Holt-Oram syndrome (HOS) is an autosomal dominant condition characterised by the association of congenital heart defect (CHD), with or without rhythm disturbances and radial defects, due to TBX5 ...variants. The diagnosis is challenged by the variability of expression and the large phenotypic overlap with other conditions, like Okihiro syndrome, TAR syndrome or Fanconi disease. We retrospectively reviewed 212 patients referred for suspicion of HOS between 2002 and 2014, who underwent TBX5 screening. A TBX5 variant has been identified in 78 patients, representing the largest molecular series ever described. In the cohort, 61 met the previously described diagnostic criteria and 17 have been considered with an uncertain HOS diagnosis. A CHD was present in 91% of the patients with a TBX5 variant, atrial septal defects being the most common (61.5%). The genotype-phenotype study highlights the importance of some critical features in HOS: the septal characteristic of the CHD, the bilateral and asymmetric characteristics of the radial defect and the presence of shoulder or elbow mobility defect. Besides, 21 patients presented with an overlapping condition. Among them, 13 had a typical HOS presentation. We discuss the strategies that could be adopted to improve the molecular delineation of the remaining typical patients.
Purpose
The purpose of this paper is to explore the concept of occupational disidentification through the lens of conservation of resources (COR) theory (Hobfoll, 1989, 1998). Occupational ...disidentification is conceptualized as a coping strategy, or an investment of resources to cope with poor perceived prestige of the occupation, which represents a threat to an individual’s resource: one’s self-esteem. However, occupational disidentification, as an avoidance coping strategy, generates a loss of cognitive and emotional resources leading to emotional exhaustion and, in turn, departure from the organization.
Design/methodology/approach
The research hypotheses are tested among two samples of employees working in health and social services (Study 1, N=544), and in home care services (Study 2, N=113). Measures of employees’ attitudes were collected at the same time, and turnover was collected 18 months (Study 1) and 12 months (Study 2) later.
Findings
Research hypotheses are all supported. Occupational disidentification partially mediates the occupational prestige-emotional exhaustion relationship, and emotional exhaustion partially mediates the occupational disidentification-turnover intention relationship. Perceived organizational support moderates the negative relationship between perceived occupational prestige and occupational disidentification.
Originality/value
The main contribution of this study is the conceptualization of occupational disidentification within the theoretical framework of COR. In that vein, the study provides: a deeper understanding of the mechanisms explaining and buffering occupational disidentification, and empirical evidence of the key role of emotional exhaustion to explain the consequences of occupational disidentification.
Microtubules are cytoskeletal polymers of tubulin involved in many cellular functions. Their dynamic instability is controlled by numerous compounds and proteins, including colchicine and stathmin ...family proteins. The way in which microtubule instability is regulated at the molecular level has remained elusive, mainly because of the lack of appropriate structural data. Here, we present the structure, at 3.5 Å resolution, of tubulin in complex with colchicine and with the stathmin-like domain (SLD) of RB3. It shows the interaction of RB3-SLD with two tubulin heterodimers in a curved complex capped by the SLD amino-terminal domain, which prevents the incorporation of the complexed tubulin into microtubules. A comparison with the structure of tubulin in protofilaments shows changes in the subunits of tubulin as it switches from its straight conformation to a curved one. These changes correlate with the loss of lateral contacts and provide a rationale for the rapid microtubule depolymerization characteristic of dynamic instability. Moreover, the tubulin-colchicine complex sheds light on the mechanism of colchicine's activity: we show that colchicine binds at a location where it prevents curved tubulin from adopting a straight structure, which inhibits assembly.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Blepharocheilodontic (BCD) syndrome is a rare autosomal dominant condition characterized by eyelid malformations, cleft lip/palate, and ectodermal dysplasia. The molecular basis of BCD syndrome ...remains unknown.
We recruited 11 patients from 8 families and performed exome sequencing for 5 families with de novo BCD syndrome cases and targeted Sanger sequencing in the 3 remaining families.
