Glucose challenge increases circulating progenitor cells in Asian Indian male subjects with normal glucose tolerance which is compromised in subjects with pre-diabetes: A pilot study

<p>Abstract</p> <p>Background</p> <p>Haematopoietic stem cells undergo mobilization from bone marrow to blood in response to physiological stimuli such as ischemia and tissue injury. The aim of study was to determine the kinetics of circulating CD34⁺and CD133⁺CD34⁺progenitor cells in response to 75 g glucose load in subjects with normal and impaired glucose metabolism.</p> <p>Methods</p> <p>Asian Indian male subjects (n = 50) with no prior history of glucose imbalance were subjected to 2 hour oral glucose tolerance test (OGTT). 24 subjects had normal glucose tolerance (NGT), 17 subjects had impaired glucose tolerance (IGT) and 9 had impaired fasting glucose (IFG). The IGT and IFG subjects were grouped together as pre-diabetes group (n = 26). Progenitor cell counts in peripheral circulation at fasting and 2 hour post glucose challenge were measured using direct two-color flow cytometry.</p> <p>Results</p> <p>The pre-diabetes group was more insulin resistant (p < 0.0001) as measured by homeostasis assessment model (HOMA-IR) compared to NGT group. A 2.5-fold increase in CD34⁺cells (p = 0.003) and CD133⁺CD34⁺(p = 0.019) cells was seen 2 hours post glucose challenge in the NGT group. This increase for both the cell types was attenuated in subjects with IGT. CD34⁺cell counts in response to glucose challenge inversely correlated with neutrophil counts (ρ = -0.330, p = 0.019), while post load counts of CD133⁺CD34⁺cells inversely correlated with serum creatinine (ρ = -0.312, p = 0.023).</p> <p>Conclusion</p> <p>There is a 2.5-fold increase in the circulating levels of haematopoietic stem cells in response to glucose challenge in healthy Asian Indian male subjects which is attenuated in subjects with pre-diabetes.</p

Gene expression and matrix turnover in overused and damaged tendons

Chronic, painful conditions affecting tendons, frequently known as tendinopathy, are very common types of sporting injury. The tendon extracellular matrix is substantially altered in tendinopathy, and these changes are thought to precede and underlie the clinical condition. The tendon cell response to repeated minor injuries or “overuse” is thought to be a major factor in the development of tendinopathy. Changes in matrix turnover may also be effected by the cellular response to physical load, altering the balance of matrix turnover and changing the structure and composition of the tendon. Matrix turnover is relatively high in tendons exposed to high mechanical demands, such as the supraspinatus and Achilles, and this is thought to represent either a repair or tissue maintenance function. Metalloproteinases are a large family of enzymes capable of degrading all of the tendon matrix components, and these are thought to play a major role in the degradation of matrix during development, adaptation and repair. It is proposed that some metalloproteinase enzymes are required for the health of the tendon, and others may be damaging, leading to degeneration of the tissue. Further research is required to investigate how these enzyme activities are regulated in tendon and altered in tendinopathy. A profile of all the metalloproteinases expressed and active in healthy and degenerate tendon is required and may lead to the development of new drug therapies for these common and debilitating sports injuries

Clonality of HTLV-2 in natural infection

Human T-lymphotropic virus type 1 (HTLV-1) and type 2 (HTLV-2) both cause lifelong persistent infections, but differ in their clinical outcomes. HTLV-1 infection causes a chronic or acute T-lymphocytic malignancy in up to 5% of infected individuals whereas HTLV-2 has not been unequivocally linked to a T-cell malignancy. Virus-driven clonal proliferation of infected cells both in vitro and in vivo has been demonstrated in HTLV-1 infection. However, T-cell clonality in HTLV-2 infection has not been rigorously characterized. In this study we used a high-throughput approach in conjunction with flow cytometric sorting to identify and quantify HTLV-2-infected T-cell clones in 28 individuals with natural infection. We show that while genome-wide integration site preferences in vivo were similar to those found in HTLV-1 infection, expansion of HTLV-2-infected clones did not demonstrate the same significant association with the genomic environment of the integrated provirus. The proviral load in HTLV-2 is almost confined to CD8+ T-cells and is composed of a small number of often highly expanded clones. The HTLV-2 load correlated significantly with the degree of dispersion of the clone frequency distribution, which was highly stable over ∼8 years. These results suggest that there are significant differences in the selection forces that control the clonal expansion of virus-infected cells in HTLV-1 and HTLV-2 infection. In addition, our data demonstrate that strong virus-driven proliferation per se does not predispose to malignant transformation in oncoretroviral infections

Applications of simulation within the healthcare context

This is a pre-print of an article published in Journal of the Operation Research Society. The definitive publisher-authenticated version Katsaliaki, K., Mustafee, N.,(2010). Applications of simulation within the healthcare context. Journal of the Operation Research Society. 62, 1431-1451 is available online at: http://www.palgrave-journals.com/jors/journal/v62/n8/full/jors201020a.htmlA large number of studies have applied simulation to a multitude of issues related to healthcare. These studies have been published over a number of unrelated publishing outlets, and this may hamper the widespread reference and use of such resources. In this paper we analyse existing research in healthcare simulation in order to categorise and synthesise it in a meaningful manner. Hence, the aim of this paper is to conduct a review of the literature pertaining to simulation research within healthcare in order to ascertain its current development. A review of approximately 250 high quality journal papers published between 1970 and 2007 on healthcare-related simulation research was conducted. The results present: a classification of the healthcare publications according to the simulation techniques they employ; the impact of published literature in healthcare simulation; a report on demonstration and implementation of the studies’ results; the sources of funding; and the software used. Healthcare planners and researchers will benefit from this study by having ready access to an indicative article collection of simulation techniques applied in healthcare problems that are clustered under meaningful headings. This study facilitates the understanding of the potential of different simulation techniques for solving diverse healthcare problems

