Stable kilohertz rate molecular beam laser ablation sources

A stable kilohertz (kHz) rate laser ablation/desorption supersonic molecular beam source for use in kHz rate laser experiments was discussed. The source was based based upon strong nonresonant interaction of a dithering laser focus with a rotating and translating solid rod. The kHz laser ablation of a high temperature refractory metal (niobium) for use in studied of metal clusters was also demonstrated. The kHz laser desorption and jet cooling of an involatile biomolecule (the DNA based guanine) for use in spectroscopic and dynamical studies was described.open151

Antagonistic paralogs control a switch between growth and pathogen resistance in C. elegans

Immune genes are under intense, pathogen-induced pressure, which causes these genes to diversify over evolutionary time and become species-specific. Through a forward genetic screen we recently described a C. elegans-specific gene called pals-22 to be a repressor of “Intracellular Pathogen Response” or IPR genes. Here we describe pals-25, which, like pals-22, is a species-specific gene of unknown biochemical function. We identified pals-25 in a screen for suppression of pals-22 mutant phenotypes and found that mutations in pals-25 suppress all known phenotypes caused by mutations in pals-22. These phenotypes include increased IPR gene expression, thermotolerance, and immunity against natural pathogens, including Nematocida parisii microsporidia and the Orsay virus. Mutations in pals-25 also reverse the reduced lifespan and slowed growth of pals-22 mutants. Transcriptome analysis indicates that pals-22 and pals-25 control expression of genes induced not only by natural pathogens of the intestine, but also by natural pathogens of the epidermis. Indeed, in an independent forward genetic screen we identified pals-22 as a repressor and pals-25 as an activator of epidermal defense gene expression. In summary, the species-specific pals-22 and pals-25 genes act as a switch to regulate a program of gene expression, growth, and defense against diverse natural pathogens in C. elegans

Genetic variation in the HLA region is associated with susceptibility to herpes zoster.

Herpes zoster, commonly referred to as shingles, is caused by the varicella zoster virus (VZV). VZV initially manifests as chicken pox, most commonly in childhood, can remain asymptomatically latent in nerve tissues for many years and often re-emerges as shingles. Although reactivation may be related to immune suppression, aging and female sex, most inter-individual variability in re-emergence risk has not been explained to date. We performed a genome-wide association analyses in 22,981 participants (2280 shingles cases) from the electronic Medical Records and Genomics Network. Using Cox survival and logistic regression, we identified a genomic region in the combined and European ancestry groups that has an age of onset effect reaching genome-wide significance (P>1.0 × 10(-8)). This region tags the non-coding gene HCP5 (HLA Complex P5) in the major histocompatibility complex. This gene is an endogenous retrovirus and likely influences viral activity through regulatory functions. Variants in this genetic region are known to be associated with delay in development of AIDS in people infected by HIV. Our study provides further suggestion that this region may have a critical role in viral suppression and could potentially harbor a clinically actionable variant for the shingles vaccine

The 'COmorBidity in Relation to AIDS' (COBRA) cohort: Design, methods and participant characteristics

BACKGROUND: Persons living with HIV on combination antiretroviral therapy (cART) may be at increased risk of the development of age-associated non-communicable comorbidities (AANCC) at relatively young age. It has therefore been hypothesised that such individuals, despite effective cART, may be prone to accelerated aging. OBJECTIVE: The COmorBidity in Relation to AIDS (COBRA) cohort study was designed to investigate the potential causal link between HIV and AANCC, amongst others, in a cohort of middle-aged individuals with HIV with sustained viral suppression on cART and otherwise comparable HIV-negative controls. METHODS: Longitudinal cohort study of HIV-positive subjects ≥45 years of age, with sustained HIV suppression on cART recruited from two large European HIV treatment centres and similarly-aged HIV-negative controls recruited from sexual health centres and targeted community groups. Both HIV-positive and HIV-negative subjects were assessed at study entry and again at follow-up after 2 years. RESULTS: Of the 134 HIV-positive individuals with a median (IQR) age of 56 (51, 62) years recruited, 93% were male, 88% of white ethnicity and 86% were men who have sex with men (MSM). Similarly, the 79 HIV-negative subjects had a median (IQR) age of 57 (52, 64) and 92% were male, 97% of white ethnicity and 80% were MSM. CONCLUSIONS: The results from the COBRA study will be a significant resource to understand the link between HIV and AANCC and the pathogenic mechanisms underlying this link. COBRA will inform future development of novel prognostic tools for earlier diagnosis of AANCC and of novel interventions which, as an adjunct to cART, may prevent AANCC

HER2/neu overexpression in the development of muscle-invasive transitional cell carcinoma of the bladder

