Gut γδ T cells as guardians, disruptors and instigators of cancer

Colorectal cancer is the third most common cancer worldwide with nearly 2 million cases per year. Immune cells and inflammation are a critical component of colorectal cancer progression, and they are used as reliable prognostic indicators of patient outcome. With the growing appreciation for immunology in colorectal cancer, interest is growing on the role γδ T cells have to play, as they represent one of the most prominent immune cell populations in gut tissue. This group of cells consists of both resident populations—γδ intraepithelial lymphocytes (γδ IELs)—and transient populations that each has unique functions. The homeostatic role of these γδ T cell subsets is to maintain barrier integrity and prevent microorganisms from breaching the mucosal layer, which is accomplished through crosstalk with enterocytes and other immune cells. Recent years have seen a surge in discoveries regarding the regulation of γδ IELs in the intestine and the colon with particular new insights into the butyrophilin family. In this review, we discuss the development, specialities, and functions of γδ T cell subsets during cancer progression. We discuss how these cells may be used to predict patient outcome, as well as how to exploit their behavior for cancer immunotherapy

Neural correlates of sexual cue reactivity in individuals with and without compulsive sexual behaviours

Although compulsive sexual behaviour (CSB) has been conceptualized as a "behavioural" addiction and common or overlapping neural circuits may govern the processing of natural and drug rewards, little is known regarding the responses to sexually explicit materials in individuals with and without CSB. Here, the processing of cues of varying sexual content was assessed in individuals with and without CSB, focusing on neural regions identified in prior studies of drug-cue reactivity. 19 CSB subjects and 19 healthy volunteers were assessed using functional MRI comparing sexually explicit videos with non-sexual exciting videos. Ratings of sexual desire and liking were obtained. Relative to healthy volunteers, CSB subjects had greater desire but similar liking scores in response to the sexually explicit videos. Exposure to sexually explicit cues in CSB compared to non-CSB subjects was associated with activation of the dorsal anterior cingulate, ventral striatum and amygdala. Functional connectivity of the dorsal anterior cingulate-ventral striatum-amygdala network was associated with subjective sexual desire (but not liking) to a greater degree in CSB relative to non-CSB subjects. The dissociation between desire or wanting and liking is consistent with theories of incentive motivation underlying CSB as in drug addictions. Neural differences in the processing of sexual-cue reactivity were identified in CSB subjects in regions previously implicated in drug-cue reactivity studies. The greater engagement of corticostriatal limbic circuitry in CSB following exposure to sexual cues suggests neural mechanisms underlying CSB and potential biological targets for interventions

Impact of clerkship in the attitudes toward psychiatry among Portuguese medical students

<p>Abstract</p> <p>Background</p> <p>Given the shortage of human resources and the launching of a new Mental Health Plan, recruitment of psychiatrists is currently a major concern in Portugal, as well as in several other countries. Medical students' attitude toward psychiatry has been pointed as a predictor of recruitment. This study aims to evaluate the medical students' perception of psychiatry before and after a clerkship, and the impact on their intention to pursue psychiatry as a future specialty option.</p> <p>Methods</p> <p>Two self-report questionnaires were administered to all 6^thyear students in a medical school in Lisbon, before and after a 4-weeks full-time psychiatric clerkship, in order to evaluate attitudes toward psychiatry and intention to follow psychiatry in the future. Statistical analysis included Wilcoxon and Chi-square tests.</p> <p>Results</p> <p>153 students (60.8% female) filled in both questionnaires (no dropouts). After the clerkship, there was a significant improvement regarding the overall merits of psychiatry, efficacy, role definition and functioning of psychiatrists, use of legal powers to hospitalize patients and specific medical school factors. There was also a significant increase of students decided or considering the possibility to take a residency in psychiatry.</p> <p>However, perceptions of low prestige and negative pressure from family and peers regarding a future choice of psychiatry remained unchanged in about one-third of the students.</p> <p>Conclusions</p> <p>The results indicate clearly that the clerkship had a favorable overall impact on the student attitude towards psychiatry, as well as in the number of students considering a future career in psychiatry. Attitudes toward psychiatry seems a promising outcome indicator of the clerkship's quality, but further research is needed in order to assess its reliability as a sound predictor of recruitment.</p

