Miracle-dz/UniFAR-FTUs huggingface dataset:
Definition of a putative pathological region in PARK2 associated with autism spectrum disorder through in silico analysis of its functional structure

Objective The PARK2 gene encodes Parkin, a component of a multiprotein E3 ubiquitin ligase complex that targets substrate proteins for proteasomal degradation. PARK2 mutations are frequently associated with Parkinson’s disease, but structural alterations have also been described in patients with neurodevelopmental disorders (NDD), suggesting a pathological effect ubiquitous to neurodevelopmental and neurodegenerative brain processes. The present study aimed to define the critical regions for NDD within PARK2. Materials and methods To clarify PARK2 involvement in NDDs, we examined the frequency and location of copy number variants (CNVs) identified in patients from our sample and reported in the literature and relevant databases, and compared with control populations. Results Overall, the frequency of PARK2 CNVs was higher in controls than in NDD cases. However, closer inspection of the CNV location in PARK2 showed that the frequency of CNVs targeting the Parkin C-terminal, corresponding to the ring-between-ring (RBR) domain responsible for Parkin activity, is significantly higher in NDD cases than in controls. In contrast, CNVs targeting the N-terminal of Parkin, including domains that regulate ubiquitination activity, are very common both in cases and in controls. Conclusion Although PARK2 may be a pathological factor for NDDs, likely not all variants are pathogenic, and a conclusive assessment of PARK2 variant pathogenicity requires an accurate analysis of their location within the coding region and encoded functional domains.
Genetic variation in GABR&bgr;1 and the risk for developing alcohol dependence

Associations between the &ggr;-aminobutyric acid type-A receptors (GABAA) and alcohol dependence risk have been reported, although the receptor subunit driving the association is unclear. Recent work in mice has highlighted a possible role for variants in the Gabr &bgr;1 subunit (Gabr&bgr;1) in alcohol dependence risk, although this gene does not contain any common nonsynonymous variants in humans. However, the GABAA receptor is a heteropentamer so multiple potential variants within the gene complex could generate the alcohol dependence phenotype. The association between GABR&bgr;1 variants and alcohol dependence risk was explored in a British and Irish population of alcohol-dependent cases (n=450) and ancestrally-matched controls screened to exclude current or historical alcohol misuse (n=555). Twelve common single nucleotide polymorphisms (SNPs) and a rare nonsynonymous variant, rs41311286, were directly genotyped; imputation was then performed across the whole gene. No allelic association was observed between alcohol dependence risk and any of the directly genotyped or imputed SNPs. However, post-hoc testing for genotypic association identified five common intronic SNPs that showed modest evidence for association after correction for multiple testing; two, rs76112682 and rs141719901, were in complete linkage disequilibrium [Pcorrected=0.02, odds ratio (95% confidence interval)=5.9 (1.7–2.06)]. These findings provide limited support for an association between GABR&bgr;1 and the risk for developing alcohol dependence; further testing in expanded cohorts may be warranted.
American Academy of Otolaryngology—Head and Neck Surgery Foundation Clinical Practice Guidelines: Allergic Rhinitis

Program Description: Allergic rhinitis is a worldwide health problem affecting 30 to 60 million people in the United States annually, including up to 30% of adults and as many as 40% of children. The multidisciplinary, AAO-HNSF-developed Clinical Practice Guideline: Allergic Rhinitis, will be presented. The evidence-based recommendations are designed for clinicians involved in the diagnosis and management of patients with allergic rhinitis. Educational Objectives: (1) Properly diagnosis allergic rhinitis. (2) Differentiate between allergic and non-allergic rhinitis. (3) Know when to perform allergy testing; and understand the role of immunotherapy (sublingual and subcutaneous).
Apolipoprotein E variants and genetic susceptibility to combat-related post-traumatic stress disorder: a meta-analysis

