bluuebunny/crossref_metadata_2025_split huggingface dataset:
A prognostic model for amputation in critical lower limb ischemia
Authors: Klomp HM , Steyerberg EW , Wittens CHA , van Urk H , Habbema JDF ,   For the ESES study group
Published: April 2009

Abstract In a (negative) multicenter randomized trial on management for inoperable critical lower limb ischemia, comparing spinal cord stimulation and best medical treatment, a number of pre-defined factors were analyzed for prognostic value. We included a radiological arterial disease score, modified from the SVS/ISCVS runoff score. The purpose of this analysis was to evaluate clinical factors and commonly used circulatory measurements for prognostic modeling in patients with critical lower limb ischemia. We determined the incidence of amputation and its relation to various pre-defined risk factors. A total of 120 patients with critical limb ischemia were included in the study. The integrity of circulation in the affected limb was evaluated on five levels: suprainguinal, infrainguinal, popliteal, infrapopliteal and pedal. A total radiological arterial disease score was calculated from 1 (full integrity of circulation) to 20 (maximally compromised state). We used Cox regression analysis to quantify prognostic effects and differential treatment (predictive) effects. Major amputation occurred in 33% of the patients at 6 months and in 51% at 2 years. The presence of ischemic skin lesions and the radiological arterial disease score were independent prognostic factors for amputation. Patients with ulcerations or gangrene had a higher amputation risk (hazard ratio 2.38, p = 0.018 and 2.30, p = 0.036 respectively) as well as patients with a higher radiological arterial disease score (hazard ratio 1.17 per increment, p = 0.003). We did not observe significant interactions between prognostic factors and the effect of spinal cord stimulation. In conclusion, in patients with critical lower limb ischemia, the presence of ischemic skin lesions and the described radiological arterial disease score can be used to estimate amputation risk.
Short series of emergency stent-graft repair of symptomatic penetrating thoracic aortic ulcers (PTAU)
Authors: Girn HRS , McPherson S , Nicholson T , Mavor AID , Homer-Vanniasinkam S , Gough MJ 
Published: April 2009

Abstract Acute penetrating thoracic aortic ulcers (PTAU) are associated with vessel rupture, particularly when intramural haematoma (IMH) is present. Although surgical repair is the treatment of choice for PTAU in the aortic arch, definitive treatment of PTAU in other locations of the thoracic aorta remains controversial, particularly in this frail cohort of patients. Recent series of elective and semi-elective endovascular stent-graft repair of PTAU of the descending thoracic aorta show comparable results with the previously advocated best medical management. We report our results from a retrospective, observational study of acute stent-graft repair of symptomatic PTAU. Between 2000 and 2005, 11 patients (seven male, four female; median age 71 years) presented with acute PTAU. CT scans demonstrated an associated IMH in six, a contained leak in three or rupture in four unstable patients. All were covered by a single endovascular stent [Gore (5), Talent (5), Zenith (1); 10 inserted via the groin and one via iliac conduit within 1 week of presentation (five < 24 h). Technical success was 90.90% (10/11) and 3/11 (27%) died within 30 days (two ARDS, one a persistent leak and rupture at 48 h). One patient developed transient paraplegia; three haemothoraces required chest drains, one of which subsequently required empyema drainage. In survivors, CT scans were satisfactory, with no further intervention required at 32.5 (6–66) months of median follow-up. In conclusion, endovascular management of acute PTAU appears effective and durable with mortality rates that are likely to be better than for open surgery. However, haemodynamic compromise at presentation remains a robust denominator of over-all survival.
Prevalence of HTLV-1 infection in type 2 diabetic patients in Mashhad, northeastern Iran
Authors: Taghavi Morteza , Fatemi Seddigheh 
Published: April 2009

