Mutations in the Histone Modifier PRDM6 Are Associated with Isolated Nonsyndromic Patent Ductus Arteriosus.

Nonsyndromic patent ductus arteriosus (PDA) is a common congenital heart defect (CHD) with both inherited and acquired causes, but the disease mechanisms have remained elusive. Using combined genome-wide linkage analysis and whole-exome sequencing (WES), we identified independent mutations in PRDM6, which encodes a nuclear protein that is specific to vascular smooth muscle cells (VSMC), has histone methyl transferase activities, and acts as a transcriptional suppressor of contractile proteins. In vitro assays showed that the mutations cause loss of function either by intracellular redistribution of the protein and/or by alteration of its methyltransferase activities. Wild-type embryonic ductus arteriosus (DA) exhibited high levels of PRDM6, which rapidly declined postnatally as the number of VSMCs necessary for ductus contraction increased. This dynamic change suggests that PRDM6 plays a key role in maintaining VSMCs in an undifferentiated stage in order to promote their proliferation and that its loss of activity results in premature differentiation and impaired remodeling of the DA. Our findings identify PRDM6 mutations as underlying genetic causes of nonsyndromic isolated PDA in humans and implicates the wild-type protein in epigenetic regulation of ductus remodeling.

Network Structure of Autism Spectrum Disorder Behaviors and Its Evolution in Preschool Children: Insights from a New Longitudinal Network Analysis Method.

Network modeling of the social, communication and restrictive/repetitive behaviors (RRBs) included in the definition of Autism Spectrum Disorder was performed. The Autism Diagnostic Interview-Revised (ADI-R) assessed behaviors in 139 pre-school cases at two cross-sections that averaged 34.8 months apart. Cross-sectional networks were based on the correlation matrix of the ADI-R behavioral items and the "bootCross" method was developed and enabled the estimation of a longitudinal network. At both stages, RRB items/nodes formed a consistent peripheral cluster, while social and communication nodes formed a core cluster that diverged with time. These differences in the nature and evolution of the RRB and socio-communicative dimensions indicate that their inter-behavior dynamics are very different. The most central behaviors across stages are proposed as prime targets for efficient therapeutic intervention.

Network Analysis of Behaviors in the Depression and Autism Realms: Inter-Relationships and Clinical Implications.

Depression-, anxiety-, OCD- and autism-related behaviors were assessed in 118 high-functioning individuals with autism spectrum disorders (ASD) and in 2016 controls. The ASD group had a higher rate of clinical depression and markedly higher "insomnia" and "restlessness" scores. Network analysis and hierarchical cluster analysis in the ASD group revealed that depression and anxiety items clustered together, but separately from autism-related items. Compared to controls, "insomnia" and "restlessness" items in the ASD network of depression items were much more central (higher closeness, and betweenness centrality). Combined networks of depression-, anxiety-, and OCD-related items revealed that the control group depression item module was not preserved in ASD. The results indicate that depression is atypical in autism and suggest specific intervention targets.

Leech endoparasitism: report of a case and review of the literature.

We report the case of an 11-year-old boy who presented with fresh blood in his mouth and a history of sore throat during the past 2 weeks that was unresponsive to antibiotic therapy. Inspection of the oral cavity revealed a black circular mass attached to the posterior wall of the oropharynx. This mass was determined to be a live engorged leech. Leech endoparasitism is caused by aquatic leeches that attach themselves to mucus membranes of body cavities after the host has swum in bodies of fresh water or drunk from unsafe water sources. Pharyngeal hirudiniasis may present in different forms depending on the exact location of the parasite in the body and must be included in the list of differential diagnosis for common conditions such as pharyngitis, hemoptysis or anemia in pediatric patients living in endemic areas.

Network Analysis of Anxiety in the Autism Realm.

The anxiety and autism realms are each complicated and heterogeneous, and relationships between the two areas are especially complex. Network analysis offers a promising approach to the phenotypic complexities of typical and atypical human behavior. The Revised Children's Anxiety and Depression Scale (RCADS) was used to assess anxiety in 126 high-functioning 9-13 year-olds with ASDs. Network graphs of Autism Diagnostic Observation Schedule items and RCADS anxiety total score, social, generalized, panic and separation anxiety subscores consistently found the anxiety node (score) to be highly peripheral. Also, the networks of RCADS anxiety items themselves were similar for the ASDs group and a general population comparison group (n = 2017). The results suggest anxiety is not a central part of autism and that anxiety is dynamically similar (aspects of anxiety relate to one another in a similar manner) in high-functioning autism and the general population.

