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171.
Michiel?B?HaesekerEmail author Evelien?Pijpers Nicole?HTM?Dukers-Muijrers Patty?Nelemans Christian?JPA?Hoebe Cathrien?A?Bruggeman Annelies?Verbon Valère?J?Goossens 《Immunity & ageing : I & A》2013,10(1):30
Background
Studies about associations of infections with herpes viruses and other pathogens, such as Chlamydia pneumoniae (CP) and Helicobacter pylori (HP) with cardiovascular disease (CVD), diabetes mellitus (DM), frailty and/or mortality are conflicting. Since high levels of antibodies against these pathogens occur in the elderly, the role of these pathogens in morbidity and mortality of vulnerable elderly was explored.Results
Blood samples of 295 community dwelling psycho-geriatric patients were tested for IgG antibodies to herpes simplex virus type 1 and 2, varicella zoster virus, Epstein Barr virus (EBV), cytomegalovirus (CMV), human herpes virus type 6 (HHV6), CP and HP. Frailty was defined with an easy-to-use previously described frailty risk score. Relative risks (RR) with 95% confidence intervals were calculated to evaluate associations between CVD, DM, frailty and pathogens. Pathogens as a predictor for subsequent mortality were tested using Kaplan Meier analyses and Cox proportional hazard models. The mean age was 78 (SD: 6.7) years, 20% died, 44% were defined as frail, 20% had DM and 49% had CVD. Presence of CMV antibody titers was associated with frailty, as shown by using both qualitative and quantitative tests, RR ratio 1.4 (95% CI: 1.003-2.16) and RR ratio 1.5 (95% CI: 1.06-2.30), respectively. High IgG antibody titers of HHV6 and EBV were associated with DM, RR ratio 3.3 (95% CI: 1.57-6.49). None of the single or combined pathogens were significantly associated with mortality and/or CVD.Conclusions
Prior CMV infection is associated with frailty, which could be in line with the concept that CMV might have an important role in immunosenescence, while high IgG titers of HHV6 and EBV are associated with DM. No association between a high pathogen burden and morbidity and/or mortality could be demonstrated.172.
Nynke A. Groenewold Bennard Doornbos Marij Zuidersma Nicole Vogelzangs Brenda W. J. H. Penninx André Aleman Peter de Jonge 《PloS one》2013,8(1)
Depression in myocardial infarction patients is often a first episode with a late age of onset. Two studies that compared depressed myocardial infarction patients to psychiatric patients found similar levels of somatic symptoms, and one study reported lower levels of cognitive/affective symptoms in myocardial infarction patients. We hypothesized that myocardial infarction patients with first depression onset at a late age would experience fewer cognitive/affective symptoms than depressed patients without cardiovascular disease. Combined data from two large multicenter depression studies resulted in a sample of 734 depressed individuals (194 myocardial infarction, 214 primary care, and 326 mental health care patients). A structured clinical interview provided information about depression diagnosis. Summed cognitive/affective and somatic symptom levels were compared between groups using analysis of covariance, with and without adjusting for the effects of recurrence and age of onset. Depressed myocardial infarction and primary care patients reported significantly lower cognitive/affective symptom levels than mental health care patients (F (2,682) = 6.043, p = 0.003). Additional analyses showed that the difference between myocardial infarction and mental health care patients disappeared after adjusting for age of onset but not recurrence of depression. These group differences were also supported by data-driven latent class analyses. There were no significant group differences in somatic symptom levels. Depression after myocardial infarction appears to have a different phenomenology than depression observed in mental health care. Future studies should investigate the etiological factors predictive of symptom dimensions in myocardial infarction and late-onset depression patients. 相似文献
173.
Sayali S. Dixit Tiannan Wang Eiffel John Q. Manzano Shin Yoo Jeongkyung Lee David Y. Chiang Nicole Ryan Jonathan L. Respress Vijay K. Yechoor Xander H. T. Wehrens 《PloS one》2013,8(3)
Altered insulin secretion contributes to the pathogenesis of type 2 diabetes. This alteration is correlated with altered intracellular Ca2+-handling in pancreatic β cells. Insulin secretion is triggered by elevation in cytoplasmic Ca2+ concentration ([Ca2+]cyt) of β cells. This elevation in [Ca2+]cyt leads to activation of Ca2+/calmodulin-dependent protein kinase II (CAMKII), which, in turn, controls multiple aspects of insulin secretion. CaMKII is known to phosphorylate ryanodine receptor 2 (RyR2), an intracellular Ca2+-release channel implicated in Ca2+-dependent steps of insulin secretion. Our data show that RyR2 is CaMKII phosphorylated in a pancreatic β-cell line in a glucose-sensitive manner. However, it is not clear whether any change in CaMKII-mediated phosphorylation underlies abnormal RyR2 function in β cells and whether such a change contributes to alterations in insulin secretion. Therefore, knock-in mice with a mutation in RyR2 that mimics its constitutive CaMKII phosphorylation, RyR2-S2814D, were studied. This mutation led to a gain-of-function defect in RyR2 indicated by increased basal RyR2-mediated Ca2+ leak in islets of these mice. This chronic in vivo defect in RyR2 resulted in basal hyperinsulinemia. In addition, S2814D mice also developed glucose intolerance, impaired glucose-stimulated insulin secretion and lowered [Ca2+]cyt transients, which are hallmarks of pre-diabetes. The glucose-sensitive Ca2+ pool in islets from S2814D mice was also reduced. These observations were supported by immunohistochemical analyses of islets in diabetic human and mouse pancreata that revealed significantly enhanced CaMKII phosphorylation of RyR2 in type 2 diabetes. Together, these studies implicate that the chronic gain-of-function defect in RyR2 due to CaMKII hyperphosphorylation is a novel mechanism that contributes to pathogenesis of type 2 diabetes. 相似文献
174.
