Identification of ORC1/CDC6-Interacting Factors in Trypanosoma brucei Reveals Critical Features of Origin Recognition Complex Architecture

DNA Replication initiates by formation of a pre-replication complex on sequences termed origins. In eukaryotes, the pre-replication complex is composed of the Origin Recognition Complex (ORC), Cdc6 and the MCM replicative helicase in conjunction with Cdt1. Eukaryotic ORC is considered to be composed of six subunits, named Orc1–6, and monomeric Cdc6 is closely related in sequence to Orc1. However, ORC has been little explored in protists, and only a single ORC protein, related to both Orc1 and Cdc6, has been shown to act in DNA replication in Trypanosoma brucei. Here we identify three highly diverged putative T. brucei ORC components that interact with ORC1/CDC6 and contribute to cell division. Two of these factors are so diverged that we cannot determine if they are eukaryotic ORC subunit orthologues, or are parasite-specific replication factors. The other we show to be a highly diverged Orc4 orthologue, demonstrating that this is one of the most widely conserved ORC subunits in protists and revealing it to be a key element of eukaryotic ORC architecture. Additionally, we have examined interactions amongst the T. brucei MCM subunits and show that this has the conventional eukaryotic heterohexameric structure, suggesting that divergence in the T. brucei replication machinery is limited to the earliest steps in origin licensing

GHD Diagnostics in Europe and the US: An Audit of National Guidelines and Practice

Introduction: Almost 20 years after the first international guidelines on the diagnosis and treatment of GHD have been published, clinical practice varies significantly. The low accuracy of endocrine tests for GHD and the burden caused by ineffective treatment of individual patients were strong motives for national endocrine societies to set up national guidelines regarding how to diagnose GHD in childhood. This audit aims to review the current state and identify common changes, which may improve the diagnostic procedure. Methods: A group of eight German pediatric endocrinologists contacted eight pediatric endocrinologists from Spain, France, Poland, the UK, the Netherlands, Denmark, Italy, and the US. Each colleague responded as a representative for the own country to a detailed questionnaire containing 22 open questions about national rules, guidelines, and practice with respect to GHD diagnostics and GH prescription. The results were presented and discussed in a workshop and then documented in this study which was reviewed by all participants. Results: National guidelines are available in 7 of 9 countries. GH is prescribed by pediatric endocrinologists in most countries. Some countries have established boards that review and monitor prescriptions. Preferred GH stimulation tests and chosen cutoffs vary substantially. Overall, a trend to lowering the GH cutoff was identified. Priming is becoming more popular and now recommended in 5 out of 9 countries; however, with different protocols. The definition of pretest-conditions that qualify the patient to undergo GH testing varies substantially in content and strictness. The most frequently used clinical sign is low height velocity, but definition varies. Height, IGF-1, and bone age are additional parameters recommended in some countries. Conclusions: GHD diagnostics varies substantially in eight European countries and in the US. It seems appropriate to undertake further efforts to harmonize endocrine diagnostics in Europe and the US based on available scientific evidence

Airway surface liquid pH is not acidic in children with cystic fibrosis

© 2017 The Author(s). Modulation of airway surface liquid (ASL) pH has been proposed as a therapy for cystic fibrosis (CF). However, evidence that ASL pH is reduced in CF is limited and conflicting. The technical challenges associated with measuring ASL pH in vivo have precluded accurate measurements in humans. In order to address this deficiency, ASL pH was measured in vivo in children using a novel luminescent technology integrated with fibre-optic probes. Here we show that ASL pH in children with CF is similar to that of children without CF. Findings were supported by highly controlled direct pH measurements in primary human airway epithelial cell culture models, which also suggest that the potential ASL pH gradient produced by defective apical ion transport is balanced out by paracellular shunting of acid/base. Thus, reduced baseline ASL pH is unlikely to be an important pathobiological factor in early CF lung disease

Latino Mother/Daughter Dyadic Attachment as a Mediator for Substance Use Disorder and Emotional Abuse

