New insights into elastin and vascular disease

Elastin is synthesized and secreted by vascular smooth muscle cells and is the major extracellular matrix component deposited in the arterial wall. When last reviewed by this journal in 1994, the link between elastin and a rare occlusive vascular disease had just been established. Since that time, it has become increasingly clear that elastin is a critical autocrine factor that maintains vascular homeostasis through a combination of biomechanical support and biologic signaling. This review examines the complexity of elastin-smooth muscle cell interactions, and how new insights may impact understanding of the pathogenesis and treatment of vascular disease.     

17β-Estradiol and estrogen receptor α protect right ventricular function in pulmonary hypertension via BMPR2 and apelin

Women with pulmonary arterial hypertension (PAH) exhibit better right ventricular (RV) function and survival than men; however, the underlying mechanisms are unknown. We hypothesized that 17β-estradiol (E2), through estrogen receptor α (ER-α), attenuates PAH-induced RV failure (RVF) by upregulating the procontractile and prosurvival peptide apelin via a BMPR2-dependent mechanism. We found that ER-α and apelin expression were decreased in RV homogenates from patients with RVF and from rats with maladaptive (but not adaptive) RV remodeling. RV cardiomyocyte apelin abundance increased in vivo or in vitro after treatment with E2 or ER-α agonist. Studies employing ER-α–null or ER-β–null mice, ER-α loss-of-function mutant rats, or siRNA demonstrated that ER-α is necessary for E2 to upregulate RV apelin. E2 and ER-α increased BMPR2 in pulmonary hypertension RVs and in isolated RV cardiomyocytes, associated with ER-α binding to the Bmpr2 promoter. BMPR2 is required for E2-mediated increases in apelin abundance, and both BMPR2 and apelin are necessary for E2 to exert RV-protective effects. E2 or ER-α agonist rescued monocrotaline pulmonary hypertension and restored RV apelin and BMPR2. We identified what we believe to be a novel cardioprotective E2/ER-α/BMPR2/apelin axis in the RV. Harnessing this axis may lead to novel RV-targeted therapies for PAH patients of either sex.     

Implementing the Street Psychiatry Model in New Haven,CT: Community-Based Care for People Experiencing Unsheltered Homelessness

Community Mental Health Journal - “Street psychiatry” is an innovative model that serves people experiencing unsheltered homelessness, a vulnerable population with increased rates of...     

New Insights into Understanding the Mechanisms,Pathogenesis, and Management of Malignant Mesotheliomas

