Miracle-dz/UniFAR-FTUs huggingface dataset:
A systematic review of body temperature variations in older people.

AIM The purpose of this systematic review was to determine the extent to which the research literature indicates body temperature norms in the geriatric population. OBJECTIVES The specific questions addressed were to examine normal body temperature values in persons 60 years of age and older; determine differences in temperature values depending on non-invasive measurement site and measurement device used; and, examine the degree and extent of temperature variability according to time of day and time of year. BACKGROUND The traditional 'normal' temperature of 98.6 degrees F/37 degrees C may in fact be lower in older people due to the ageing process. Age-associated changes in vasomotor sweating function, skeletal muscle response, temperature perception and physical behaviours may influence the ability to maintain optimum temperature. DESIGN A systematic literature review. METHODS A search of multiple databases yielded 22 papers which met inclusion criteria. Studies were included which focused on temperature measurement, sampled persons 60 years of age and older, collected data from non-invasive temperature measurement sites and which used a prospective study design. Studies were independently appraised using a structured appraisal format. RESULTS Temperature normal values by site were rectal 98.8 degrees F/37.1 degrees C, ear-based 98.3 degrees F/36.8 degrees C, urine 97.6 degrees F/36.5 degrees C, oral 97.4 degrees F/36.3 degrees C and axillary 97.1 degrees F/36.2 degrees C. Temperature exhibited a 0.7 degrees F/0.4 degrees C diurnal and 0.2 degrees F/0.1 degrees C circannual variation. CONCLUSIONS Synthesis of data indicated that normal body temperature values in older people by sites were rectal 0.7 degrees F/0.4 degrees C, ear-based 0.3 degrees F/0.2 degrees C, oral 1.2 degrees F/0.7 degrees C, axillary 0.6 degrees F/0.3 degrees C lower than adults' acceptable value from those traditionally found in nursing textbooks. RELEVANCE TO CLINICAL PRACTICE Given the fact that normal body temperature values were consistently lower than values reported in the literature, clinicians may need to re-evaluate the point at which interventions for abnormal temperatures are initiated.
Hypertonie in der Schwangerschaft: Diagnostik und Therapie

Hypertension in Pregnancy. Diagnosis and Management. Up to 10% of pregnant women present with hypertension (office blood pressure  140/ 90 mmHg) being either preexistent or induced by the pregnancy as a result of impaired placental development. Approximately a quarter of them will develop preeclampsia, a multiorgan disease with high risk for morbidity and mortality of mother and child. Measurement of blood pressure needs strict adherence to rules and use of devices validated for pregnant women. As white coat hypertension is common, elevated blood pressure has to be checked by ambulatory 24-hour monitoring. Current national guidelines differ in their definitions and recommendations concerning monitoring, cut-off and target values of blood pressure as well as selection of drugs. The following definitions and recommendation on the available literature should be taken as proposals to manage hypertensive pregnant women. Office blood pressure above 160/100 mmHg measured on two different occasions should in any case be lowered to < 150/100 mmHg, preferentially by taking advantage of life style measures. In case of coexisting organ damage blood pressure above 140/90 mmHg should be lowered to 130–140/< 90 mmHg. If preeclampsia is present, cut-off for initiating treatment is 150/100 mmHg with a target of 130–150/< 100 mmHg. First-line drugs are labetalol, -methyldopa and nifedipine. Second line drugs encompass other dihydropyridine calcium channel blockers, hydralazine, clonidine and prazosin, for emergencies also intravenous urapidil. ACE-blockers, ARBs, direct renin inhibitors, and spironolactone are contraindicated. Management of a pregnant woman with hypertension always requires close cooperation of obstetricians and hypertension experts. J Hypertonie 2015; 19 (4): 107–113.
Identification of N-terminal Residues of Sonic Hedgehog Important for Palmitoylation by Hedgehog Acyltransferase*