Objective The aim of this study was to evaluate the prevalence of human T cell leukaemia virus type 1 (HTLV-1) infection among patients with type 2 diabetes mellitus in Mashhad in northeastern Iran. Methods A total of 266 consecutive type 2 diabetic patients (mean age 54.36±11.58 years) attending our unit were compared with 60,892 non-diabetic blood donors for the presence of HTLV-1 infection. Serological testing for HTLV-1 was undertaken using an enzyme-linked immunosorbent assay, and a polymerase chain reaction (PCR) was performed in positive HTLV-1 samples. Results PCR confirmed HTLV-1 infection in ten patients. The prevalence of HTLV-1 infection was more than five-fold higher in the diabetic patients than the blood donor group (3.75 vs. 0.663%; p<0.001). There was no apparent association between HTLV-1 infection and age, sex, body mass index, diabetes duration or glycaemic control. Conclusions A higher prevalence of HTLV-1 infection was detected in diabetic patients and this should be borne in mind when treating type 2 diabetic patients in regions where HTLV-1 infection is endemic. Br J Diabetes Vasc Dis 2009; 9:81—83
A human polymorphism affects NEDD4L subcellular targeting by leading to two isoforms that contain or lack a C2 domain
Authors: Garrone Nicholas F , Blazer-Yost Bonnie L , Weiss Robert B , Lalouel Jean-Marc , Rohrwasser Andreas 
Published: April 2009

Abstract

Background
Ubiquitination serves multiple cellular functions, including proteasomal degradation and the control of stability, function, and intracellular localization of a wide variety of proteins. NEDD4L is a member of the HECT class of E3 ubiquitin ligases. A defining feature of NEDD4L protein isoforms is the presence or absence of an amino-terminal C2 domain, a class of subcellular, calcium-dependent targeting domains. We previously identified a common variant in human NEDD4L that generates isoforms that contain or lack a C2 domain.

Results
To address the potential functional significance of the NEDD4L common variant on NEDD4L subcellular localization, NEDD4L isoforms that either contained or lacked a C2 domain were tagged with enhanced green fluorescent protein, transfected into Xenopus laevis kidney epithelial cells, and imaged by performing confocal microscopy on live cells. We report that the presence or absence of this C2 domain exerts differential effects on the subcellular distribution of NEDD4L, the ability of C2 containing and lacking NEDD4L isoforms to mobilize in response to a calcium stimulus, and the intracellular transport of subunits of the NEDD4L substrate, ENaC. Furthermore, the ability of the C2-containing isoform to influence β-ENaC mobilization from intracellular pools involves the NEDD4L active site for ubiquitination. We propose a model to account for the potential impact of this common genetic variant on protein function at the cellular level.

Conclusion
NEDD4L isoforms that contain or lack a C2 domain target different intracellular locations. Additionally, whereas the C2-containing NEDD4L isoform is capable of shuttling between the plasma membrane and intracellular compartments in response to calcium stimulus the C2-lacking isoform can not. The C2-containing isoform differentially affects the mobilization of ENaC subunits from intracellular pools and this trafficking step requires NEDD4L ubiquitin ligase activity. This observation suggests a new mechanism for the requirement for the PY motif in cAMP-mediated exocytosis of ENaC. We have elucidated how a common genetic variant can underlie significant functional diversity in NEDD4L at the cellular level. We propose a model that describes how that functional variation may influence blood pressure. Moreover, our observations regarding differential function of the NEDD4L isoforms may impact other aspects of physiology that involve this ubiquitin ligase.
Reverse transcription-quantitative polymerase chain reaction: description of a RIN-based algorithm for accurate data normalization
Authors: Ho-Pun-Cheung Alexandre , Bascoul-Mollevi Caroline , Assenat Eric , Boissière-Michot Florence , Bibeau Frédéric , Cellier Dominic , Ychou Marc , Lopez-Crapez Evelyne 
Published: April 2009

Abstract

Background
Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) is the gold standard technique for mRNA quantification, but appropriate normalization is required to obtain reliable data. Normalization to accurately quantitated RNA has been proposed as the most reliable method for in vivo biopsies. However, this approach does not correct differences in RNA integrity.

Results
In this study, we evaluated the effect of RNA degradation on the quantification of the relative expression of nine genes (18S, ACTB, ATUB, B2M, GAPDH, HPRT, POLR2L, PSMB6 and RPLP0) that cover a wide expression spectrum. Our results show that RNA degradation could introduce up to 100% error in gene expression measurements when RT-qPCR data were normalized to total RNA. To achieve greater resolution of small differences in transcript levels in degraded samples, we improved this normalization method by developing a corrective algorithm that compensates for the loss of RNA integrity. This approach allowed us to achieve higher accuracy, since the average error for quantitative measurements was reduced to 8%. Finally, we applied our normalization strategy to the quantification of EGFR, HER2 and HER3 in 104 rectal cancer biopsies. Taken together, our data show that normalization of gene expression measurements by taking into account also RNA degradation allows much more reliable sample comparison.

