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1.
Malcolm A. West Lisa Loughney Daniel Lythgoe Christopher P. Barben Valerie L. Adams William E. Bimson Michael P. W. Grocott Sandy Jack Graham J. Kemp 《PloS one》2014,9(12)
Background
In the United Kingdom, patients with locally advanced rectal cancer routinely receive neoadjuvant chemoradiotherapy. However, the effects of this on physical fitness are unclear. This pilot study is aimed to investigate the effect of neoadjuvant chemoradiotherapy on objectively measured in vivo muscle mitochondrial function and whole-body physical fitness.Methods
We prospectively studied 12 patients with rectal cancer who completed standardized neoadjuvant chemoradiotherapy, recruited from a large tertiary cancer centre, between October 2012 and July 2013. All patients underwent a cardiopulmonary exercise test and a phosphorus magnetic resonance spectroscopy quadriceps muscle exercise-recovery study before and after neoadjuvant chemoradiotherapy. Data were analysed and reported blind to patient identity and clinical course. Primary variables of interest were the two physical fitness measures; oxygen uptake at estimated anaerobic threshold and oxygen uptake at Peak exercise (ml.kg−1.min−1), and the post-exercise phosphocreatine recovery rate constant (min−1), a measure of muscle mitochondrial capacity in vivo.Results
Median age was 67 years (IQR 64–75). Differences (95%CI) in all three primary variables were significantly negative post-NACRT: Oxygen uptake at estimated anaerobic threshold −2.4 ml.kg−1.min−1 (−3.8, −0.9), p = 0.004; Oxygen uptake at Peak −4.0 ml.kg−1.min−1 (−6.8, −1.1), p = 0.011; and post-exercise phosphocreatine recovery rate constant −0.34 min−1 (−0.51, −0.17), p<0.001.Conclusion
The significant decrease in both whole-body physical fitness and in vivo muscle mitochondrial function raises the possibility that muscle mitochondrial mechanisms, no doubt multifactorial, may be important in deterioration of physical fitness following neoadjuvant chemoradiotherapy. This may have implications for targeted interventions to improve physical fitness pre-surgery.Trial Registration
Clinicaltrials.gov registration NCT01859442相似文献2.
Liesbeth Van Huffel Charles R. V. Tomson Johannes Ruige Ionut Nistor Wim Van Biesen Davide Bolignano 《PloS one》2014,9(11)
Background
Obesity and sedentary lifestyle are major health problems and key features to develop cardiovascular disease. Data on the effects of lifestyle interventions in diabetics with chronic kidney disease (CKD) have been conflicting.Study Design
Systematic review.Population
Diabetes patients with CKD stage 3 to 5.Search Strategy and Sources
Medline, Embase and Central were searched to identify papers.Intervention
Effect of a negative energy balance on hard outcomes in diabetics with CKD.Outcomes
Death, cardiovascular events, glycaemic control, kidney function, metabolic parameters and body composition.Results
We retained 11 studies. There are insufficient data to evaluate the effect on mortality to promote negative energy balance. None of the studies reported a difference in incidence of Major Adverse Cardiovascular Events. Reduction of energy intake does not alter creatinine clearance but significantly reduces proteinuria (mean difference from −0.66 to −1.77 g/24 h). Interventions with combined exercise and diet resulted in a slower decline of eGFR (−9.2 vs. −20.7 mL/min over two year observation; p<0.001). Aerobic and resistance exercise reduced HbA1c (−0.51 (−0.87 to −0.14); p = 0.007 and −0.38 (−0.72 to −0.22); p = 0.038, respectively). Exercise interventions improve the overall functional status and quality of life in this subgroup. Aerobic exercise reduces BMI (−0.74% (−1.29 to −0.18); p = 0.009) and body weight (−2.2 kg (−3.9 to −0.6); p = 0.008). Resistance exercise reduces trunk fat mass (−0,7±0,1 vs. +0,8 kg ±0,1 kg; p = 0,001−0,005). In none of the studies did the intervention cause an increase in adverse events.Limitations
All studies used a different intervention type and mixed patient groups.Conclusions
There is insufficient evidence to evaluate the effect of negative energy balance interventions on mortality in diabetic patients with advanced CKD. Overall, these interventions have beneficial effects on glycaemic control, BMI and body composition, functional status and quality of life, and no harmful effects were observed. 相似文献3.
