrane-spanning domain, C/N terminus, and nonmissense mutations. There were 27 aborted cardiac arrest and 78 sudden cardiac death events from birth through 40 years of age. After multivariable adjustment for clinical factors, the presence of C-loop mutations was associated with the highest risk for aborted cardiac arrest or sudden cardiac death (hazard ratio versus nonmissense mutations=2.75; 95% confidence interval, 1.29–5.86;
P
=0.009). β-Blocker therapy was associated with a significantly greater reduction in the risk of aborted cardiac arrest or sudden cardiac death among patients with C-loop mutations than among all other patients (hazard ratio=0.12; 95% confidence interval, 0.02–0.73;
P
=0.02; and hazard ratio=0.82; 95% confidence interval, 0.31–2.13;
P
=0.68, respectively;
P
for interaction=0.04). Cellular expression studies showed that membrane spanning and C-loop mutations produced a similar decrease in current, but only C-loop mutations showed a pronounced reduction in channel activation in response to β-adrenergic stimulation.

Conclusions—

Patients with C-loop missense mutations in the
KCNQ1
channel exhibit a high risk for life-threatening events and derive a pronounced benefit from treatment with β-blockers. Reduced channel activation after sympathetic activation can explain the increased clinical risk and response to therapy in patients with C-loop mutations.
Late Results of Percutaneous Mitral Commissurotomy up to 20 Years
Authors: Bouleti Claire , Iung Bernard , Laouénan Cédric , Himbert Dominique , Brochet Eric , Messika-Zeitoun David , Détaint Delphine , Garbarz Eric , Cormier Bertrand , Michel Pierre-Louis , Mentré France , Vahanian Alec 
Published: March 2012

Background—
Long-term follow-up after percutaneous mitral commissurotomy enables predictive factors of late results to be identified.

Methods and Results—

Late results of percutaneous mitral commissurotomy were assessed in 1024 consecutive patients. Good immediate results, defined as valve area ≥1.5 cm
2
without mitral regurgitation >2/4, were obtained in 912 patients (89%). These 912 patients were randomly split into 2 cohorts comprising 609 and 303 patients that were used to develop and validate, respectively, a scoring system predicting late functional results. The 20-year rate of good functional results (survival without cardiovascular death, mitral surgery, or repeat percutaneous mitral commissurotomy and in New York Heart Association class I or II) was 30.2±2.0%. A multivariable Cox model identified 7 predictive factors of poor late functional results: higher final mean gradient (
P
<0.0001), interaction between age and final mitral valve area (
P
<0.0001) showing that the impact of valve area decreases with age, interaction between sex and valve calcification (
P
<0.0001) showing that the impact of valve anatomy is stronger in men, and interaction between rhythm and New York Heart Association class showing an impact of New York Heart Association class only in patients in atrial fibrillation (
P
<0.0001). A 13-point score enabled 3 risk groups to be defined, corresponding to predicted good functional results of 55.1%, 29.1%, and 10.5% at 20 years in the validation cohort.

Conclusions—
Twenty years after percutaneous mitral commissurotomy in a population of patients with varied characteristics, 30% still had good functional results. Prediction of late functional results is multifactorial and strongly determined by age and the quality of immediate results. A simple validated scoring system is useful for estimating individual patient outcome.
Human endogenous retrovirus type W envelope expression in blood and brain cells provides new insights into multiple sclerosis disease
Authors: Perron Hervé , Germi Raphaëlle , Bernard Corinne , Garcia-Montojo Marta , Deluen Cécile , Farinelli Laurent , Faucard Raphaël , Veas Francisco , Stefas Ilias , Fabriek Babs O , Van-Horssen Jack , Van-der-Valk Paul , Gerdil Claire , Mancuso Roberta , Saresella Marina , Clerici Mario , Marcel Sébastien , Creange Alain , Cavaretta Rosella , Caputo Domenico , Arru Giannina , Morand Patrice , Lang Alois B , Sotgiu Stefano , Ruprecht Klemens , Rieckmann Peter , Villoslada Pablo , Chofflon Michel , Boucraut Jose , Pelletier Jean , Hartung Hans-Peter 
Published: March 2012

