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121.
The circulating lymphocytes of 88 consecutive patients following autologous, conventional, or T-cell depleted bone marrow transplantation were serially analyzed for B-cell surface antigen expression and function. In the majority of patients, except for those who developed chronic graft-versus-host disease, the number of circulating CD20+ B cell normalized by the fourth posttransplant month. The earliest detectable B cells normally expressed HLA-DR, CD19, surface immunoglobulin (slg), CD21, Leu-8, and lacked expression of CD10 (CALLA). In addition, the circulating B cells expressed CD1c, CD38, CD5, and CD23 for the first year following transplant, antigens that are normally expressed on a small percentage of circulating B cells in normal adults, but highly expressed on cord blood B cells. Similar to cord blood B cells, patient B cells isolated during the first year following transplant, proliferated normally to Staphylococcus aureus Cowan strain I (SAC), and produced IgM, but minimal or no IgG when stimulated with pokeweed mitogen and SAC, unlike normal adult B cells that produce both. The similar phenotype and function of posttransplant and cord blood B cells, and their similar rate of decline in patients and normal children adds further evidence to support the hypothesis that B-cell differentiation posttransplant is recapitulating normal B-cell ontogeny. 相似文献
122.
Ethical challenges in nursing homes – staff's opinions and experiences with systematic ethics meetings with participation of residents’ relatives
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123.
Gerhard Smekal Serge P. von Duvillard Maximilian H?rmandinger Roland Moll Mario Heller Rochus Pokan David W. Bacharach Linda M. LeMura Paul Arciero 《Journal of Sports Science and Medicine》2015,14(4):799-810
The purpose of the study was to measure the demands of off-road cycling via portable spirometry, leg-power output (PO), heart rate (HR) and blood lactate (BLa) concentration. Twenty-four male competitive cyclists (age: 29±7.2 yrs, height: 1.79 ± 0.05 m, body mass: 70.0 ± 4.9 kg, VO2peak: 64.9 ± 7.5 ml·kg-1·min-1) performed simulated mountain bike competitions (COMP) and laboratory tests (LabT). From LabT, we determined maximal workload and first and second ventilatory thresholds (VT1, VT2). A high-performance athlete (HPA) was used for comparison with three groups of subjects with different sport-specific performance levels. Load profiles of COMP were also investigated during uphill, flat and downhill cycling. During the COMP, athletes achieved a mean oxygen uptake (VO2COMP) of 57.0 ± 6.8 ml·kg-1·min-1 vs. 71.1 ml·kg-1·min-1 for the HPA. The POCOMP was 2.66±0.43 W·kg-1 and 3.52 W·kg-1 for the HPA. POCOMP, VO2COMP and HRCOMP were compared to corresponding variables at the VT2 of LabT. LabT variables correlated with racing time (RTCOMP) and POCOMP (p < 0.01 to <0.001; r-0.59 to -0.80). The VO2peak (LabT) accounted for 65% of variance of a single COMP test. VO2COMP, POCOMP and also endurance variables measured from LabTs were found as important determinants for cross-country performance. The high average VO2COMP indicates that a high aerobic capacity is a prerequisite for successful COMP. Findings derived from respiratory gas measures during COMPs might be useful when designing mountain bike specific training.
Key points
- Cross- country cycling is characterized by high oxygen costs due to the high muscle mass simultaneously working to fulfill the demands of this kind of sports.
- Heart rate and blood lactate concentration measures are not sensitive enough to assess the energy requirements of COMP. Therefore, respiratory gas and power output measures are helpful to provide new information to physiological profile of cross- country cycling.
- An excellent cycling-specific capacity is a prerequisite for successful off-road cycling.
- Data determined from LabT might be utilized to describe semi-specific abilities of MB- athletes on a cycle ergometer, while data originating from COMP might be useful when designing a mountain bike specific training.
124.
Solaf M Elsayed Raoul Heller Michaela Thoenes Maha S Zaki Daniel Swan Ezzat Elsobky Christine Zühlke Inga Ebermann Gudrun Nürnberg Peter Nürnberg Hanno J Bolz 《European journal of human genetics : EJHG》2014,22(2):286-288
Although many genes have been identified for the autosomal recessive cerebellar ataxias (ARCAs), several patients are unlinked to the respective loci, suggesting further genetic heterogeneity. We combined homozygosity mapping and exome sequencing in a consanguineous Egyptian family with congenital ARCA, mental retardation and pyramidal signs. A homozygous 5-bp deletion in SPTBN2, the gene whose in-frame mutations cause autosomal dominant spinocerebellar ataxia type 5, was shown to segregate with ataxia in the family. Our findings are compatible with the concept of truncating SPTBN2 mutations acting recessively, which is supported by disease expression in homozygous, but not heterozygous, knockout mice, ataxia in Beagle dogs with a homozygous frameshift mutation and, very recently, a homozygous SPTBN2 nonsense mutation underlying infantile ataxia and psychomotor delay in a human family. As there was no evidence for mutations in 23 additional consanguineous families, SPTBN2-related ARCA is probably rare. 相似文献
125.
