bluuebunny/crossref_metadata_2025_split huggingface dataset:
Variants in KCNQ1 increase type II diabetes susceptibility in South Asians: A study of 3,310 subjects from India and the US
Authors: Been Latonya F , Ralhan Sarju , Wander Gurpreet S , Mehra Narinder K , Singh JaiRup , Mulvihill John J , Aston Christopher E , Sanghera Dharambir K 
Published: January 2011

Abstract

Background
Polymorphisms in intron 15 of potassium voltage-gated channel, KQT-like subfamily member 1 (KCNQ1) gene have been associated with type II diabetes (T2D) in Japanese genome-wide association studies (GWAS). More recently a meta-analysis of European GWAS has detected a new independent signal associated with T2D in intron 11 of the KCNQ1 gene. The purpose of this investigation is to examine the role of these variants with T2D in populations of Asian Indian descent from India and the US.

Methods
We examined the association between four variants in the KCNQ1 gene with T2D and related quantitative traits in a total of 3,310 Asian Indian participants from two different cohorts comprising 2,431 individuals of the Punjabi case-control cohort from the Sikh Diabetes Study and 879 migrant Asian Indians living in the US.

Results
Our data confirmed the association of a new signal at the KCNQ1 locus (rs231362) with T2D showing an allelic odds ratio (OR) of 1.24 95%CI [1.08-1.43], p = 0.002 in the Punjabi cohort. A moderate association with T2D was also seen for rs2237895 in the Punjabi (OR 1.14; p = 0.036) and combined cohorts (meta-analysis OR 1.14; p = 0.018). Three-site haplotype analysis of rs231362, rs2237892, rs2237895 exhibited considerably stronger evidence of association of the GCC haplotype with T2D showing OR of 1.24 95%CI [1.00-1.53], p = 0.001, permutation p = 8 × 10-4 in combined cohorts. The 'C' risk allele carriers of rs2237895 had significantly reduced measures of HOMA-B in the US cohort (p = 0.008) as well as in combined cohort in meta-analysis (p = 0.009).

Conclusions
Our investigation has confirmed that the variation within the KCNQ1 locus confers a significant risk to T2D among Asian Indians. Haplotype analysis further suggested that the T2D risk associated with KCNQ1 SNPs may be derived from 'G' allele of rs231362 and 'C' allele of rs2237895 and this appears to be mediated through β cell function.
Clinical and molecular characterization of Wilson's disease in China: identification of 14 novel mutations
Authors: Li Xin-Hua , Lu Yi , Ling Yun , Fu Qing-Chun , Xu Jie , Zang Guo-Qing , Zhou Feng , De-Min Yu , Han Yue , Zhang Dong-Hua , Gong Qi-Ming , Lu Zhi-Meng , Kong Xiao-Fei , Wang Jian-She , Zhang Xin-Xin 
Published: January 2011

Abstract

Background
Wilson's disease (WND) is a rare autosomal recessive disorder. Here we have evaluated 62 WND cases (58 probands) from the Chinese Han population to expand our knowledge of ATP7B mutations and to more completely characterize WND in China.

Methods
The coding and promoter regions of the ATP7B gene were analyzed by direct sequencing in 62 Chinese patients (58 probands) with WND (male, n = 37; female, n = 25; age range, 2 ~ 61 years old).

Results
Neurologic manifestations were associated with older age at diagnosis (p < 0.0001) and longer diagnostic delay (p < 0.0001). Age at diagnosis was also correlated with urinary copper concentration (r = 0.58, p < 0.001). Forty different mutations, including 14 novel mutations, were identified in these patients. Common mutations included p.Arg778Leu (31.9%) and p.Pro992Leu (11.2%). Homozygous p.Arg778Leu and nonsense mutation/frameshift mutations were more often associated with primary hepatic manifestations (p = 0.0286 and p = 0.0383, respectively) and higher alanine transaminase levels at diagnosis (p = 0.0361 and p = 0.0047, respectively). Nonsense mutation/frameshift mutations were also associated with lower serum ceruloplasmin (p = 0.0065).

