Individual differences in dopamine uptake in the dorsomedial striatum prior to cocaine exposure predict motivation for cocaine in male rats.

A major theme of addiction research has focused on the neural substrates of individual differences in the risk for addiction; however, little is known about how vulnerable populations differ from those that are relatively protected. Here, we prospectively measured dopamine (DA) neurotransmission prior to cocaine exposure to predict the onset and course of cocaine use. Using in vivo voltammetry, we first generated baseline profiles of DA release and uptake in the dorsomedial striatum (DMS) and nucleus accumbens of drug-naïve male rats prior to exposing them to cocaine using conditioned place preference (CPP) or operant self-administration. We found that the innate rate of DA uptake in the DMS strongly predicted motivation for cocaine and drug-primed reinstatement, but not CPP, responding when "price" was low, or extinction. We then assessed the impact of baseline variations in DA uptake on cocaine potency in the DMS using ex vivo voltammetry in naïve rats and in rats with DA transporter (DAT) knockdown. DA uptake in the DMS of naïve rats predicted the neurochemical response to cocaine, such that rats with innately faster rates of DA uptake demonstrated higher cocaine potency at the DAT and rats with DAT knockdown displayed reduced potency compared to controls. Together, these data demonstrate that inherent variability in DA uptake in the DMS predicts the behavioral response to cocaine, potentially by altering the apparent potency of cocaine.

Reaching key populations through key venues: Insights from the Jamaica HIV Prevention Program.

INTRODUCTION: HIV prevention strategies often include outreach to female sex workers at social venues identified as places where people meet new sexual partners. Patrons and staff at these venues may include female sex workers, their clients, as well as others who have high rates of new sexual partnerships. Few studies have compared HIV/STI among venue-based and general populations, across types of venues, or by sub-group of the venue population. Program planners often assume that the prevalence of infection is highest among female sex workers and considerably lower among other people at these venues, but there are few empiric studies assessing the prevalence of infection by sex worker status and type of venue. METHODS: In 2011, we used the PLACE method to identify public venues where people meet new sexual partners across Jamaica. The study team visited all venues with reported sex work as well as a 10% random sample of other venues and subsequently interviewed and tested a probability sample of 991 venue patrons and workers for HIV and other STI. RESULTS: Community informants identified 1207 venues. All venues where sex work was reported (735 venues) and a random sample of the remainder (134 of 472) were selected for onsite visits. Of these, 585 were found and operational. At a stratified random sample of venues, survey teams interviewed and tested 717 women and 274 men. 394 women reported recent sex work and 211 of these women reported soliciting clients on the street. Women exchanging sex for money were more likely to be infected with HIV (5.4% vs 1.0%; OR = 5.6, 95% CI = 1.8,17.3) or syphilis (11.7% vs. 5.8%, OR = 2.2, 95% CI = 1.7,4,0) than other women, but not significantly more likely to be infected with gonorrhea (8.4% vs 7.8%; OR = 1.1,95% CI = 0.6,1.9), chlamydia (16.2% vs 21.6%;OR = 0.7,95% CI = 0.5,1.0) or trichomoniasis (23.0% vs 17.0%, OR = 1.5,95% CI = 0.9,2.2). Women at venues were more likely to report sex work and multiple partners than women interviewed in a 2008 national population-based household survey commissioned by the Ministry of Health. CONCLUSIONS: In Jamaica, although the highest HIV prevalence was among street-based sex workers, the risk of HIV and STI extends to men and women at high risk venues, even those who do not self-identify as sex workers. Findings confirm the appropriateness of outreach to all men and women at these venues.

Age at Sexual Initiation and Sexual and Health Risk Behaviors Among Jamaican Adolescents and Young Adults.

Current policies limit access to sexual and reproductive health services for adolescents younger than 16 years in Jamaica. Using data from a national survey, we explored the relationship between age at sexual initiation and subsequent sexual risk behaviors in a random sample of 837 Jamaican adolescents and young adults aged 15-24 years. In the sample overall, 21.0% had not yet had sex. Among the 661 sexually active participants, the mean age at first sex was 14.7 years. High percentages of sexually active youth reported engaging in risk behaviors such as inconsistent condom use (58.8%), multiple sex partners (44.5%), and transactional sex (43.0%). Age of sexual initiation for males was unrelated to subsequent sexual risk behaviors. However, earlier sexual debut for females was associated with their number of partners during the preceding year. Findings underscore the potential benefits of access to sexual and reproductive education and services at earlier ages than current policies allow. Interventions before and during the period of sexual debut may reduce sexual risk for Jamaican adolescents and young adults.

"Do you think your main partner has other sex partners?" A simple question provides insight into sexual risk in Jamaica.

