Miracle-dz/UniFAR-FTUs huggingface dataset:
Estrogen Receptor α Regulates β-Cell Formation During Pancreas Development and Following Injury

Identifying pathways for β-cell generation is essential for cell therapy in diabetes. We investigated the potential of 17β-estradiol (E2) and estrogen receptor (ER) signaling for stimulating β-cell generation during embryonic development and in the severely injured adult pancreas. E2 concentration, ER activity, and number of ERα transcripts were enhanced in the pancreas injured by partial duct ligation (PDL) along with nuclear localization of ERα in β-cells. PDL-induced proliferation of β-cells depended on aromatase activity. The activation of Neurogenin3 (Ngn3) gene expression and β-cell growth in PDL pancreas were impaired when ERα was turned off chemically or genetically (ERα−/−), whereas in situ delivery of E2 promoted β-cell formation. In the embryonic pancreas, β-cell replication, number of Ngn3+ progenitor cells, and expression of key transcription factors of the endocrine lineage were decreased by ERα inactivation. The current study reveals that E2 and ERα signaling can drive β-cell replication and formation in mouse pancreas.
Use of β blockers and the risk of death in hospitalised patients with acute exacerbations of COPD

Background: Cardiovascular disease is a major cause of death in patients with chronic obstructive pulmonary disease (COPD) and predicts hospitalisation for acute exacerbation, in-hospital death and post-discharge mortality. Although β blockers improve cardiovascular outcomes, patients with COPD often do not receive them owing to concerns about possible adverse pulmonary effects. There are no published data about β blocker use among inpatients with COPD exacerbations. A study was undertaken to identify factors associated with β blocker use in this setting and to determine whether their use is associated with decreased in-hospital mortality. Methods: Administrative data from the University of Alabama Hospital were reviewed and patients admitted between October 1999 and September 2006 with an acute exacerbation of COPD as a primary diagnosis or as a secondary diagnosis with a primary diagnosis of acute respiratory failure were identified. Demographic data, co-morbidities and medication use were recorded and subjects receiving β blockers were compared with those who did not. Multivariate regression analysis was performed to determine predictors of in-hospital death after controlling for known covariates and the propensity to receive β blockers. Results: 825 patients met the inclusion criteria. In-hospital mortality was 5.2%. Those receiving β blockers (n = 142) were older and more frequently had cardiovascular disease than those who did not. In multivariate analysis adjusting for potential confounders including the propensity score, β blocker use was associated with reduced mortality (OR = 0.39; 95% CI 0.14 to 0.99). Age, length of stay, number of prior exacerbations, the presence of respiratory failure, congestive heart failure, cerebrovascular disease or liver disease also predicted in-hospital mortality (p<0.05). Conclusions: The use of β blockers by inpatients with exacerbations of COPD is well tolerated and may be associated with reduced mortality. The potential protective effect of β blockers in this population warrants further study.
Obesity in MENX Rats Is Accompanied by High Circulating Levels of Ghrelin and Improved Insulin Sensitivity

Ghrelin, the natural ligand of the growth hormone secretagogue receptor type 1a (GHS-R1a), is mainly secreted from the stomach and regulates food intake and energy homeostasis. p27 regulates cell cycle progression in many cell types. Here, we report that rats affected by the multiple endocrine neoplasia syndrome MENX, caused by a p27 mutation, develop pancreatic islet hyperplasia containing elevated numbers of ghrelin-producing ε-cells. The metabolic phenotype of MENX-affected rats featured high endogenous acylated and unacylated plasma ghrelin levels. Supporting increased ghrelin action, MENX rats show increased food intake, enhanced body fat mass, and elevated plasma levels of triglycerides and cholesterol. Ghrelin effect on food intake was confirmed by treating MENX rats with a GHS-R1a antagonist. At 7.5 months, MENX-affected rats show decreased mRNA levels of hypothalamic GHS-R1a, neuropeptide Y (NPY), and agouti-related protein (AgRP), suggesting that prolonged hyperghrelinemia may lead to decreased ghrelin efficacy. In line with ghrelin’s proposed role in glucose metabolism, we find decreased glucose-stimulated insulin secretion in MENX rats, while insulin sensitivity is improved. In summary, we provide a novel nontransgenic rat model with high endogenous ghrelin plasma levels and, interestingly, improved glucose tolerance. This model might aid in identifying new therapeutic approaches for obesity and obesity-related diseases, including type 2 diabetes.
DNA CpG Methylation (5-Methylcytosine) and Its Derivative (5-Hydroxymethylcytosine) Alter Histone Posttranslational Modifications at the Pomc Promoter, Affecting the Impact of Perinatal Diet on Leanness and Obesity of the Offspring