Serum hyaluronate as a non-invasive marker of hepatic fibrosis and inflammation in HBeAg-negative chronic hepatitis B.

BACKGROUND: HBV infection is a serious global heath problem. It is crucial to monitor this disease more closely with a non-invasive marker in clinical trials. We aimed to evaluate the predictive value of serum hyaluronate for the presence of extensive liver fibrosis and inflammation. METHODS: 28 healthy volunteers and 65 patients with HBeAg negative chronic hepatitis B were enrolled. Liver biopsies scored according to Ishak system. Association of serum hyaloronate with liver fibrosis and inflammation were assessed, and cut off points for serum hyaluronate levels were identified by receiver operating characteristics (ROC) curves and their values for prediction of fibrosis and inflammation were assessed. RESULTS: In patients with CHB serum hyaluronate had the most significant correlation and predictive values for the liver fibrosis and inflammation comparing to the other variables. At the cut off point of 126.4 ngm/ml it could discriminate extensive fibrosis from milder ones with sensitivity of 90.9% and specificity of 98.1%. With the same value it could discriminate extensive inflammation from their milder counterparts with sensitivity of 63.6% and specificity of 92.6%. CONCLUSION: Serum hyaluronate was the best predictor of extensive liver fibrosis and inflammation and it could discriminate subgroups of patients with chronic hepatitis B. It could be used as a non-invasive test to monitor these patients more closely with developing anti viral agents in clinical trials.

Network approach to autistic traits: group and subgroup analyses of ADOS item scores.

A network conceptualization might contribute to understanding the occurrence and interacting nature of behavioral traits in the autism realm. Networks were constructed based on correlations of item scores of the Autism Diagnostic Observation Schedule for Modules 1, 2 and 3 obtained for a group of 477 Dutch individuals with developmental disorders. After combining Modules, networks were obtained and compared for male versus female, high- versus low-functioning, seizure versus non-seizure, autism spectrum disorder versus intellectual disability, and younger versus older subjects. The network visualizations and calculated network parameters provide new perspectives that generate new hypothesis and suggest follow-up studies. The approach should be useful in characterizing individuals and groups, in elucidating mechanisms of trait generation and routes to outcome phenotypes, and in suggesting points of intervention.

Liver histology and HBV DNA levels in chronically HBV infected patients with persistently normal alanine aminotransferase.

BACKGROUND: Data on histological activity and HBV DNA levels in patients with chronic HBV infection and persistently normal alanine aminotransferase levels are sparse. We aimed to investigate the histological activity and HBV DNA levels in these patients. METHODS: There were 132 patients with HBeAg negative chronic HBV infection and persistently normal alanine aminotransferase levels that were included prospectively. Data were dichotomized according to the median levels. Associations of histology with HBV DNA and other variables were assessed. RESULTS: A total of 80 patients were male. The median age was 36 years. The median baseline HBV DNA was 2.9Log10 IU/mL. There were 50 cases (38%) with a total score > or = 5, 53 cases (40.2%) had grade > or = 4 and 40 cases (30.3%) had stage > or = 2. A baseline HBV DNA <2000 IU/mL was seen in 24 cases (48%) of those with total score > or = 5, 28 cases (53%) of those with grade > or = 4 and 9 cases (22.5%) with stage > or = 2. Multivariate analysis of baseline HBV DNA above the median level significantly predicted the total score, grade and stage with an adjusted odds ratio of 5.43, 3.47, and 4.23, respectively when compared to below median values. A second liver biopsy was performed in 61 patients. The median time interval between the two biopsies was 40 months. Total scores of 23 cases (38%) progressed by > or = 2 scores and the HBV DNA of 18 cases (22.5%) increased by > or = 1 Log10 IU when compared to baseline values. CONCLUSION: HBeAg negative chronic HBV infection with persistently normal alanine aminotransferase is not a silent disease. Active liver disease may be seen in such patients with viral loads less than 2000 IU/mL.