To estimate the association between a simple measure of sexual partner concurrency and sexually transmitted infection (STI) we conducted a cross-sectional population-based household survey (n = 1795) and targeted surveys of people at venues where people meet sexual partners (n = 1580) to ask about sexual behaviour. Persons interviewed at venues were tested for HIV, gonorrhoea, chlamydia, and trichomoniasis. We compared the association between STI and reporting a partner had other partners. More women than men reported their main partner had other partners. Thirteen percent of all women in the population-based survey and 14.4% in the targeted survey reported having one partner in the past 12 months and that partner had additional partners. STI prevalence was significantly associated with reporting a partner had other partners (36.8% vs. 30.2%; prevalence ratio [PR] 1.2; 95% confidence interval [CI] 1.1, 1.4). Construction of complete sexual networks is costly and not routinely feasible. We recommend adding a question to cross-sectional surveys used to monitor sexual behaviour about whether the respondent believes his or her partner has other sexual partners. Although subject to bias, the question was useful in Jamaica to identify a group of women with only one sexual partner at increased risk of infection.

mll ortholog containing functional domains of human MLL is expressed throughout the zebrafish lifespan and in haematopoietic tissues.

Infant leukaemia is an embryonal disease in which the underlying MLL translocations initiate in utero. Zebrafish offer unique potential to understand how MLL impacts haematopoiesis from the earliest embryonic timepoints and how translocations cause leukaemia as an embryonal process. In this study, a zebrafish mll cDNA syntenic to human MLL spanning the 5' to 3' UTRs, was cloned from embryos, and mll expression was characterized over the zebrafish lifespan. The protein encoded by the 35-exon ORF exhibited 46·4% overall identity to human MLL and 68-100% conservation in functional domains (AT-hooks, SNL, CXXC, PHD, bromodomain, FYRN, taspase1 sites, FYRC, SET). Maternally supplied transcripts were detected at 0-2 hpf. Strong ubiquitous early zygotic expression progressed to a cephalo-caudal gradient during later embryogenesis. mll was expressed in the intermediate cell mass (ICM) where primitive erythrocytes are produced and in the kidney where definitive haematopoiesis occurs in adults. mll exhibits high cross species conservation, is developmentally regulated in haematopoietic and other tissues and is expressed from the earliest embryonic timepoints throughout the zebrafish lifespan. Haematopoietic tissue expression validates using zebrafish for MLL haematopoiesis and leukaemia models.

Mechanisms underlying metabolic and neural defects in zebrafish and human multiple acyl-CoA dehydrogenase deficiency (MADD).

In humans, mutations in electron transfer flavoprotein (ETF) or electron transfer flavoprotein dehydrogenase (ETFDH) lead to MADD/glutaric aciduria type II, an autosomal recessively inherited disorder characterized by a broad spectrum of devastating neurological, systemic and metabolic symptoms. We show that a zebrafish mutant in ETFDH, xavier, and fibroblast cells from MADD patients demonstrate similar mitochondrial and metabolic abnormalities, including reduced oxidative phosphorylation, increased aerobic glycolysis, and upregulation of the PPARG-ERK pathway. This metabolic dysfunction is associated with aberrant neural proliferation in xav, in addition to other neural phenotypes and paralysis. Strikingly, a PPARG antagonist attenuates aberrant neural proliferation and alleviates paralysis in xav, while PPARG agonists increase neural proliferation in wild type embryos. These results show that mitochondrial dysfunction, leading to an increase in aerobic glycolysis, affects neurogenesis through the PPARG-ERK pathway, a potential target for therapeutic intervention.

The Bloodgen Project of the European Union, 2003-2009.

The Bloodgen project was funded by the European Commission between 2003 and 2006, and involved academic blood centres, universities, and Progenika Biopharma S.A., a commercial supplier of genotyping platforms that incorporate glass arrays. The project has led to the development of a commercially available product, BLOODchip, that can be used to comprehensively genotype an individual for all clinically significant blood groups. The intention of making this system available is that blood services and perhaps even hospital blood banks would be able to obtain extended information concerning the blood group of routine blood donors and vulnerable patient groups. This may be of significant use in the current management of multi-transfused patients who become alloimmunised due to incomplete matching of blood groups. In the future it can be envisaged that better matching of donor-patient blood could be achieved by comprehensive genotyping of every blood donor, especially regular ones. This situation could even be extended to genotyping every individual at birth, which may prove to have significant long-term health economic benefits as it may be coupled with detection of inborn errors of metabolism.

Robin Coombs: his life and contribution to haematology and transfusion medicine.