Background
The data of MARCH (Metformin and AcaRbose in Chinese as the initial Hypoglycaemic treatment) trial demonstrated that acarbose and metformin have similar efficacy as initial therapy for hemoglobin A1c (HbA1c) reduction in Chinese patients with newly diagnosed type 2 diabetes. We investigated whether the therapeutic efficacy was diversified under different body mass index (BMI) status.Methods
All 784 subjects were divided into normal-weight group (BMI<24 kg/m2), overweight group (BMI 24–28 kg/m2) and obese group (BMI≥28 kg/m2). Patients were assigned to 48 weeks of therapy with acarbose or metformin, respectively. The clinical trial registry number was ChiCTR-TRC-08000231.Results
The reduction of HbA1c levels and the proportion of patients with HbA1c of 6.5% or less were similar in the three groups after acarbose and metformin treatment. In overweight group, fasting blood glucose (FBG) after metformin treatment showed greater decline compared to acarbose group at 48 weeks [−1.73 (−1.99 to −1.46) vs. −1.37 (−1.61 to −1.12), P<0.05), however the decrease of 2 h post-challenge blood glucose (PBG) after acarbose treatment at 48 weeks was bigger compared to metformin group [−3.34 (−3.83 to−2.84) vs. −2.35 (−2.85 to −1.85), P<0.01 ]. Both acarbose and metformin treatment resulted in a significant decrease in waist circumference, hip circumference, weight and BMI in the three groups (all P<0.05).Conclusion
Acarbose and metformin decreased HbA1c levels similarly regardless of BMI status of Chinese type 2 diabetic patients. Acarbose and metformin resulted in a significant and modest improvement of anthropometric parametres in different BMI status. Thus, acarbose treatment may contribute a similar effect on plasma glucose control compared to metformin, even in obesity patients.Trial Registration
ChiCTR.org ChiCTR-TRC-08000231 相似文献4.
Robert M. Weiss Donald D. Lund Yi Chu Robert M. Brooks Kathy A. Zimmerman Ramzi El Accaoui Melissa K. Davis Georges P. Hajj M. Bridget Zimmerman Donald D. Heistad 《PloS one》2013,8(6)
Background
There are no rigorously confirmed effective medical therapies for calcific aortic stenosis. Hypercholesterolemic Ldlr −/− Apob 100/100 mice develop calcific aortic stenosis and valvular cardiomyopathy in old age. Osteoprotegerin (OPG) modulates calcification in bone and blood vessels, but its effect on valve calcification and valve function is not known.Objectives
To determine the impact of pharmacologic treatment with OPG upon aortic valve calcification and valve function in aortic stenosis-prone hypercholesterolemic Ldlr −/− Apob 100/100 mice.Methods
Young Ldlr −/− Apob 100/100 mice (age 2 months) were fed a Western diet and received exogenous OPG or vehicle (N = 12 each) 3 times per week, until age 8 months. After echocardiographic evaluation of valve function, the aortic valve was evaluated histologically. Older Ldlr −/− Apob 100/100 mice were fed a Western diet beginning at age 2 months. OPG or vehicle (N = 12 each) was administered from 6 to 12 months of age, followed by echocardiographic evaluation of valve function, followed by histologic evaluation.Results
In Young Ldlr −/− Apob 100/100 mice, OPG significantly attenuated osteogenic transformation in the aortic valve, but did not affect lipid accumulation. In Older Ldlr −/− Apob 100/100 mice, OPG attenuated accumulation of the osteoblast-specific matrix protein osteocalcin by ∼80%, and attenuated aortic valve calcification by ∼ 70%. OPG also attenuated impairment of aortic valve function.Conclusions
OPG attenuates pro-calcific processes in the aortic valve, and protects against impairment of aortic valve function in hypercholesterolemic aortic stenosis-prone Ldlr −/− Apob 100/100 mice. 相似文献5.