Background: The envelope protein from multiple sclerosis (MS) associated retroviral element (MSRV), a member of the Human Endogenous Retroviral family ‘W’ (HERV-W), induces dysimmunity and inflammation. Objective: The objective of this study was to confirm and specify the association between HERV-W/MSRV envelope (Env) expression and MS. Methods: 103 MS, 199 healthy controls (HC) and controls with other neurological diseases (28), chronic infections (30) or autoimmunity (30) were analysed with an immunoassay detecting Env in serum. Env RNA or DNA copy numbers in peripheral blood mononuclear cells (PBMC) were determined by a quantitative polymerase chain reaction (PCR). Env was detected by immunohistology in the brains of patients with MS with three specific monoclonals. Results: Env antigen was detected in a serum of 73% of patients with MS with similar prevalence in all clinical forms, and not in chronic infection, systemic lupus, most other neurological diseases and healthy donors ( p<0.01). Cases with chronic inflammatory demyelinating polyneuropathy (5/8) and rare HC (4/103) were positive. RNA expression in PBMC and DNA copy numbers were significantly elevated in patients with MS versus HC ( p<0.001). In patients with MS, DNA copy numbers were significantly increased in chronic progressive MS (secondary progressive MS vs relapsing–remitting MS (RRMS) p<0.001; primary progressive MS vs RRMS –<0.02). Env protein was evidenced in macrophages within MS brain lesions with particular concentrations around vascular elements. Conclusion: The association between MS disease and the MSRV-type HERV-W element now appears quite strong, as evidenced ex-vivo from serum and PBMC with post-mortem confirmation in brain lesions. Chronic progressive MS, RRMS and clinically isolated syndrome show different ELISA (Enzyme-Linked Immunosorbent Assay) and/or PCR profiles suggestive of an increase with disease evolution, and amplicon sequencing confirms the association with particular HERV-W elements.
von Willebrand factor (VWF) propeptide binding to VWF D′D3 domain attenuates platelet activation and adhesion
Authors: Madabhushi Sri R. , Shang Chengwei , Dayananda Kannayakanahalli M. , Rittenhouse-Olson Kate , Murphy Mary , Ryan Thomas E. , Montgomery Robert R. , Neelamegham Sriram 
Published: March 2012

AbstractNoncovalent association between the von Willebrand factor (VWF) propeptide (VWFpp) and mature VWF aids N-terminal multimerization and protein compartmentalization in storage granules. This association is currently thought to dissipate after secretion into blood. In the present study, we examined this proposition by quantifying the affinity and kinetics of VWFpp binding to mature VWF using surface plasmon resonance and by developing novel anti-VWF D′D3 mAbs. Our results show that the only binding site for VWFpp in mature VWF is in its D′D3 domain. At pH 6.2 and 10mM Ca2+, conditions mimicking intracellular compartments, VWFpp-VWF binding occurs with high affinity (KD = 0.2nM, koff = 8 × 10−5 s−1). Significant, albeit weaker, binding (KD = 25nM, koff = 4 × 10−3 s−1) occurs under physiologic conditions of pH 7.4 and 2.5mM Ca2+. This interaction was also observed in human plasma (KD = 50nM). The addition of recombinant VWFpp in both flow-chamber–based platelet adhesion assays and viscometer-based shear-induced platelet aggregation and activation studies reduced platelet adhesion and activation partially. Anti-D′D3 mAb DD3.1, which blocks VWFpp binding to VWF-D′D3, also abrogated platelet adhesion, as shown by shear-induced platelet aggregation and activation studies. Our data demonstrate that VWFpp binding to mature VWF occurs in the circulation, which can regulate the hemostatic potential of VWF by reducing VWF binding to platelet GpIbα.
KAP1 regulates gene networks controlling mouse B-lymphoid cell differentiation and function
Authors: Santoni de Sio Francesca R. , Massacand Joanna , Barde Isabelle , Offner Sandra , Corsinotti Andrea , Kapopoulou Adamandia , Bojkowska Karolina , Dagklis Antonis , Fernandez Marylise , Ghia Paolo , Thomas James H. , Pinschewer Daniel , Harris Nicola , Trono Didier 
Published: March 2012