Background: Sonic hedgehog (Shh) is a secreted protein that needs to be palmitoylated to signal. Results: The first six amino acids of mature Shh are sufficient for palmitoylation. Conclusion: Hedgehog acyltransferase, the enzyme that palmitoylates Shh, recognizes N-terminal substrate residues. Significance: This serves as a model for understanding how secreted morphogens are modified by distinct palmitoyl acyltransferases. Sonic Hedgehog (Shh) is a secreted morphogen that regulates embryonic development. After removal of the signal peptide, Shh is processed to the mature, active form through autocleavage and a series of lipid modifications, including the attachment of palmitate. Covalent attachment of palmitate to the N-terminal cysteine of Shh is catalyzed by Hedgehog acyltransferase (Hhat) and is critical for proper signaling. The sequences within Shh that are responsible for palmitoylation by Hhat are not known. Here we show that the first six amino acids of mature Shh (CGPGRG) are sufficient for Hhat-mediated palmitoylation. Alanine scanning mutagenesis was used to determine the role of each amino acid and the positional sequence requirement in a cell-based Shh palmitoylation assay. Mutation of residues in the GPGR sequence to Ala had no effect on palmitoylation, provided that a positively charged residue was present within the first seven residues. The N-terminal position exhibited a strong but not exclusive requirement for Cys. Constructs with an N-terminal Ala were not palmitoylated. However, an N-terminal Ser served as a substrate for Hhat, but not the Drosophila melanogaster ortholog Rasp, highlighting a critical difference between the mammalian and fly enzymes. These findings define residues and regions within Shh that are necessary for its recognition as a substrate for Hhat-mediated palmitoylation. Finally, we report the results of a bioinformatics screen to identify other potential Hhat substrates encoded in the human genome.
Pharmacogenetics and the pharmacy profession : a sociological exploration

Pharmacy, particularly in the community setting, has been subject to significant changes over the last three decades. Running concurrently to these changes has been the development of the field of pharmacogenetics, or ‘personalised medicine’, which is likely to have significant impacts on hospital and community pharmacy practice. Despite this, little sociological research has been undertaken to map the contemporary pharmacy landscape into which pharmacogenetics may be integrated and the effects that pharmacogenetics may have on pharmacy. Through 38 semi-structured interviews with diverse practitioners, this thesis addresses these gaps in the academic literature by positing a novel sociological model through which contemporary pharmacy practice may be analysed and examining the potential impacts of pharmacogenetics on it. It is argued that a dual approach to the management of medicines intersects both community and hospital pharmacy. Within this dual medicines management model, codified, organisational interests in medicines management are practised alongside a more negotiated approach which is enacted through what has been called here the ‘pharmacy gaze’. The pharmacy gaze characterises the ways in which medicines and the patient bodies to which they are administered are co-constructed by pharmacists through discourses of risk and toxicity. Pharmacogenetics, it is argued, represents a way in which the pharmacy gaze, and patient bodies within it, may be increasingly molecularised and risk and toxicity increasingly managed at the genetic level within pharmacy practice. Within this, a number of ‘pharmacogenetic futures’ involving pharmacy testing, patient counselling and practitioner education are presented although these are argued to be highly speculative and to present a number of macro- and micro-level challenges for policy makers and pharmacists. The thesis concludes by making a number of recommendations as to how some of these challenges may be addressed.
Allergen-Specific Immunotherapy for the Treatment of Allergic Rhinoconjunctivitis and/or Asthma: Comparative Effectiveness Review

Authors' objectives Allergic rhinitis is highly prevalent in North America, affecting 20 to 40 percent of the population. Nearly 9 percent of Americans suffer from asthma, with more than half having evidence of atopy. This comparative effectiveness review describes the effectiveness and safety of subcutaneous immunotherapy and sublingual immunotherapy (off-label use of subcutaneous-aqueous allergens for sublingual desensitization) compared with other therapies for treatment of allergic rhinoconjunctivitis and asthma.
What is the genetic relationship between anxiety and depression?