We identified five CDH1 heterozygous missense mutations and three CTNND1 heterozygous truncating mutations leading to loss-of-function or haploinsufficiency. Establishment of detailed genotype-phenotype correlations was not possible because of the size of the cohort; however, the phenotype seems to appear more severe in case of CDH1 mutations. Functional analysis of CDH1 mutations confirmed their deleterious impact and suggested accelerated E-cadherin degradation.
Mutations in CDH1 encoding the E-cadherin were previously reported in hereditary diffuse gastric cancer as well as in nonsyndromic cleft lip/palate. Mutations in CTNND1 have never been reported before. The encoded protein, p120ctn, prevents E-cadherin endocytosis and stabilizes its localization at the cell surface. Conditional deletion of Cdh1 and Ctnnd1 in various animal models induces features reminiscent of BCD syndrome and underlines critical role of the E-cadherin-p120ctn interaction in eyelid, craniofacial, and tooth development. Our data assert BCD syndrome as a CDH1 pathway-related disorder due to mutations in CDH1 and CTNND1 and widen the phenotypic spectrum of E-cadherin anomalies.Genet Med advance online publication 09 March 2017.
Cancer patients are at high risk for acute kidney injury (AKI), which is associated with high morbidity and mortality. We sought to appraise the incidence, risk factors, and outcome of AKI in a large ...multicentre cohort study of critically ill patients with haematological malignancies.
We used a retrospective analysis of a prospectively collected database. The study was carried out in 17 university or university-affiliated centres in France and Belgium between 2010 and 2012. AKI was defined according to the Acute Kidney Injury Network (AKIN) definition.
Of the 1011 patients admitted into the intensive care unit (ICU) during the study period, 1009 were included in this study. According to the AKIN definition, 671 patients (66.5%) developed an AKI during their ICU stay, of which 258 patients (38.4%) were AKI stage 1, 75 patients (11.2%) AKI stage 2 and 338 patients (50.4%) AKI stage 3. After adjustment for confounders, main adverse risk factors of AKI were older age, severity non-renal Sequential Organ Failure Assessment (SOFA), history of hypertension, tumour lysis syndrome, exposure to nephrotoxic agents and myeloma. Hospital mortality was 44.3% in patients with AKI and 25.4% in patients without AKI (P < 0.0001). After adjustment for confounders, AKI was independently associated with hospital mortality OR 1.65 (95% CI 1.19-2.29). Overall, 271 patients required renal replacement therapy (RRT), of whom 57.2% died during their hospital stay as compared with 31.2% (P < 0.0001) in those not requiring RRT.
Two-thirds of critically ill patients with haematological malignancies developed AKI. Hospital mortality in this population of patients developing AKI or requiring RRT is close to that in general ICU population.
Systematic face-to-face pre-HIV test counseling is costly and may discourage clients to present for regular testing. In a randomized, controlled, non-inferiority trial conducted in four facilities ...providing free-of-charge anonymous HIV testing in Thailand, participants received either: standard counseling according to national guidelines (reference); computer-assisted counseling: interactive counseling on a tablet computer followed by an invitation to ask questions to the counselor; or on-demand counseling: invitation to ask questions to the counselor. Primary endpoint was a HIV retest within 7 months after enrolment visit. Following the planned interim analysis, on-demand counseling was discontinued for futility. In the final analysis in 1036 HIV-uninfected at-risk participants, computer-assisted counseling was non-inferior to standard counseling and had similar acceptability and improvements in HIV knowledge and sexual risk behaviors; however, it significantly reduced the time spent by counselors on counseling. Implementation of pre-HIV test computer-assisted counseling may ease the burden on staff involved in HIV testing.