Malignant mesothelioma (MM) is a relatively rare but devastating tumor that is increasing worldwide. Yet, because of difficulties in early diagnosis and resistance to conventional therapies, MM remains a challenge for pathologists and clinicians to treat. In recent years, much has been revealed regarding the mechanisms of interactions of pathogenic fibers with mesothelial cells, crucial signaling pathways, and genetic and epigenetic events that may occur during the pathogenesis of these unusual, pleiomorphic tumors. These observations support a scenario whereby mesothelial cells undergo a series of chronic injury, inflammation, and proliferation in the long latency period of MM development that may be perpetuated by durable fibers, the tumor microenvironment, and inflammatory stimuli. One culprit in sustained inflammation is the activated inflammasome, a component of macrophages or mesothelial cells that leads to production of chemotactic, growth-promoting, and angiogenic cytokines. This information has been vital to designing novel therapeutic approaches for patients with MM that focus on immunotherapy, targeting growth factor receptors and pathways, overcoming resistance to apoptosis, and modifying epigenetic changes.CME Accreditation Statement: This activity (“ASIP 2013 AJP CME Program in Pathogenesis”) has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Society for Clinical Pathology (ASCP) and the American Society for Investigative Pathology (ASIP). ASCP is accredited by the ACCME to provide continuing medical education for physicians.The ASCP designates this journal-based CME activity (“ASIP 2013 AJP CME Program in Pathogenesis”) for a maximum of 48 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.CME Disclosures: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose.Malignant mesotheliomas (MMs), among the most aggressive tumors, arise most often from the mesothelial cells that line the pleura, peritoneum, and, occasionally, the pericardium. Because of the multifaceted properties of mesothelium that maintain a protective barrier but also produce components of the extracellular matrix, hyaluronan and other lubricants, chemokines and cytokines, and fibrinolytic and procoagulant factors, understanding its complex biology is a challenge. The intermediate filament pattern of mesothelial cells, suggesting an epithelial–mesodermal hybrid morphology, and their several patterns of differentiation during the neoplastic process suggest their transformation to malignancy is complicated and raises the question of whether one is studying a single tumor type or multiple subgroups of tumors.MMs are most commonly attributed to occupational exposures to asbestos, a regulatory term for a group of fibrous silicates that occur as needle-like amphiboles (crocidolite, amosite tremolite, anthophyllite, and antigorite) or curly serpentine (chrysotile) fibers. Although each of these fibers has its own distinctive properties, the fibrous nature and biopersistance of these inhaled fibers may be key to carcinogenic events that occur during the long latency periods (mean, 30 to 45 years) of most MMs. Most intensely investigated are chrysotile, the most commonly used type of asbestos historically (>90% use worldwide), and crocidolite, the asbestos type associated most often with MMs in humans^1,2 (Figures 1 and 2). The morphology of crocidolite asbestos is similar to nonasbestos fibers of erionite or Libby amphibole, other naturally occurring minerals associated with the development of MMs.^5,6 However, 20% to 25% of individuals with MM have no documented exposure to asbestos or other fibers, suggesting familial susceptibility (sporadic or idiopathic MM), unknown exposure to in-place or naturally occurring asbestos, or other causative agents, such as chemicals, radiation, and viruses.⁷Open in a separate windowFigure 1Properties of chrysotile (white) asbestos. A: Image of bundle of curly chrysotile fibers before processing. B: Scanning electron micrograph of chrysotile fibers (arrows) causing deformation of red blood cells. Chrysotile is positively charged, hemolytic, and cytolytic, primarily due to its magnesium content. Leaching of magnesium renders chrysotile less toxic and also results in chrysotile fiber dissolution over time. C: Scanning electron micrograph of interaction of long chrysotile fiber with the respiratory epithelium of the alveolar duct junction after inhalation by rats. Arrowheads show points of contact with and between epithelial cells. Subsequent penetration into and between cells leads to fiber deposition in the lung interstitum and access to the visceral pleura and pleural space. D: Polarized microscopy showing chrysotile fibers and fibrils.Photomicrograph is a courtesy of Lee Poye (J3 Resources, Inc., Houston, TX) Original magnification, ×100.Open in a separate windowFigure 2Properties of crocidolite, or blue, asbestos. A: Riebeckito ore showing veins of crocidolite asbestos fibers (arrow) before processing. B: Scanning electron micrograph showing morphology of needle-like fibers. C: Early penetration of a crocidolite fiber into the differentiated tracheobronchial epithelium in tracheal organ culture. D: Growth of metaplastic cells over long fibers of crocidolite observed at 1 month in this model.³ These events have not been captured in the pleura in animal inhalation models or in clinical specimens in humans, but mesothelial cells undergo proliferation, as measured by cell counts, or immunochemical markers have been observed in response to crocidolite asbestos in vitro and after inhalation by rats.⁴Because asbestos fibers neither appear to be metabolized nor directly interact with DNA, they are unlike most chemical carcinogens. The sensitivity of human mesothelial cells to fibers of high aspect (length to diameter) ratio is also perplexing, as are the phenomena governing fiber transport to the parietal pleura where most MMs are thought to develop. Although much insight exists on understanding how fibers (particularly high iron-containing amphibole asbestos types) generate reactive oxygen and nitrogen species to induce inflammation and cell signaling pathways important in proliferation and transformation, how these cellular events converge in the pathogenesis of MM remains enigmatic. This review amalgamates current observations in the field and their implications in strategies to prevent and manage MMs in patients.     

Depression or resilience? A participatory study to identify an appropriate assessment tool with Kanien’kéha (Mohawk) and Inuit in Quebec

Purpose

We present a study on selection of a psychometric scale to be clinically used among Indigenous people with depression. Our aim was to select a psychometric tool for cultural adaptation with Mohawk and Inuit in Quebec.

Methods

We selected three depression scales and three protective factor scales based on: strong validity for psychometric properties, evidence for good psychometric qualities across translations, avoidance of cognitively complex sentences, brevity, and clarity. We submitted the scales for consultation, and followed qualitative participatory methods with Mohawks of Kahnawake and Inuit from Nunavik living in an urban environment. We collected data through ten focus groups with advisory committees, and carried out a thematic analysis of the information.