Conclusion
We developed a new normalization method of RT-qPCR data that compensates for loss of RNA integrity and therefore allows accurate gene expression quantification in human biopsies.
Rapamycin weekly maintenance dosing and the potential efficacy of combination sorafenib plus rapamycin but not atorvastatin or doxycycline in tuberous sclerosis preclinical models
Authors: Lee Nancy , Woodrum Chelsey L , Nobil Alison M , Rauktys Aubrey E , Messina Michael P , Dabora Sandra L 
Published: April 2009

AbstractBackgroundTuberous sclerosis complex (TSC) is an autosomal dominant tumor suppressor syndrome, characterized by hamartomatous growths in the brain, skin, kidneys, lungs, and heart, which lead to significant morbidity. TSC is caused by mutations in theTSC1orTSC2genes, whose products, hamartin and tuberin, form a tumor suppressor complex that regulates the PI3K/Akt/mTOR pathway. Early clinical trials show that TSC-related kidney tumors (angiomyolipomas) regress when treated with the mammalian target of rapamycin (mTOR) inhibitor, rapamycin (also known as sirolimus). Although side effects are tolerable, responses are incomplete, and tumor regrowth is common when rapamycin is stopped. Strategies for future clinical trials may include the investigation of longer treatment duration and combination therapy of other effective drug classes.ResultsHere, we examine the efficacy of a prolonged maintenance dose of rapamycin inTsc2+/-mice with TSC-related kidney tumors. Cohorts were treated with rapamycin alone or in combination with interferon-gamma (IFN-g). The schedule of rapamycin included one month of daily doses before and after five months of weekly doses. We observed a 94.5% reduction in kidney tumor burden inTsc2+/-mice treated (part one) daily with rapamycin (8 mg/kg) at 6 months ≤ age < 7 months, (part 2) weekly with rapamycin (16 mg/kg) at 7 months ≤ age < 12 months, and (part 3) daily with rapamycin (8 mg/kg) at 12 months ≤ age < 13 months; but we did not observe any improvement with combination IFN-g plus rapamycin in this study. We also used aTsc2-/-subcutaneous tumor model to evaluate other classes of drugs including sorafenib, atorvastatin, and doxycycline. These drugs were tested as single agents and in combination with rapamycin. Our results demonstrate that the combination of rapamycin and sorafenib increased survival and may decrease tumor volume as compared to rapamycin treatment alone while sorafenib as a single agent was no different than control. Atorvastatin and doxycycline, either as single agents or in combination with rapamycin, did not improve outcomes as compared with controls.ConclusionOur results indicate that prolonged treatment with low doses of mTOR inhibitors may result in more complete and durable TSC-related tumor responses, and it would be reasonable to evaluate this strategy in a clinical trial. Targeting the Raf/Mek/Erk and/or VEGF pathways in combination with inhibiting the mTOR pathway may be another useful strategy for the treatment of TSC-related tumors.
Locating sex-specific evidence on clinical questions in MEDLINE: a search filter for use on OvidSP™
Authors: Moerman Clara J , Deurenberg Rikie , Haafkens Joke A 
Published: April 2009

Abstract

Background
Many recently published clinical studies report sex-specific data. This information may help to improve clinical decision-making for both sexes, but it is not easily accessible in MEDLINE. The aim of this project was to develop and validate a search filter that would facilitate the retrieval of studies reporting high quality sex-specific data on clinical questions.

Methods
A filter was developed by screening titles, abstracts and Medical Subject Headings (MeSH) in a set of 80 high quality and relevant papers, 75 of which were identified through a review of clinical guidelines and five through other means. The filter, for use on OvidSP™, consists of nine command lines for searching free text words in the title, abstract and MeSH of a paper. It was able to identify 74/80 (92.5%) of the articles from which it was derived. The filter was evaluated in a set of 622 recently published original studies on Alzheimer's disease and on asthma. It was validated against a reference of 98 studies from this set, which provided high quality, clinically relevant, sex-specific evidence. Recall and precision were used as performance measures.