Anxiety and depression share a long, close history in psychiatric nosology and treatment. The anxiety disorders, individually and as a group, exhibit remarkably high rates of comorbidity with each other and with major depression. Analyses done in large‐scale epidemiologic surveys have identified major patterns of phenomenological overlap between these conditions. Researchers have tested hypotheses of shared genetic etiologies as a potential basis of this relationship. In general, available family studies have found mixed evidence for co‐aggregation of anxiety and depressive disorders, while twin studies more definitively indicate that shared genetic risk factors largely account for this comorbidity. Some of this appears to be accounted for by genetic variation in personality traits that broadly predispose to anxiety and depression. Molecular genetic studies of these conditions, though too early to draw firm conclusions, thus far provide tentative support for specific genetic loci that may generally influence susceptibility across the anxiety‐depressive spectrum. © 2008 Wiley‐Liss, Inc.
Therapist effects in randomised controlled trials: what to do about them.

AIMS AND OBJECTIVES The aim of this study is to describe and compare three statistical methods to allow for therapist effects in individually randomised controlled trials. BACKGROUND In an individually randomised controlled trial where the intervention is delivered by a health professional it seems likely that the effectiveness of the intervention, independent of any treatment effect, could depend on the skill of the health professional delivering it. This leads to a potential clustering of the outcomes for the patients being treated by the same health professional. DESIGN Retrospective statistical analysis of outcomes from four example randomised controlled trial datasets with potential clustering by health professional. METHODS Three methods to allow for clustering are described: cluster level analysis; random effects models and marginal models. These models were fitted to continuous outcome data from four example randomised controlled trial datasets with potential clustering by health professional. RESULTS The cluster level models produced the widest confidence intervals. Little difference was found between the estimates of the regression coefficients for the treatment effect and confidence intervals between the individual patient level models for the datasets. The conclusions reached for each dataset match those published in the original papers. The intracluster correlation coefficient ranged from <0.001-0.04 for the outcomes, which shows only minor levels of clustering within the datasets. CONCLUSIONS The models, which use individual level data are to be preferred. Treatment coefficients from these models have different interpretations. The choice of model should depend on the scientific question being asked. RELEVANCE TO CLINICAL PRACTICE We recommend that researchers should be aware of any potential clustering, by health professional, in their randomised controlled trial and use appropriate methods to account for this clustering in the statistical analysis of the data.
Quality assurance in medical and public health genetics services: A systematic review

As genetic services grow in scope, issues of quality assessment in genetic services are emerging. These efforts are well developed for molecular and cytogenetic testing and laboratories, and newborn screening programs, but assessing quality in clinical services has lagged, perhaps owing to the small work force and the recent evolution from a few large training programs to multiple training sites. We surveyed the English language, peer‐reviewed literature to summarize the knowledge‐base of quality assessment of genetics services, organized into the tripartite categories of the Donabedian model of “structure,” “process,” and “outcome. ” MEDLINE searches from 1990 to July 2008, yielded 2,143 articles that addressed both “medical/genetic screening and counseling” and “quality indicators, control, and assurance. ” Of the 2,143 titles, 131 articles were extracted for in‐depth analysis, and 55 were included in this review. Twenty‐nine articles focused on structure, 19 on process, and seven on outcomes. Our review underscored the urgent need for a coherent model that will provide health care organizations with tools to assess, report, monitor, and improve quality. The structure, process, and outcomes domains that make up the quality framework provide a comprehensive lens through which to examine quality in medical genetics. © 2009 Wiley‐Liss, Inc.
Public definitions of success in weight management

Objective: To examine perceptions of success in weight control and future weight-control intentions in a community sample. Design: Cross-sectional postal survey. Subjects: There were 1500 adults randomly selected from the Electoral Roll of Victoria (47% response). Setting: Community. Main outcome measures: Retrospective weight change over previous 12 months; perceived weight-control success; future weight-control intentions. Statistical analyses: Pearson's χ² tests were used to compare perceived weight-control success by sex, and by age, education level, initial BMI, amount of weight change and weight-loss behaviour within sex. ANOVA was used to compare mean weight change associated with perceived weight control success within sex, and within age, education, body mass index and weight-loss behaviour by sex. The distribution (frequency) of weight-control intentions are reported within perceived weight-control success and amount of weight change. Results: One in two (53%) reported maintaining their weight within 1kg in the preceding 12 months, 26% of men and 21% of women reported weight gain and 20% of men and 26% of women reported weight loss. Almost one-third (30%) of those who maintained their weight considered themselves unsuccessful. A majority of those who lost weight considered themselves successful at controlling their weight. However, more than 45% of men who gained weight also considered themselves successful. Those who considered themselves unsuccessful experienced less weight loss (1.1 ± 3.9kg) than those who considered themselves quite successful (-1.4 ± 4.5 kg, P
Phosphatidylethanolamine Deficiency in Mammalian Mitochondria Impairs Oxidative Phosphorylation and Alters Mitochondrial Morphology*