175.
A Double-Blind,Randomised, Crossover Trial of Two Botulinum Toxin Type A in Patients with Spasticity
Fábio Coelho Guarany Paulo Dornelles Picon Nicole Ruas Guarany Antonio Cardoso dos Santos Bianca Paula Mentz Chiella Carolina Rocha Barone Lúcia Costa Cabral Fendt Pedro Schestatsky 《PloS one》2013,8(2)
Background
Botulinum toxin type A (btxA) is one of the main treatment choices for patients with spasticity. Prosigne® a new released botulinum toxin serotype A may have the same effectiveness as Botox® in focal dystonia. However, there are no randomized clinical trials comparing these formulations in spasticity treatment. The aim of our study was to compare the efficacy and safety of Prosigne® with Botox® in the treatment of spasticity.Methodology/Principal Findings
We performed a double-blind, randomized, crossover study consisting of 57 patients with clinically meaningful spasticity. The patients were assessed at baseline, 4 and 12 weeks after Prosigne® or Botox® administration. The main outcomes were changes in the patients’ Modified Ashworth Scale (MAS), Functional Independence Measure (FIM) and Pediatric Evaluation of Disability Inventory (PEDI) scores and adverse effects related to the botulinum toxin. Both of the toxins were significantly effective in relieving the level of spasticity in adults and children. There were no significant differences found between the Prosigne® and Botox® treatments regarding their MAS, FIM and PEDI scores. Likewise, the incidence of adverse effects was similar between the two groups.Conclusion
Our results suggest that Prosigne® and Botox® are both efficient and comparable with respect to their efficacy and safety for the three month treatment of spasticity.Trial Registration
ClinicalTrials.gov . NCT00819065相似文献176.
Rotaviruses are implicated as a viral trigger for the acceleration of type 1 diabetes in children. Infection of adult non-obese diabetic (NOD) mice with rotavirus strain RRV accelerates diabetes development, whereas RRV infection in infant NOD mice delays diabetes onset. In this study of infant mice, RRV titers and lymphocyte populations in the intestine, mesenteric lymph nodes (MLN) and thymus of NOD mice were compared with those in diabetes-resistant BALB/c and C57BL/6 mice. Enhanced intestinal RRV infection occurred in NOD mice compared with the other mouse strains. This was associated with increases in the frequency of CD8αβ TCRαβ intraepithelial lymphocytes, and their PD-L1 expression. Virus spread to the MLN and T cell numbers there also were greatest in NOD mice. Thymic RRV infection is shown here in all mouse strains, often in combination with alterations in T cell ontogeny. Infection lowered thymocyte numbers in infant NOD and C57BL/6 mice, whereas thymocyte production was unaltered overall in infant BALB/c mice. In the NOD mouse thymus, effector CD4+ T cell numbers were reduced by infection, whereas regulatory T cell numbers were maintained. It is proposed that maintenance of thymic regulatory T cell numbers may contribute to the increased suppression of inflammatory T cells in response to a strong stimulus observed in pancreatic lymph nodes of adult mice infected as infants. These findings show that rotavirus replication is enhanced in diabetes-prone mice, and provide evidence that thymic T cell alterations may contribute to the delayed diabetes onset following RRV infection. 相似文献
177.
Objective
To evaluate whether multisystemic therapy (MST) is more cost-effective than statutory interventions that are currently available for young offenders in England.Method
A cost-offset evaluation of MST based on data from a randomised controlled trial conducted in North London, England, comparing MST with usual services provided by two youth offending teams (YOT). Service costs were compared to cost savings in terms of rates of criminal re-offending.Results
108 adolescents, aged 11–17 years, were randomly allocated to MST+YOT (n = 56) or YOT alone (n = 52). Reductions in offending were evident in both groups, but were higher in the MST+YOT group. At 18-month follow-up, the MST+YOT group cost less in terms of criminal activity (£9,425 versus £11,715, p = 0.456). The MST+YOT group were significantly cheaper in terms of YOT services than the YOT group (£3,402 versus £4,619, p = 0.006), but more expensive including the cost of MST, although not significantly so (£5,687 versus £4,619, p = 0.195). The net benefit per young person for the 18-month follow-up was estimated to be £1,222 (95% CI −£5,838 to £8,283).Conclusions
The results reported in this study support the finding that MST+YOT has scope for cost-savings when compared to YOT alone. However, the limitations of the study in terms of method of economic evaluation, outcome measures used and data quality support the need for further research. 相似文献178.