Deep Brain Stimulation of Nucleus Accumbens Region in Alcoholism Affects Reward Processing

The influence of bilateral deep brain stimulation (DBS) of the nucleus nucleus (NAcc) on the processing of reward in a gambling paradigm was investigated using H2[15O]-PET (positron emission tomography) in a 38-year-old man treated for severe alcohol addiction. Behavioral data analysis revealed a less risky, more careful choice behavior under active DBS compared to DBS switched off. PET showed win- and loss-related activations in the paracingulate cortex, temporal poles, precuneus and hippocampus under active DBS, brain areas that have been implicated in action monitoring and behavioral control. Except for the temporal pole these activations were not seen when DBS was deactivated. These findings suggest that DBS of the NAcc may act partially by improving behavioral control

An ethnographic study of Latino preschool children's oral health in rural California: Intersections among family, community, provider and regulatory sectors

<p>Abstract</p> <p>Background</p> <p>Latino children experience a higher prevalence of caries than do children in any other racial/ethnic group in the US. This paper examines the intersections among four societal sectors or contexts of care which contribute to oral health disparities for low-income, preschool Latino¹children in rural California.</p> <p>Methods</p> <p>Findings are reported from an ethnographic investigation, conducted in 2005–2006, of family, community, professional/dental and policy/regulatory sectors or contexts of care that play central roles in creating or sustaining low income, rural children's poor oral health status. The study community of around 9,000 people, predominantly of Mexican-American origin, was located in California's agricultural Central Valley. Observations in homes, community facilities, and dental offices within the region were supplemented by in-depth interviews with 30 key informants (such as dental professionals, health educators, child welfare agents, clinic administrators and regulatory agents) and 47 primary caregivers (mothers) of children at least one of whom was under 6 years of age.</p> <p>Results</p> <p>Caregivers did not always recognize visible signs of caries among their children, nor respond quickly unless children also complained of pain. Fluctuating seasonal eligibility for public health insurance intersected with limited community infrastructure and civic amenities, including lack of public transportation, to create difficulties in access to care. The non-fluoridated municipal water supply is not widely consumed because of fears about pesticide pollution. If the dentist brought children into the clinic for multiple visits, this caused the accompanying parent hardship and occasionally resulted in the loss of his or her job. Few general dentists had received specific training in how to handle young patients. Children's dental fear and poor provider-parent communication were exacerbated by a scarcity of dentists willing to serve rural low-income populations. Stringent state fiscal reimbursement policies further complicated the situation.</p> <p>Conclusion</p> <p>Several societal sectors or contexts of care significantly intersected to produce or sustain poor oral health care for children. Parental beliefs and practices, leading for example to delay in seeking care, were compounded by lack of key community or economic resources, and the organization and delivery of professional dental services. In the context of state-mandated policies and procedures, these all worked to militate against children receiving timely care that would considerably reduce oral health disparities among this highly disadvantaged population.</p

Coronary Artery Calcium Scores: Current Thinking and Clinical Applications

Most incident coronary disease occurs in previously asymptomatic individuals who were considered to be at a lower risk by traditional screening methods. There is a definite advantage if these individuals could be reclassified into a higher risk category, thereby impacting disease outcomes favorably. Coronary artery calcium scores have been recognized as an independent marker for adverse prognosis in coronary disease. Multiple population based studies have acknowledged the shortcomings of risk prediction models such as the Framingham risk score or the Procam score. The science behind coronary calcium is discussed briefly followed by a review of current thinking on calcium scores. An attempt has been made to summarize the appropriate indications and use of calcium scores

Transcription forms and remodels supercoiling domains unfolding large-scale chromatin structures

