Primary pulmonary hypertension is associated with reduced pulmonary vascular expression of type II bone morphogenetic protein receptor

BACKGROUND: Mutations in the type II receptor for bone morphogenetic protein (BMPR-II), a receptor member of the transforming growth factor-beta (TGF-beta) superfamily, underlie many familial and sporadic cases of primary pulmonary hypertension (PPH). METHODS AND RESULTS: Because the sites of expression of BMPR-II in the normal and hypertensive lung are unknown, we studied the cellular localization of BMPR-II and the related type I and II receptors for TGF-beta by immunohistochemistry in lung sections from patients undergoing heart-lung transplantation for PPH (n=11, including 3 familial cases) or secondary pulmonary hypertension (n=6) and from unused donor lungs (n=4). In situ hybridization was performed for BMPR-II mRNA. Patients were screened for the presence of mutations in BMPR2. In normal lungs, BMPR-II expression was prominent on vascular endothelium, with minimal expression in airway and arterial smooth muscle. In pulmonary hypertension cases, the intensity of BMPR-II immunostaining varied between lesions but involved endothelial and myofibroblast components. Image analysis confirmed that expression of BMPR-II was markedly reduced in the peripheral lung of PPH patients, especially in those harboring heterozygous BMPR2 mutations. A less marked reduction was also observed in patients with secondary pulmonary hypertension. In contrast, there was no difference in level of staining for TGF-betaRII or the endothelial marker CD31. CONCLUSIONS: The cellular localization of BMPR-II is consistent with a role in the formation of pulmonary vascular lesions in PPH, and reduced BMPR-II expression may contribute to the process of vascular obliteration in severe pulmonary hypertension

Attachment, Coping, and Suicidal Behavior in Male Prisoners

The present study explored the differences between adult male prisoners with and without a history of suicidal behavior on adult attachment dimensions, coping styles, and hopelessness. The role of adult attachment and coping styles as predictors of hopelessness was also explored. The sample included 206 male prisoners from two Category B prisons in the United Kingdom. The Attachment Styles Questionnaire (ASQ), Coping Styles Questionnaire (CSQ-3), and Beck Hopelessness Scale (BHS) measured attachment, coping, and hopelessness. Prisoners with a history of suicidal behavior reported significantly higher levels of attachment anxiety, attachment avoidance, and maladaptive coping strategies. Elevated levels of attachment difficulties and maladaptive coping styles were associated with heightened levels of hopelessness. Emotional coping strategies mediated the influence of attachment anxiety and attachment avoidance on hopelessness. The study highlights the potential utility of adult attachment conceptualizations and coping skills interventions with prisoners at risk of suicidal behavior

Effects of Psychopathy on Neurocognitive Domains of Impulsivity in Abstinent Opiate and Stimulant Users

Background: Psychopathy and substance use disorders (SUDs) are both characterized by neurocognitive impairments reflecting higher levels of impulsivity such as reward-driven decision-making and deficient inhibitory control. Previous studies suggest that psychopathy may exacerbate decision-making deficits, but it may be unrelated to other neurocognitive impairments among substance dependent individuals (SDIs). The aim of the present study was to examine the role of psychopathy and its interpersonal-affective and impulsive-antisocial dimensions in moderating the relationships between dependence on different classes of drugs and neurocognitive domains of impulsivity.Method: We tested 693 participants (112 heroin mono-dependent individuals, 71 heroin polysubstance dependent individuals, 115 amphetamine mono-dependent individuals, 76 amphetamine polysubstance dependent individuals, and 319 non-substance dependent control individuals). Participants were administered the Psychopathy Checklist: Screening Version (PCL:SV) and seven neurocognitive tasks measuring impulsive choice/decision-making (Iowa Gambling Task; Cambridge Gambling Task; Kirby Delay Discounting Task; Balloon Analog Risk Task), and impulsive action/response inhibition (Go/No-Go Task, Immediate Memory Task, and Stop Signal Task).Results: A series of hierarchical multiple regressions revealed that the interpersonal-affective dimension of psychopathy moderated the association between decision-making, response inhibition and both amphetamine and heroin dependence, albeit differently. For amphetamine users, low levels of interpersonal-affective traits predicted poor decision-making on the Iowa Gambling Task and better response inhibition on the Stop Signal task. In contrast, in heroin users high interpersonal-affective psychopathy traits predicted lower risk taking on the Cambridge Gambling Task and better response inhibition on the Go/No-Go task. The impulsive-antisocial dimension of psychopathy predicted poor response inhibition in both amphetamine and heroin users.Conclusions: Our findings reveal that psychopathy and its dimensions had both common and unique effects on neurocognitive function in heroin and amphetamine dependent individuals. Our results suggest that the specific interactions between psychopathy dimensions and dependence on different classes of drugs may lead to either deficient or superior decision-making and response inhibition performance in SDIs, suggesting that psychopathy may paradoxically play a protective role for some neurocognitive functions in specific subtypes of substance users

Skin Conductance Responses to a Discrete Threat in Virtual Reality: Associations with Psychopathy and Anxiety