Bodo B. Beck Jennifer B. Phillips Malte P. Bartram Jeremy Wegner Michaela Thoenes Andrea Pannes Josephina Sampson Raoul Heller Heike Göbel Friederike Koerber Antje Neugebauer Andrea Hedergott Gudrun Nürnberg Peter Nürnberg Holger Thiele Janine Altmüller Mohammad R. Toliat Simon Staubach Kym M. Boycott Enza Maria Valente Andreas R. Janecke Tobias Eisenberger Carsten Bergmann Lars Tebbe Yang Wang Yundong Wu Andrew M. Fry Monte Westerfield Uwe Wolfrum Hanno J. Bolz 《Human mutation》2014,35(10):1153-1162
We describe a consanguineous Iraqi family with Leber congenital amaurosis (LCA), Joubert syndrome (JBTS), and polycystic kidney disease (PKD). Targeted next‐generation sequencing for excluding mutations in known LCA and JBTS genes, homozygosity mapping, and whole‐exome sequencing identified a homozygous missense variant, c.317G>C (p.Arg106Pro), in POC1B, a gene essential for ciliogenesis, basal body, and centrosome integrity. In silico modeling suggested a requirement of p.Arg106 for the formation of the third WD40 repeat and a protein interaction interface. In human and mouse retina, POC1B localized to the basal body and centriole adjacent to the connecting cilium of photoreceptors and in synapses of the outer plexiform layer. Knockdown of Poc1b in zebrafish caused cystic kidneys and retinal degeneration with shortened and reduced photoreceptor connecting cilia, compatible with the human syndromic ciliopathy. A recent study describes homozygosity for p.Arg106ProPOC1B in a family with nonsyndromic cone‐rod dystrophy. The phenotype associated with homozygous p.Arg106ProPOC1B may thus be highly variable, analogous to homozygous p.Leu710Ser in WDR19 causing either isolated retinitis pigmentosa or Jeune syndrome. Our study indicates that POC1B is required for retinal integrity, and we propose POC1B mutations as a probable cause for JBTS with severe PKD. 相似文献
126.
Verena Limperger Ulrich C. Klostermeier Gili Kenet Susanne Holzhauer Martine Alhenc Gelas Ulrich Finckh Ralf Junker Christine Heller Barbara Zieger Karin Kurnik Ralf Knöfler Rolf Mesters Susan Halimeh Ulrike Nowak‐Göttl 《British journal of haematology》2014,167(3):385-393
Venous thromboembolism [TE] is a multifactorial disease and protein C deficiency [PCD] constitutes a major risk factor. In the present study the prevalence of PCD and the clinical presentation at TE onset, including neonatal purpura fulminans, in a cohort of children are reported. In 367 unselected children (0·1–19 years) recruited between July 1996 and December 2013, a comprehensive thrombophilia screening was performed along with recording of anamnestic data. Twenty‐five of 338 children (7·4%) had PCD. Mean age at first TE onset was 10 years (range 0·1–18). Leading thromboembolic manifestations were neonatal purpura fulminans (n = 5), TE of cerebral veins (n = 3), stroke (n = 2) deep veinthrombosis (DVT) of the leg (n = 10), DVT & pulmonary embolism (n = 2) and DVT & pelvic veins (n = 3). Concomitant risk factors for TE were identified in 12 patients, whereas 13 children spontaneously developed TE. A positive family history of DVT was found in 10 children. In this unselected cohort of paediatric patients with symptomatic TE the overall prevalence of PCD was 7·4%; 1·5% presented with neonatal purpura fulminans. Given its clinical implication for patients and family members, thrombophilia testing should be performed and the benefit of medical or educational interventions should be evaluated in this high‐risk population. 相似文献
127.
