Functional characterization of five NR5A1 gene mutations found in patients with 46,XY disorders of sex development

Steroidogenic factor‐1 (SF1), encoded by the NR5A1 gene, is a key regulator of steroidogenesis and reproductive development. NR5A1 mutations described in 46,XY patients with disorders of sex development (DSD) can be associated with a range of conditions of phenotypes; however, the genotype–phenotype correlation remains elusive in many cases. In the present study, we describe the impact of five NR5A1 variants (three novel: p.Arg39Cys, p.Ser32Asn, and p.Lys396Argfs*34; and two previously described: p.Cys65Tyr and p.Cys247*) on protein function, identified in seven patients with 46,XY DSD. In vitro functional analyses demonstrate that NR5A1 mutations impair protein functions and result in the DSD phenotype observed in our patients. Missense mutations in the DNA binding domain and the frameshift mutation p.Lys396Argfs*34 lead to both, markedly affected transactivation assays, and loss of DNA binding, whereas the mutation p.Cys247* retained partial transactivation capacity and the ability to bind a consensus SF1 responsive element. SF1 acts in a dose‐dependent manner and regulates a cascade of genes involved in the sex determination and steroidogenesis, but in most cases reported so far, still lead to a sufficient adrenal steroidogenesis and function, just like in our cases, in which heterozygous mutations are associated to 46,XY DSD with intact adrenal steroid biosynthesis.     

MCV、RDW、LDH和SF联合检测对骨髓增生异常综合征与巨幼细胞贫血鉴别诊断的临床意义

目的探讨MCV、RDW、乳酸脱氢酶（LDH）和铁蛋白（SF）联合检测对骨髓增生异常综合征（MDS）和巨幼细胞贫血（MA）鉴别诊断的临床意义。方法选取临床确诊的29例巨幼细胞贫血和34例骨髓增生异常综合征的初诊患者,严格按照操作规程,应用德国罗氏公司生产的RocheMODU-LARPPI自动生化分析仪采用酶速率法原理测定血浆LDH,用全自动电化学发光免疫分析仪E170采用电化学发光原理检测血浆铁蛋白及应用美国雅培CD3700全自动血常规仪测定全血各项参数并自动演算出MCV和RDW数值。两组之间比较采用t检验。结果 MDS组和MA组的MCV、RDW、LDH和SF比较均存在显著性差异（P〈0.05）。结论联合检测MCV、RDW、LDH和SF对鉴别诊断MDS和MA具有临床意义,并有显著的社会效应,值得临床推广应用。     

Amygdalar shape analysis method using surface contour aligning,spherical mapping,and probabilistic subregional segmentation

The objective of this study was to develop a reliable method for the shape analysis of the amygdala, a structure that is important in gaining a better understanding of the limbic system in the human brain. The goal of this study was threefold; to develop (1) a robust method for aligning the contour of the amygdala; (2) a reproducible method for extracting surface parameters of the amygdala using a spherical mapping technique; and (3) a standardized approach for statistical assessment and visualization of shape alterations by applying the probabilistic maps of amygdalar subregions. This technique was validated by conducting an artificial phantom study and by assessing sex-related amygdalar shape differences using T1-weighted images from healthy volunteers. In the phantom study, the region with atrophy was detected successfully through the shape analysis process. In the human study, the average radii of the centromedial (CM) subregion in the left amygdala and laterobasal (LB), superficial (SF) and CM subregions in the right amygdala were different between sexes (t-tests, p = 0.02, 0.04, 0.04, and 0.002, respectively). In addition, focal regions with larger radii in amygdalae of men than those of women were found predominantly on the surfaces of bilateral SF and bilateral CM subregions, after the volumes of the amygdala had been scaled to the unit volume (1000 mm³) (Mann–Whitney U-test, false discovery rate corrected p < 0.05, clustered vertex points > 25). Regions with smaller radii in amygdalae of men were found predominantly on the anterior surfaces of the right LB and SF subregions (Mann–Whitney U-test, false discovery rate corrected p < 0.05, clustered vertex points > 25). This is generally in agreement with previous findings from animal studies. The current method may be used for measuring subtle local shape changes of the amygdala in various psychiatric or neurologic disorders.     