A maternal high-fat diet (HFD) alters the offspring's feeding regulation, leading to obesity. This phenomenon is partially mediated by aberrant expression of the hypothalamic anorexigenic neuropeptide proopiomelanocortin (POMC). Nevertheless, although some individual offspring suffer from morbid obesity, others escape the malprogramming. It is suggested that this difference is due to epigenetic programming. In this study, we report that in lean offspring of non-HFD–fed dams, essential promoter regions for Pomc expression were enriched with 5-hydroxymethylcytosine (5hmC) together with a reduction in the level of 5-methylcytosine (5mC). Moreover, 5hmC was negatively correlated whereas 5mC was positively correlated with body weight in offspring from both HFD- and control-fed dams. We further found that Pomc expression in obese offspring is determined by a two-step epigenetic inhibitory mechanism in which CpG methylation is linked with histone posttranslational modifications. An increase in CpG methylation at the Poxmc promoter enables binding of methyl-binding domain 1 (MBD1) to 5mC, but not to its derivative 5hmC. MBD1 then interacts with SET domain bifurcated 1 methyltransferase to promote bimethylation on the histone 3 lysine 9 residue, reducing Pomc mRNA expression. These results suggest an epigenetic regulatory mechanism that affects obesity-prone or resilient traits.
Religion in trauma care: grand narratives and sacred rituals

This article outlines major religious practices observed in the UK and discusses how associated spiritual and religious custom and rites should be honoured by emergency practitioners. The article does not intend to be an all encompassing text on religion but to heighten awareness among emergency practitioners about various spiritual and religious considerations affecting patients and families under their care during critical and sometimes life-changing events in their life.
Chemistry, pharmacology and medicinal properties of Peganum harmala L.

Peganum harmala L. is known as Syrian rue, Wild rue and Harmal. P. harmala extracts are considered important for drug development, because they are reported to have numerous pharmacological activities in the Middle East, especially in Iran and Egypt. For a long time P. harmala has been used in traditional medicines for the relief of pain and as an antiseptic agent. P. harmala also have antibacterial, antifungal, antiviral, antioxidant, antidiabetic, antitumor, antileishmanial, insecticidal and cytotoxic activities and hepatoprotective and antinociceptive effects. Harmaline, harmine, harmalol, harman, quinazoline derivatives, vasicine, vasicinone, anthroquinons and fixed oils are reported from seeds and roots of this plant. This plant is used as a medicine in Turkey, Syria, Iran, Pakistan, India, Egypt and Spain. This article presents comprehensive analyzed information on the botanical, chemical and pharmacological aspects of P. harmala. Key words: Peganum harmala, zygophyllaceae, phytochemical, pharmacological properties.
Nonsuppressed Glucagon After Glucose Challenge as a Potential Predictor for Glucose Tolerance