Clévio Nóbrega Isabel Nascimento-Ferreira Isabel Onofre David Albuquerque Hirokazu Hirai Nicole Déglon Luís Pereira de Almeida 《PloS one》2013,8(1)
Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is an autosomal dominantly-inherited neurodegenerative disorder caused by the over-repetition of a CAG codon in the MJD1 gene. This expansion translates into a polyglutamine tract that confers a toxic gain-of-function to the mutant protein – ataxin-3, leading to neurodegeneration in specific brain regions, with particular severity in the cerebellum. No treatment able to modify the disease progression is available. However, gene silencing by RNA interference has shown promising results. Therefore, in this study we investigated whether lentiviral-mediated allele-specific silencing of the mutant ataxin-3 gene, after disease onset, would rescue the motor behavior deficits and neuropathological features in a severely impaired transgenic mouse model of MJD. For this purpose, we injected lentiviral vectors encoding allele-specific silencing-sequences (shAtx3) into the cerebellum of diseased transgenic mice expressing the targeted C-variant of mutant ataxin-3 present in 70% of MJD patients. This variation permits to discriminate between the wild-type and mutant forms, maintaining the normal function of the wild-type allele and silencing only the mutant form. Quantitative analysis of rotarod performance, footprint and activity patterns revealed significant and robust alleviation of gait, balance (average 3-fold increase of rotarod test time), locomotor and exploratory activity impairments in shAtx3-injected mice, as compared to control ones injected with shGFP. An important improvement of neuropathology was also observed, regarding the number of intranuclear inclusions, calbindin and DARPP-32 immunoreactivity, fluorojade B and Golgi staining and molecular and granular layers thickness. These data demonstrate for the first time the efficacy of gene silencing in blocking the MJD-associated motor-behavior and neuropathological abnormalities after the onset of the disease, supporting the use of this strategy for therapy of MJD. 相似文献
179.
Sandeep Chhabra Nicholas Barlow Olan Dolezal Meghan K. Hattarki Janet Newman Thomas S. Peat Bim Graham James D. Swarbrick 《PloS one》2013,8(4)
As the second essential enzyme of the folate biosynthetic pathway, the potential antimicrobial target, HPPK (6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase), catalyzes the Mg2+-dependant transfer of pyrophosphate from the cofactor (ATP) to the substrate, 6-hydroxymethyl-7,8-dihydropterin. Recently, we showed that 8-mercaptoguanine (8-MG) bound at the substrate site (KD ∼13 µM), inhibited the S. aureus enzyme (SaHPPK) (IC50 ∼ 41 µM), and determined the structure of the SaHPPK/8-MG complex. Here we present the synthesis of a series of guanine derivatives, together with their HPPK binding affinities, as determined by SPR and ITC analysis. The binding mode of the most potent was investigated using 2D NMR spectroscopy and X-ray crystallography. The results indicate, firstly, that the SH group of 8-MG makes a significant contribution to the free energy of binding. Secondly, direct N
9 substitution, or tautomerization arising from N
7 substitution in some cases, leads to a dramatic reduction in affinity due to loss of a critical N
9-H···Val46 hydrogen bond, combined with the limited space available around the N
9 position. The water-filled pocket under the N
7 position is significantly more tolerant of substitution, with a hydroxyl ethyl 8-MG derivative attached to N
7 (compound 21a) exhibiting an affinity for the apo enzyme comparable to the parent compound (KD ∼ 12 µM). In contrast to 8-MG, however, 21a displays competitive binding with the ATP cofactor, as judged by NMR and SPR analysis. The 1.85 Å X-ray structure of the SaHPPK/21a complex confirms that extension from the N
7 position towards the Mg2+-binding site, which affords the only tractable route out from the pterin-binding pocket. Promising strategies for the creation of more potent binders might therefore include the introduction of groups capable of interacting with the Mg2+ centres or Mg2+ -binding residues, as well as the development of bitopic inhibitors featuring 8-MG linked to a moiety targeting the ATP cofactor binding site. 相似文献
180.
Ben Lopman Yosselin Vicu?a Fabian Salazar Nely Broncano Matthew D. Esona Carlos Sandoval Nicole Gregoricus Michael D. Bowen Daniel Payne Martiza Vaca Martha Chico Umesh Parashar Philip J. Cooper 《PloS one》2013,8(7)