Background Apolipoprotein E (APOE) has recently been studied as a risk factor for association with developing combat-related post-traumatic stress disorder (PTSD) in the military population. These studies have yielded inconsistent findings. The present study carried out a meta-analysis to establish whether the APOE polymorphism confers increased susceptibility to combat-related PTSD. Methods PubMed, Medline, Embase, PsycInfo, and Google Scholar were searched for potential publications relating to patients with PTSD in military settings with combat exposure. Studies provided proper PTSD screening and genotype data on APOE gene variants were all considered for selection in the review. A random-effect model was used to calculate the pooled effect size (Cohen’s d) and summary statistics. Sensitivity analyses and meta-regression were used to assess the between-study heterogeneity. Egger’s test and rank-correlation test were also carried out to evaluate any potential publication bias. Results Our study showed a significant association between the APOE e4 gene variant and increased risk for developing combat-related PTSD, with an overall effect size of d equal to 0.28 (95% confidence interval: 0.10–0.45) for e4 carriers versus noncarriers. In contrast, no statistically significant association was found for the APOE e2 variant (d=0.59; 95% confidence interval: −0.29–1.47). Conclusion The current meta-analysis provides corroborating evidence that supports the fact that the presence of the APOE e4 polymorphism confers greater susceptibility to combat-related PTSD. Future studies with a larger sample size and better consistency in reporting standards are warranted to further evaluate these associations.
MGDG, PG and SQDG regulate the activity of light-dependent protochlorophyllide oxidoreductase.

Light-dependent protochlorophyllide oxidoreductase (POR) is a plant enzyme involved in the chlorophyll biosynthesis pathway. POR reduces one of the double bonds of the protochlorophyllide (Pchlide) using NADPH and light. In the present study, we found out that phosphatidylglycerol and sulfoquinovosyl diacylglycerol are allosteric regulators of the nucleotide binding, which increase the affinity towards NADPH a 100-fold. Moreover, we showed for the first time that NADH can, like NADPH, form active complexes with Pchlide and POR, however, at much higher concentrations. Additionally, monogalactosyldiacylglycerol (MGDG) was shown to be the main factor responsible for the red shift of the fluorescence emission maximum of Pchlide:POR:NADPH complexes. Importantly, the emission maximum at 654 nm was obtained only for the reaction mixtures supplemented with MGDG and at least one of the negatively charged plant lipids. Moreover, the site-directed mutagenesis allowed us to identify amino acid residues that may be responsible for lipid binding and Pchlide coordination. Our experiments allowed us to identify six different Pchlide:POR complexes that differ in the fluorescence emission maxima of the pigment. The results presented here reveal the contribution of thylakoid lipids in the regulation of the chlorophyll biosynthesis pathway; however, the molecular mechanisms of this process are to be clarified.
Lipopolysaccharide of Aggregatibacter actinomycetemcomitans up-regulates inflammatory cytokines, prostaglandin E2 synthesis and osteoclast formation in interleukin-1 receptor antagonist-deficient mice.

BACKGROUND AND OBJECTIVE The interleukin (IL)-1 receptor antagonist (Ra) binds to IL-1 receptors and inhibits IL-1 activity. However, it is unclear whether the IL-1Ra plays a protective role in periodontal disease. The purpose of this study was to compare IL-1Ra knockout (KO) and wild-type (WT) mice in regard to proinflammatory cytokine production, osteoclast formation and bone resorption in response to periodontal bacterial lipopolysaccharide (LPS). MATERIAL AND METHODS Peritoneal macrophages (Mφs) were obtained from 13-wk-old IL-1Ra KO and WT mice. Peritoneal Mφs were cultured with or without 10 μg/mL of Aggregatibacter actinomycetemcomitans LPS for 24 h. The levels of IL-1alpha (IL-1α), IL-1beta (IL-1β), tumor necrosis factor-α (TNF-α) and IL-6 were measured in periotoneal Mφs supernatant fluid (PM-SF) using an ELISA. Bone marrow cells were obtained from the mice and stimulated with PM-SF for 9 d, then stained with TRAP. The frequency of TRAP-positive multinucleated giant cell formation was calculated based on a fusion index. PM-SF-stimulated calvarial bone resorption was analyzed using micro-computed tomography, and calvarial histological analysis was performed using hematoxylin and eosin and TRAP staining. The expression of cyclooxygenase-2 (Cox2), prostanoid receptor EP4 (Ep4) and Rank mRNAs in bone marrow cells were measured using real-time quantitative PCR, while prostaglandin E2 (PGE2 ) production was determined by ELISA. RESULTS The levels of IL-1α, IL-1β, TNF-α and IL-6 in IL-1Ra KO mice PM-SF stimulated with A. actinomycetemcomitans LPS were significantly increased by approximately 4- (p < 0.05), 5- (p < 0.05), 1.3- (p < 0.05) and 6- (p < 0.05) fold, respectively, compared with the levels in WT mice. Moreover, osteoclast formation, expression of Rank, Ep4 and Cox2 mRNAs and production of PGE2 were significantly increased by approximately 2- (p < 0.05), 1.6- (p < 0.05), 2.5- (p < 0.05), 1.6- (p < 0.05) and 1.9- (p < 0.05) fold, respectively, in IL-1Ra KO mice stimulated with A. actinomycetemcomitans LPS compared with WT mice. CONCLUSION IL-1Ra regulates IL-1 activity and appears to reduce the levels of other inflammatory cytokines, including TNF-α and IL-6, while it also reduces expression of the EP4 receptor related to prostanoid sensitivity and osteoclast formation. These results suggest that IL-1Ra is an important molecule for inhibition of inflammatory periodontal bone resorption.
Successful same-sex pairing in Laysan albatross