Background: The contribution of phosphatidylethanolamine (PE) to mammalian mitochondrial function was unknown. Results: A decrease in mitochondrial PE impairs cell growth, respiratory capacity, and ATP production and profoundly alters mitochondrial morphology. Conclusion: Mitochondrial PE is required for normal morphology and function of mammalian mitochondria. Significance: Modest reduction of mitochondrial PE might contribute to mitochondrial dysfunction in some disease states. Mitochondrial dysfunction is implicated in neurodegenerative, cardiovascular, and metabolic disorders, but the role of phospholipids, particularly the nonbilayer-forming lipid phosphatidylethanolamine (PE), in mitochondrial function is poorly understood. Elimination of mitochondrial PE (mtPE) synthesis via phosphatidylserine decarboxylase in mice profoundly alters mitochondrial morphology and is embryonic lethal (Steenbergen, R., Nanowski, T. S., Beigneux, A., Kulinski, A., Young, S. G., and Vance, J. E. (2005) J. Biol. Chem. 280, 40032–40040). We now report that moderate <30% depletion of mtPE alters mitochondrial morphology and function and impairs cell growth. Acute reduction of mtPE by RNAi silencing of phosphatidylserine decarboxylase and chronic reduction of mtPE in PSB-2 cells that have only 5% of normal phosphatidylserine synthesis decreased respiratory capacity, ATP production, and activities of electron transport chain complexes (C) I and CIV but not CV. Blue native-PAGE analysis revealed defects in the organization of CI and CIV into supercomplexes in PE-deficient mitochondria, correlated with reduced amounts of CI and CIV proteins. Thus, mtPE deficiency impairs formation and/or membrane integration of respiratory supercomplexes. Despite normal or increased levels of mitochondrial fusion proteins in mtPE-deficient cells, and no reduction in mitochondrial membrane potential, mitochondria were extensively fragmented, and mitochondrial ultrastructure was grossly aberrant. In general, chronic reduction of mtPE caused more pronounced mitochondrial defects than did acute mtPE depletion. The functional and morphological changes in PSB-2 cells were largely reversed by normalization of mtPE content by supplementation with lyso-PE, a mtPE precursor. These studies demonstrate that even a modest reduction of mtPE in mammalian cells profoundly alters mitochondrial functions.
Deregulation of Apoptotic Factors Bcl-xL and Bax Confers Apoptotic Resistance to Myeloid-derived Suppressor Cells and Contributes to Their Persistence in Cancer*

Background: The mechanism underlying MDSC persistence in tumor-bearing hosts is elusive. Results: IRF8 is down-regulated in MDSCs, resulting in Fas, Bax, and Bcl-xL deregulation and decreased spontaneous apoptosis. Conclusion: Increased resistance to Fas-mediated apoptosis is at least partially responsible for MDSC accumulation. Significance: Targeting Bcl-xL is potentially an effective approach to suppress MDSCs in cancer therapy. Myeloid-derived suppressor cells (MDSCs) are heterogeneous immature myeloid cells that accumulate in response to tumor progression. Compelling data from mouse models and human cancer patients showed that tumor-induced inflammatory mediators induce MDSC differentiation. However, the mechanisms underlying MDSC persistence is largely unknown. Here, we demonstrated that tumor-induced MDSCs exhibit significantly decreased spontaneous apoptosis as compared with myeloid cells with the same phenotypes from tumor-free mice. Consistent with the decreased apoptosis, cell surface Fas receptor decreased significantly in tumor-induced MDSCs. Screening for changes of key apoptosis mediators downstream the Fas receptor revealed that expression levels of IRF8 and Bax are diminished, whereas expression of Bcl-xL is increased in tumor-induced MDSCs. We further determined that IRF8 binds directly to Bax and Bcl-x promoter in primary myeloid cells in vivo, and IRF8-deficient MDSC-like cells also exhibit increased Bcl-xL and decreased Bax expression. Analysis of CD69 and CD25 levels revealed that cytotoxic T lymphocytes (CTLs) are partially activated in tumor-bearing hosts. Strikingly, FasL but not perforin and granzymes were selectively activated in CTLs in the tumor-bearing host. ABT-737 significantly increased the sensitivity of MDSCs to Fas-mediated apoptosis in vitro. More importantly, ABT-737 therapy increased MDSC spontaneous apoptosis and decreased MDSC accumulation in tumor-bearing mice. Our data thus determined that MDSCs use down-regulation of IRF8 to alter Bax and Bcl-xL expression to deregulate the Fas-mediated apoptosis pathway to evade elimination by host CTLs. Therefore, targeting Bcl-xL is potentially effective in suppression of MDSC persistence in cancer therapy.
The genetics of lissencephaly

