Immune modulation and increased neurotrophic factor production in multiple sclerosis patients treated with testosterone

<p>Abstract</p> <p>Background</p> <p>Multiple sclerosis is a chronic inflammatory disease of the central nervous system with a pronounced neurodegenerative component. It has been suggested that novel treatment options are needed that target both aspects of the disease. Evidence from basic and clinical studies suggests that testosterone has an immunomodulatory as well as a potential neuroprotective effect that could be beneficial in MS.</p> <p>Methods</p> <p>Ten male MS patients were treated with 10 g of gel containing 100 mg of testosterone in a cross-over design (6 month observation period followed by 12 months of treatment). Blood samples were obtained at three-month intervals during the observation and the treatment period. Isolated blood peripheral mononuclear cells (PBMCs) were used to examine lymphocyte subpopulation composition by flow cytometry and <it>ex vivo </it>protein production of cytokines (IL-2, IFNγ, TNFα, IL-17, IL-10, IL-12p40, TGFβ1) and growth factors (brain-derived neurotrophic factor BDNF, platelet-derived growth factor PDGF-BB, nerve growth factor NGF, and ciliary neurotrophic factor CNTF). Delayed type hypersensitivity (DTH) skin recall tests were obtained before and during treatment as an <it>in vivo </it>functional immune measure.</p> <p>Results</p> <p>Testosterone treatment significantly reduced DTH recall responses and induced a shift in peripheral lymphocyte composition by decreasing CD4+ T cell percentage and increasing NK cells. In addition, PBMC production of IL-2 was significantly decreased while TGFβ1 production was increased. Furthermore, PBMCs obtained during the treatment period produced significantly more BDNF and PDGF-BB.</p> <p>Conclusion</p> <p>These results are consistent with an immunomodulatory effect of testosterone treatment in MS. In addition, increased production of BDNF and PDGF-BB suggests a potential neuroprotective effect.</p> <p>Trial Registration</p> <p>NCT00405353 <url>http://www.clinicaltrials.gov</url></p

Nonlinear Optical Properties of Polyynes: An Experimental Prediction for Carbyne

We present the experimental determination of the vibrational contribution to molecular second hyperpolarizability (Îvib) of very long polyynes that have been recently made available thanks to progress in chemical synthesis. Based on a simple theoretical model, the available experimental data allow estimating the asymptotic behavior of the vibrational contribution to molecular hyperpolarizability for increasing chain length

Supermultiplexed optical imaging and barcoding with engineered polyynes

Optical multiplexing has a large impact in photonics, the life sciences and biomedicine. However, current technology is limited by a 'multiplexing ceiling' from existing optical materials. Here we engineered a class of polyyne-based materials for optical supermultiplexing. We achieved 20 distinct Raman frequencies, as 'Carbon rainbow', through rational engineering of conjugation length, bond-selective isotope doping and end-capping substitution of polyynes. With further probe functionalization, we demonstrated ten-color organelle imaging in individual living cells with high specificity, sensitivity and photostability. Moreover, we realized optical data storage and identification by combinatorial barcoding, yielding to our knowledge the largest number of distinct spectral barcodes to date. Therefore, these polyynes hold great promise in live-cell imaging and sorting as well as in high-throughput diagnostics and screening

Non-Lytic, Actin-Based Exit of Intracellular Parasites from C. elegans Intestinal Cells

The intestine is a common site for invasion by intracellular pathogens, but little is known about how pathogens restructure and exit intestinal cells in vivo. The natural microsporidian parasite N. parisii invades intestinal cells of the nematode C. elegans, progresses through its life cycle, and then exits cells in a transmissible spore form. Here we show that N. parisii causes rearrangements of host actin inside intestinal cells as part of a novel parasite exit strategy. First, we show that N. parisii infection causes ectopic localization of the normally apical-restricted actin to the basolateral side of intestinal cells, where it often forms network-like structures. Soon after this actin relocalization, we find that gaps appear in the terminal web, a conserved cytoskeletal structure that could present a barrier to exit. Reducing actin expression creates terminal web gaps in the absence of infection, suggesting that infection-induced actin relocalization triggers gap formation. We show that terminal web gaps form at a distinct stage of infection, precisely timed to precede spore exit, and that all contagious animals exhibit gaps. Interestingly, we find that while perturbations in actin can create these gaps, actin is not required for infection progression or spore formation, but actin is required for spore exit. Finally, we show that despite large numbers of spores exiting intestinal cells, this exit does not cause cell lysis. These results provide insight into parasite manipulation of the host cytoskeleton and non-lytic escape from intestinal cells in vivo

A reflection on HIV/AIDS research after 25 years

Dr. Robert C. Gallo provides a personal reflection on the 25 year history of AIDS

Genomic survey of the non-cultivatable opportunistic human pathogen, Enterocytozoon bieneusi