Masahiro Ishikawa Hiromu Ito Toshiyuki Kitaori Koichi Murata Hideyuki Shibuya Moritoshi Furu Hiroyuki Yoshitomi Takayuki Fujii Koji Yamamoto Shuichi Matsuda 《PloS one》2014,9(8)
Objective
The purpose of this study was to investigate chemokine profiles and their functional roles in the early phase of fracture healing in mouse models.Methods
The expression profiles of chemokines were examined during fracture healing in wild-type (WT) mice using a polymerase chain reaction array and histological staining. The functional effect of monocyte chemotactic protein-1 (MCP-1) on primary mouse bone marrow stromal cells (mBMSCs) was evaluated using an in vitro migration assay. MCP-1−/− and C-C chemokine receptor 2 (CCR2)−/− mice were fractured and evaluated by histological staining and micro-computed tomography (micro-CT). RS102895, an antagonist of CCR2, was continuously administered in WT mice before or after rib fracture and evaluated by histological staining and micro-CT. Bone graft exchange models were created in WT and MCP-1−/− mice and were evaluated by histological staining and micro-CT.Results
MCP-1 and MCP-3 expression in the early phase of fracture healing were up-regulated, and high levels of MCP-1 and MCP-3 protein expression observed in the periosteum and endosteum in the same period. MCP-1, but not MCP-3, increased migration of mBMSCs in a dose-dependent manner. Fracture healing in MCP-1−/− and CCR2−/− mice was delayed compared with WT mice on day 21. Administration of RS102895 in the early, but not in the late phase, caused delayed fracture healing. Transplantation of WT-derived graft into host MCP-1−/− mice significantly increased new bone formation in the bone graft exchange models. Furthermore, marked induction of MCP-1 expression in the periosteum and endosteum was observed around the WT-derived graft in the host MCP-1−/− mouse. Conversely, transplantation of MCP-1−/− mouse-derived grafts into host WT mice markedly decreased new bone formation.Conclusions
MCP-1/CCR2 signaling in the periosteum and endosteum is essential for the recruitment of mesenchymal progenitor cells in the early phase of fracture healing. 相似文献6.
Ida Casorelli Tania Pannellini Gabriele De Luca Paolo Degan Federica Chiera Ivano Iavarone Alessandro Giuliani Alessia Butera Monica Boirivant Piero Musiani Margherita Bignami 《PloS one》2010,5(8)
Background
The Mutyh DNA glycosylase is involved in the repair of oxidized DNA bases. Mutations in the human MUTYH gene are responsible for colorectal cancer in familial adenomatous polyposis. Since defective DNA repair genes might contribute to the increased cancer risk associated with inflammatory bowel diseases, we compared the inflammatory response of wild-type and Mutyh−/− mice to oxidative stress.Methodology/Principal Findings
The severity of colitis, changes in expression of genes involved in DNA repair and inflammation, DNA 8-oxoguanine levels and microsatellite instability were analysed in colon of mice treated with dextran sulfate sodium (DSS). The Mutyh−/− phenotpe was associated with a significant accumulation of 8-oxoguanine in colon DNA of treated mice. A single DSS cycle induced severe acute ulcerative colitis in wild-type mice, whereas lesions were modest in Mutyh−/− mice, and this was associated with moderate variations in the expression of several cytokines. Eight DSS cycles caused chronic colitis in both wild-type and Mutyh−/− mice. Lymphoid hyperplasia and a significant reduction in Foxp3+ regulatory T cells were observed only in Mutyh−/− mice.Conclusions
The findings indicate that, in this model of ulcerative colitis, Mutyh plays a major role in maintaining intestinal integrity by affecting the inflammatory response. 相似文献7.
Osama M. A. Ibrahim Murat Dogru Yukihiro Matsumoto Ayako Igarashi Takashi Kojima Tais Hitomi Wakamatsu Takaaki Inaba Takahiko Shimizu Jun Shimazaki Kazuo Tsubota 《PloS one》2014,9(7)
Purpose
The purpose of our study was to investigate alterations in the meibomian gland (MG) in Cu, Zn-Superoxide Dismutase-1 knockout (Sod1 −/−) mouse.Methods
Tear function tests [Break up time (BUT) and cotton thread] and ocular vital staining test were performed on Sod1 −/− male mice (n = 24) aged 10 and 50 weeks, and age and sex matched wild–type (+/+) mice (n = 25). Tear and serum samples were collected at sacrifice for inflammatory cytokine assays. MG specimens underwent Hematoxylin and Eosin staining, Mallory staining for fibrosis, Oil Red O lipid staining, TUNEL staining, immunohistochemistry stainings for 4HNE, 8-OHdG and CD45. Transmission electron microscopic examination (TEM) was also performed.Results
Corneal vital staining scores in the Sod1 −/− mice were significantly higher compared with the wild type mice throughout the follow-up. Tear and serum IL-6 and TNF-α levels also showed significant elevations in the 10 to 50 week Sod1 −/− mice. Oil Red O staining showed an accumulation of large lipid droplets in the Sod1 −/− mice at 50 weeks. Immunohistochemistry revealed both increased TUNEL and oxidative stress marker stainings of the MG acinar epithelium in the Sod1 −/− mice compared to the wild type mice. Immunohistochemistry staining for CD45 showed increasing inflammatory cell infiltrates from 10 to 50 weeks in the Sod1 −/− mice compared to the wild type mice. TEM revealed prominent mitochondrial changes in 50 week Sod1 −/− mice.Conclusions
Our results suggest that reactive oxygen species might play a vital role in the pathogensis of meibomian gland dysfunction. The Sod1 −/− mouse appears to be a promising model for the study of reactive oxygen species associated MG alterations. 相似文献8.