Robin Coombs was the last survivor of the distinguished group of immunologists that included Philip Gell, John Humphrey, John Marrack, Peter Medawar and Robert White and who were responsible for the renaissance of British Immunology after the Second World War. He is best remembered for describing the antiglobulin test that bears his name. The antiglobulin test revolutionised the diagnosis of haemolytic diseases and the compatibility testing of blood for transfusion. In all, Coombs authored over 200 scientific papers. Haemagglutination reactions became widely used in the diagnosis of a range of infectious agents. Together with Philip Gell, he devised the classification of allergic reactions; these were published in the textbook "Clinical Aspects of Immunology", which he and Gell first edited in 1963 and which became the leading textbook on medical immunology. Robin Coombs was also one of the founders of the British Society for Immunology.

Small world - advance of microarrays: current status and future trends.

Microarrays have the potential to become the next generation blood-testing platform. This commentary covers various aspects of such development presented in part at the Scotblood 2006 Meeting. Current mandatory testing includes antibody and antigen determination in both blood grouping and microbiology testing. While antibody determination is limited to phenotypic assays, antigen detection can be accomplished by genotyping or phenotyping. Applicability of various types of assays to microarrays, precision and sensitivity levels and correlation between genotyping and phenotyping results are briefly discussed and some of the main questions that need to be answered highlighted in future trends.

Localization of TrkC to Schwann cells and effects of neurotrophin-3 signaling at neuromuscular synapses.

Neurotrophins and their receptors, the Trks, are differentially expressed among the cell types that make up neuromuscular and other synapses, but the function and directionality of neurotrophin signaling at synapses are poorly understood. Here we demonstrate, via immunostaining, Western blotting, and RT-PCR analyses, that TrkC, the receptor for neurotrophin-3 (NT3), is expressed by mouse perisynaptic and myelinating Schwann cells from birth through adulthood and is unaltered after denervation. Analyses of transgenic mice in which the NT3 coding sequence is replaced by lacZ showed that NT3 is expressed in motor neurons and Schwann cells during perinatal development, but not in adult mice. In muscle, NT3 is expressed by intrafusal muscle fibers within spindles, as has been previously reported. Surprisingly, NT3 is also expressed in extrafusal muscle fibers during perinatal life and in adults. Genetic approaches were used to explore the roles of NT3 and TrkC signaling at neuromuscular synapses. Overexpression of NT3 in muscle fibers during development resulted in an increased number of perisynaptic Schwann cells at neuromuscular synapses, without altering synaptic size, suggesting that muscle-derived NT3 might act as a mitogen or trophic factor for Schwann cells. Conditional deletion of NT3 from motor neurons did not alter the number of Schwann cells or other aspects of neuromuscular synaptic structure, suggesting that motor-neuron-derived NT3 is not required for normal development of perisynaptic Schwann cells or synapses. Together, these results demonstrate that NT3 expression is developmentally regulated in skeletal muscle and may modulate the number of Schwann cells at neuromuscular synapses.

Intravascular survival of red cells coated with a mutated human anti-D antibody engineered to lack destructive activity.

Alloimmune feto-maternal destruction of blood cells is thought to be mediated by binding of alloantibodies to Fc receptors on effector cells. Blocking the antigen using inert antibodies might prolong cell survival. We have performed a "proof of principle" study in volunteers to measure the intravascular survival of autologous red cells coated with human recombinant IgG antibody containing a novel constant region, G1Deltanab, devoid of in vitro cytotoxic activity. RhD-positive red blood cells (RBCs), labeled with chromium-51 or technetium-99m, were separately coated to equal levels with wild-type IgG1 or G1Deltanab anti-D antibody (Fog-1). After re-injection, there was complete, irreversible clearance of IgG1-coated RBCs by 200 minutes, concomitant with appearance of radiolabel in plasma. Gamma camera imaging revealed accumulation in spleen and, at higher coating levels, in liver. In contrast, clearance of G1Deltanab-coated cells was slower, incomplete, and transient, with whole blood counts falling to 7% to 38% injected dose by about 200 minutes before increasing to 12% to 67% thereafter. There was no appearance of plasma radiolabel and no hepatic accumulation. These findings suggest that G1Deltanab-coated RBCs were not hemolysed but temporarily sequestered in the spleen and that our approach merits investigation in larger studies.

Running endurance abnormality in mdx mice.

The mdx mouse lacks dystrophin and has histological features of Duchenne muscular dystrophy but little weakness in the first year of life. We report here an early deficit in voluntary wheel running, as assayed with a computerized wheel. All mdx mice showed an intermittent running pattern, in contrast to the continuous running seen in controls. The average continuous running time differed significantly between mdx and control mice at all ages tested (5-21 weeks). This assay is noninvasive, has the advantage of unbiased automatic data collection, and should be useful for quantifying the mdx deficit in therapeutic studies.