Glucagon levels are classically suppressed after glucose challenge. It is still not clear as to whether a lack of suppression contributes to hyperglycemia and thus to the development of diabetes. We investigated the association of postchallenge change in glucagon during oral glucose tolerance tests (OGTTs), hypothesizing that higher postchallenge glucagon levels are observed in subjects with impaired glucose tolerance (IGT). Glucagon levels were measured during OGTT in a total of 4,194 individuals without diabetes in three large European cohorts. Longitudinal changes in glucagon suppression were investigated in 50 participants undergoing a lifestyle intervention. Only 66–79% of participants showed suppression of glucagon at 120 min (fold change glucagon120/0 <1) during OGTT, whereas 21–34% presented with increasing glucagon levels (fold change glucagon120/0 ≥1). Participants with nonsuppressed glucagon120 had a lower risk of IGT in all cohorts (odds ratio 0.44–0.53, P < 0.01). They were also leaner and more insulin sensitive and had lower liver fat contents. In the longitudinal study, an increase of fold change glucagon120/0 was associated with an improvement in insulin sensitivity (P = 0.003). We characterize nonsuppressed glucagon120 during the OGTT. Lower glucagon suppression after oral glucose administration is associated with a metabolically healthier phenotype, suggesting that it is not an adverse phenomenon.
Adipocyte Glucocorticoid Receptor Deficiency Attenuates Aging- and HFD-Induced Obesity and Impairs the Feeding-Fasting Transition

Glucocorticoids (GCs) are important regulators of systemic energy metabolism, and aberrant GC action is linked to metabolic dysfunctions. Yet, the extent to which normal and pathophysiological energy metabolism depend on the GC receptor (GR) in adipocytes remains unclear. Here, we demonstrate that adipocyte GR deficiency in mice significantly impacts systemic metabolism in different energetic states. Plasma metabolomics and biochemical analyses revealed a marked global effect of GR deficiency on systemic metabolite abundance and, thus, substrate partitioning in fed and fasted states. This correlated with a decreased lipolytic capacity of GR-deficient adipocytes under postabsorptive and fasting conditions, resulting from impaired signal transduction from β-adrenergic receptors to adenylate cyclase. Upon prolonged fasting, the impaired lipolytic response resulted in abnormal substrate utilization and lean mass wasting. Conversely, GR deficiency attenuated aging-/diet-associated obesity, adipocyte hypertrophy, and liver steatosis. Systemic glucose tolerance was improved in obese GR-deficient mice, which was associated with increased insulin signaling in muscle and adipose tissue. We conclude that the GR in adipocytes exerts central but diverging roles in the regulation of metabolic homeostasis depending on the energetic state. The adipocyte GR is indispensable for the feeding-fasting transition but also promotes adiposity and associated metabolic disorders in fat-fed and aged mice.
An Expanded Genome-Wide Association Study of Type 2 Diabetes in Europeans

To characterize type 2 diabetes (T2D)-associated variation across the allele frequency spectrum, we conducted a meta-analysis of genome-wide association data from 26,676 T2D case and 132,532 control subjects of European ancestry after imputation using the 1000 Genomes multiethnic reference panel. Promising association signals were followed up in additional data sets (of 14,545 or 7,397 T2D case and 38,994 or 71,604 control subjects). We identified 13 novel T2D-associated loci (P < 5 × 10−8), including variants near the GLP2R, GIP, and HLA-DQA1 genes. Our analysis brought the total number of independent T2D associations to 128 distinct signals at 113 loci. Despite substantially increased sample size and more complete coverage of low-frequency variation, all novel associations were driven by common single nucleotide variants. Credible sets of potentially causal variants were generally larger than those based on imputation with earlier reference panels, consistent with resolution of causal signals to common risk haplotypes. Stratification of T2D-associated loci based on T2D-related quantitative trait associations revealed tissue-specific enrichment of regulatory annotations in pancreatic islet enhancers for loci influencing insulin secretion and in adipocytes, monocytes, and hepatocytes for insulin action–associated loci. These findings highlight the predominant role played by common variants of modest effect and the diversity of biological mechanisms influencing T2D pathophysiology.
A Low-Frequency Inactivating AKT2 Variant Enriched in the Finnish Population Is Associated With Fasting Insulin Levels and Type 2 Diabetes Risk