Sebastian Hofmann Attila Braun Rastislav Pozgaj Martina Morowski Timo V?gtle Bernhard Nieswandt 《PloS one》2014,9(12)
Background
Platelets are anuclear cell fragments derived from bone marrow megakaryocytes that safeguard vascular integrity by forming thrombi at sites of vascular injury. Although the early events of thrombus formation—platelet adhesion and aggregation—have been intensively studied, less is known about the mechanisms and receptors that stabilize platelet-platelet interactions once a thrombus has formed. One receptor that has been implicated in this process is the signaling lymphocyte activation molecule (SLAM) family member CD84, which can undergo homophilic interactions and becomes phosphorylated upon platelet aggregation.Objective
The role of CD84 in platelet physiology and thrombus formation was investigated in CD84-deficient mice.Methods and Results
We generated CD84-deficient mice and analyzed their platelets in vitro and in vivo. Cd84−/− platelets exhibited normal activation and aggregation responses to classical platelet agonists. Furthermore, CD84 deficiency did not affect integrin-mediated clot retraction and spreading of activated platelets on fibrinogen. Notably, also the formation of stable three-dimensional thrombi on collagen-coated surfaces under flow ex vivo was unaltered in the blood of Cd84−/− mice. In vivo, Cd84−/− mice exhibited unaltered hemostatic function and arterial thrombus formation.Conclusion
These results show that CD84 is dispensable for thrombus formation and stabilization, indicating that its deficiency may be functionally compensated by other receptors or that it may be important for platelet functions different from platelet-platelet interactions. 相似文献9.
Danese M Joiner Kennen D Less Emily M Van Wieren Yu-Wen Zhang Daniel Hess Bart O Williams 《Arthritis research & therapy》2014,16(2):R81
Introduction
Ligament and meniscal damage can cause joint disease. Arthritic joints contain increased amounts of epidermal growth factor receptor (EGFR) protein, and polymorphisms in EGFR are associated with arthritis risk. The role of endogenous EGFR regulation during joint disease due to ligament and meniscal trauma is unknown. Mitogen-inducible gene 6 (MIG-6) can reduce EGFR phosphorylation and downstream signaling. We examined the effect of EGFR modulation by MIG-6 on joint disease development after ligament and meniscus injury.Methods
Knee ligament transection and meniscus removal were performed surgically on mice homozygous for a global inactivating mutation in MIG-6 (Mig-6−/−) and in wild-type (WT) animals.Results
Two weeks after surgery, Mig-6−/−mice had bone erosion as well as greater fibrous tissue area and serum RANKL concentration than WT mice. Four weeks after surgery, Mig-6−/−mice had less cartilage and increased cell proliferation relative to contralateral control and WT knees. Increased apoptotic cells and growth outside the articulating region occurred in Mig-6−/−mice. Tibia trabecular bone mineral density (BMD) and the number of trabeculae were lower in surgically treated knees relative to the respective control knees for both groups. BMD, as well as trabecular thickness and number, were lower in surgically treated knees from Mig-6−/−mice relative to WT surgically treated knees. Phosphorylated EGFR staining in surgically treated knees decreased for WT mice and increased for Mig-6−/−mice. Fewer inflammatory cells were present in the knees of WT mice.Conclusion
Mig-6−/−mice have rapid and increased joint damage after ligament and meniscal trauma. Mig-6 modification could lessen degenerative disease development after this type of injury. 相似文献10.