AbstractChromatin remodeling is fundamental for B-cell differentiation. In the present study, we explored the role of KAP1, the cofactor of KRAB-ZFP transcriptional repressors, in this process. B-lymphoid–specific Kap1-KO mice displayed reduced numbers of mature B cells, lower steady-state levels of Abs, and accelerated rates of decay of neutralizing Abs after viral immunization. Transcriptome analyses of Kap1-deleted B splenocytes revealed an up-regulation of PTEN, the enzymatic counteractor of PIK3 signaling, and of genes encoding DNA-damage response factors, cell-cycle regulators, and chemokine receptors. ChIP/seq studies established that KAP1 bound at or close to several of these genes and controlled chromatin status at their promoters. Genome wide, KAP1 binding sites lacked active B cell–specific enhancers and were enriched in repressive histone marks, further supporting a role for this molecule in gene silencing in vivo. Likely responsible for tethering KAP1 to at least some of these targets, a discrete subset of KRAB-ZFPs is enriched in B lymphocytes. Our results therefore reveal the role of KRAB/KAP1–mediated epigenetic regulation in B-cell development and homeostasis.
Detecting disease-associated genes with confounding variable adjustment and the impact on genomic meta-analysis: With application to major depressive disorder
Authors: Wang Xingbin , Lin Yan , Song Chi , Sibille Etienne , Tseng George C 
Published: March 2012

AbstractBackgroundDetecting candidate markers in transcriptomic studies often encounters difficulties in complex diseases, particularly when overall signals are weak and sample size is small. Covariates including demographic, clinical and technical variables are often confounded with the underlying disease effects, which further hampers accurate biomarker detection. Our motivating example came from an analysis of five microarray studies in major depressive disorder (MDD), a heterogeneous psychiatric illness with mostly uncharacterized genetic mechanisms.ResultsWe applied a random intercept model to account for confounding variables and case-control paired design. A variable selection scheme was developed to determine the effective confounders in each gene. Meta-analysis methods were used to integrate information from five studies and post hoc analyses enhanced biological interpretations. Simulations and application results showed that the adjustment for confounding variables and meta-analysis improved detection of biomarkers and associated pathways.ConclusionsThe proposed framework simultaneously considers correction for confounding variables, selection of effective confounders, random effects from paired design and integration by meta-analysis. The approach improved disease-related biomarker and pathway detection, which greatly enhanced understanding of MDD neurobiology. The statistical framework can be applied to similar experimental design encountered in other complex and heterogeneous diseases.
Modulation of TTX-sensitive voltage-dependent Na+ channels by β-bungarotoxin in rat cerebellar neurons
Authors: Guo Da , Xiang Wei , Seebahn Angela , Becker Cord-Michael , Strauß Olaf 
Published: March 2012

Abstract

Background
The modulation of voltage-dependent Na+ channels by lipid metabolites such as arachidonic acid or eicosanoids plays a role in physiological functions as well as in degenerative diseases. So far TTX-resistant channels were found mainly to be regulated by lipid metabolites.

Results
We investigated the lipid-dependent modulation of TTX-sensitive (TTX-s) Na+ channels using β-bungarotoxin (β-BuTX, 10 pM), which has an intrinsic phospholipase-A2 activity, and indomethacin (10 μM), which blocks cyclooxygenase activity in primary cerebellar neurons. To investigate TTX-s Na+ channels, whole-currents were measured under K+-free conditions and blocked by 10 nM TTX. The currents resulting from calculating the difference of currents measured in the presence and the absence of TTX were used for further analysis. Application of indomethacin mainly changed the current kinetics but has only minor effects on voltage-dependence. In contrast β-BuTX increased the maximal current amplitude and shifted the voltage-dependent activation towards more negative potentials. The effects of β-BuTX were blocked by indomethacin. Analysis of lipid metabolites which accumulate by treatment with β-BuTX using MALDI-TOF MS showed an increase of cyclooxygenase reaction products in relation to arachidonic acid.