Conclusions
We identified 14 novel mutations and found that the spectrum of mutations of ATP7B in China is quite distinct from that of Western countries. The mutation type plays a role in predicting clinical manifestations. Genetic testing is a valuable tool to detect WND in young children, especially in patients younger than 8 years old. Four exons (8, 12, 13, and 16) and two mutations (p.Arg778Leu, p.Pro992Leu) should be considered high priority for cost-effective testing in China.
SMARCB1/INI1 germline mutations contribute to 10% of sporadic schwannomatosis
Authors: Rousseau Guillaume , Noguchi Tetsuro , Bourdon Violaine , Sobol Hagay , Olschwang Sylviane 
Published: January 2011

Abstract

Background
Schwannomatosis is a disease characterized by multiple non-vestibular schwannomas. Although biallelic NF2 mutations are found in schwannomas, no germ line event is detected in schwannomatosis patients. In contrast, germline mutations of the SMARCB1 (INI1) tumor suppressor gene were described in familial and sporadic schwannomatosis patients.

Methods
To delineate the SMARCB1 gene contribution, the nine coding exons were sequenced in a series of 56 patients affected with a variable number of non-vestibular schwannomas.

Results
Nine variants scattered along the sequence of SMARCB1 were identified. Five of them were classified as deleterious. All five patients carrying a SMARCB1 mutation had more multiple schwannomas, corresponding to 10.2% of patients with schwannomatosis. They were also diagnosed before 35 years of age.

Conclusions
These results suggest that patients with schwannomas have a significant probability of carrying a SMARCB1 mutation. Combined with data available from other studies, they confirm the clinical indications for genetic screening of the SMARCB1 gene.
Incidence of bone metastases and skeletal-related events in breast cancer patients: A population-based cohort study in Denmark
Authors: Jensen Annette Ø , Jacobsen Jacob B , Nørgaard Mette , Yong Mellissa , Fryzek Jon P , Sørensen Henrik T 
Published: January 2011

Abstract

Background
Breast cancer (BrCa) is the most commonly diagnosed cancer among women in the industrialized world. More than half of women presenting with metastatic BrCa develop bone metastases. Bone metastases increase the risk of skeletal-related events (SREs), defined as pathological fractures, spinal cord compression, bone pain requiring palliative radiotherapy, and orthopaedic surgery. Both bone metastases and SREs are associated with unfavorable prognosis and greatly affect quality of life. Few epidemiological data exist on SREs after primary diagnosis of BrCa and subsequent bone metastasis. We therefore estimated the incidence of bone metastases and SREs in newly-diagnosed BrCa patients in Denmark from 1999 through 2007.

Methods
We estimated the overall and annual incidence of bone metastases and SREs in newly-diagnosed breast cancer patients in Denmark from January 1, 1999 to December 31, 2007 using the Danish National Patient Registry (DNPR), which covers all Danish hospitals. We estimated the cumulative incidence of bone metastases and SREs and associated 95% confidence intervals (CI) using the Kaplan-Meier method.

Results
Of the 35,912 BrCa patients, 178 (0.5%) presented with bone metastases at the time of primary breast cancer diagnosis, and of these, 77 (43.2%) developed an SRE during follow up. A total of 1,272 of 35,690 (3.6%) BrCa patients without bone metastases at diagnosis developed bone metastases during a median follow-up time of 3.4 years. Among these patients, 590 (46.4%) subsequently developed an SRE during a median follow-up time of 0.7 years. Incidence rates of bone metastases were highest the first year after the primary BrCa diagnosis, particularly among patients with advanced BrCa at diagnosis. Similarly, incidence rates of a first SRE was highest the first year after first diagnosis of a bone metastasis.

Conclusions
The high incidence of SREs following the first year after first diagnosis of a bone metastasis underscores the need for early BrCa detection and research on effective treatments to delay the onset of SREs.
A human ribonuclease induces apoptosis associated with p21WAF1/CIP1induction and JNK inactivation
Authors: Castro Jessica , Ribó Marc , Navarro Susanna , Nogués Maria Victòria , Vilanova Maria , Benito Antoni 
Published: January 2011

Abstract

Background
Ribonucleases are promising agents for use in anticancer therapy. Among the different ribonucleases described to be cytotoxic, a paradigmatic example is onconase which manifests cytotoxic and cytostatic effects, presents synergism with several kinds of anticancer drugs and is currently in phase II/III of its clinical trial as an anticancer drug against different types of cancer. The mechanism of cytotoxicity of PE5, a variant of human pancreatic ribonuclease carrying a nuclear localization signal, has been investigated and compared to that of onconase.

Methods
Cytotoxicity was measured by the MTT method and by the tripan blue exclusion assay. Apoptosis was assessed by flow cytometry, caspase enzymatic detection and confocal microscopy. Cell cycle phase analysis was performed by flow cytometry. The expression of different proteins was analyzed by western blot.

