A POT1 mutation implicates defective telomere end fill-in and telomere truncations in Coats plus

Coats plus (CP) can be caused by mutations in the CTC1 component of CST, which promotes polymerase α (polα)/primase-dependent fill-in throughout the genome and at telomeres. The cellular pathology relating to CP has not been established. We identified a homozygous POT1 S322L substitution (POT1^CP) in two siblings with CP. POT1^CP induced a proliferative arrest that could be bypassed by telomerase. POT1^CP was expressed at normal levels, bound TPP1 and telomeres, and blocked ATR signaling. POT1^CP was defective in regulating telomerase, leading to telomere elongation rather than the telomere shortening observed in other telomeropathies. POT1^CP was also defective in the maintenance of the telomeric C strand, causing extended 3′ overhangs and stochastic telomere truncations that could be healed by telomerase. Consistent with shortening of the telomeric C strand, metaphase chromosomes showed loss of telomeres synthesized by leading strand DNA synthesis. We propose that CP is caused by a defect in POT1/CST-dependent telomere fill-in. We further propose that deficiency in the fill-in step generates truncated telomeres that halt proliferation in cells lacking telomerase, whereas, in tissues expressing telomerase (e.g., bone marrow), the truncations are healed. The proposed etiology can explain why CP presents with features distinct from those associated with telomerase defects (e.g., dyskeratosis congenita).     

Related carbapenemase-producing <Emphasis Type="Italic">Klebsiella</Emphasis> isolates detected in both a hospital and associated aquatic environment in Sweden

Carbapenem antibiotics are one of the last-resort agents against multidrug-resistant (MDR) bacteria. The occurrence of carbapenemase-producing Enterobacteriaceae (CPE) in wastewater and aquatic environments is an indication of MDR bacteria in the community. This study evaluated CPE in aquatic environments and compared them to the local hospital isolates in Sweden. Phenotypic and genotypic analyses of antibiotic resistance of environmental and clinical CPE were performed. The relatedness of the isolates and possible clonal dissemination was evaluated using phylogenetic and phyloproteomic analysis. Klebsiella oxytoca carrying carbapenemase genes (bla_VIM-1, bla_IMP-29) were isolated from wastewater and the recipient river, while K. oxytoca (bla_VIM-1) and Klebsiella pneumoniae (bla_VIM-1, bla_OXA-48, bla_NDM-1, bla_KPC-3) were isolated from patients at the local clinics or hospital. The K. oxytoca classified as sequence type 172 (ST172) isolated from the river was genotypically related to two clinical isolates recovered from patients. The similarity between environmental and clinical isolates suggests the dispersion of bla_VIM-1 producing K. oxytoca ST172 from hospital to aquatic environment and the likelihood of its presence in the community. This is the first report of CPE in aquatic environments in Sweden; therefore, surveillance of aquatic and hospital environments for CPE in other urban areas is important to determine the major transfer routes in order to formulate strategies to prevent the spread of MDR bacteria.     

Critical Analysis of Compositions and Protective Efficacies of Oral Killed Cholera Vaccines

Two cholera vaccines, sold as Shanchol and Dukoral, are currently available. This review presents a critical analysis of the protective efficacies of these vaccines. Children under 5 years of age are very vulnerable to cholera and account for the highest incidence of cholera cases and more than half of the resulting deaths. Both Shanchol and Dukoral are two-spaced-dose oral vaccines comprising large numbers of killed cholera bacteria. The former contains Vibrio cholerae O1 and O139 cells, and the latter contains V. cholerae O1 cells with the recombinant B subunit of cholera toxin. In a field trial in Kolkata (India), Shanchol, the preferred vaccine, protected 45% of the test subjects in all of the age groups and only 17% of the children under 5 years of age during the first year of surveillance. In a field trial in Peru, two spaced doses of Dukoral offered negative protection in children under 5 years of age and little protection (15%) in vaccinees over 6 years of age during the first year of surveillance. Little is known about Dukoral''s long-term protective efficacy. Both of these vaccines have questionable compositions, using V. cholerae O1 strains isolated in 1947 that have been inactivated by heat and formalin treatments that may denature protein. Immunological studies revealed Dukoral''s reduced and short-lived efficacy, as measured by several immunological endpoints. Various factors, such as the necessity for multiple doses, poor protection of children under 5 years of age, the requirement of a cold supply chain, production costs, and complex logistics of vaccine delivery, greatly reduce the suitability of either of these vaccines for endemic or epidemic cholera control in resource-poor settings.     

Spousal relations and well‐being: A comparative analysis of Jewish and Arab dual‐earner families in Israel

The study examined differences in division of household tasks and spousal support among a sample of educated dual‐earner families from two national groups in Israel: Jews (n = 116), and Arabs (n = 163). The contribution of the spousal interaction variables (household roles and spousal support) toward explaining two dimensions of psychological well‐being (burnout and life satisfaction) was also examined. The research findings indicate that in general, the Arabs maintain a more traditional orientation toward gender roles than their Jewish counterparts. Arab men showed a greater tendency to perform outside tasks than their Jewish counterparts who participate more in domestic chores. By contrast, no differences were found between the two groups with regard to the mutual support provided by spouses. Gender role attitudes were found to be a key predictor of the two psychological well‐being dimensions in both national groups. Regarding sex differences, men of both nationalities were more likely than women to report that they perform all types of household tasks. Concomitantly, the women reported higher levels of burnout, while no differences between the sexes were found with respect to life satisfaction. © 2003 Wiley Periodicals, Inc.     