Results
The filter demonstrated 81/98 (83%) recall and 81/125 (65%) precision in retrieving relevant articles on Alzheimer's disease and on asthma. In comparison, only 30/98 (31%) recall would have been achieved if sex-specific MeSH terms only had been used.

Conclusion
This sex-specific search filter performs well in retrieving relevant papers, while its precision rate is good. It performs better than a search with sex-specific MeSH. The filter can be useful to anyone seeking sex-specific clinical evidence (e.g., guideline organizations, researchers, medical educators, clinicians).
Contribution of type 2 diabetes associated loci in the Arabic population from Tunisia: a case-control study
Authors: Ezzidi Intissar , Mtiraoui Nabil , Cauchi Stéphane , Vaillant Emmanuel , Dechaume Aurélie , Chaieb Molka , Kacem Maha , Almawi Wassim Y , Froguel Philippe , Mahjoub Touhami , Vaxillaire Martine 
Published: April 2009

Abstract

Background
Candidate gene and genome-wide association studies have both reproducibly identified several common Single Nucleotide Polymorphisms (SNPs) that confer type 2 diabetes (T2D) risk in European populations. Our aim was to evaluate the contribution to T2D of five of these established T2D-associated loci in the Arabic population from Tunisia.

Methods
A case-control design comprising 884 type 2 diabetic patients and 513 control subjects living in the East-Center of Tunisia was used to analyze the contribution to T2D of the following SNPs: E23K in KCNJ11/Kir6.2, K121Q in ENPP1, the -30G/A variant in the pancreatic β-cell specific promoter of Glucokinase, rs7903146 in TCF7L2 encoding transcription factor 7-like2, and rs7923837 in HHEX encoding the homeobox, hematopoietically expressed transcription factor.

Results

TCF7L2-rs7903146 T allele increased susceptibility to T2D (OR = 1.25 [1.06–1.47], P = 0.006) in our study population. This risk was 56% higher among subjects carrying the TT genotype in comparison to those carrying the CC genotype (OR = 1.56 [1.13–2.16], P = 0.002). No allelic or genotypic association with T2D was detected for the other studied polymorphisms.

Conclusion
In the Tunisian population, TCF7L2-rs7903146 T allele confers an increased risk of developing T2D as previously reported in the European population and many other ethnic groups. In contrast, none of the other tested SNPs that influence T2D risk in the European population was associated with T2D in the Tunisian Arabic population. An insufficient power to detect minor allelic contributions or genetic heterogeneity of T2D between different ethnic groups can explain these findings.
Anti-metastatic effects of viral and non-viral mediated Nk4 delivery to tumours
Authors: Buhles Alexandra , Collins Sara A , van Pijkeren Jan P , Rajendran Simon , Miles Michelle , O'Sullivan Gerald C , O'Hanlon Deirdre M , Tangney Mark 
Published: April 2009