Paternal obesity is associated with IGF2 hypomethylation in newborns: results from a Newborn Epigenetics Study (NEST) cohort

Data from epidemiological and animal model studies suggest that nutrition during pregnancy may affect the health status of subsequent generations. These transgenerational effects are now being explained by disruptions at the level of the epigenetic machinery. Besides in vitro environmental exposures, the possible impact on the reprogramming of methylation profiles at imprinted genes at a much earlier time point, such as during spermatogenesis or oogenesis, has not previously been considered. In this study, our aim was to determine associations between preconceptional obesity and DNA methylation profiles in the offspring, particularly at the differentially methylated regions (DMRs) of the imprinted Insulin-like Growth Factor 2 (IGF2) gene

Challenges to the development of antigen-specific breast cancer vaccines

Continued progress in the development of antigen-specific breast cancer vaccines depends on the identification of appropriate target antigens, the establishment of effective immunization strategies, and the ability to circumvent immune escape mechanisms. Methods such as T cell epitope cloning and serological expression cloning (SEREX) have led to the identification of a number target antigens expressed in breast cancer. Improved immunization strategies, such as using dendritic cells to present tumor-associated antigens to T lymphocytes, have been shown to induce antigen-specific T cell responses in vivo and, in some cases, objective clinical responses. An outcome of successful tumor immunity is the evolution of antigen-loss tumor variants. The development of a polyvalent breast cancer vaccine, directed against a panel of tumor-associated antigens, may counteract this form of immune escape

Complete analysis of the B-cell response to a protein antigen, from in vivo germinal centre formation to 3-D modelling of affinity maturation

Somatic hypermutation of immunoglobulin variable region genes occurs within germinal centres (GCs) and is the process responsible for affinity maturation of antibodies during an immune response. Previous studies have focused almost exclusively on the immune response to haptens, which may be unrepresentative of epitopes on protein antigens. In this study, we have exploited a model system that uses transgenic B and CD4&lt;sup&gt;+&lt;/sup&gt; T cells specific for hen egg lysozyme (HEL) and a chicken ovalbumin peptide, respectively, to investigate a tightly synchronized immune response to protein antigens of widely differing affinities, thus allowing us to track many facets of the development of an antibody response at the antigen-specific B cell level in an integrated system &lt;i&gt;in&lt;/i&gt; &lt;i&gt;vivo&lt;/i&gt;. Somatic hypermutation of immunoglobulin variable genes was analysed in clones of transgenic B cells proliferating in individual GCs in response to HEL or the cross-reactive low-affinity antigen, duck egg lysozyme (DEL). Molecular modelling of the antibody–antigen interface demonstrates that recurring mutations in the antigen-binding site, selected in GCs, enhance interactions of the antibody with DEL. The effects of these mutations on affinity maturation are demonstrated by a shift of transgenic serum antibodies towards higher affinity for DEL in DEL-cOVA immunized mice. The results show that B cells with high affinity antigen receptors can revise their specificity by somatic hypermutation and antigen selection in response to a low-affinity, cross-reactive antigen. These observations shed further light on the nature of the immune response to pathogens and autoimmunity and demonstrate the utility of this novel model for studies of the mechanisms of somatic hypermutation

When are declines in condom use while using PrEP a concern? Modelling insights from a Hillbrow, South Africa case study.

INTRODUCTION: Oral pre-exposure prophylaxis (PrEP) is a promising new prevention approach for those most at risk of HIV infection. However, there are concerns that behavioural disinhibition, specifically reductions in condom use, might limit PrEP's protective effect. This study uses the case of female sex workers (FSWs) in Johannesburg, South Africa, to assess whether decreased levels of condom use following the introduction of PrEP may limit HIV risk reduction. METHOD: We developed a static model of HIV risk and compared HIV-risk estimates before and after the introduction of PrEP to determine the maximum tolerated reductions in condom use with regular partners and clients for HIV risk not to change. The model incorporated the effects of increased STI exposure owing to decreased condom use. Noting that condom use with regular partners is generally low, we also estimated the change in condom use tolerated with clients only, to still achieve 50 and 90% risk reduction on PrEP. The model was parameterized using data from Hillbrow, Johannesburg. Sensitivity analyses were performed to ascertain the robustness of our results. RESULTS: Reductions in condom use could be tolerated by FSWs with lower baseline condom use (65%). For scenarios where 75% PrEP effectiveness is attained, 50% HIV-risk reduction on PrEP would be possible even with 100% reduction in condom use from consistent condom use as high as 70% with clients. Increased exposure to STIs through reductions in condom use had limited effect on the reductions in condom use tolerated for HIV risk not to increase on PrEP. CONCLUSIONS: PrEP is likely to be of benefit in reducing HIV risk, even if reductions in condom use do occur. Efforts to promote consistent condom use will be critical for FSWs with high initial levels of condom use, but with challenges in adhering to PrEP