Evaluating glucose-lowering treatment in older people with diabetes: Lessons from the IMPERIUM trial
Alan J. Sinclair MD Simon R. Heller MD Richard E. Pratley MD Ran Duan PhD Robert J. Heine MD Andreas Festa MD Jacek Kiljański MD 《Diabetes, obesity & metabolism》2020,22(8):1231-1242
Understanding the benefits and risks of treatments to be used by older individuals (≥65 years old) is critical for informed therapeutic decisions. Glucose-lowering therapy for older patients with diabetes should be tailored to suit their clinical condition, comorbidities and impaired functional status, including varying degrees of frailty. However, despite the rapidly growing population of older adults with diabetes, there are few dedicated clinical trials evaluating glucose-lowering treatment in older people. Conducting clinical trials in the older population poses multiple significant challenges. Despite the general agreement that individualizing treatment goals and avoiding hypoglycaemia is paramount for the therapy of older people with diabetes, there are conflicting perspectives on specific glycaemic targets that should be adopted and on use of specific drugs and treatment strategies. Assessment of functional status, frailty and comorbidities is not routinely performed in diabetes trials, contributing to insufficient characterization of older study participants. Moreover, significant operational barriers and problems make successful enrolment and completion of such studies difficult. In this review paper, we summarize the current guidelines and literature on conducting such trials, as well as the learnings from our own clinical trial (IMPERIUM) that assessed different glucose-lowering strategies in older people with type 2 diabetes. We discuss the importance of strategies to improve study design, enrolment and attrition. Apart from summarizing some practical advice to facilitate the successful conduct of studies, we highlight key gaps and needs that warrant further research. 相似文献
128.
Simon Heller MD Ildiko Lingvay MD Steven P. Marso MD Athena Philis-Tsimikas MD Thomas R. Pieber MD Neil R. Poulter FMedSci Richard E. Pratley MD Elise Hachmann-Nielsen MD Kajsa Kvist PhD Martin Lange MD Alan C. Moses MD Marie Trock Andresen MD John B. Buse MD DEVOTE Study Group 《Diabetes, obesity & metabolism》2020,22(12):2241-2247
129.
Zoungas S Chalmers J Ninomiya T Li Q Cooper ME Colagiuri S Fulcher G de Galan BE Harrap S Hamet P Heller S MacMahon S Marre M Poulter N Travert F Patel A Neal B Woodward M;ADVANCE Collaborative Group 《Diabetologia》2012,55(3):636-643
Aims/hypothesis
There is conflicting evidence regarding appropriate glycaemic targets for patients with type 2 diabetes. Here, we investigate the relationship between HbA1c and the risks of vascular complications and death in such patients.Methods
Eleven thousand one hundred and forty patients were randomised to intensive or standard glucose control in the Action in Diabetes and Vascular disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) trial. Glycaemic exposure was assessed as the mean of HbA1c measurements during follow-up and prior to the first event. Adjusted risks for each HbA1c decile were estimated using Cox models. Possible differences in the association between HbA1c and risks at different levels of HbA1c were explored using linear spline models.Results
There was a non-linear relationship between mean HbA1c during follow-up and the risks of macrovascular events, microvascular events and death. Within the range of HbA1c studied (5.5?C10.5%), there was evidence of ??thresholds??, such that below HbA1c levels of 7.0% for macrovascular events and death, and 6.5% for microvascular events, there was no significant change in risks (all p?>?0.8). Above these thresholds, the risks increased significantly: every 1% higher HbA1c level was associated with a 38% higher risk of a macrovascular event, a 40% higher risk of a microvascular event and a 38% higher risk of death (all p?0.0001).Conclusions/interpretation
In patients with type 2 diabetes, HbA1c levels were associated with lower risks of macrovascular events and death down to a threshold of 7.0% and microvascular events down to a threshold of 6.5%. There was no evidence of lower risks below these levels but neither was there clear evidence of harm.Trial Registration:
ClinicalTrial.gov NCT00145925Funding:
Servier and the National Health and Medical Research Council of Australia (project grant ID 211086 and programme grant IDs 358395 and 571281) 相似文献130.
Pogoryelov D Klyszejko AL Krasnoselska GO Heller EM Leone V Langer JD Vonck J Müller DJ Faraldo-Gómez JD Meier T 《Proceedings of the National Academy of Sciences of the United States of America》2012,109(25):E1599-E1608
ATP synthase membrane rotors consist of a ring of c-subunits whose stoichiometry is constant for a given species but variable across different ones. We investigated the importance of c/c-subunit contacts by site-directed mutagenesis of a conserved stretch of glycines (GxGxGxGxG) in a bacterial c(11) ring. Structural and biochemical studies show a direct, specific influence on the c-subunit stoichiometry, revealing c(<11), c(12), c(13), c(14), and c(>14) rings. Molecular dynamics simulations rationalize this effect in terms of the energetics and geometry of the c-subunit interfaces. Quantitative data from a spectroscopic interaction study demonstrate that the complex assembly is independent of the c-ring size. Real-time ATP synthesis experiments in proteoliposomes show the mutant enzyme, harboring the larger c(12) instead of c(11), is functional at lower ion motive force. The high degree of compliance in the architecture of the ATP synthase rotor offers a rationale for the natural diversity of c-ring stoichiometries, which likely reflect adaptations to specific bioenergetic demands. These results provide the basis for bioengineering ATP synthases with customized ion-to-ATP ratios, by sequence modifications. 相似文献