Unrelated same-sex individuals pairing together and cooperating to raise offspring over many years is a rare occurrence in the animal kingdom. Cooperative breeding, in which animals help raise offspring that are not their own, is often attributed to kin selection when individuals are related, or altruism when individuals are unrelated. Here we document long-term pairing of unrelated female Laysan albatross (Phoebastria immutabilis) and show how cooperation may have arisen as a result of a skewed sex ratio in this species. Thirty-one per cent of Laysan albatross pairs on Oahu were female–female, and the overall sex ratio was 59% females as a result of female-biased immigration. Female–female pairs fledged fewer offspring than male–female pairs, but this was a better alternative than not breeding. In most female–female pairs that raised a chick in more than 1 year, at least one offspring was genetically related to each female, indicating that both females had opportunities to reproduce. These results demonstrate how changes in the sex ratio of a population can shift the social structure and cause cooperative behaviour to arise in a monogamous species, and they also underscore the importance of genetically sexing monomorphic species.
Ivermectin interacts with human ABCG2.

Ivermectin is an antiparasitic drug frequently administered to humans. It has a limited brain exposure that is attributed to the efflux activity of ABCB1/Abcb1. ABCG2/Abcg2 is also a major transporter present in most pharmacologically important barriers. However, interaction of ivermectin with Abcg2 shows species specificity and in many studies was confounded by the masking effect of ABCB1/Abcb1. In this study using cellular and membrane assays we show that ivermectin displays a high-affinity interaction with human ABCG2 with IC(50) values in the 1-1.5 µM range. This interaction may have implications in human ABCG2-mediated drug-drug interactions of ivermectin.
UGT2B17 genotype and pharmacokinetic profile of testosterone during substitution therapy in men with hypogonadism

References 1. Turgeon, D. , Carrier, J-S. , Lévesque, É. , Hum, D.W. , Bélanger, A. (2001) Relative enzymatic activity, Protein Stability, and Tissue Distribution of Human Steroid-Metabolizing UGT2B Subfamily Members. Endocrinology. 142; 778-787 2. Jakobsson, J., Ekström, L. , Inotsume, N. , Garle, M. , Lorentzon, M. , Ohlsson, C. , Roh, H. -K. , Carlström, K. , Rane, A. (2006). Large differences in testosterone excretion in Korean and Swedish men are strongly associated with a UDP-Glucuronosyl transferase 2B17 polymorphism. The Journal of Clinical Endocrinology & Metabolism, 91; 687-693 3. Juul, A. , Sørensen, K. , Aksglaede, L. , Garn, I. , Rajpert-De Meyts, E. , Hullstein, I. , Hemmersbach, P., Ottesen, A.M.: A common deletion in the uridine diphoshate gluguronyltransferase (UGT) 2B17 gene is a strong determinant of androgen excretion in healthy pubertal boys (2009). The Journal of Clinical Endocrinology & Metabolism, 94; 1005-1011 4. Schulze, JJ, Lundmark, J., Garle, M. , Skilving, I. , Ekström, L. , Rane, A. (2008); Doping test results dependent on genotype of uridine diphospho-glucuronosyl transferase 2B17, the major enzyme for testosterone glucuronidation. J Clin Endocrinol Metab. 93; 2500-2506. Table 1. Primary diagnoses stratified according to the UGT2B17 genotype. Introduction • Testosterone is mainly excreted in the urine as testosterone glucuronide. Glucuronidation is partly dependent on the UGT2B17 genotype (1) and testosterone glucuronide excretion is lower in men having the UGT2B17 deletion polymorphism (2-4).
Outcome research in obesity: lessons from the QUOVADIS study