The mortality from transitional cell carcinoma (TCC) of the urinary bladder increases significantly with the progression of superficial or locally invasive disease (pTa/pT1) to detrusor muscle-invasive disease (pT2+). The most common prognostic markers in clinical use are tumour stage and grade, which are subject to considerable intra- and interobserver variation. Polysomy 17 and HER2/neu gene amplification and protein overexpression have been associated with more advanced disease. Standardised techniques of fluorescence in situ hybridisation and immunohistochemistry, which are currently applied to other cancers with a view to offering anti-HER2/neu therapies, were applied to tumour pairs comprising pre- and postinvasive disease from 25 patients undergoing treatment for bladder cancer. In the preinvasive tumours, increased HER2/neu copy number was observed in 76% of cases and increased chromosome 17 copy number in 88% of cases, and in the postinvasive group these values were 92 and 96%, respectively (not significantly different P=0.09 and 0.07, respectively). HER2 gene amplification rates were 8% in both groups. Protein overexpression rates were 76 and 52%, respectively, in the pre- and postinvasive groups (P=0.06). These results suggest that HER2/neu abnormalities occur prior to and persist with the onset of muscle-invasive disease. Gene amplification is uncommon and other molecular mechanisms must account for the high rates of protein overexpression. Anti-HER2/neu therapy might be of use in the treatment of TCC

A systematic review and meta-synthesis of the impact of low back pain on people's lives

Copyright @ 2014 Froud et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.Background - Low back pain (LBP) is a common and costly problem that many interpret within a biopsychosocial model. There is renewed concern that core-sets of outcome measures do not capture what is important. To inform debate about the coverage of back pain outcome measure core-sets, and to suggest areas worthy of exploration within healthcare consultations, we have synthesised the qualitative literature on the impact of low back pain on people’s lives. Methods - Two reviewers searched CINAHL, Embase, PsycINFO, PEDro, and Medline, identifying qualitative studies of people’s experiences of non-specific LBP. Abstracted data were thematic coded and synthesised using a meta-ethnographic, and a meta-narrative approach. Results - We included 49 papers describing 42 studies. Patients are concerned with engagement in meaningful activities; but they also want to be believed and have their experiences and identity, as someone ‘doing battle’ with pain, validated. Patients seek diagnosis, treatment, and cure, but also reassurance of the absence of pathology. Some struggle to meet social expectations and obligations. When these are achieved, the credibility of their pain/disability claims can be jeopardised. Others withdraw, fearful of disapproval, or unable or unwilling to accommodate social demands. Patients generally seek to regain their pre-pain levels of health, and physical and emotional stability. After time, this can be perceived to become unrealistic and some adjust their expectations accordingly. Conclusions - The social component of the biopsychosocial model is not well represented in current core-sets of outcome measures. Clinicians should appreciate that the broader impact of low back pain includes social factors; this may be crucial to improving patients’ experiences of health care. Researchers should consider social factors to help develop a portfolio of more relevant outcome measures.Arthritis Research U

Variation in Community Structure across Vertical Intertidal Stress Gradients: How Does It Compare with Horizontal Variation at Different Scales?

In rocky intertidal habitats, the pronounced increase in environmental stress from low to high elevations greatly affects community structure, that is, the combined measure of species identity and their relative abundance. Recent studies have shown that ecological variation also occurs along the coastline at a variety of spatial scales. Little is known, however, on how vertical variation compares with horizontal variation measured at increasing spatial scales (in terms of sampling interval). Because broad-scale processes can generate geographical patterns in community structure, we tested the hypothesis that vertical ecological variation is higher than fine-scale horizontal variation but lower than broad-scale horizontal variation. To test this prediction, we compared the variation in community structure across intertidal elevations on rocky shores of Helgoland Island with independent estimates of horizontal variation measured at the scale of patches (quadrats separated by 10s of cm), sites (quadrats separated by a few m), and shores (quadrats separated by 100s to 1000s of m). The multivariate analyses done on community structure supported our prediction. Specifically, vertical variation was significantly higher than patch- and site-scale horizontal variation but lower than shore-scale horizontal variation. Similar patterns were found for the variation in abundance of foundation taxa such as Fucus spp. and Mastocarpus stellatus, suggesting that the effects of these canopy-forming algae, known to function as ecosystem engineers, may explain part of the observed variability in community structure. Our findings suggest that broad-scale processes affecting species performance increase ecological variability relative to the pervasive fine-scale patchiness already described for marine coasts and the well known variation caused by vertical stress gradients. Our results also indicate that experimental research aiming to understand community structure on marine shores should benefit from applying a multi-scale approach

Cognitive function, depressive symptoms and syphilis in HIV-positive and HIV-negative individuals