Stephanie S. Tseng-Rogenski Heekyung Chung Maike B. Wilk Shuai Zhang Moriya Iwaizumi John M. Carethers 《PloS one》2012,7(11)
Background
Elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) is a genetic signature observed in 60% of sporadic colorectal cancers (CRCs). Unlike microsatellite unstable CRCs where hypermethylation of the DNA mismatch repair (MMR) gene hMLH1’s promoter is causal, the precise cause of EMAST is not clearly defined but points towards hMSH3 deficiency.Aim
To examine if hMSH3 deficiency causes EMAST, and to explore mechanisms for its deficiency.Methods
We measured −4 bp framshifts at D8S321 and D20S82 loci within EGFP-containing constructs to determine EMAST formation in MMR-proficient, hMLH1−/−, hMSH6−/−, and hMSH3−/− CRC cells. We observed the subcellular location of hMSH3 with oxidative stress.Results
D8S321 mutations occurred 31-and 40-fold higher and D20S82 mutations occurred 82-and 49-fold higher in hMLH1−/− and hMSH3−/− cells, respectively, than in hMSH6−/− or MMR-proficient cells. hMSH3 knockdown in MMR-proficient cells caused higher D8S321 mutation rates (18.14 and 11.14×10−4 mutations/cell/generation in two independent clones) than scrambled controls (0 and 0.26×10−4 mutations/cell/generation; p<0.01). DNA sequencing confirmed the expected frameshift mutations with evidence for ongoing mutations of the constructs. Because EMAST-positive tumors are associated with inflammation, we subjected MMR-proficient cells to oxidative stress via H2O2 to examine its effect on hMSH3. A reversible nuclear-to-cytosol shift of hMSH3 was observed upon H2O2 treatment.Conclusion
EMAST is dependent upon the MMR background, with hMSH3−/− more prone to frameshift mutations than hMSH6−/−, opposite to frameshift mutations observed for mononucleotide repeats. hMSH3−/− mimics complete MMR failure (hMLH1−/−) in inducing EMAST. Given the observed heterogeneous expression of hMSH3 in CRCs with EMAST, hMSH3-deficiency appears to be the event that commences EMAST. Oxidative stress, which causes a shift of hMSH3’s subcellular location, may contribute to an hMSH3 loss-of-function phenotype by sequestering it to the cytosol. 相似文献11.
Objective
Intravenous adenosine induces temporary bradycardia. This is due to the activation of extracellular adenosine receptors (ARs). While adenosine can signal through any of four ARs (A1AR, A2AAR, A2BAR, A3AR), previous ex vivo studies implicated the A1AR in the heart-rate slowing effects. Here, we used comparative genetic in vivo studies to address the contribution of individual ARs to the heart-rate slowing effects of intravascular adenosine.Methods and Results
We studied gene-targeted mice for individual ARs to define their in vivo contribution to the heart-rate slowing effects of adenosine. Anesthetized mice were treated with a bolus of intravascular adenosine, followed by measurements of heart-rate and blood pressure via a carotid artery catheter. These studies demonstrated dose-dependent slowing of the heart rate with adenosine treatment in wild-type, A2AAR−/−, A2BAR−/−, or A3AR−/− mice. In contrast, adenosine-dependent slowing of the heart-rate was completely abolished in A1AR−/− mice. Moreover, pre-treatment with a specific A1AR antagonist (DPCPX) attenuated the heart-rate slowing effects of adenosine in wild-type, A2AAR−/−, or A2BAR−/− mice, but did not alter hemodynamic responses of A1AR−/− mice.Conclusions
The present studies combine pharmacological and genetic in vivo evidence for a selective role of the A1AR in slowing the heart rate during adenosine bolus injection. 相似文献12.
Ilaria Nichele Alberto Zamò Anna Bertolaso Francesco Bifari Martina Tinelli Marta Franchini Roberta Stradoni Fiorenza Aprili Giovanni Pizzolo Mauro Krampera 《PloS one》2012,7(12)
Background
small B-cell neoplasms can show plasmacytic differentiation and may potentially progress to aggressive lymphoma (DLBCL). Epstein-Barr virus (EBV) infection may cause the transformation of malignant cells in vitro.Design and Method
we established VR09 cell line with plasmacytic differentiation, obtained from a case of atypical, non-CLL B-cell chronic lymphoproliferative disease with plasmacytic features. We used flow cytometry, immunohistochemistry, polymerase chain reaction, cytogenetic analysis and florescence in situ hybridization in the attempt at thoroughly characterizing the cell line. We showed VR09 tumorigenic potential in vivo, leading to the development of activated DLBCL with plasmacytic features.Results
VR09 cells displayed plasmacytic appearance and grew as spherical tumors when inoculated subcutaneously into immunodeficient Rag2−/− γ-chain−/− mice. VR09 cell line and tumors displayed the phenotype of activated stage of B cell maturation, with secretory differentiation (CD19+ CD20+ CD79a+ CD79b+/− CD138+ cyclin D1- Ki67 80% IgM+ IgD+ MUM1+ MNDA+ CD10- CD22+ CD23+ CD43+ K+, λ- Bcl2+ Bcl6-) and they presented episomal EBV genome, chromosome 12 trisomy, lack of c-MYC rearrangement and Myd88 gene mutation, presence of somatic hypermutation in the VH region, and wild-type p53.Conclusion
This new EBV-positive cell line may be useful to further characterize in vivo activated DLBCL with plasmacytic features. 相似文献13.
