Retinal glycoprotein enrichment by concanavalin a enabled identification of novel membrane autoantigen synaptotagmin-1 in equine recurrent uveitis.

Complete knowledge of autoantigen spectra is crucial for understanding pathomechanisms of autoimmune diseases like equine recurrent uveitis (ERU), a spontaneous model for human autoimmune uveitis. While several ERU autoantigens were identified previously, no membrane protein was found so far. As there is a great overlap between glycoproteins and membrane proteins, the aim of this study was to test whether pre-enrichment of retinal glycoproteins by ConA affinity is an effective tool to detect autoantigen candidates among membrane proteins. In 1D Western blots, the glycoprotein preparation allowed detection of IgG reactions to low abundant proteins in sera of ERU patients. Synaptotagmin-1, a Ca2+-sensing protein in synaptic vesicles, was identified as autoantigen candidate from the pre-enriched glycoprotein fraction by mass spectrometry and was validated as a highly prevalent autoantigen by enzyme-linked immunosorbent assay. Analysis of Syt1 expression in retinas of ERU cases showed a downregulation in the majority of ERU affected retinas to 24%. Results pointed to a dysregulation of retinal neurotransmitter release in ERU. Identification of synaptotagmin-1, the first cell membrane associated autoantigen in this spontaneous autoimmune disease, demonstrated that examination of tissue fractions can lead to the discovery of previously undetected novel autoantigens. Further experiments will address its role in ERU pathology

Polarisation of equine pregnancy outcome associated with a maternal MHC class I allele: preliminary evidence

Identification of risk factors which are associated with severe clinical signs can assist in the management of disease outbreaks and indicate future research areas. Pregnancy loss during late gestation in the mare compromises welfare, reduces fecundity and has financial implications for horse owners. This retrospective study focussed on the identification of risk factors associated with pregnancy loss among 46 Thoroughbred mares on a single British stud farm, with some but not all losses involving equid herpesvirus-1 (EHV-1) infection. In a sub-group of 30 mares, association between pregnancy loss and the presence of five common Thoroughbred horse haplotypes of the equine Major Histocompatibility Complex (MHC) was assessed. This involved development of sequence specific, reverse transcriptase polymerase chain reactions and in several mares, measurement of cytotoxic T lymphocyte activity. Of the 46 mares, 10 suffered late gestation pregnancy loss or neonatal foal death, five of which were EHV-1 positive. Maternal factors including age, parity, number of EHV-1 specific vaccinations and the number of days between final vaccination and foaling or abortion were not significantly associated with pregnancy loss. In contrast, a statistically significant association between the presence of the MHC class I B2 allele and pregnancy loss was identified, regardless of the fetus / foal’s EHV-1 status (p=0.002). In conclusion, this study demonstrated a significantly positive association between pregnancy loss in Thoroughbred mares and a specific MHC class I allele in the mother. This association requires independent validation and further investigation of the mechanism by which the mare’s genetic background contributes to pregnancy outcome

Attrition and bias in the MRC cognitive function and ageing study: an epidemiological investigation

BACKGROUND: Any hypothesis in longitudinal studies may be affected by attrition and poor response rates. The MRC Cognitive Function and Ageing study (MRC CFAS) is a population based longitudinal study in five centres with identical methodology in England and Wales each recruiting approximately 2,500 individuals. This paper aims to identify potential biases in the two-year follow-up interviews. METHODS: Initial non-response: Those not in the baseline interviews were compared in terms of mortality to those who were in the baseline interviews at the time of the second wave interviews (1993–1996). Longitudinal attrition: Logistic regression analysis was used to examine baseline differences between individuals who took part in the two-year longitudinal wave compared with those who did not. RESULTS: Initial non-response: Individuals who moved away after sampling but before baseline interview were 1.8 times more likely to die by two years (95% Confidence interval(CI) 1.3–2.4) compared to respondents, after adjusting for age. The refusers had a slightly higher, but similar mortality pattern to responders (Odds ratio 1.2, 95%CI 1.1–1.4). Longitudinal attrition: Predictors for drop out due to death were being older, male, having impaired activities of daily living, poor self-perceived health, poor cognitive ability and smoking. Similarly individuals who refused were more likely to have poor cognitive ability, but had less years of full-time education and were more often living in their own home though less likely to be living alone. There was a higher refusal rate in the rural centres. Individuals who moved away or were uncontactable were more likely to be single, smokers, demented or depressed and were less likely to have moved if in warden-controlled accommodation at baseline. CONCLUSIONS: Longitudinal estimation of factors mentioned above could be biased, particularly cognitive ability and estimates of movements from own home to residential homes. However, these differences could also affect other investigations, particularly the estimates of incidence and longitudinal effects of health and psychiatric diseases, where the factors shown here to be associated with attrition are risk factors for the diseases. All longitudinal studies should investigate attrition and this may help with aspects of design and with the analysis of specific hypotheses

Utilization of acute and long-term care in the last year of life: comparison with survivors in a population-based study