Abstract
The most common cause of death of cancer sufferers is through the occurrence of metastases. The metastatic behaviour of tumour cells is regulated by extracellular growth factors such as hepatocyte growth factor (HGF), a ligand for the c-Met receptor tyrosine kinase, and aberrant expression/activation of the c-Met receptor is closely associated with metastatic progression. Nk4 (also known as Interleukin (IL)32b) is a competitive antagonist of the HGF c-Met system and inhibits c-Met signalling and tumour metastasis. Nk4 has an additional anti-angiogenic activity independent of its HGF-antagonist function. Angiogenesis-inhibitory as well as cancer-specific apoptosis inducing effects make the Nk4 sequence an attractive candidate for gene therapy of cancer. This study investigates the inhibition of tumour metasasis by gene therapy mediated production of Nk4 by the primary tumour. Optimal delivery of anti-cancer genes is vital in order to achieve the highest therapeutic responses. Non-viral plasmid delivery methods have the advantage of safety and ease of production, providing immediate transgene expression, albeit short-lived in most tumours. Sustained presence of anti-angiogenic molecules is preferable with anti-angiogenic therapies, and the long-term expression mediated by Adeno-associated Virus (AAV) might represent a more appropriate delivery in this respect. However, the incubation time required by AAV vectors to reach appropriate gene expression levels hampers efficacy in many fast-growing murine tumour models. Here, we describe murine trials assessing the effects of Nk4 on the spontaneously metastatic Lewis Lung Carcinoma (LLC) model when delivered to primary tumour via plasmid lipofection or AAV2 vector. Intratumoural AAV-Nk4 administration produced the highest therapeutic response with significant reduction in both primary tumour growth and incidence of lung metastases. Plasmid-mediated therapy also significantly reduced metastatic growth, but with moderate reduction in primary subcutaneous tumour growth. Overall, this study demonstrates the potential for Nk4 gene therapy of metastatic tumours, when delivered by AAV or non-viral methods.
Analysis of transcribed human endogenous retrovirus W env loci clarifies the origin of multiple sclerosis-associated retrovirus envsequences
Authors: Laufer Georg , Mayer Jens , Mueller Benedikt F , Mueller-Lantzsch Nikolaus , Ruprecht Klemens 
Published: April 2009

AbstractBackgroundMultiple sclerosis-associated retrovirus (MSRV) RNA sequences have been detected in patients with multiple sclerosis (MS) and are related to the multi-copy human endogenous retrovirus family type W (HERV-W). Only one HERV-W locus (ERVWE1) codes for a complete HERV-W Env protein (Syncytin-1). Syncytin-1 and the putative MSRV Env protein have been involved in the pathogenesis of MS. The origin of MSRV and its precise relation to HERV-W were hitherto unknown.ResultsBy mapping HERV-WenvcDNA sequences (n = 332) from peripheral blood mononuclear cells of patients with MS and healthy controls onto individual genomic HERV-Wenvelements, we identified seven transcribed HERV-Wenvloci in these cells, including ERVWE1. Transcriptional activity of individual HERV-Wenvelements did not significantly differ between patients with MS and controls. Remarkably, almost 30% of HERV-WenvcDNAs were recombined sequences that most likely arosein vitrobetween transcripts from different HERV-Wenvelements. Re-analysis of published MSRVenvsequences revealed that all of them can be explained as originating from genomic HERV-Wenvloci or recombinations among them. In particular, a MSRVenvclone previously used for the generation of monoclonal antibody 6A2B2, detecting an antigen in MS brain lesions, appears to be derived from a HERV-Wenvlocus on chromosome Xq22.3. This locus harbors a long open reading frame for an N-terminally truncated HERV-W Env protein.ConclusionOur data clarify the origin of MSRVenvsequences, have important implications for the status of MSRV, and open the possibility that a protein encoded by a HERV-Wenvelement on chromosome Xq22.3 may be expressed in MS brain lesions.
Screening for Alpha 1 antitrypsin deficiency in Tunisian subjects with obstructive lung disease: a feasibility report
Authors: Denden Sabri , Zorzetto Michele , Amri Fethi , Knani Jalel , Ottaviani Stefania , Scabini Roberta , Gorrini Marina , Ferrarotti Ilaria , Campo Ilaria , Chibani Jemni Ben , Khelil Amel Haj , Luisetti Maurizio 
Published: April 2009

Abstract

Background
AATD is one of the most common inherited disorders in the World. However, it is generally accepted that AATD in North African populations is not a risk factor for lung and/or liver disease, based on a number of small studies. We therefore planned a screening study for detection of AATD in patients with OLD in a cohort of patients from Kairouan in central Tunisia. Methods: One hundred twenty patients with OLD (asthma, emphysema, COPD) were enrolled in the screening programme. Laboratory diagnosis for AATD was performed according to current diagnostic standards.

Results
We found that 6/120 OLD patients carried an AAT deficient allele, 1 PI*MZ, 1 PI*MPlowel, 3 PI*MMmalton, 1 PI*MMwurzburg.

Conclusion
this pilot study demonstrated that alleles related to deficiency of AAT are not absent in the Tunisian population, and that rare AATD variants prevailed over commonest PI*Z variant. These results would support a larger scale screening for AATD in Tunisia.