Outcome research in obesity is aimed at the identification of clinically meaningful goals. Over the years, the focus has moved from surrogate health markers to cardiovascular risk and survival. The 7–10% weight loss recommended by guidelines is a target easily attained with any treatment, but does not guarantee physical and psychological benefits unless it is accompanied by weight loss maintenance, a target very difficult to achieve with either behavior treatment or pharmacological intervention. A reduced cardiovascular risk profile is associated with weight loss, irrespective of the treatment program. In contrast, no controlled studies have so far documented an increased survival, but evidence has been provided by epidemiological surveys. Also bariatric surgery, promoting a larger weight loss and good weight loss maintenance, has failed to demonstrate an improved survival. Health‐related quality of life is an additional significant outcome, approved by international agencies. Concern regarding a possible detrimental effect of dieting on mood and depression is not substantiated by the results of controlled studies. The high prevalence of obesity and its consequences pose a serious and unresolved challenge to the medical community and the definition of outcome measures is a key issue for the assessment of results. Drug Dev. Res. 67:260–270, 2006. © 2006 Wiley‐Liss, Inc.
Molecular evolution of the hyaluronan synthase 2 gene in mammals: implications for adaptations to the subterranean niche and cancer resistance

The naked mole-rat (NMR) Heterocephalus glaber is a unique and fascinating mammal exhibiting many unusual adaptations to a subterranean lifestyle. The recent discovery of their resistance to cancer and exceptional longevity has opened up new and important avenues of research. Part of this resistance to cancer has been attributed to the fact that NMRs produce a modified form of hyaluronan—a key constituent of the extracellular matrix—that is thought to confer increased elasticity of the skin as an adaptation for living in narrow tunnels. This so-called high molecular mass hyaluronan (HMM-HA) stems from two apparently unique substitutions in the hyaluronan synthase 2 enzyme (HAS2). To test whether other subterranean mammals with similar selection pressures also show molecular adaptation in their HAS2 gene, we sequenced the HAS2 gene for 11 subterranean mammals and closely related species, and combined these with data from 57 other mammals. Comparative screening revealed that one of the two putatively important HAS2 substitutions in the NMR predicted to have a significant effect on hyaluronan synthase function was uniquely shared by all African mole-rats. Interestingly, we also identified multiple other amino acid substitutions in key domains of the HAS2 molecule, although the biological consequences of these for hyaluronan synthesis remain to be determined. Despite these results, we found evidence of strong purifying selection acting on the HAS2 gene across all mammals, and the NMR remains unique in its particular HAS2 sequence. Our results indicate that more work is needed to determine whether the apparent cancer resistance seen in NMR is shared by other members of the African mole-rat clade.
Social economic inequalities and mental health II. Methodological aspects and literature review

Summary Objective - This study provides a framework for mental health inequalities beginners. It describes the methods used to measure socio economic inequalities and the inter-relations with different aspects of mental health: residence, mental health services organisation and main diagnostic categories. Method - Literature electronic-search on Medline, Psyclit, Econlit, Social Science Index and SocioSearch usingand relating the key-words inequalities, deprivation, poverty, socio-economic status, social class, occupational class, mental health for the period 1965-2002 (June). The articles selected were integrated with manual search (publications of the same authors, cross-references, working documents and reports of international andregional organisations). Results - Inequality is not an absolute concept and, mainly, it has been changing during the last years. For example, the integration and re-definition of variables that capture, in simple indices, a complex reality; the accent on social more than on economic aspects; the geo-validity and time-reference of the inequality's indices. Moreover, the inequalities could be the result of individual preferences, in this case, the social selectionand social causation issues will raise the suitability for a public intervention. Conclusions - Up to now, research has been mainly concentrated in describing and measuring health inequalities. For designing effective interventions, policy makers need to ground decisions on health-socioeconomic inequalities explanatory models. Declaration of Interest this work was partly funded by the Department of the Public Health Sciences “G. Sanarelli” of the University of Rome “La Sapienza” and the Department of Medicine and Public Health of the University of Verona.
Correlation of Body Mass Index and Waist Hip Ratio with lipid and hormone profile in women in menopausal transition