Objective
Protein Z (PZ) is a vitamin K-dependent coagulation factor without catalytic activity. Evidence points towards PZ as an independent risk factor for the occurrence of human peripheral arterial disease. However, the role of PZ in ischemia-driven angiogenesis and vascular healing processes has not been elucidated so far.Approach
Angiogenic potency of PZ was assessed in established in vitro assays using endothelial cells. PZ-deficient (PZ−/−) mice and their wild-type littermates (PZ+/+) were subjected to hindlimb ischemia. Furthermore, PZ−/− mice were exposed to PZ expressing adenovirus (AdV-PZ) or control adenovirus (AdV-GFP). In an additional set of animals, PZ−/− mice were exposed to AdV-PZ and AdV-GFP, each in combination with the CXCR4 antagonist AMD3100.Results
In vitro, PZ stimulated migratory activity and capillary-like tube formation of endothelial cells comparable to SDF-1. PZ−/− mice exhibited diminished hypoxia-driven neovascularization and reperfusion in post-ischemic hindlimbs, which was restored by adenoviral gene transfer up to levels seen in PZ+/+ mice. The stimulatory impact of PZ on endothelial cells in vitro was abolished by siRNA targeting against PZ and PZ was not able to restore reduced migration after knock-down of CXCR4. The increased surface expression of CXCR4 on PZ-stimulated endothelial cells and the abrogated restoration of PZ−/− mice via AdV-PZ after concomitant treatment with the CXCR4 antagonist AMD3100 supports the idea that PZ mediates angiogenesis via a G-protein coupled pathway and involves the SDF-1/CXCR4 axis. This is underlined by the fact that addition of the G-protein inhibitor PTX to PZ-stimulated endothelial cells abolished the effect of PZ on capillary-like tube formation.Conclusions
The results of the current study reveal a role of PZ in ischemia-induced angiogenesis, which involves a G-protein coupled pathway and a raised surface expression of CXCR4. Our findings thereby extend the involvement of PZ from the coagulation cascade to a beneficial modulation of vascular homeostasis. 相似文献14.
Isabelle Jéru Véronique Hentgen Emmanuelle Cochet Philippe Duquesnoy Ga?lle Le Borgne Emmanuel Grimprel Katia Stankovic Stojanovic Sonia Karabina Gilles Grateau Serge Amselem 《PloS one》2013,8(7)
Background
Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disorder due to MEFV mutations and one of the most frequent Mediterranean genetic diseases. The observation of many heterozygous patients in whom a second mutated allele was excluded led to the proposal that heterozygosity could be causal. However, heterozygosity might be coincidental in many patients due to the very high rate of mutations in Mediterranean populations.Objective
To better delineate the pathogenicity of heterozygosity in order to improve genetic counselling and disease management.Methods
Complementary statistical approaches were used: estimation of FMF prevalence at population levels, genotype comparison in siblings from 63 familial forms, and genotype study in 557 patients from four Mediterranean populations.Results
At the population level, we did not observe any contribution of heterozygosity to disease prevalence. In affected siblings of patients carrying two MEFV mutations, 92% carry two mutated alleles, whereas 4% are heterozygous with typical FMF diagnosis. We demonstrated statistically that patients are more likely to be heterozygous than healthy individuals, as shown by the higher ratio heterozygous carriers/non carriers in patients (p<10−7–p<0.003). The risk for heterozygotes to develop FMF was estimated between 2.1×10−3 and 5.8×10−3 and the relative risk, as compared to non carriers, between 6.3 and 8.1.Conclusions
This is the first statistical demonstration that heterozygosity is not responsible for classical Mendelian FMF per se, but constitutes a susceptibility factor for clinically-similar multifactorial forms of the disease. We also provide a first estimate of the risk for heterozygotes to develop FMF. 相似文献15.
Hai-Feng Shu Tao Yang Si-Xun Yu Hai-Dong Huang Ling-Li Jiang Jian-Wen Gu Yong-Qin Kuang 《PloS one》2014,9(7)
Background
Although some trials assessed the effectiveness of aerobic exercise for Parkinson''s disease (PD), the role of aerobic exercise in the management of PD remained controversial.Objective
The purpose of this systematic review is to evaluate the evidence about whether aerobic exercise is effective for PD.Methods
Seven electronic databases, up to December 2013, were searched to identify relevant studies. Two reviewers independently extracted data and assessed methodological quality based on PEDro scale. Standardised mean difference (SMD) and 95% confidence intervals (CI) of random-effects model were calculated. And heterogeneity was assessed based on the I2 statistic.Results
18 randomized controlled trials (RCTs) with 901 patients were eligible. The aggregated results suggested that aerobic exercise should show superior effects in improving motor actions (SMD, −0.57; 95% CI −0.94 to −0.19; p = 0.003), balance (SMD, 2.02; 95% CI 0.45 to 3.59; p = 0.01), and gait (SMD, 0.33; 95% CI 0.17 to 0.49; p<0.0001) in patients with PD, but not in quality of life (SMD, 0.11; 95% CI −0.23 to 0.46; p = 0.52). And there was no valid evidence on follow-up effects of aerobic exercise for PD.Conclusion
Aerobic exercise showed immediate beneficial effects in improving motor action, balance, and gait in patients with PD. However, given no evidence on follow-up effects, large-scale RCTs with long follow-up are warrant to confirm the current findings. 相似文献16.