Conclusions
In summary, we conclude that TTX-sensitive Na+ channels can be directly modulated by cyclooxygenase reaction products leading to higher activity at less depolarized potentials and subsequent higher excitability of neurons. Since activation of cyclooxygenase is also involved in pathways leading to apoptotic cells death this could play a role in degenerative diseases of the CNS and highlights a possible protective effect of cyclooxygenase inhibition.
Rates of IUCD discontinuation and its associated factors among the clients of a social franchising network in Pakistan
Authors: Azmat Syed Khurram , Shaikh Babar Tasneem , Hameed Waqas , Bilgrami Mohsina , Mustafa Ghulam , Ali Muhammad , Ishaque Muhammad , Hussain Wajahat , Ahmed Aftab 
Published: March 2012

Abstract

Background
Modern Intrauterine contraceptive device (IUCD) is very safe, highly effective reversible and inexpensive family planning method which offers 5-10 years of protection against pregnancy. The contraceptive use in Pakistan has been merely 30% for over a decade with IUCD being the least used method. Higher discontinuation rates are documented in developing countries; however no such data is available for Pakistan. Marie Stopes Society (MSS) established a social franchise outlets network branded as 'SURAJ' (Sun) in Pakistan to provide quality family planning services. This study attempts to determine IUCD discontinuation rates and its associated risk factors. Using a semi-structured questionnaire, a cross-sectional study was conducted with 3000 clients who availed IUCD services from Suraj provider 6, 12 and 24 month back,. Data were analyzed in SPSS 17.0; adjusted prevalence ratios were calculated to see associations between discontinuation and its risk factors.

Case presentation
We found that 22.7% of the IUCD acceptors experienced some health problem; while the overall discontinuation rate was 18.9% with average time of usage of 7.4 (SD ± 5.8) months before discontinuation. Half of them showed health concerns (49.8%); of which a majority (70.2%) returned to Suraj provider for IUCD removal. Women living in Punjab, residing at a travelling time of 30-60 minutes and no previous use of contraceptive are more likely to discontinue IUCD. However, among total women 81.7% still expressed willingness to avail IUCD services from Suraj provider in future, if needed.

Conclusion
The findings suggest a need for training the providers and field workers to prevent early discontinuation of IUCD among the Suraj clients and by addressing the health concerns through proper counseling, continued follow-up and immediate medical aid/referral in case of complications.
Peroxisome deficiency but not the defect in ether lipid synthesis causes activation of the innate immune system and axonal loss in the central nervous system
Authors: Bottelbergs Astrid , Verheijden Simon , Van Veldhoven Paul P , Just Wilhelm , Devos Rita , Baes Myriam 
Published: March 2012

AbstractBackgroundMice with peroxisome deficiency in neural cells (Nestin-Pex5−/−)develop a neurodegenerative phenotype leading to motor and cognitive disabilities and early death. Major pathologies at the end stage of disease include severe demyelination, axonal degeneration and neuroinflammation. We now investigated the onset and progression of these pathological processes, and their potential interrelationship. In addition, the putative role of oxidative stress, the impact of plasmalogen depletion on the neurodegenerative phenotype, and the consequences of peroxisome elimination in the postnatal period were studied.MethodsImmunohistochemistry in association with gene expression analysis was performed onNestin-Pex5−/−mice to document demyelination, axonal damage and neuroinflammation. AlsoGnpat−/−mice, with selective plasmalogen deficiency andCMV-Tx-Pex5−/−mice, with tamoxifen induced generalized loss of peroxisomes were analysed.ResultsActivation of the innate immune system is a very early event in the pathological process inNestin-Pex5−/−mice which evolves in chronic neuroinflammation. The complement factor C1q, one of the earliest up regulated transcripts, was expressed on neurons and oligodendrocytes but not on microglia. Transcripts of other pro- and anti-inflammatory genes and markers of phagocytotic activity were already significantly induced before detecting pathologies with immunofluorescent staining. Demyelination, macrophage activity and axonal loss co-occurred throughout the brain. As in patients with mild peroxisome biogenesis disorders who develop regressive changes, demyelination in cerebellum and brain stem preceded major myelin loss in corpus callosum of bothNestin-Pex5−/−andCMV-Tx-Pex5−/−mice. These lesions were not accompanied by generalized oxidative stress throughout the brain. AlthoughGnpat−/−mice displayed dysmyelination and Purkinje cell axon damage in cerebellum, confirming previous observations, no signs of inflammation or demyelination aggravating with age were observed.ConclusionsPeroxisome inactivity triggers a fast neuroinflammatory reaction, which is not solely due to the depletion of plasmalogens. In association with myelin abnormalities this causes axon damage and loss.
Tailored enrichment strategy detects low abundant small noncoding RNAs in HIV-1 infected cells
Authors: Althaus Claudia F , Vongrad Valentina , Niederöst Barbara , Joos Beda , Di Giallonardo Francesca , Rieder Philip , Pavlovic Jovan , Trkola Alexandra , Günthard Huldrych F , Metzner Karin J , Fischer Marek 
Published: March 2012