Background. It is well-known that the use of care services is most intensive in the last phase of life. However, so far only a few determinants of end-of-life care utilization are known. The aims of this study were to describe the utilization of acute and long-term care among older adults in their last year of life as compared to those not in their last year of life, and to examine which of a broad range of determinants can account for observed differences in care utilization. Methods. Data were used from the Longitudinal Aging Study Amsterdam (LASA). In a random, age and sex stratified population-based cohort of 3107 persons aged 55 ? 85 years at baseline and representative of the Netherlands, follow-up cycles took place at 3, 6 and 9 years. Those who died within one year directly after a cycle were defined as the "end-of-life group" (n = 262), and those who survived at least three years after a cycle were defined as the "survivors". Utilization of acute and long-term care services, including professional and informal care, were recorded at each cycle, as well as a broad range of health-related and psychosocial variables. Results. The end-of-life group used more care than the survivors. In the younger-old this difference was most pronounced for acute care, and in the older-old, for long-term care. Use of both acute and long-term home care in the last year of life was fully accounted for by health problems. Use of institutional care at the end of life was partly accounted for by health problems, but was not fully explained by the determinants included. Conclusion. This study shows that severity of health problems are decisive in the explanation of the increase in use of care services towards the end-of-life. This information is essential for an appropriate allocation of professional health care to the benefit of older persons themselves and their informal caregivers. © 2009 Pot et al; licensee BioMed Central Ltd

Assessing nonresponse bias at follow-up in a large prospective cohort of relatively young and mobile military service members

<p>Abstract</p> <p>Background</p> <p>Nonresponse bias in a longitudinal study could affect the magnitude and direction of measures of association. We identified sociodemographic, behavioral, military, and health-related predictors of response to the first follow-up questionnaire in a large military cohort and assessed the extent to which nonresponse biased measures of association.</p> <p>Methods</p> <p>Data are from the baseline and first follow-up survey of the Millennium Cohort Study. Seventy-six thousand, seven hundred and seventy-five eligible individuals completed the baseline survey and were presumed alive at the time of follow-up; of these, 54,960 (71.6%) completed the first follow-up survey. Logistic regression models were used to calculate inverse probability weights using propensity scores.</p> <p>Results</p> <p>Characteristics associated with a greater probability of response included female gender, older age, higher education level, officer rank, active-duty status, and a self-reported history of military exposures. Ever smokers, those with a history of chronic alcohol consumption or a major depressive disorder, and those separated from the military at follow-up had a lower probability of response. Nonresponse to the follow-up questionnaire did not result in appreciable bias; bias was greatest in subgroups with small numbers.</p> <p>Conclusions</p> <p>These findings suggest that prospective analyses from this cohort are not substantially biased by non-response at the first follow-up assessment.</p

T cell immunoengineering with advanced biomaterials

Recent advances in biomaterials design offer the potential to actively control immune cell activation and behaviour. Many human diseases, such as infections, cancer, and autoimmune disorders, are partly mediated by inappropriate or insufficient activation of the immune system. T cells play a central role in the host immune response to these diseases, and so constitute a promising cell type for manipulation. In vivo, T cells are stimulated by antigen presenting cells (APC), therefore to design immunoengineering biomaterials that control T cell behaviour, artificial interfaces that mimic the natural APC-T cell interaction are required. This review draws together research in the design and fabrication of such biomaterial interfaces, and highlights efforts to elucidate key parameters in T cell activation, such as substrate mechanical properties and spatial organization of receptors, illustrating how they can be manipulated by bioengineering approaches to alter T cell function

Physical inactivity in Parkinson’s disease

Patients with Parkinson’s disease (PD) are likely to become physically inactive, because of their motor, mental, and emotional symptoms. However, specific studies on physical activity in PD are scarce, and results are conflicting. Here, we quantified daily physical activities in a large cohort of PD patients and another large cohort of matched controls. Moreover, we investigated the influence of disease-related factors on daily physical activities in PD patients. Daily physical activity data of PD patients (n = 699) were collected in the ParkinsonNet trial and of controls (n = 1,959) in the Longitudinal Aging Study Amsterdam (LASA); data were determined using the LAPAQ, a validated physical activity questionnaire. In addition, variables that may affect daily physical activities in PD were recorded, including motor symptoms, depression, disability in daily life, and comorbidity. Patients were physically less active; a reduction of 29% compared to controls (95% CI, 10–44%). Multivariate regression analyses demonstrated that greater disease severity, gait impairment, and greater disability in daily living were associated with less daily physical activity in PD (R2 = 24%). In this large study, we show that PD patients are about one-third less active compared to controls. While disease severity, gait, and disability in daily living predicted part of the inactivity, a portion of the variance remained unexplained, suggesting that additional determinants may also affect daily physical activities in PD. Because physical inactivity has many adverse consequences, work is needed to develop safe and enjoyable exercise programs for patients with PD

Bone Loss in Diabetes: Use of Antidiabetic Thiazolidinediones and Secondary Osteoporosis

Clinical evidence indicates that bone status is affected in patients with type 2 diabetes mellitus (T2DM). Regardless of normal or even high bone mineral density, T2DM patients have increased risk of fractures. One class of antidiabetic drugs, thiazolidinediones (TZDs), causes bone loss and further increases facture risk, placing TZDs in the category of drugs causing secondary osteoporosis. Risk factors for development of TZD-induced secondary osteoporosis are gender (women), age (elderly), and duration of treatment. TZDs exert their antidiabetic effects by activating peroxisome proliferator-activated receptor-γ (PPAR-γ) nuclear receptor, which controls glucose and fatty acid metabolism. In bone, PPAR-γ controls differentiation of cells of mesenchymal and hematopoietic lineages. PPAR-γ activation with TZDs leads to unbalanced bone remodeling: bone resorption increases and bone formation decreases. Laboratory research evidence points toward a possible separation of unwanted effects of PPAR-γ on bone from its beneficial antidiabetic effects by using selective PPAR-γ modulators. This review also discusses potential pharmacologic means to protect bone from detrimental effects of clinically used TZDs (pioglitazone and rosiglitazone) by using combinational therapy with approved antiosteoporotic drugs, or by using lower doses of TZDs in combination with other antidiabetic therapy. We also suggest a possible orthopedic complication, not yet supported by clinical studies, of delayed fracture healing in T2DM patients on TZD therapy