Effie Viguiliouk Cyril W. C. Kendall Sonia Blanco Mejia Adrian I. Cozma Vanessa Ha Arash Mirrahimi Viranda H. Jayalath Livia S. A. Augustin Laura Chiavaroli Lawrence A. Leiter Russell J. de Souza David J. A. Jenkins John L. Sievenpiper 《PloS one》2014,9(7)
Background
Tree nut consumption has been associated with reduced diabetes risk, however, results from randomized trials on glycemic control have been inconsistent.Objective
To provide better evidence for diabetes guidelines development, we conducted a systematic review and meta-analysis of randomized controlled trials to assess the effects of tree nuts on markers of glycemic control in individuals with diabetes.Data Sources
MEDLINE, EMBASE, CINAHL, and Cochrane databases through 6 April 2014.Study Selection
Randomized controlled trials ≥3 weeks conducted in individuals with diabetes that compare the effect of diets emphasizing tree nuts to isocaloric diets without tree nuts on HbA1c, fasting glucose, fasting insulin, and HOMA-IR.Data Extraction and Synthesis
Two independent reviewer’s extracted relevant data and assessed study quality and risk of bias. Data were pooled by the generic inverse variance method and expressed as mean differences (MD) with 95% CI’s. Heterogeneity was assessed (Cochran Q-statistic) and quantified (I2).Results
Twelve trials (n = 450) were included. Diets emphasizing tree nuts at a median dose of 56 g/d significantly lowered HbA1c (MD = −0.07% [95% CI:−0.10, −0.03%]; P = 0.0003) and fasting glucose (MD = −0.15 mmol/L [95% CI: −0.27, −0.02 mmol/L]; P = 0.03) compared with control diets. No significant treatment effects were observed for fasting insulin and HOMA-IR, however the direction of effect favoured tree nuts.Limitations
Majority of trials were of short duration and poor quality.Conclusions
Pooled analyses show that tree nuts improve glycemic control in individuals with type 2 diabetes, supporting their inclusion in a healthy diet. Owing to the uncertainties in our analyses there is a need for longer, higher quality trials with a focus on using nuts to displace high-glycemic index carbohydrates.Trial Registration
ClinicalTrials.gov NCT01630980相似文献17.
Kazufumi Honda Takuji Okusaka Klaus Felix Shoji Nakamori Naohiro Sata Hideo Nagai Tatsuya Ioka Akihiko Tsuchida Takeshi Shimahara Masashi Shimahara Yohichi Yasunami Hideya Kuwabara Tomohiro Sakuma Yoshihiko Otsuka Norihito Ota Miki Shitashige Tomoo Kosuge Markus W. Büchler Tesshi Yamada 《PloS one》2012,7(10)
Background
Among the more common human malignancies, invasive ductal carcinoma of the pancreas has the worst prognosis. The poor outcome seems to be attributable to difficulty in early detection.Methods
We compared the plasma protein profiles of 112 pancreatic cancer patients with those of 103 sex- and age-matched healthy controls (Cohort 1) using a newly developed matrix-assisted laser desorption/ionization (oMALDI) QqTOF (quadrupole time-of-flight) mass spectrometry (MS) system.Results
We found that hemi-truncated apolipoprotein AII dimer (ApoAII-2; 17252 m/z), unglycosylated apolipoprotein CIII (ApoCIII-0; 8766 m/z), and their summed value were significantly decreased in the pancreatic cancer patients [P = 1.36×10−21, P = 4.35×10−14, and P = 1.83×10−24 (Mann-Whitney U-test); area-under-curve values of 0.877, 0.798, and 0.903, respectively]. The significance was further validated in a total of 1099 plasma/serum samples, consisting of 2 retrospective cohorts [Cohort 2 (n = 103) and Cohort 3 (n = 163)] and a prospective cohort [Cohort 4 (n = 833)] collected from 8 medical institutions in Japan and Germany.Conclusions
We have constructed a robust quantitative MS profiling system and used it to validate alterations of modified apolipoproteins in multiple cohorts of patients with pancreatic cancer. 相似文献18.