Abstract

Background
The various classes of small noncoding RNAs (sncRNAs) are important regulators of gene expression across divergent types of organisms. While a rapidly increasing number of sncRNAs has been identified over recent years, the isolation of sncRNAs of low abundance remains challenging. Virally encoded sncRNAs, particularly those of RNA viruses, can be expressed at very low levels. This is best illustrated by HIV-1 where virus encoded sncRNAs represent approximately 0.1-1.0% of all sncRNAs in HIV-1 infected cells or were found to be undetected. Thus, we applied a novel, sequence targeted enrichment strategy to capture HIV-1 derived sncRNAs in HIV-1 infected primary CD4+ T-lymphocytes and macrophages that allows a greater than 100-fold enrichment of low abundant sncRNAs.

Results
Eight hundred and ninety-two individual HIV-1 sncRNAs were cloned and sequenced from nine different sncRNA libraries derived from five independent experiments. These clones represent up to 90% of all sncRNA clones in the generated libraries. Two hundred and sixteen HIV-1 sncRNAs were distinguishable as unique clones. They are spread throughout the HIV-1 genome, however, forming certain clusters, and almost 10% show an antisense orientation. The length of HIV-1 sncRNAs varies between 16 and 89 nucleotides with an unexpected peak at 31 to 50 nucleotides, thus, longer than cellular microRNAs or short-interfering RNAs (siRNAs). Exemplary HIV-1 sncRNAs were also generated in cells infected with different primary HIV-1 isolates and can inhibit HIV-1 replication.

Conclusions
HIV-1 infected cells generate virally encoded sncRNAs, which might play a role in the HIV-1 life cycle. Furthermore, the enormous capacity to enrich low abundance sncRNAs in a sequence specific manner highly recommends our selection strategy for any type of investigation where origin or target sequences of the sought-after sncRNAs are known.
Variation in metabolic responses to meal challenges differing in glycemic index in healthy women: Is it meaningful?
Authors: Krishnan Sridevi , Newman John W , Hembrooke Tara A , Keim Nancy L 
Published: March 2012

Abstract

Background
Established clinical tests are commonly used in disease diagnosis, but tools that enhance identification of metabolic dysfunctions are needed. This study was conducted to identify typical and atypical metabolite temporal patterns in response to paired meal challenge tests.

Design
Metabolic responses to high and low glycemic index (GI) meals were tested in 24 healthy pre-menopausal women, aged 20-50 y, with BMI of 25-30 kg/m2 using a cross-over design. On test days, blood glucose, insulin, leptin and non-esterified fatty acids were measured after an overnight fasting, and for 8 h following test meal consumption. The data were range scaled, and multivariate statistics were used to assess the presence of distinct response groups to the meal challenge tests.

Results
As expected, participants showed higher circulating glucose and insulin in response to the high GI compared to the low GI meal challenge. However, using range-scaling and Principal Component Analysis, three distinct groups were identified based on differential responses to the paired challenges. Members of the most populated group (n = 18) displayed little deviation from the expected response to the two meal challenges. Two minor groups (n = 3/group) with distinct responses were observed, one suggestive of sub-clinical insulin resistance, and the other suggestive of hyperleptinemia.

Conclusions
The differential responses of glucose, insulin and leptin to low and high glycemic test meals revealed three response groups. Dietary intervention studies traditionally evaluate group responses, and aim to identify the overall effect in the population studied. In contrast, our study analyzed the variance in the meal challenge responses, using an integrated physiological approach, rather than a reductionist approach. This phenotyping approach may be useful for detecting subclinical metabolic dysfunctions, and it could contribute to improved personalized nutrition management. This study is registered in ClinicalTrials.gov, record #200210295