BACKGROUND: To date, no studies have investigated emotional abuse of adult Latina women by their mothers despite evidence that emotional maternal abuse may significantly contribute to the emotional abuse experienced by Latina women in their lifetime. METHODS: Cross-sectional data including 316 women was analyzed using mediation and logistic regression. RESULTS: Overall, 7.1% of mothers and 24.1% of daughters abused drugs; and, 19.5% of daughters were emotionally abused by their mothers. Mother's attachment to her daughter mediated the association between mother's drug abuse and emotionally abusing her adult daughter (Indirect effect: 0.863). DISCUSSION: Latina women can serve as perpetrators of emotional abuse of their adult children. Since drug-abusing daughters are more likely to be victims of emotional abuse by their mothers and drug-abusing mothers are more likely to abuse their daughters, drug-rehabilitation practitioners should incorporate a family abuse component into rehabilitation programs

Specialist prescribing of psychotropic drugs to older persons in Sweden - a register-based study of 188 024 older persons

<p>Abstract</p> <p>Background</p> <p>The situation for older persons with mental disorders other than dementia disorders has scarcely been studied. The older population is increasing worldwide and along with this increase the prevalence of mental disorders will also rise. The treatment of older persons with mental disorders entails complex challenges, with drugs constituting the major medical treatment. Knowledge of geriatric psychiatry is essential for providing older persons with appropriate treatment and care. This study aimed to evaluate the prescription of drugs for mental disorders to older persons (≥65) in Sweden, focused on the medical specialties of the prescribing physicians.</p> <p>Methods</p> <p>Data concerning drug treatment for older persons from 2006 to 2008 was gathered from the Swedish Prescribed Drug Register. Mental disorders, defined as affective, psychotic and anxiety disorders (ICD-10 F20-42) were evaluated in order to identify associated drugs. Included was a total of 188 024 older individuals, who collectively filled 2 013 079 prescriptions for the treatment of mental disorders. Descriptive analyses were performed, including frequency distribution and 95% CI. The competence of the prescribers was analyzed by subdividing them into five groups: geriatricians, psychiatrists, general practitioners (GPs), other specialists, and physicians without specialist education.</p> <p>Results</p> <p>GPs represented the main prescribers, whereas geriatricians and psychiatrists rarely prescribed drugs to older persons. Benzodiazepines and tricyclic antidepressants were the most commonly prescribed drugs. Women were prescribed drugs from geriatricians and psychiatrists to a greater extent than men.</p> <p>Conclusions</p> <p>This study examined the prescription of psychotropic drugs to older persons. Physicians specialized in older persons’ disorders and mental health were rarely the prescribers of these drugs. Contrary to clinical guidelines, benzodiazepines and tricyclic antidepressants were commonly prescribed to older persons, emphasizing the need for continuous examination of pharmaceutical treatment for older persons. The results indicate a future need of more specialists in geriatrics and psychiatry.</p

Asthma and chronic obstructive airway diseases are associated with osteoporosis and fractures: A literature review

The objective was to assess the association between asthma and/or chronic obstructive airway diseases (COAD), and osteoporosis, and appraise treatments of osteoporosis in these patients. MEDLINE and Excerpta Medica were searched for original research with control groups which tested the above association. One cohort and nine cross-section studies of bone density in patients with asthma and/or COAD were retrieved. These demonstrated clinically important bone density reductions of up to 29% in subjects, dependent upon daily oral corticosteroids, by a variety of measurement techniques, at various bone sites. Bone density reduction has also been less consistently reported in the absence of oral corticosteroids, suggesting that other factors including high-dose inhaled corticosteroids may have a role. Fracture studies. Three studies in oral corticosteroid-dependent asthmatics demonstrated a vertebral fracture prevalence up to 56%, and annual vertebral fracture incidence of up to 42%. The strength of the available evidence is limited, but suggests that patients with asthma and/or COAD are at increased risk of osteoporosis. The evidence of the association between osteoporosis and inhaled corticosteroids is much more limited than for oral corticosteroids. Bisphosphonates are promising agents to maintain and/or promote bone mass in this patient group.Brian Smith, Patrick Phillips, Richard Helle