PUF60 variants cause a syndrome of ID, short stature, microcephaly, coloboma, craniofacial, cardiac, renal and spinal features.

PUF60 encodes a nucleic acid-binding protein, a component of multimeric complexes regulating RNA splicing and transcription. In 2013, patients with microdeletions of chromosome 8q24.3 including PUF60 were found to have developmental delay, microcephaly, craniofacial, renal and cardiac defects. Very similar phenotypes have been described in six patients with variants in PUF60, suggesting that it underlies the syndrome. We report 12 additional patients with PUF60 variants who were ascertained using exome sequencing: six through the Deciphering Developmental Disorders Study and six through similar projects. Detailed phenotypic analysis of all patients was undertaken. All 12 patients had de novo heterozygous PUF60 variants on exome analysis, each confirmed by Sanger sequencing: four frameshift variants resulting in premature stop codons, three missense variants that clustered within the RNA recognition motif of PUF60 and five essential splice-site (ESS) variant. Analysis of cDNA from a fibroblast cell line derived from one of the patients with an ESS variants revealed aberrant splicing. The consistent feature was developmental delay and most patients had short stature. The phenotypic variability was striking; however, we observed similarities including spinal segmentation anomalies, congenital heart disease, ocular colobomata, hand anomalies and (in two patients) unilateral renal agenesis/horseshoe kidney. Characteristic facial features included micrognathia, a thin upper lip and long philtrum, narrow almond-shaped palpebral fissures, synophrys, flared eyebrows and facial hypertrichosis. Heterozygote loss-of-function variants in PUF60 cause a phenotype comprising growth/developmental delay and craniofacial, cardiac, renal, ocular and spinal anomalies, adding to disorders of human development resulting from aberrant RNA processing/spliceosomal function

Mid-Rapidity Direct-Photon Production in p+p Collisions at sqrt(s) = 200 GeV

A measurement of direct photons in p+p collisions at sqrt(s)=200 GeV is presented. A photon excess above background from pi^0 --> gamma+gamma, eta --> gamma+gamma, and other decays is observed in the transverse momentum range 5.5 < p_T < 7 GeV/c. The result is compared to a next-to-leading-order perturbative QCD calculation. Within errors, good agreement is found between the QCD calculation and the measured result.Comment: 330 authors, 7 pages text, RevTeX, 2 figures, 2 tables. Submitted to Physical Review D. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (or will be) publicly available at http://www.phenix.bnl.gov/papers.htm

Combined search for the quarks of a sequential fourth generation

Results are presented from a search for a fourth generation of quarks produced singly or in pairs in a data set corresponding to an integrated luminosity of 5 inverse femtobarns recorded by the CMS experiment at the LHC in 2011. A novel strategy has been developed for a combined search for quarks of the up and down type in decay channels with at least one isolated muon or electron. Limits on the mass of the fourth-generation quarks and the relevant Cabibbo-Kobayashi-Maskawa matrix elements are derived in the context of a simple extension of the standard model with a sequential fourth generation of fermions. The existence of mass-degenerate fourth-generation quarks with masses below 685 GeV is excluded at 95% confidence level for minimal off-diagonal mixing between the third- and the fourth-generation quarks. With a mass difference of 25 GeV between the quark masses, the obtained limit on the masses of the fourth-generation quarks shifts by about +/- 20 GeV. These results significantly reduce the allowed parameter space for a fourth generation of fermions.Comment: Replaced with published version. Added journal reference and DO

Reducing anemia prevalence in Afghanistan: socioeconomic correlates and the particular role of agricultural assets

This research aims to examine the socio-economic correlates of anemia in women, and potential sources of iron in household diets in Afghanistan. It also examines whether ownership of agricultural (particularly livestock) assets and their use in food production has a role in alleviating anaemia, especially where local markets may be inadequate. We analyse data from the 2010/11 Afghanistan Multiple Indicator Cluster Survey, estimating a logistic regression to examine how anemia status of women is associated with socio-economic covariates. A key result found is that sheep ownership has a protective effect in reducing anemia (prevalence odds ratio of sheep ownership on anemia of 0.83, 95% confidence interval (CI): 0.73–0.94) after controlling for wealth and other covariates. This association is found to be robust to alternative model specifications. Given the central role of red meat in heme iron provision and absorption of non-heme iron, we hypothesise that sheep ownership promotes mutton consumption from own-production in a setting where market-sourced provision of nutritious food is a challenge. We then use the 2011/12 National Risk and Vulnerability Assessment household data to understand the Afghan diet from the perspective of dietary iron provision, and to understand interactions between own-production, market sourcing and mutton consumption. Sheep ownership is found to increase the likelihood that a household consumed mutton (odds ratio of 1.27, 95% CI: 1.15–1.42), the number of days in the week that mutton was consumed (prevalence rate ratio of 1.24. 95% CI: 1.12–1.37) and the quantity of mutton consumed (7 grams/person/week). In the subsample of mutton consumers, households sourcing mutton mostly from own production consumed mutton 1.5 days more frequently on average than households relying on market purchase, resulting in 100 grams per person per week higher mutton intake. Thus this analysis lends support to the notion that the linkage between sheep ownership and anemia risk is at least partly due to consumption arising from own-production in the presence of market incompleteness