To identify novel coding association signals and facilitate characterization of mechanisms influencing glycemic traits and type 2 diabetes risk, we analyzed 109,215 variants derived from exome array genotyping together with an additional 390,225 variants from exome sequence in up to 39,339 normoglycemic individuals from five ancestry groups. We identified a novel association between the coding variant (p.Pro50Thr) in AKT2 and fasting plasma insulin (FI), a gene in which rare fully penetrant mutations are causal for monogenic glycemic disorders. The low-frequency allele is associated with a 12% increase in FI levels. This variant is present at 1.1% frequency in Finns but virtually absent in individuals from other ancestries. Carriers of the FI-increasing allele had increased 2-h insulin values, decreased insulin sensitivity, and increased risk of type 2 diabetes (odds ratio 1.05). In cellular studies, the AKT2-Thr50 protein exhibited a partial loss of function. We extend the allelic spectrum for coding variants in AKT2 associated with disorders of glucose homeostasis and demonstrate bidirectional effects of variants within the pleckstrin homology domain of AKT2.
Resisting the ‘condom every time for anal sex’ health education message

Objective: Ensuring men who have sex with men (MSM) adopt and maintain condom use for anal sex is a challenging health education goal. In order to inform the development of social marketing practices to encourage safe-sex practices, the views of MSM about a key HIV health education message (‘using a condom every time for anal sex’) were sought. Design: Individual and paired interviews were conducted face-to-face and online, with a total of 22 MSM who identified as low users of condoms. Transcripts of interviews were analysed thematically. Setting: Online and various locations in Auckland, New Zealand. Results: Two main themes were identified in relation to the men’s views of the condom every time message: (a) awareness and appropriateness of the message; and (b) resistance to the message. The men interviewed reported a contradictory view with respect to the condom every time message. While it is viewed as an appropriate message for MSM as a group, for some individual men, particularly those in relationships, the message has little resonance. One solution offered was for the sexual practices of such men to be recognized and for appropriate and more relevant health education messages to be developed. Conclusion: Addressing the gulf between professional and (some) lay understandings of what is appropriate for messages that seek to encourage men to adopt and to maintain condom use, and therefore reduce the chances of HIV infection, remains a significant challenge for health promotion agencies.
Metabolic Syndrome, Insulin Resistance, and Cognitive Dysfunction: Does Your Metabolic Profile Affect Your Brain?

Dementia and type 2 diabetes are both characterized by long prodromal phases, challenging the study of potential risk factors and their temporal relation. The progressive relation among metabolic syndrome, insulin resistance (IR), and dementia has recently been questioned, wherefore the aim of this study was to assess the potential association among these precursors of type 2 diabetes and cognitive dysfunction. Using data from the Prospective Epidemiological Risk Factor (PERF) Study (n = 2,103), a prospective study of elderly women in Denmark, we found that impaired fasting plasma glucose concentration was associated with 44% (9–91%) larger probability of cognitive dysfunction. In addition, subjects above the HOMA-IR threshold (HOMA-IR >2.6) had 47% (9–99%) larger odds of cognitive dysfunction. The associations could indicate that a significant proportion of dementia cases in women is likely to be preventable by effective prevention and control of the insulin homeostasis.
Hypothalamic Inflammation in Human Obesity Is Mediated by Environmental and Genetic Factors

Obesity is associated with hypothalamic inflammation (HI) in animal models. In the current study, we examined the mediobasal hypothalamus (MBH) of 57 obese human subjects and 54 age- and sex- matched nonobese control subjects by MRI and analyzed the T2 hyperintensity as a measure of HI. Obese subjects exhibited T2 hyperintensity in the left but not the right MBH, which was strongly associated with systemic low-grade inflammation. MRS revealed the number of neurons in the left hypothalamic region to be similar in obese versus control subjects, suggesting functional but not structural impairment due to the inflammatory process. To gain mechanistic insights, we performed nutritional analysis and 16S rDNA microbiome sequencing, which showed that high-fat diet induces reduction of Parasutterella sp. in the gut, which is significantly correlated with MBH T2 hyperintensity. In addition to these environmental factors, we found subjects carrying common polymorphisms in the JNK or the MC4R gene to be more susceptible to HI. Finally, in a subgroup analysis, bariatric surgery had no effect on MBH T2 hyperintensity despite inducing significant weight loss and improvement of peripheral insulin sensitivity. In conclusion, obesity in humans is associated with HI and disturbances in the gut-brain axis, which are influenced by both environmental and genetic factors.
Association between parental consumer attitudes with their children’s sensory taste preferences as well as their food choice