Gender-specific association between iron status and the history of attempted suicide: implications for gender paradox of suicide behaviors

PURPOSE: Iron deficiency (ID) has been linked with high impulsivity, and an increased risk of ID was reported among suicide attempters. We hypothesized that poor iron status might be prevalent among suicide attempters, who have high impulsivity. METHODS: As a part of the third National Health and Nutrition Examination Survey (1988-1994), a set of iron indices were measured in 2598 men and 2975 women aged 17-39 years, who completed a mental disorder diagnostic interview. RESULTS: Using non-attempters as reference within each gender, we observed a gender-dependent association between poor iron status and the history of attempted suicide. For male attempters (n=74), the prevalence ratios (PR) of abnormal serum ferritin, serum iron and protoporphyrin were 18.3 (95%CI=3.3-101.7), 3.2 (1.1-9.4) and 5.4(1.8-15.6). In contrast, the PR of abnormal serum ferritin for female attempters (n=217) was 0.3 (0.1-0.6). The hematological indices did not differ significantly between attempters and non-attempters among either men or women. Compared with non-attempters, male attempters were prone to a higher odds [17.5 (4.2-72.4)] while female attempters to a lower odds [0.6 (0.3-1.1)] of ID. CONCLUSION: These data suggest new opportunities for exploring biological bases of gender paradox of suicidal behaviors and a novel way to enhance therapeutic and preventive interventions against suicide.     

Replication cycle of chikungunya: A re-emerging arbovirus

Arboviruses (or arthropod-borne viruses), represent a threat for the new century. The 2005-2006 year unprecedented epidemics of chikungunya virus (CHIKV) in the French Reunion Island in the Indian Ocean, followed by several outbreaks in other parts of the world such as India, have attracted the attention of clinicians, scientists, and state authorities about the risks linked to this re-emerging mosquito-borne virus. CHIKV, which belongs to the Alphaviruses genus, was not previously regarded as a highly pathogenic arbovirus. However, this opinion was challenged by the death of several CHIKV-infected persons in Reunion Island. The epidemic episode began in December 2005 and four months later the seroprevalence survey report indicated that 236,000 persons, more than 30% of Reunion Island population, had been infected with CHIKV, among which 0.4-0.5% of cases were fatal. Since the epidemic peak, the infection case number has continued to increase to almost 40% of the population, with a total of more than 250 fatalities. Although information available on CHIKV is growing quite rapidly, we are still far from understanding the strategies required for the ecologic success of this virus, virus replication, its interactions with its vertebrate hosts and arthropod vectors, and its genetic evolution. In this paper, we summarize the current knowledge of CHIKV genomic organization, cell tropism, and the virus replication cycle, and evaluate the possibility to predict its future evolution. Such understanding may be applied in order to anticipate future epidemics and reduce the incidence by development and application of, for example, vaccination and antiviral therapy.     

Functional outcome and health-related quality of life 10 years after moderate-to-severe traumatic brain injury

Objectives – To describe the functional outcome and health‐related quality of life (HRQL) 10 years after moderate‐to‐severe traumatic brain injury (TBI). Material and methods – A retrospective, population‐based study of 62 survivors of working‐age with moderate‐to‐severe TBI injured in 1995/1996, and hospitalized at the Trauma Referral Center in Eastern Norway. Functional status was measured by the Glasgow Outcome Scale‐Extended (GOS‐E). HRQL was assessed by the SF‐36 questionnaire. Results – The mean current‐age was 40.8 years. The frequency of epilepsy was 19% and the depression rate 31%. A majority had good recovery (48%) or moderate disability (44%). Employment rate was 58%. Functional and employment status were associated with initial injury severity in contrast to HRQL. Study patients had significantly lower scores in all SF‐36 dimensions when compared with the general Norwegian population. Conclusion – At 10‐years follow‐up, our study population is still in their most productive years and affected domains should be considered in long‐term follow‐up and intervention programs.     

