Emergency Medical Service responses as latent social capital toward Deliberate Self-Harm, Suicidality and Suicide.

Escalation in Deliberate Self-Harm (DSH) is indicative of a rise in poor mental health and/or a failure of social and health services. The phenomenon of DSH exacerbates mental illness sequela, while being an essential indicator of suicide risk. Globally, about 800 000 people commit suicide yearly, averaging almost one suicide every 40 s. Based on a Retrospective Cross-Sectional Study, the aim sought to establish the scope of the DSH, suicidality and suicide case-load from a Western Cape Emergency Medical Services (EMS) prehospital perspective. A census of 3 years of EMS Incident Management Records (IMR) from a large rural district with seven local municipalities was undertaken using a novel data collection instrument. The 2976 (N) mental health-related incidents that met the inclusion criteria (from 413 712 cases) suggest a presentation rate of 7 per 1000 EMS calls. Sixty percent (n = 1776) were regarded to have deliberately self-harmed, attempted suicide or committed suicide. Overdose/deliberate self-poisoning accounted for 52% (n = 1550) of all the DSH caseload of the study. Attempted suicide accounted for 2.7% (n = 83) and Suicide for 3.4% (n = 102) of the suicidality case-load from the study, respectively. Suicide averaged 2.8. suicides per month in the Garden Route District over the 3-year period. Men were five times more likely to commit suicide than women, commonly using strangulation, while women mostly ingested household detergents and poison, and overdosed on chronic medication. Understandably, the EMS needs to assess its own capability to respond, treat, and transport health-care users with DSH and suicidality. This study demonstrates the EMS 'everyday' exposure to DSH, suicidality and suicide case-load. It represents a critical first step in the problem-space definition upon which a determination of the need for EMS responses can be based, to interrupt suicidality by removing methods of harm and strengthening the mental health economy through social capital investment.

Rapid Proteasomal Degradation of Mutant Proteins Is the Primary Mechanism Leading to Tumorigenesis in Patients With Missense AIP Mutations.

CONTEXT: The pathogenic effect of mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene (AIPmuts) in pituitary adenomas is incompletely understood. We have identified the primary mechanism of loss of function for missense AIPmuts. OBJECTIVE: This study sought to analyze the mechanism/speed of protein turnover of wild-type and missense AIP variants, correlating protein half-life with clinical parameters. DESIGN AND SETTING: Half-life and protein-protein interaction experiments and cross-sectional analysis of AIPmut positive patients' data were performed in a clinical academic research institution. PATIENTS: Data were obtained from our cohort of pituitary adenoma patients and literature-reported cases. INTERVENTIONS: Protein turnover of endogenous AIP in two cell lines and fifteen AIP variants overexpressed in HEK293 cells was analyzed via cycloheximide chase and proteasome inhibition. Glutathione-S-transferase pull-down and quantitative mass spectrometry identified proteins involved in AIP degradation; results were confirmed by coimmunoprecipitation and gene knockdown. Relevant clinical data was collected. MAIN OUTCOME MEASURES: Half-life of wild-type and mutant AIP proteins and its correlation with clinical parameters. RESULTS: Endogenous AIP half-life was similar in HEK293 and lymphoblastoid cells (43.5 and 32.7 h). AIP variants were divided into stable proteins (median, 77.7 h; interquartile range [IQR], 60.7-92.9 h), and those with short (median, 27 h; IQR, 21.6-28.7 h) or very short (median, 7.7 h; IQR, 5.6-10.5 h) half-life; proteasomal inhibition rescued the rapid degradation of mutant proteins. The experimental half-life significantly correlated with age at diagnosis of acromegaly/gigantism (r = 0.411; P = .002). The FBXO3-containing SKP1-CUL1-F-box protein complex was identified as the E3 ubiquitin-ligase recognizing AIP. CONCLUSIONS: AIP is a stable protein, driven to ubiquitination by the SKP1-CUL1-F-box protein complex. Enhanced proteasomal degradation is a novel pathogenic mechanism for AIPmuts, with direct implications for the phenotype.

Landscape of Familial Isolated and Young-Onset Pituitary Adenomas: Prospective Diagnosis in AIP Mutation Carriers.

CONTEXT: Familial isolated pituitary adenoma (FIPA) due to aryl hydrocarbon receptor interacting protein (AIP) gene mutations is an autosomal dominant disease with incomplete penetrance. Clinical screening of apparently unaffected AIP mutation (AIPmut) carriers could identify previously unrecognized disease. OBJECTIVE: To determine the AIP mutational status of FIPA and young pituitary adenoma patients, analyzing their clinical characteristics, and to perform clinical screening of apparently unaffected AIPmut carrier family members. DESIGN: This was an observational, longitudinal study conducted over 7 years. SETTING: International collaborative study conducted at referral centers for pituitary diseases. PARTICIPANTS: FIPA families (n 216) and sporadic young-onset (30 y) pituitary adenoma patients (n 404) participated in the study. INTERVENTIONS: We performed genetic screening of patients for AIPmuts, clinical assessment of their family members, and genetic screening for somatic GNAS1 mutations and the germline FGFR4 p.G388R variant. MAIN OUTCOME MEASURE(S): We assessed clinical disease in mutation carriers, comparison of characteristics of AIPmut positive and negative patients, results of GNAS1, and FGFR4 analysis. RESULTS: Thirty-seven FIPA families and 34 sporadic patients had AIPmuts. Patients with truncating AIPmuts had a younger age at disease onset and diagnosis, compared with patients with nontruncating AIPmuts. Somatic GNAS1 mutations were absent in tumors from AIPmut-positive patients, and the studied FGFR4 variant did not modify the disease behavior or penetrance in AIPmut-positive individuals. A total of 164 AIPmut-positive unaffected family members were identified; pituitary disease was detected in 18 of those who underwent clinical screening. CONCLUSIONS: A quarter of the AIPmut carriers screened were diagnosed with pituitary disease, justifying this screening and suggesting a variable clinical course for AIPmut-positive pituitary adenomas.