Shaoyan Zhang Daniel Skinner Stephen Bradley Hicks Mark O. Bevensee Eric J. Sorscher Ahmed Lazrak Sadis Matalon Carmel M. McNicholas Bradford A. Woodworth 《PloS one》2014,9(8)
Introduction
We have previously demonstrated that Sinupret, an established treatment prescribed widely in Europe for respiratory ailments including rhinosinusitis, promotes transepithelial chloride (Cl−) secretion in vitro and in vivo. The present study was designed to evaluate other indicators of mucociliary clearance (MCC) including ciliary beat frequency (CBF) and airway surface liquid (ASL) depth, but also investigate the mechanisms that underlie activity of this bioflavonoid.Methods
Primary murine nasal septal epithelial (MNSE) [wild type (WT) and transgenic CFTR−/−], human sinonasal epithelial (HSNE), WT CFTR-expressing CFBE and TMEM16A-expressing HEK cultures were utilized for the present experiments. CBF and ASL depth measurements were performed. Mechanisms underlying transepithelial Cl− transport were determined using pharmacologic manipulation in Ussing chambers, Fura-2 intracellular calcium [Ca2+]i imaging, cAMP signaling, regulatory domain (R-D) phosphorylation of CFTR, and excised inside out and whole cell patch clamp analysis.Results
Sinupret-mediated Cl− secretion [ΔISC(µA/cm2)] was pronounced in WT MNSE (20.7+/−0.9 vs. 5.6+/−0.9(control), p<0.05), CFTR−/− MNSE (10.1+/−1.0 vs. 0.9+/−0.3(control), p<0.05) and HSNE (20.7+/−0.3 vs. 6.4+/−0.9(control), p<0.05). The formulation activated Ca2+ signaling and TMEM16A channels, but also increased CFTR channel open probability (Po) without stimulating PKA-dependent pathways responsible for phosphorylation of the CFTR R-domain and resultant Cl− secretion. Sinupret also enhanced CBF and ASL depth.Conclusion
Sinupret stimulates CBF, promotes transepithelial Cl− secretion, and increases ASL depth in a manner likely to enhance MCC. Our findings suggest that direct stimulation of CFTR, together with activation of Ca2+-dependent TMEM16A secretion account for the majority of anion transport attributable to Sinupret. These studies provide further rationale for using robust Cl− secretagogue based therapies as an emerging treatment modality for common respiratory diseases of MCC including acute and chronic bronchitis and CRS. 相似文献19.
Ruyang Zhang Yang Zhao Minjie Chu Amar Mehta Yongyue Wei Yao Liu Pengcheng Xun Jianling Bai Hao Yu Li Su Hongxi Zhang Zhibin Hu Hongbing Shen Feng Chen David C. Christiani 《PloS one》2013,8(3)
Background
Occupational exposure to endotoxin is associated with decrements in pulmonary function, but how much variation in this association is explained by genetic variants is not well understood.Objective
We aimed to identify single nucleotide polymorphisms (SNPs) that are associated with the rate of forced expiratory volume in one second (FEV1) decline by a large scale genetic association study in newly-hired healthy young female cotton textile workers.Methods
DNA samples were genotyped using the Illumina Human CVD BeadChip. Change rate in FEV1 was modeled as a function of each SNP genotype in linear regression model with covariate adjustment. We controlled the type 1 error in study-wide level by permutation method. The false discovery rate (FDR) and the family-wise error rate (FWER) were set to be 0.10 and 0.15 respectively.Results
Two SNPs were found to be significant (P<6.29×10−5), including rs1910047 (P = 3.07×10−5, FDR = 0.0778) and rs9469089 (P = 6.19×10−5, FDR = 0.0967), as well as other eight suggestive (P<5×10−4) associated SNPs. Gene-gene and gene-environment interactions were also observed, such as rs1910047 and rs1049970 (P = 0.0418, FDR = 0.0895); rs9469089 and age (P = 0.0161, FDR = 0.0264). Genetic risk score analysis showed that the more risk loci the subjects carried, the larger the rate of FEV1 decline occurred (P trend = 3.01×10−18). However, the association was different among age subgroups (P = 7.11×10−6) and endotoxin subgroups (P = 1.08×10−2). Functional network analysis illustrates potential biological connections of all interacted genes.Conclusions
Genetic variants together with environmental factors interact to affect the rate of FEV1 decline in cotton textile workers. 相似文献20.