The expression gradient of the morphogen Sonic Hedgehog (SHH) is crucial in establishing the number and the identity of the digits during anteroposterior patterning of the limb. Its anterior ectopic ...expression is responsible for preaxial polydactyly (PPD). Most of these malformations are due to the gain-of-function of the Zone of Polarizing Activity Regulatory Sequence, the only limb-specific enhancer of SHH known to date. We report a family affected with a novel condition associating PPD and hypertrichosis of the upper back, following an autosomal dominant mode of inheritance. This phenotype is consistent with deregulation of SHH expression during limb and follicle development. In affected members, we identified a 2 kb deletion located ~240 kb upstream from the SHH promoter. The deleted sequence is capable of repressing the transcriptional activity of the SHH promoter in vitro, consistent with a silencer activity. We hypothesize that the deletion of this silencer could be responsible for SHH deregulation during development, leading to a PPD-hypertrichosis phenotype.
In Europe, many flaviviruses are endemic (West Nile, Usutu, tick-borne encephalitis viruses) or occasionally imported (dengue, yellow fever viruses). Due to the temporal and geographical ...co-circulation of flaviviruses in Europe, flavivirus differentiation by diagnostic tests is crucial in the adaptation of surveillance and control efforts. Serological diagnosis of flavivirus infections is complicated by the antigenic similarities among the Flavivirus genus. Indeed, most flavivirus antibodies are directed against the highly immunogenic envelope protein, which contains both flavivirus cross-reactive and virus-specific epitopes. Serological assay results should thus be interpreted with care and confirmed by comparative neutralization tests using a panel of viruses known to circulate in Europe. However, antibody cross-reactivity could be advantageous in efforts to control emerging flaviviruses because it ensures partial cross-protection. In contrast, it might also facilitate subsequent diseases, through a phenomenon called antibody-dependent enhancement mainly described for dengue virus infections. Here, we review the serological methods commonly used in WNV diagnosis and surveillance in Europe. By examining past and current epidemiological situations in different European countries, we present the challenges involved in interpreting flavivirus serological tests and setting up appropriate surveillance programs; we also address the consequences of flavivirus circulation and vaccination for host immunity.
In recent years, a number of zoonotic flaviviruses have emerged worldwide, and wild birds serve as their major reservoirs. Epidemiological surveys of bird populations at various geographical scales ...can clarify key aspects of the eco-epidemiology of these viruses. In this study, we aimed at exploring the presence of flaviviruses in the western Mediterranean by sampling breeding populations of the yellow-legged gull (Larus michahellis), a widely distributed, anthropophilic, and abundant seabird species. For 3 years, we sampled eggs from 19 breeding colonies in Spain, France, Algeria, and Tunisia. First, ELISAs were used to determine if the eggs contained antibodies against flaviviruses. Second, neutralization assays were used to identify the specific flaviviruses present. Finally, for colonies in which ELISA-positive eggs had been found, chick serum samples and potential vectors, culicid mosquitoes and soft ticks (Ornithodoros maritimus), were collected and analyzed using serology and PCR, respectively. The prevalence of flavivirus-specific antibodies in eggs was highly spatially heterogeneous. In northeastern Spain, on the Medes Islands and in the nearby village of L'Escala, 56% of eggs had antibodies against the flavivirus envelope protein, but were negative for neutralizing antibodies against three common flaviviruses: West Nile, Usutu, and tick-borne encephalitis viruses. Furthermore, little evidence of past flavivirus exposure was obtained for the other colonies. A subset of the Ornithodoros ticks from Medes screened for flaviviral RNA tested positive for a virus whose NS5 gene was 95% similar to that of Meaban virus, a flavivirus previously isolated from ticks of Larus argentatus in western France. All ELISA-positive samples subsequently tested positive for Meaban virus neutralizing antibodies. This study shows that gulls in the western Mediterranean Basin are exposed to a tick-borne Meaban-like virus, which underscores the need of exploring the spatial and temporal distribution of this flavivirus as well as its potential pathogenicity for animals and humans.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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