People with high levels of psychopathic traits are often described as fearless and lacking in emotional depth, particularly when evaluating threats in their environments. Skin conductance responsivity (SCR) to negative emotional stimuli represents a robust autonomic correlate of conduct problem behavior in children (Fanti et al., in Neuroscience and Biobehavioral Reviews, 100, 98–107, 2019). However, studies that have examined threat-related processing in youth with conduct problems have tended to use a variety of negative stimuli that might induce various and unspecific negative emotions. Few studies have taken in to account the moderating effects of anxiety on the relationship of distinct psychopathic traits (e.g., narcissism, callousness, impulsivity) with SCR to a fear inducing stimulus. In this study, we examined SCR to a virtual reality rollercoaster drop – that is, a discrete fear inducing event – in a sample of 75 youths (61 males; M = 14 years, SD = 1.4) enrolled in a non-mainstream school. The rollercoaster drop was used to more clearly examine an event-related response to a discrete threat, rather than examining SCR throughout the rollercoaster ride. We used the teacher-reported Antisocial Process Screening Device (Frick & Hare, in Antisocial process screening device: APSD. Toronto: Multi-Health Systems, 2001) to examine the relations of distinct psychopathic traits with SCR and self-reported anxiety. Lower anxiety was associated with higher callousness, but only in youths with low SCR to discrete threat. These findings suggest that fear and anxiety show complex and interactive relations with distinct psychopathic traits

Complete genome sequence of the first KPC-type carbapenemase-positive Proteus mirabilis strain from a bloodstream infection

Sequencing of the blaKPC-positive strain Proteus mirabilis AOUC-001 was performed using both the MiSeq and PacBio RS II platforms and yielded a single molecule of 4,272,433 bp, representing the complete chromosome. Genome analysis showed the presence of several acquired resistance determinants, including two copies of blaKPC-2 carried on a fragment of a KPC-producing plasmid previously described in Klebsiella pneumoniae

Complete Genome Sequence and Comparative Metabolic Profiling of the Prototypical Enteroaggregative Escherichia coli Strain 042

Background \ud Escherichia coli can experience a multifaceted life, in some cases acting as a commensal while in other cases causing intestinal and/or extraintestinal disease. Several studies suggest enteroaggregative E. coli are the predominant cause of E. coli-mediated diarrhea in the developed world and are second only to Campylobacter sp. as a cause of bacterial-mediated diarrhea. Furthermore, enteroaggregative E. coli are a predominant cause of persistent diarrhea in the developing world where infection has been associated with malnourishment and growth retardation. \ud \ud Methods \ud In this study we determined the complete genomic sequence of E. coli 042, the prototypical member of the enteroaggregative E. coli, which has been shown to cause disease in volunteer studies. We performed genomic and phylogenetic comparisons with other E. coli strains revealing previously uncharacterised virulence factors including a variety of secreted proteins and a capsular polysaccharide biosynthetic locus. In addition, by using Biolog™ Phenotype Microarrays we have provided a full metabolic profiling of E. coli 042 and the non-pathogenic lab strain E. coli K-12. We have highlighted the genetic basis for many of the metabolic differences between E. coli 042 and E. coli K-12. \ud \ud Conclusion \ud This study provides a genetic context for the vast amount of experimental and epidemiological data published thus far and provides a template for future diagnostic and intervention strategies

Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia

BACKGROUND: Most patients with familial primary pulmonary hypertension have defects in the gene for bone morphogenetic protein receptor II (BMPR2), a member of the transforming growth factor beta (TGF-beta) superfamily of receptors. Because patients with hereditary hemorrhagic telangiectasia may have lung disease that is indistinguishable from primary pulmonary hypertension, we investigated the genetic basis of lung disease in these patients. METHODS: We evaluated members of five kindreds plus one individual patient with hereditary hemorrhagic telangiectasia and identified 10 cases of pulmonary hypertension. In the two largest families, we used microsatellite markers to test for linkage to genes encoding TGF-beta-receptor proteins, including endoglin and activin-receptor-like kinase 1 (ALK1), and BMPR2. In subjects with hereditary hemorrhagic telangiectasia and pulmonary hypertension, we also scanned ALK1 and BMPR2 for mutations. RESULTS: We identified suggestive linkage of pulmonary hypertension with hereditary hemorrhagic telangiectasia on chromosome 12q13, a region that includes ALK1. We identified amino acid changes in activin-receptor-like kinase 1 that were inherited in subjects who had a disorder with clinical and histologic features indistinguishable from those of primary pulmonary hypertension. Immunohistochemical analysis in four subjects and one control showed pulmonary vascular endothelial expression of activin-receptor-like kinase 1 in normal and diseased pulmonary arteries. CONCLUSIONS: Pulmonary hypertension in association with hereditary hemorrhagic telangiectasia can involve mutations in ALK1. These mutations are associated with diverse effects, including the vascular dilatation characteristic of hereditary hemorrhagic telangiectasia and the occlusion of small pulmonary arteries that is typical of primary pulmonary hypertension

A simple method for directional transcriptome sequencing using Illumina technology.

High-throughput sequencing of cDNA has been used to study eukaryotic transcription on a genome-wide scale to single base pair resolution. In order to compensate for the high ribonuclease activity in bacterial cells, we have devised an equivalent technique optimized for studying complete prokaryotic transcriptomes that minimizes the manipulation of the RNA sample. This new approach uses Illumina technology to sequence single-stranded (ss) cDNA, generating information on both the direction and level of transcription throughout the genome. The protocol, and associated data analysis programs, are freely available from http://www.sanger.ac.uk/Projects/Pathogens/Transcriptome/. We have successfully applied this method to the bacterial pathogens Salmonella bongori and Streptococcus pneumoniae and the yeast Schizosaccharomyces pombe. This method enables experimental validation of genetic features predicted in silico and allows the easy identification of novel transcripts throughout the genome. We also show that there is a high correlation between the level of gene expression calculated from ss-cDNA and double-stranded-cDNA sequencing, indicting that ss-cDNA sequencing is both robust and appropriate for use in quantitative studies of transcription. Hence, this simple method should prove a useful tool in aiding genome annotation and gene expression studies in both prokaryotes and eukaryotes