A systematic review of dietary, nutritional, and physical activity interventions for the prevention of prostate cancer progression and mortality

PURPOSE: Given the long-term, although potentially fatal, nature of prostate cancer, there is increasing observational evidence for the reduction in disease progression and mortality through changes in lifestyle factors. METHODS: We systematically reviewed dietary, nutritional, and physical activity randomized interventions aimed at modifying prostate cancer progression and disease-specific mortality, including a detailed assessment of risk of bias and methodological quality. RESULTS: Forty-four randomized controlled trials of lifestyle interventions, with prostate cancer progression or mortality outcomes, were identified. Substantial heterogeneity of the data prevented a meta-analysis. The included trials involved 3,418 prostate cancer patients, median 64 men per trial, from 13 countries. A trial of a nutritional supplement of pomegranate seed, green tea, broccoli, and turmeric; a trial comparing flaxseed, low-fat diet, flaxseed, and low-fat diet versus usual diet; and a trial supplementing soy, lycopene, selenium, and coenzyme Q10, all demonstrated beneficial effects. These trials were also assessed as having low risk of bias and high methodological quality (as were seven other trials with no evidence of benefit). The remaining trials were either underpowered, at high or unclear risk of bias, inadequately reported, of short duration or measured surrogate outcomes of unproven relationship to mortality or disease progression, which precluded any benefits reported being reliable. CONCLUSION: Large, well-designed randomized trials with clinical endpoints are recommended for lifestyle modification interventions. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s10552-015-0659-4) contains supplementary material, which is available to authorized users

Assessment of PULP score in predicting 30-day perforated duodenal ulcer morbidity, and comparison of its performance with Boey and ASA, a retrospective study

Background: /aim: Scores commonly employed to risk stratify perforated peptic ulcer patients include ASA (American Society of Anesthesiologists), Boey and peptic ulcer perforation score (PULP). However, few studies assessed and compared the accuracy indices of these three scores in predicting post PPU repair 30-day morbidity. We assessed accuracy indices of PULP, and compared them to Boey and ASA in predicting post perforated duodenal (PDU) ulcer repair 30-day morbidity. Methods: Retrospective chart review of all PDU patients (perforated duodenal ulcers only) at the largest two hospitals in Qatar (N = 152). Data included demographic, clinical, laboratory, operative, and post repair 30-day morbidity. Area under the Curve (AUC), sensitivity and specificity were computed for each of the 3 scores. Multivariate logistic regression assessed the accuracy indices of each score. Results: All patients were males (M age 37.41 years). Post PDU repair 30-day morbidity was 10.5% (16 morbidities). Older age, higher ASA (?3), Boey (?1) or PULP (?8) scores, shock on admission and preoperative comorbidities; and conversely, lower hemoglobin and albumin were all positively significantly associated with higher post PDU 30-day morbidity. PULP displayed the largest AUC (72%), and was the only score to significantly predict 30-day morbidity. The current study is the first to report the sensitivity and specificity of these three scores for post PDU repair 30-day morbidity; and first to assess accuracy indices for PULP in predicting post PDU repair 30-day morbidity. Conclusion: PULP score had the largest AUC and was the only score to significantly predict post PDU repair 30-day morbidity.Scopu

Mechanisms Underlying Interferon-γ-Induced Priming of Microglial Reactive Oxygen Species Production.

Microglial priming and enhanced reactivity to secondary insults cause substantial neuronal damage and are hallmarks of brain aging, traumatic brain injury and neurodegenerative diseases. It is, thus, of particular interest to identify mechanisms involved in microglial priming. Here, we demonstrate that priming of microglia with interferon-γ (IFN γ) substantially enhanced production of reactive oxygen species (ROS) following stimulation of microglia with ATP. Priming of microglial ROS production was substantially reduced by inhibition of p38 MAPK activity with SB203580, by increases in intracellular glutathione levels with N-Acetyl-L-cysteine, by blockade of NADPH oxidase subunit NOX2 activity with gp91ds-tat or by inhibition of nitric oxide production with L-NAME. Together, our data indicate that priming of microglial ROS production involves reduction of intracellular glutathione levels, upregulation of NADPH oxidase subunit NOX2 and increases in nitric oxide production, and suggest that these simultaneously occurring processes result in enhanced production of neurotoxic peroxynitrite. Furthermore, IFNγ-induced priming of microglial ROS production was reduced upon blockade of Kir2.1 inward rectifier K+ channels with ML133. Inhibitory effects of ML133 on microglial priming were mediated via regulation of intracellular glutathione levels and nitric oxide production. These data suggest that microglial Kir2.1 channels may represent novel therapeutic targets to inhibit excessive ROS production by primed microglia in brain pathology