Results
We show that the cytotoxicity of PE5 is produced through apoptosis, that it does not require the proapoptotic activity of p53 and is not prevented by the multiple drug resistance phenotype. We also show that PE5 and onconase induce cell death at the same extent although the latter is also able to arrest the cell growth. We have compared the cytotoxic effects of both ribonucleases in the NCI/ADR-RES cell line by measuring their effects on the cell cycle, on the activation of different caspases and on the expression of different apoptosis- and cell cycle-related proteins. PE5 increases the number of cells in S and G2/M cell cycle phases, which is accompanied by the increased expression of cyclin E and p21WAF1/CIP1 together with the underphosphorylation of p46 forms of JNK. Citotoxicity of onconase in this cell line does not alter the cell cycle phase distribution and it is accompanied by a decreased expression of XIAP

Conclusions
We conclude that PE5 kills the cells through apoptosis associated with the p21WAF1/CIP1 induction and the inactivation of JNK. This mechanism is significantly different from that found for onconase.
Comparative effectiveness of lifestyle interventions on cardiovascular risk factors among a Dutch overweight working population: A randomized controlled trial
Authors: Dekkers Johanna C , van Wier Marieke F , Ariëns Geertje AM , Hendriksen Ingrid JM , Pronk Nico P , Smid Tjabe , van Mechelen Willem 
Published: January 2011

Abstract

Background
Overweight (Body Mass Index [BMI] ≥ 25 kg/m2) and obesity (BMI≥ 30 kg/m2) are associated with increased cardiovascular risk, posing a considerable burden to public health. The main aim of this study was to investigate lifestyle intervention effects on cardiovascular risk factors in healthy overweight employees.

Methods
Participants were 276 healthy overweight employees (69.2% male; mean age 44.0 years [SD 9.2]; mean BMI 29.7 kg/m2 [SD 3.1]). They were randomized to one of two intervention groups receiving a six month lifestyle intervention with behavior counseling by phone (phone group) or e-mail (Internet group), or to a control group receiving usual care. Body weight, height, waist circumference, sum of skinfolds, blood pressure, total cholesterol level and predicted aerobic fitness were measured at baseline, at 6 and at 24 months. Regression analyses included the 141 participants with complete data.

Results
At 6 months a significant favorable effect on total cholesterol level (-0.2 mmol/l, 95%CI -0.5 to -0.0) was observed in the phone group and a trend for improved aerobic fitness (1.9 ml/kg/min, 95%CI -0.2 to 3.9) in the Internet group. At two years, favorable trends for body weight (-2.1 kg, 95%CI -4.4 to 0.2) and aerobic fitness (2.3 ml/kg/min, 95%CI -0.2 to 4.8) were observed in the Internet group.

Conclusions
The intervention effects were independent of the used communication mode. However short-term results were in favor of the phone group and long-term results in favor of the internet group. Thus, we found limited evidence for our lifestyle intervention to be effective in reducing cardiovascular risk in a group of apparently healthy overweight workers.

Trial registration

ISRCTN04265725
Evaluation of a pilot cooperative medical scheme in rural China: impact on gender patterns of health care utilization and prescription practices
Authors: Jiang Qicheng , Jiang Zhen , Zhao Ming , Tao Jie , Ling Chunsun , Cherry Nicola 
Published: January 2011

Abstract

Background
In 2003 the Chinese government introduced voluntary cooperative medical schemes (CMS), soon to be in place throughout rural China. Families who chose to enroll do so as a single unit and nothing is known about any differential effect of these new schemes on family members. This study evaluates the impact of one pilot CMS in Anhui Province on health care use by girls aged less than 5 years and women 65 years or older, and on the pattern and cost of prescriptions.

Methods
Health care records were extracted covering a 10 year period, before, during and after the pilot CMS in 4 townships, one with the intervention and 3 comparison townships without. The impact of the intervention on the age and gender distribution of patients presenting for health care and on the prescription of certain drugs was assessed by logistic regression. The cost of prescriptions before, during and after the intervention period was also assessed.

Results
203,058 registration and 643,588 prescription records were identified. During the intervention there was a reduced likelihood overall that a patient was female (OR = 0.92: 95%CI 0.87 - 0.97) at the intervention site. Girls aged < 5 years had an increased likelihood of health care (OR = 1.41: 95%CI 1.23 - 1.59) during the CMS, but women ≥ 65 years were relatively disadvantaged (OR = 0.84: 95%CI 0.75 - 0.95). The use of antibiotics and systemic steroids increased disproportionately at the intervention site for patients ≥ 5 years. Prescription costs at the township hospital also increased at the intervention site, particularly for older men.