DNA supercoiling is an inherent consequence of twisting DNA and is critical for regulating gene expression and DNA replication. However, DNA supercoiling at a genomic scale in human cells is uncharacterized. To map supercoiling we used biotinylated-trimethylpsoralen as a DNA structure probe to show the genome is organized into supercoiling domains. Domains are formed and remodeled by RNA polymerase and topoisomerase activities and are flanked by GC-AT boundaries and CTCF binding sites. Under-wound domains are transcriptionally active, enriched in topoisomerase I, “open” chromatin fibers and DNaseI sites, but are depleted of topoisomerase II. Furthermore DNA supercoiling impacts on additional levels of chromatin compaction as under-wound domains are cytologically decondensed, topologically constrained, and decompacted by transcription of short RNAs. We suggest that supercoiling domains create a topological environment that facilitates gene activation providing an evolutionary purpose for clustering genes along chromosomes

The Effects of Apolipoprotein F Deficiency on High Density Lipoprotein Cholesterol Metabolism in Mice

Apolipoprotein F (apoF) is 29 kilodalton secreted sialoglycoprotein that resides on the HDL and LDL fractions of human plasma. Human ApoF is also known as Lipid Transfer Inhibitor protein (LTIP) based on its ability to inhibit cholesteryl ester transfer protein (CETP)-mediated transfer events between lipoproteins. In contrast to other apolipoproteins, ApoF is predicted to lack strong amphipathic alpha helices and its true physiological function remains unknown. We previously showed that overexpression of Apolipoprotein F in mice reduced HDL cholesterol levels by 20–25% by accelerating clearance from the circulation. In order to investigate the effect of physiological levels of ApoF expression on HDL cholesterol metabolism, we generated ApoF deficient mice. Unexpectedly, deletion of ApoF had no substantial impact on plasma lipid concentrations, HDL size, lipid or protein composition. Sex-specific differences were observed in hepatic cholesterol content as well as serum cholesterol efflux capacity. Female ApoF KO mice had increased liver cholesteryl ester content relative to wild type controls on a chow diet (KO: 3.4+/−0.9 mg/dl vs. WT: 1.2+/−0.3 mg/dl, p<0.05). No differences were observed in ABCG1-mediated cholesterol efflux capacity in either sex. Interestingly, ApoB-depleted serum from male KO mice was less effective at promoting ABCA1-mediated cholesterol efflux from J774 macrophages relative to WT controls

Brucellosis Vaccines: Assessment of Brucella melitensis Lipopolysaccharide Rough Mutants Defective in Core and O-Polysaccharide Synthesis and Export

Background: The brucellae are facultative intracellular bacteria that cause brucellosis, one of the major neglected zoonoses. In endemic areas, vaccination is the only effective way to control this disease. Brucella melitensis Rev 1 is a vaccine effective against the brucellosis of sheep and goat caused by B. melitensis, the commonest source of human infection. However, Rev 1 carries a smooth lipopolysaccharide with an O-polysaccharide that elicits antibodies interfering in serodiagnosis, a major problem in eradication campaigns. Because of this, rough Brucella mutants lacking the O-polysaccharide have been proposed as vaccines. Methodology/Principal Findings: To examine the possibilities of rough vaccines, we screened B. melitensis for lipopolysaccharide genes and obtained mutants representing all main rough phenotypes with regard to core oligosaccharide and O-polysaccharide synthesis and export. Using the mouse model, mutants were classified into four attenuation patterns according to their multiplication and persistence in spleens at different doses. In macrophages, mutants belonging to three of these attenuation patterns reached the Brucella characteristic intracellular niche and multiplied intracellularly, suggesting that they could be suitable vaccine candidates. Virulence patterns, intracellular behavior and lipopolysaccharide defects roughly correlated with the degree of protection afforded by the mutants upon intraperitoneal vaccination of mice. However, when vaccination was applied by the subcutaneous route, only two mutants matched the protection obtained with Rev 1 albeit at doses one thousand fold higher than this reference vaccine. These mutants, which were blocked in O-polysaccharide export and accumulated internal O-polysaccharides, stimulated weak anti-smooth lipopolysaccharide antibodies. Conclusions/Significance: The results demonstrate that no rough mutant is equal to Rev 1 in laboratory models and question the notion that rough vaccines are suitable for the control of brucellosis in endemic areas.This work was funded by the European Commission (Research Contract QLK2-CT-2002-00918) and the Ministerio de Ciencia y Tecnología of Spain (Proyecto AGL2004-01162/GAN)