Background We investigated the association between the consumer attitudes of European parents and their children’s taste preferences and food choice. Furthermore, we studied whether the parental consumer attitudes were related to education level. Methods This analysis included 1,407 IDEFICS study children aged 6.0 to 11.8 years and from 7 European countries, who participated in the sensory taste perception module between 2007 and 2010. Parental consumer attitude was operationalized as ‘trusting in foods known from advertisements’ (trusting advertisements) and as ‘not avoiding additives in food’ (not avoiding additives). Parents reported their educational attainment and completed a food frequency questionnaire for their children. Consumption frequencies of sweet, fatty and processed foods as well as a healthy diet adherence score were calculated. Children performed fat, sweet and umami taste preference tests. Multivariable logistic models were used to analyse the association between parental consumer attitudes and their children’s taste preference frequencies as well as parental education. Linear regression models were used to analyse the association between parental consumer attitudes and their children’s food consumption. Results Parental consumer attitudes were not associated with children’s fat, sweet and umami taste preferences. Children of parents trusting advertisements consumed more frequently processed foods (β = 1.21, 95% CI: 0.49; 1.93). Children of parents not avoiding additives consumed more often sweet, fatty and processed foods and had a lower healthy diet adherence score (β = 2.37, 95% CI: 1.03; 3.70; β = 2.27, 95% CI: 1.12; 3.43; β = 0.91, 95% CI: 0.22; 1.59; β = -2.87, 95% CI: -3.89; -1.85, respectively). Unfavourable parental consumer attitudes were associated with a lower parental education level across Europe (Compared to high education: Odds Ratio (OR) of trusting advertisements with medium education: 1.04, 95% CI: 0.77; 1.40; OR with low education: 2.01, 95% CI: 1.15; 3.54; OR of not avoiding additives with medium education: 1.91, 95% CI: 1.44; 2.54; OR with low education: 1.76, 95% CI: 0.96; 3.24). Conclusions Across Europe, unfavourable parental consumer attitudes are associated with a lower diet quality of their children. Parental consumer attitudes in turn were associated with their own level of education. This has implications for policy makers, interventions and health promotion programmes that aim to promote healthy eating.
DELUSIONAL SUICIDE BEHAVIOR OF PATIENTS WITH SCHIZOPHRENIA AND METHODS OF ITS PREVENTION

The study involved 320 patients with schizophrenia hospitalized in a psychiatric hospital in connection with various forms of suicidal behavior. The study developed a typology of mechanisms of suicidal behavior of schizophrenics. Analysis of the experience of the Zyprexa (olanzapine) when treating patients with schizophrenia with delusional motivation for suicidal behavior has shown that the drug provides enduring reduction of delusional disorders and reduces the risk of recurrent suicidal behavior. NATALYA RASPOPOVA, EVGENY PANOV
STAPES, FISSULA ANTE FENESTRAM AND ASSOCIATED STRUCTURES IN MAN: III. FROM EMBRYOS 6.7 TO 50 MM. IN LENGTH

In earlier articles 1 the major steps in the rapid embryologic development of the stapes and those in the slower alteration of postnatal specimens were described and illustrated, selected stages between 7½2 weeks (22.8 mm.) and 70 years being utilized; the morphologic aspects of the closely related vestibular rim and fissular prolongation were considered at the same time. In the present phase of the investigation a more inclusive and numerically larger set of stages is being studied, ranging between that of the embryo 6.7 mm. in length and that of an adult aged 75 years. By this means, detailed information on the morphogenesis and increment will be added, and hiatuses in present knowledge of stapedial form will be closed. The current article will carry the stapedial history through stages at which the cartilage has assumed definitely stirrup-shaped form; subsequent articles will account separately for equally crucial morphogenetic epochs. MATERIAL AND