Conclusions
This evaluation suggests that all family members did not benefit equally from the pilot CMS and that women ≥ 65 years may be disadvantaged by the newly available reimbursements of health care costs through the CMS. It points to the need, in future evaluations, to use individuals rather than families as the unit of analysis, in order to determine whether such health care inequalities are wide-spread and persistent or are reduced in the longer term. The results also support earlier concerns about the influence of new funding resources on prescription practices and the need for regulation of for-profit prescribing.
IgG-class anti-PF4/heparin antibodies and symptomatic DVT in orthopedic surgery patients receiving different anti-thromboembolic prophylaxis therapeutics
Authors: Motokawa Satoru , Torigoshi Takafumi , Maeda Yumi , Maeda Kazushige , Jiuchi Yuka , Yamaguchi Takayuki , Someya Shinsuke , Shindo Hiroyuki , Migita Kiyoshi 
Published: January 2011

Abstract

Background
Heparin-induced thrombocytopenia (HIT) is a thromboembolic complication that can occur with unfractionated heparin (UFH) or low molecular weight heparin (LMWH). Our objective was to determine and compare the incidence of IgG-class HIT antibodies in patients undergoing total hip arthroplasty (THA) or total knee arthroplasty (TKA) with different antithrombotic prophylaxis therapies and their contributions to the occurrence of venous thromboembolism (VTE).

Methods
A prospective observational study was performed for 374 Japanese patients undergoing THA or TKA to determine the incidence of VTE. IgG-class anti-PF4/heparin antibodies were measured using IgG-specific EIA before and after the operation.

Results
In the clinical outcome, the incidence of symptomatic deep vein thrombosis (DVT) was 15.0% (56/374, TKA; 35, THA; 21) and pulmonary emboli (PE) were not observed. The total seroconversion incidence of IgG-class PF4/heparin antibodies was 19.8% (74/374). The seroconversion incidence of IgG-class PF4/heparin antibodies was higher in patients receiving UFH (32.7%) compared to those receiving LMWH (9.5%) or fondaparinux (14.8%). Furthermore, the seroconversion incidence was significantly higher in patients undergoing TKA compared to those undergoing THA. Based on multivariate analysis, seroconversion of the IgG-class PF4/heparin antibodies was independent a risk factor for symptomatic DVT.

Conclusion
Our findings show that the seroconversion of IgG-class anti-PF4/heparin antibodies differed with various anti-thrombotic prophylaxis therapeutics and was associated with the risk of DVT in a subset of patients undergoing total joint arthroplasty (TKA and THA).
A suicide gene approach using the human pro-apoptotic protein tBid inhibits HIV-1 replication
Authors: Huelsmann Peter M , Hofmann Andreas D , Knoepfel Stefanie A , Popp Jasmin , Rauch Pia , Di Giallonardo Francesca , Danke Christina , Gueckel Eva , Schambach Axel , Wolff Horst , Metzner Karin J , Berens Christian 
Published: January 2011

Abstract

Background
Regulated expression of suicide genes is a powerful tool to eliminate specific subsets of cells and will find widespread usage in both basic and applied science. A promising example is the specific elimination of human immunodeficiency virus type 1 (HIV-1) infected cells by LTR-driven suicide genes. The success of this approach, however, depends on a fast and effective suicide gene, which is expressed exclusively in HIV-1 infected cells. These preconditions have not yet been completely fulfilled and, thus, success of suicide approaches has been limited so far. We tested truncated Bid (tBid), a human pro-apoptotic protein that induces apoptosis very rapidly and efficiently, as suicide gene for gene therapy against HIV-1 infection.

Results
When tBid was introduced into the HIV-1 LTR-based, Tat- and Rev-dependent transgene expression vector pLRed(INS)2R, very efficient induction of apoptosis was observed within 24 hours, but only in the presence of both HIV-1 regulatory proteins Tat and Rev. Induction of apoptosis was not observed in their absence. Cells containing this vector rapidly died when transfected with plasmids containing full-length viral genomic DNA, completely eliminating the chance for HIV-1 replication. Viral replication was also strongly reduced when cells were infected with HIV-1 particles.