We evaluated associations between history of syphilis infection and both cognitive function and depressive symptoms in people living with HIV (PLHIV) and comparable HIV-negative controls. Syphilis serological tests, cognitive function and depression were assessed in PLHIV and controls participating in the Pharmacokinetic and Clinical Observations in People Over Fifty study. Cognitive test scores were converted to demographically adjusted T-scores (mean = 50, SD = 10) and then averaged to obtain a global T-score. Severity of depressive symptoms was assessed via the Patient Health Questionnaire-9. Associations of syphilis with global T-scores and depression were assessed using median regression. The 623 PLHIV and 246 HIV-negative controls were predominantly male (89.3% and 66.5%) with median age (interquartile range [IQR]) of 57 (53–63) and 58 (53–63) years, respectively. PLHIV had lower global cognitive T-scores (median [IQR] 48.7 [45.1, 52.1] versus 50.5 [47.0, 53.9], p < 0.001), more severe depressive symptoms (median [IQR] 4 [1, 10] versus 1 [0, 3], p < 0.001) and were more likely to report history of syphilis infection (22.0% versus 8.1%) than controls. There was no significant association between history of syphilis and global cognitive function in either PLHIV (p = 0.69) or controls (p = 0.10). Participants with a history of syphilis had more severe depressive symptoms (median [IQR] 4 [1, 9] versus 2 [0, 8], p = 0.03); however, the association became non-significant (p = 0.62) after adjusting for HIV status and potential confounders. Despite the higher prevalence of syphilis infection in PLHIV, there was no evidence of an association between history of syphilis infection and impaired cognitive function nor depressive symptoms after accounting for potential confounders

Lead Exposure: A Contributing Cause of the Current Breast Cancer Epidemic in Nigerian Women

Breast cancer incidence in Nigerian women has significantly increased during the past three decades in parallel with the rapid industrialization of that country. This suggested that the associated widespread contamination of the soil and of the water supplies by lead (Pb) and other industrial metals was a major contributing cause. Because of its many domestic, industrial, and automotive uses, Pb is of particular concern as it has been shown to promote the development of mammary tumors in murine mammary tumor virus-infected female C3H mice at levels as low of 0.5 ppm Pb in the drinking water. Lead belongs to the group of selenium-antagonistic elements that interact with selenium (Se), abolishing its anti-carcinogenic effect. Lead on chronic, low-level exposure in addition also accelerates tumor growth rates. Higher levels of Pb were found in blood and head hair samples of newly diagnosed patients with breast cancer, all with infiltrating ductal carcinoma, the most common form of breast cancer in Nigeria, seen at Obafemi Awolowo University, than in cancer-free controls from the same area. Evidence for interactions between Pb and Se was obtained from blood, hair, and tumor biopsy tissue analyses. Furthermore, the Pb levels in hair samples of the patients were directly correlated with the volumes of their tumors, in accord with the tumor growth-promoting effects of Pb. Conversely, Se levels in hair and blood were inversely correlated with the tumor volumes, consistent with the anti-proliferative effects of Se. Several other elements, e.g., Cd, Hg, Cr, Sn, and As, were detected in the scalp hair of the patients and the controls, although at significantly lower levels than those of Pb. However, correlation calculations revealed them also to interact with Se, suggesting that only a fraction of the Se in organs and tissues is actually present in bioactive forms. In metal-exposed subjects, a state of latent Se deficiency may exist, resulting in depressed immune functions and increased cancer susceptibility. Evidence is presented to show that Pb and other metals also interact with iodine, another vitally important essential trace element believed to protect against breast cancer development. Public health programs aiming at lowering the breast cancer risk of Nigerian women thus will have to include effective measures to protect the population from exposures to Pb and other industrial metals that are presently contaminating the environment and the water supplies

Genetic aberrations of c-myc and CCND1 in the development of invasive bladder cancer

Detrusor muscle invasive transitional cell carcinoma is associated with poor prognosis and is responsible for the majority of bladder cancer related deaths. Amplifications of c-myc and CCND1 are associated with detrusor-muscle-invasive transitional cell carcinoma, however, their precise role in driving disease progression is unclear. Fluorescence in situ hybridisation on archival tissue from 16 patients with primary diagnosis of ⩾pT2 transitional cell carcinoma and 15 cases with primary pTa/pT1 disease subsequently progressing to detrusor-muscle-invasion was performed, in the latter group both pre and post muscle invasive events were studied. No patients presenting with ⩾pT2 had amplification of c-myc, two out of 16 (12.5%) had CCND1 amplification. Of patients who developed ⩾pT2, two out of 15 (13.3%) had amplification of c-myc, both in ⩾pT2, five out of 15 (33.3%) had CCND1 amplification, two in pTa/pT1 tumours, three in ⩾pT2 transitional cell carcinomas. In total, two out of 31 (6.5%) of patients' ⩾pT2 TCCs were amplified for c-myc and six out of 31 (19%) were amplified for CCND1. Eighty-seven per cent (40 out of 46) of tumours were polysomic for chromosome 8 and 80% (37 out of 46) were polysomic for chromosome 11 and this reflected the high copy numbers of c-myc and CCND1 observed. In almost all cases an increase in c-myc/CCND1 copy number occurred prior to invasion and persisted in advanced disease. Amplification of CCND1 or alterations in c-myc/CCND1 early in bladder cancer may have clinical relevance in promoting and predicting progression to detrusor-muscle-invasive transitional cell carcinoma