© 2009 The Authors. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in PLoS Pathogens 5 (2009): e1000261, doi:10.1371/journal.ppat.1000261.Enterocytozoon bieneusi is the most common microsporidian associated with human disease, particularly in the immunocompromised population. In the setting of HIV infection, it is associated with diarrhea and wasting syndrome. Like all microsporidia, E. bieneusi is an obligate, intracellular parasite, but unlike others, it is in direct contact with the host cell cytoplasm. Studies of E. bieneusi have been greatly limited due to the absence of genomic data and lack of a robust cultivation system. Here, we present the first large-scale genomic dataset for E. bieneusi. Approximately 3.86 Mb of unique sequence was generated by paired end Sanger sequencing, representing about 64% of the estimated 6 Mb genome. A total of 3,804 genes were identified in E. bieneusi, of which 1,702 encode proteins with assigned functions. Of these, 653 are homologs of Encephalitozoon cuniculi proteins. Only one E. bieneusi protein with assigned function had no E. cuniculi homolog. The shared proteins were, in general, evenly distributed among the functional categories, with the exception of a dearth of genes encoding proteins associated with pathways for fatty acid and core carbon metabolism. Short intergenic regions, high gene density, and shortened protein-coding sequences were observed in the E. bieneusi genome, all traits consistent with genomic compaction. Our findings suggest that E. bieneusi is a likely model for extreme genome reduction and host dependence.This research was supported by National Institutes of Health (NIH) grants R21 AI064118 (DEA) and R21 AI52792 (ST). HGM was supported in part by NIH contracts HHSN266200400041C and HHSN2662004037C (Bioinformatics Resource Centers) and by the G. Unger Vetlesen Foundation

The devil is in the details: trends in avoidable hospitalization rates by geography in British Columbia, 1990–2000

BACKGROUND: Researchers and policy makers have focussed on the development of indicators to help monitor the success of regionalization, primary care reform and other health sector restructuring initiatives. Certain indicators are useful in examining issues of equity in service provision, especially among older populations, regardless of where they live. AHRs are used as an indicator of primary care system efficiency and thus reveal information about access to general practitioners. The purpose of this paper is to examine trends in avoidable hospitalization rates (AHRs) during a period of time characterized by several waves of health sector restructuring and regionalization in British Columbia. AHRs are examined in relation to non-avoidable and total hospitalization rates as well as by urban and rural geography across the province. METHODS: Analyses draw on linked administrative health data from the province of British Columbia for 1990 through 2000 for the population aged 50 and over. Joinpoint regression analyses and t-tests are used to detect and describe trends in the data. RESULTS: Generally speaking, non-avoidable hospitalizations constitute the vast majority of hospitalizations in a given year (i.e. around 95%) with AHRs constituting the remaining 5% of hospitalizations. Comparing rural areas and urban areas reveals that standardized rates of avoidable, non-avoidable and total hospitalizations are consistently higher in rural areas. Joinpoint regression results show significantly decreasing trends overall; lines are parallel in the case of avoidable hospitalizations, and lines are diverging for non-avoidable and total hospitalizations, with the gap between rural and urban areas being wider at the end of the time interval than at the beginning. CONCLUSION: These data suggest that access to effective primary care in rural communities remains problematic in BC given that rural areas did not make any gains in AHRs relative to urban areas under recent health sector restructuring initiatives. It remains important to continue to monitor the discrepancy between them as a reflection of inequity in service provision. In addition, it is important to consider alternative explanations for the observed trends paying particular attention to the needs of rural and urban populations and the factors influencing local service provision

Epilepsy and intellectual disability linked protein Shrm4 interaction with GABA B Rs shapes inhibitory neurotransmission

Shrm4, a protein expressed only in polarized tissues, is encoded by the KIAA1202 gene, whose mutations have been linked to epilepsy and intellectual disability. However, a physiological role for Shrm4 in the brain is yet to be established. Here, we report that Shrm4 is localized to synapses where it regulates dendritic spine morphology and interacts with the C terminus of GABA B receptors (GABA B Rs) to control their cell surface expression and intracellular trafficking via a dynein-dependent mechanism. Knockdown of Shrm4 in rat severely impairs GABA B R activity causing increased anxiety-like behaviour and susceptibility to seizures. Moreover, Shrm4 influences hippocampal excitability by modulating tonic inhibition in dentate gyrus granule cells, in a process involving crosstalk between GABA B Rs and extrasynaptic \uce-subunit-containing GABA A Rs. Our data highlights a role for Shrm4 in synaptogenesis and in maintaining GABA B R-mediated inhibition, perturbation of which may be responsible for the involvement of Shrm4 in cognitive disorders and epilepsy

Iodine-125 brachytherapy for brain tumours - a review

Iodine-125 brachytherapy has been applied to brain tumours since 1979. Even though the physical and biological characteristics make these implants particularly attractive for minimal invasive treatment, the place for stereotactic brachytherapy is still poorly defined