Lissencephaly is a spectrum of severe brain malformations caused by the failure of migrating neurons to reach optimal positions in the developing cerebral cortex. Several syndromes associated with lissencephaly have been characterized in recent years. Identification of the genetic basis of these disorders has brought fascinating insights into the mechanisms of brain development, as well as benefits to patients through improved molecular diagnosis and genetic counseling. This review explores the clinical presentation, radiological features, histological findings and molecular basis of lissencephaly with the aim of facilitating the selection and interpretation of gene tests in patients with ‘smooth brain’ phenotypes. © 2014 Wiley Periodicals, Inc.
Impaired Intestinal Calcium Absorption in Protein 4.1R-deficient Mice Due to Altered Expression of Plasma Membrane Calcium ATPase 1b (PMCA1b)*

Background: The function of protein 4.1R in small intestinal epithelia is unknown. Results: 4.1R deficiency resulted in decreased expression of PMCA1b and impaired small intestinal calcium absorption. Conclusion: Protein 4.1R plays an important role in small intestinal calcium absorption. Significance: Our results identify a novel function for protein 4.1R and offer new insights into the mechanism of calcium absorption. Protein 4.1R was first identified in the erythrocyte membrane skeleton. It is now known that the protein is expressed in a variety of epithelial cell lines and in the epithelia of many tissues, including the small intestine. However, the physiological function of 4.1R in the epithelial cells of the small intestine has not so far been explored. Here, we show that 4.1R knock-out mice exhibited a significantly impaired small intestinal calcium absorption that resulted in secondary hyperparathyroidism as evidenced by increased serum 1,25-(OH)2-vitamin D3 and parathyroid hormone levels, decreased serum calcium levels, hyperplasia of the parathyroid, and demineralization of the bones. 4.1R is located on the basolateral membrane of enterocytes, where it co-localizes with PMCA1b (plasma membrane calcium ATPase 1b). Expression of PMCA1b in enterocytes was decreased in 4.1−/− mice. 4.1R directly associated with PMCA1b, and the association involved the membrane-binding domain of 4.1R and the second intracellular loop and C terminus of PMCA1b. Our findings have enabled us to define a functional role for 4.1R in small intestinal calcium absorption through regulation of membrane expression of PMCA1b.
5p deletions: Current knowledge and future directions

Disorders resulting from 5p deletions (5p−) were first recognized by Lejeune et al. in 1963 [Lejeune et al. (1963); C R Hebd Seances Acad Sci 257:3098–3102]. 5p− is caused by partial or total deletion of the short arm of chromosome 5. The most recognizable phenotype is characterized by a high‐pitched cry, dysmorphic features, poor growth, and developmental delay. This report reviews 5p− disorders and their molecular basis. Hemizygosity for genes located within this region have been implicated in contributing to the phenotype. A review of the genes on 5p which may be dosage sensitive is summarized. Because of the growing knowledge of these specific genes, future directions to explore potential targeted therapies for individuals with 5p− are discussed. © 2015 Wiley Periodicals, Inc.