Supporting mental health, wellbeing and study skills in Higher Education:an online intervention system

Abstract Background Dealing with psychological and study skill difficulties can present a challenge for both Higher Education (HE) students, who suffer from them, but also for HE Institutions and their support services. Alternative means of support, such as online interventions, have been identified as cost-effective and efficient ways to provide inclusive support to HE students, removing many of the barriers to help-seeking as well as promoting mental health and wellbeing. Case presentation The current case study initially outlines the rigorous approach in the development of one such online intervention system, MePlusMe. It further highlights key features that constitute innovative delivery of evidence-based psychological and educational practice in the areas of mental health, promotion of wellbeing, support of mood and everyday functioning, and study-skills enhancement. Conclusions This case study aims to present the innovative features of MePlusMe in relation to current needs and evidence-basis. Finally, it presents future directions in the evaluation, assessment, and evidence of the fitness-for-purpose process

The combined expression of solute carriers is associated with a poor prognosis in highly proliferative ER+ breast cancer

Purpose: Breast cancer (BC) is a heterogeneous disease characterised by variant biology, metabolic activity, and patient outcome. Glutamine availability for growth and progression of BC is important in several BC subtypes. This study aimed to evaluate the biological and prognostic role of the combined expression of key glutamine transporters, SLC1A5, SLC7A5 and SLC3A2 in BC with emphasis on the intrinsic molecular subtypes. Methods: SLC1A5, SLC7A5 and SLC3A2 were assessed at the protein level, using immunohistochemistry on tissue microarrays constructed from a large well characterised BC cohort (n=2,248). Patients were stratified into accredited clusters based on protein expression and correlated with clinicopathological parameters, molecular subtypes, and patient outcome. Results: Clustering analysis of SLC1A5, SLC7A5 and SLC3A2 identified three clusters Low SLCs (SLC1A5-/SLC7A5-/SLC3A2-), High SLC1A5 (SLC1A5+/SLC7A5-/SLC3A2-) and High SLCs (SLC1A5+/SLC7A5+/SLC3A2+) which had distinct correlations to known prognostic factors and patient outcome (p<0.001). The key regulator of tumour cell metabolism, c-MYC, was significantly expressed in tumours in the High SLCs cluster (p<0.001). When different BC subtypes were considered, the association with the poor outcome was observed in the ER+ high proliferation/luminal B class only (p= 0.003). In multivariate analysis, SLC clusters were independent risk factor for shorter breast cancer specific survival (p= 0.001). Conclusion: The co-operative expression of SLC1A5, SLC7A5 and SLC3A2 appears to play a role in the aggressive subclass of ER+ high proliferation/ luminal BC, driven by c-MYC, and therefore have the potential to act as therapeutic targets, particularly in synergism

The prognostic significance of ALDH1A1 expression in early invasive breast cancer

Aims: Aldehyde dehydrogenase family 1 member A1 (ALDH1A1)is reportedly a key ALDH isozyme linked to the cancer stem cells (CSC) of many solid tumours, where it is involved in self-renewal, differentiation and self-protection. In this study, the prognostic significance of ALDH1A1 expression in early invasive breast cancer (BC) and its role as a BC stem cell (BCSC) were evaluated.Methods: ALDH1A1 expression was assessed, using immunohistochemistry and tissue microarrays, in a large well- characterised BC cohort. ALDH1A1 mRNA expression was also assessed at the transcriptomic levels, utilising data from the Molecular Taxonomy of Breast Cancer International Consortium. The associations of ALDH1A1 with clinicopathological parameters, other stem cell markers and patient outcomes were determined.Results: ALDH1A1 was expressed in 71% of BC cases, at both the protein and mRNA levels. High ALDH1A1 expression was associated with poor prognostic features, including high grade, poor Nottingham Prognostic Index (NPI), lymph node metastasis and highly proliferative ER+ (luminal B) and triple negative (TNBC) subtypes. ALDH1A1 expression was positively correlated with the expression of CD44, CD24, TWIST, SOX9, EPCAM and CD133. The high immunoexpression of ALDH1A1 was significantly associated with poor BC-specific survival [less than] 0.001), and specifically in the luminal B and TNBC subtypes (P=0.042 and P=0.003, respectively). The immunoexpression of ALDH1A1 was an independent predictor of poor prognosis (P=0.015).Conclusions: ALDH1A1, as assessed using IHC, seems to act as a BCSC marker associated not only with other BCSC markers but also with poor prognostic characteristics and poor outcomes, particularly in the luminal B and TNBC subtypes