Results

The advisory groups considered the measurement scales to be unsafe. The major components that hindered their acceptance were: numeric rating, self-evaluation (versus supportive interaction), and a focus on symptoms rather than supportive factors. The participants preferred the Growth and Empowerment Measure due to its empowering approach. They voiced that it is necessary to develop a culturally sensitive and safe tool which facilitates interactions between the person and the practitioner.

Conclusion

This project provides valuable information about the perspectives of local Indigenous peoples regarding mental health and factors of empowerment and resilience. The ideal tool should be flexible in terms of the content and its use as compared to the conventional psychometric strategies. A tool developed with the Indigenous perspective on wellbeing could be used in psychological and psychiatric intervention as well as in social and community services.

     

Intervention Fidelity: An Essential Component for Understanding ASD Parent Training Research and Practice

Previous research has explored the efficacy and effectiveness of autism spectrum disorder (ASD) parent training interventions. Recent trials of such programs have not replicated earlier compelling outcomes, yet the reasons for the failure of such programs to produce desired effects are unclear. The purpose of the current article is to discuss the role of intervention fidelity in elucidating the relationships between a parent training program, the implementation and sustainability of an intervention, and important child outcomes. The article will discuss the importance of assessing intervention fidelity for the identification and successful use of effective treatment strategies and will propose an integrative conceptual framework for approaching the study and evaluation of intervention fidelity with respect to ASD parent training programs.     

Risk for emerging bipolar disorder,variants, and symptoms in children with attention deficit hyperactivity disorder,now grown up

AIM: To determine the prevalence of bipolar disorder (BD) and sub-threshold symptoms in children with attention deficit hyperactivity disorder (ADHD) through 14 years’ follow-up, when participants were between 21-24 years old.METHODS: First, we examined rates of BD type I and II diagnoses in youth participating in the NIMH-funded Multimodal Treatment Study of ADHD (MTA). We used the diagnostic interview schedule for children (DISC), administered to both parents (DISC-P) and youth (DISCY). We compared the MTA study subjects with ADHD (n = 579) to a local normative comparison group (LNCG, n = 289) at 4 different assessment points: 6, 8, 12, and 14 years of follow-ups. To evaluate the bipolar variants, we compared total symptom counts (TSC) of DSM manic and hypomanic symptoms that were generated by DISC in ADHD and LNCG subjects. Then we sub-divided the TSC into pathognomonic manic (PM) and non-specific manic (NSM) symptoms. We compared the PM and NSM in ADHD and LNCG at each assessment point and over time. We also evaluated the irritability as category A2 manic symptom in both groups and over time. Finally, we studied the irritability symptom in correlation with PM and NSM in ADHD and LNCG subjects.RESULTS: DISC-generated BD diagnosis did not differ significantly in rates between ADHD (1.89%) and LNCG 1.38%). Interestingly, no participant met BD diagnosis more than once in the 4 assessment points in 14 years. However, on the symptom level, ADHD subjects reported significantly higher mean TSC scores: ADHD 3.0; LNCG 1.7; P < 0.001. ADHD status was associated with higher mean NSM: ADHD 2.0 vs LNCG 1.1; P < 0.0001. Also, ADHD subjects had higher PM symptoms than LNCG, with PM means over all time points of 1.3 ADHD; 0.9 LNCG; P = 0.0001. Examining both NSM and PM, ADHD status associated with greater NSM than PM. However, Over 14 years, the NSM symptoms declined and changed to PM over time (df 3, 2523; F = 20.1; P < 0.0001). Finally, Irritability (BD DSM criterion-A2) rates were significantly higher in ADHD than LNCG (χ² = 122.2, P < 0.0001), but irritability was associated more strongly with NSM than PM (df 3, 2538; F = 43.2; P < 0.0001).CONCLUSION: Individuals with ADHD do not appear to be at significantly greater risk for developing BD, but do show higher rates of BD symptoms, especially NSM. The greater linkage of irritability to NSM than to PM suggests caution when making BD diagnoses based on irritability alone as one of 2 (A-level) symptoms for BD diagnosis, particularly in view of its frequent presentation with other psychopathologies.