Conclusions
This suicide vector has the potential to establish a safe and effective gene therapy approach to exclusively eliminate HIV-1 infected cells before infectious virus particles are released.
Structural insights into the membrane-extracted dimeric form of the ATPase TraB from the Escherichia coli pKM101 conjugation system
Authors: Durand Eric , Waksman Gabriel , Receveur-Brechot Veronique 
Published: January 2011

Abstract

Background
Type IV secretion (T4S) systems are involved in secretion of virulence factors such as toxins or transforming molecules, or bacterial conjugation. T4S systems are composed of 12 proteins named VirB1-B11 and VirD4. Among them, three ATPases are involved in the assembly of the T4S system and/or provide energy for substrate transfer, VirB4, VirB11 and VirD4. The X-ray crystal structures of VirB11 and VirD4 have already been solved but VirB4 has proven to be reluctant to any structural investigation so far.

Results
Here, we have used small-angle X-ray scattering to obtain the first structural models for the membrane-extracted, dimeric form of the TraB protein, the VirB4 homolog encoded by the E. coli pKM101 plasmid, and for the monomeric soluble form of the LvhB4 protein, the VirB4 homolog of the T4S system encoded by the Legionella pneumophila lvh operon. We have obtained the low resolution structures of the full-length TraB and of its N- and C-terminal halves. From these SAXS models, we derive the internal organisation of TraB. We also show that the two TraB N- and C-terminal domains are independently involved in the dimerisation of the full-length protein.

Conclusions
These models provide the first structural insights into the architecture of VirB4 proteins. In particular, our results highlight the modular arrangement and functional relevance of the dimeric-membrane-bound form of TraB.
Small dense LDL particles - a predictor of coronary artery disease evaluated by invasive and CT-based techniques: a case-control study
Authors: Toft-Petersen Anne P , Tilsted Hans H , Aarøe Jens , Rasmussen Klaus , Christensen Thorkil , Griffin Bruce A , Aardestrup Inge V , Andreasen Annette , Schmidt Erik B 
Published: January 2011

Abstract

Background
Coronary angiography is the current standard method to evaluate coronary atherosclerosis in patients with suspected angina pectoris, but non-invasive CT scanning of the coronaries are increasingly used for the same purpose.
Low-density lipoprotein (LDL) cholesterol and other lipid and lipoprotein variables are major risk factors for coronary artery disease. Small dense LDL particles may be of particular importance, but clinical studies evaluating their predictive value for coronary atherosclerosis are few.

Methods
We performed a study of 194 consecutive patients with chest pain, a priori considered of low to intermediate risk for significant coronary stenosis (>50% lumen obstruction) who were referred for elective coronary angiography. Plasma lipids and lipoproteins were measured including the subtype pattern of LDL particles, and all patients were examined by coronary CT scanning before coronary angiography.

Results
The proportion of small dense LDL was a strong univariate predictor of significant coronary artery stenosis evaluated by both methods. After adjustment for age, gender, smoking, and waist circumference only results obtained by traditional coronary angiography remained statistically significant.

Conclusion
Small dense LDL particles may add to risk stratification of patients with suspected angina pectoris.
Validity of gait parameters for hip flexor contracture in patients with cerebral palsy
Authors: Choi Sun Jong , Chung Chin Youb , Lee Kyoung Min , Kwon Dae Gyu , Lee Sang Hyeong , Park Moon Soek 
Published: January 2011

Abstract

Background
Psoas contracture is known to cause abnormal hip motion in patients with cerebral palsy. The authors investigated the clinical relevance of hip kinematic and kinetic parameters, and 3D modeled psoas length in terms of discriminant validty, convergent validity, and responsiveness.

Methods
Twenty-four patients with cerebral palsy (mean age 6.9 years) and 28 normal children (mean age 7.6 years) were included. Kinematic and kinetic data were obtained by three dimensional gait analysis, and psoas lengths were determined using a musculoskeletal modeling technique. Validity of the hip parameters were evaluated.

Results
In discriminant validity, maximum psoas length (effect size r = 0.740), maximum pelvic tilt (0.710), maximum hip flexion in late swing (0.728), maximum hip extension in stance (0.743), and hip flexor index (0.792) showed favorable discriminant ability between the normal controls and the patients. In convergent validity, maximum psoas length was not significantly correlated with maximum hip extension in stance in control group whereas it was correlated with maximum hip extension in stance (r = -0.933, p < 0.001) in the patients group. In responsiveness, maximum pelvic tilt (p = 0.008), maximum hip extension in stance (p = 0.001), maximum psoas length (p < 0.001), and hip flexor index (p < 0.001) showed significant improvement post-operatively.

Conclusions
Maximum pelvic tilt, maximum psoas length, hip flexor index, and maximum hip extension in stance were found to be clinically relevant parameters in evaluating hip flexor contracture.