Cerebral ischemia-hypoxia induces intravascular coagulation and autophagy

Hypoxia is a critical factor for cell death or survival in ischemic stroke, but the pathological consequences of combined ischemia-hypoxia are not fully understood. Here we examine this issue using a modified Levine/Vannucci procedure in adult mice that consists of unilateral common carotid artery occlusion and hypoxia with tightly regulated body temperature. At the cellular level, ischemia-hypoxia produced proinflammatory cytokines and simultaneously activated both prosurvival (eg, synthesis of heat shock 70 protein, phosphorylation of ERK and AKT) and proapoptosis signaling pathways (eg, release of cytochrome c and AIF from mitochondria, cleavage of caspase-9 and -8). However, caspase-3 was not activated, and very few cells completed the apoptosis process. Instead, many damaged neurons showed features of autophagic/lysosomal cell death. At the tissue level, ischemia-hypoxia caused persistent cerebral perfusion deficits even after release of the carotid artery occlusion. These changes were associated with both platelet deposition and fibrin accumulation within the cerebral circulation and would be expected to contribute to infarction. Complementary studies in fibrinogen-deficient mice revealed that the absence of fibrin and/or secondary fibrin-mediated inflammatory processes significantly attenuated brain damage. Together, these results suggest that ischemia-hypoxia is a powerful stimulus for spontaneous coagulation leading to reperfusion deficits and autophagic/lysosomal cell death in brain.     

Why do primigravidae request caesarean section in a normal pregnancy? A qualitative study in Iran

Objective

to gain a deeper understanding of why Iranian primigravidae request caesarean section without any medical indication.

Design

qualitative study. Data were gathered through semi-structured interviews, and thematic analysis was undertaken.

Setting

four health care centres at Hamadan University of Medical Sciences, Hamadan, Iran.

Participants

14 primigravidae who requested caesarean section without any medical indication.

Findings

reasons for requesting caesarean section were related to fear of childbirth (labour pain, injury to mother or infant), complications after vaginal delivery (vaginal prolapse, urinary incontinence, sexual dysfunction), trust in obstetricians, and lack of trust in maternity ward staff.

Key conclusions and implications for practice

the main reasons given for requesting caesarean section show that there is urgent need for effective antenatal assessment to enable pregnant women to ask questions and express their concerns. In order to promote vaginal birth, there is a need to develop antenatal education and strategies to enhance women's knowledge, confidence and competence about vaginal birth. Health care providers should be re-educated about the observance of medical ethics and professional rules in their practices, and change their attitudes and behaviours to vaginal birth. Evaluation, improvement and change in maternity care policies are recommended to promote natural childbirth.     

Two consecutive hydrolethalus syndrome-affected pregnancies in a nonconsanguinous black couple: Discussion of problems in prenatal differential diagnosis of midline malformation syndromes

Hydrolethalus syndrome is a rare autosomal recessive (AR) disorder characterized by polyhydramnios, CNS abnormalities, cleft lip/palate, micrognathia, and polydactyly. Its molecular basis is unknown and prenatal diagnosis is challenging due to phenotypic overlap with several other midline malformation syndromes. A 34-year-old G3P2, nonconsanguinous, married, Africa-American woman was referred at 19 weeks of gestation after ultrasound finding of “multiple congenital anomalies.” A previous pregnancy had been terminated following ultrasound findings of polyhydramnios, cleft lip/palate, polydactyly, severe hydrocephalus, and a Dandy-Walker malformation (DWM). Level II ultrasound evaluation of the current pregnancy demonstrated all of the anomalies which had been present in her previous pregnancy. Karyotype of amniocytes was 46,XX. Autopsy following pregnancy termination confirmed ultrasound findings. The pedigree, sonographic, and autopsy findings in this case were most consistent with hydrolethalus syndrom, although other AR multiple midline malformation syndromes were considered. Our case was detected by 19 weeks. Confident differential diagnosis is difficult for the geneticist and even more so for the sonologist given the technical limitations of ultrasound. It is uncertain whether these mendelian midline malformation syndromes represent slightly different phenotypic expressions of a common genetic defect or are manifestations of allelic and or locus heterogeneity. We suggest that for prenatal diagnostic purposes, in the absence of knowledge of the molecular basis of these disorders, the fine distinctions are not crucial as long as their mendelian inheritance is recognized and presence or absence of manifestations which make them severe are ascertained. © 1993 Wiley-Liss, Inc.     

Effects of beta-hydroxy-beta-methylbutyrate supplementation on strength and body composition in trained and competitive athletes: A meta-analysis of randomized controlled trials

Objectives

The aim of this meta-analysis was to examine the evidence for the effectiveness of beta-hydroxy-beta-methylbutyrate supplementation interventions on modification in strength and body composition in trained and competitive athletes.

Referral Patterns for Dual-Energy Computed Tomography in Diagnosis and Management of Gout: Ten-Year Experience at a Canadian Institution

Purpose

To analyze the utilization, indications, and outcomes of dual-energy computed tomography (DECT) gout imaging in clinical practice.