Introduction: Menopausal transition is a period characterised by psychic, somatic changes as well as changes in reproductive capabilities of a woman. It occurs as a consequence of ovarian’s function termination, and pertains to the periods of different meanings: perimenopause, menopause and postmenopause. Although there are numerous assessments of behaviour of the lipids and lipoproteins during menopausal transition, their relation to sexual hormones and body mass is still being assessed. The aim of this study is to determine the differences and connections between body mass index (BMI) and waist-hip ratio (WHR) and lipid and hormone profile among the assessees in premenopause, perimenopause and postmenopause.Methods: The assessment was done on 150 assessees divided in three groups of 50, such as: premenopause, perimenopause and postmenopause. The assessment included the following: interview, determination of BMI, WHR, and taking of blood sample and processing of hormone, lipid and lipoprotein concentration.Results: Based on the obtained results, it may not be concluded that BMI has a positive correlation with cholesterol and VLDL concentration in postmenopause, positive correlation with apo A in perimenopause and postmenopause, and positive correlation with Lp (a) and apo B in premenopause and perimenopause, while negative correlation with HDL and estradiol concentrations in premenopause.Conclusion: WHR has negative correlation with HDL concentration in premenopause and perimenopause, and a negative correlation with estradiol concentrations in premenopause.
Disparities in Colorectal Cancer Treatment Delay Within Appalachia--The Role of For-Profit Hospitals.

BACKGROUND Appalachian residents have a higher overall cancer burden than the rest of the United States because of the unique features of the region. Treatment delays vary widely within Appalachia, with colorectal cancer patients undergoing median treatment delays of 5 days in Kentucky compared to 9 days for patients in Pennsylvania, Ohio, and North Carolina combined. OBJECTIVE This study identified the source of this disparity in treatment delay using statistical decomposition techniques. METHODOLOGY This study used linked 2006 to 2008 cancer registry and Medicare claims data for the Appalachian counties of Kentucky, Pennsylvania, Ohio, and North Carolina to estimate a 2-part model of treatment delay. An Oaxaca Decomposition of the 2-part model revealed the contribution of the individual determinants to the disparity in delay between Kentucky counties and the remaining 3 states. RESULTS The Oaxaca Decomposition revealed that the higher percentage of patients treated at for-profit facilities in Kentucky proved the key contributor to the observed disparity. In Kentucky, 22.3% patients began their treatment at a for-profit facility compared to 1.4% in the remaining states. Patients initiating treatment at for-profit facilities explained 79% of the observed difference in immediate treatment (<2 days after diagnosis) and 72% of Kentucky's advantage in log days to treatment. CONCLUSIONS The unique role of for-profit facilities led to reduced treatment delay for colorectal cancer patients in Kentucky. However, it remains unknown whether for-profit hospitals' more rapid treatment converts to better health outcomes for colorectal cancer patients.
Variation in Primary Care Service Patterns by Rural-Urban Location.

BACKGROUND Rural communities have disproportionately faced primary care shortages for decades in spite of policy efforts to prepare and attract primary care health professionals to practice in rural locales. Insight into how primary care physicians' service patterns in rural areas differ from those in less rural places is important to better inform recruitment strategies that target primary care providers and rural communities. OBJECTIVES The purpose of this research is to describe how primary care physician service patterns vary by rural-urban location for a large, privately insured population. We discuss implications of service pattern variation on policy efforts to attract primary care providers to underserved rural areas. METHODS Claims data from fully insured commercial health insurance beneficiaries were used to develop service pattern profiles for primary care providers located in 1 of 4 types of rural-urban areas in Iowa in 2009. The 4 area types are metropolitan, micropolitan, noncore area adjacent to a metro area, and noncore/nonadjacent rural area. RESULTS There were differences in primary care physicians' service patterns by rural-urban area type. Physicians in nonmetropolitan areas provided relatively more care on a per physician basis than those in the metropolitan area type, as well as more surgery, maternity, emergency, and nursing facility services than metropolitan physicians. CONCLUSION Primary care physicians who value practicing a relatively diverse range of services may find locating in rural areas an appealing choice. Health systems and policy makers seeking to attract primary care physicians to rural areas can incorporate this reality into a recruitment strategy.