beta-Catenin and actin reorganization in HGF/SF response of ST14A cells

Hepatocyte growth factor/scatter factor (HGF/SF) is a pleiotropic factor that activates proliferation, differentiation, and migration of various cell types. Its action is mediated by c-Met, a receptor endowed with tyrosine kinase activity that activates complex signaling cascades and mediates diverse cell responses. Although HGF action was first demonstrated in epithelial cells, expression of HGF and c-Met receptor has also been described in developing and adult mammalian brain. In the developing central nervous system, areas of HGF and c-Met expression are coincident with the migratory pathway of precursor cells. In the present article we report that the interaction between c-Met and HGF/SF in striatal progenitor ST14A cells triggers a signaling cascade that induces modification of cell morphology, with decreased cell-cell interactions and increased cell motility; in particular, we analyzed the reorganization of the actin cytoskeleton and the delocalization of beta-catenin and N-cadherin. The testing of other neurotrophic factors (NGF, BDNF, NT3, and CNTF) showed that the observed modifications were peculiar to HGF. We show that phosphoinositide 3-kinase inhibitor treatment, which blocks cell scattering induced by HGF/SF, does not abolish actin and beta-catenin redistribution. The effects of HGF/SF on primary spinal cord cell cultures were also investigated, and HGF/SF was found to have a possible motogenic effect on these cells. The data reported suggest that HGF could play a role in the early steps of neurogenesis as a motogenic factor.     

Predictors of deterioration in health‐related quality of life in Parkinson's disease: Results from the DATATOP trial

The aim of this study was to investigate factors associated with decline in health‐related quality of life in Parkinson's disease, by a retrospective cohort study from referral centers in Canada and the United States. Subjects were patients with early Parkinson's disease (N = 362) enrolled in a clinical trial of deprenyl (selegiline) and tocopherol (DATATOP) and followed prospectively. The main outcome measure was change in health‐related quality of life using SF‐36 Mental and Physical Component Summary scores. The mean interval between SF‐36 measurements was 1.7 ± 0.1 years, beginning 5 to 6 years after enrolment into the trial. In multivariable analysis, baseline Hamilton Depression Scale scores and self‐rated cognitive function were associated with subsequent decline in Physical Component Summary scores, while older age and Schwab and England activities of daily living scores were associated with decline in Mental Component Summary scores. The Postural Instability Gait Disorder score was the only variable found to decline concurrently with HRQOL. Our results suggest that depression, self‐rated cognitive function, and one's degree of functional independence are predictors of subsequent changes in HRQOL. Our focus in clinical care needs to be broadened beyond assessing and treating Parkinsonism, recognizing the impact of mood, cognition and function on HRQOL. © 2007 Movement Disorder Society     

Health-status of adult survivors of childhood cancer: a large-scale population-based study from the British Childhood Cancer Survivor Study

The purpose of this study was to investigate the effect of childhood cancer and its treatment on self-reported health-status in 10,189 adult survivors of childhood cancer in Britain. Age- and sex-adjusted scores on the SF-36 Mental and Physical Component Summary scales (MCS, PCS, respectively) were compared between survivors and UK norms, and between subgroups of survivors, by multiple regression. Survivors had comparable scores to UK-norms on the MCS scale (difference (D) = -0.1, 99% CI: -0.5, 0.3). The difference in scores between survivors and UK-norms on the PCS scale varied by age (p(heterogeneity) < 0.001). Young survivors (16-19 years) scored similarly to UK-norms (D = 0.5, (-1.1, 2.2), whereas the age groups of 25 and older scored statistically and clinically significantly below UK-norms (all p-values < 0.0001), with Ds ranging between -2.3 (-3.5, -1.2) and -3.7 (-5.0, -2.4). Survivors of central nervous system (CNS) and bone tumors scored significantly (p-value at all ages <0.003) below UK-norms on the PCS scale. Specifically, these survivors were substantially more limited in specific daily activities such as, for example, walking a mile (40, 63%, respectively) when compared to UK-norms (16%). In conclusion, childhood cancer survivors rate their mental health broadly similarly to those in the general population. Survivors of CNS and bone tumors report their physical health-status to be importantly below population norms. Although self-reported physical health is at least as good as in the general population among young survivors, this study suggests that perceived physical health declines more rapidly over time than in the general population.