TSC1 binding to lysosomal PIPs is required for TSC complex translocation and mTORC1 regulation.

The TSC complex is a critical negative regulator of the small GTPase Rheb and mTORC1 in cellular stress signaling. The TSC2 subunit contains a catalytic GTPase activating protein domain and interacts with multiple regulators, while the precise function of TSC1 is unknown. Here we provide a structural characterization of TSC1 and define three domains: a C-terminal coiled-coil that interacts with TSC2, a central helical domain that mediates TSC1 oligomerization, and an N-terminal HEAT repeat domain that interacts with membrane phosphatidylinositol phosphates (PIPs). TSC1 architecture, oligomerization, and membrane binding are conserved in fungi and humans. We show that lysosomal recruitment of the TSC complex and subsequent inactivation of mTORC1 upon starvation depend on the marker lipid PI3,5P2, demonstrating a role for lysosomal PIPs in regulating TSC complex and mTORC1 activity via TSC1. Our study thus identifies a vital role of TSC1 in TSC complex function and mTORC1 signaling.

The prevention of contrast-induced nephropathy.

OBJECTIVE: Contrast-induced nephropathy (CIN) is a complication which may develop after exposure to iodinated contrast media. The resulting acute kidney injury (AKI) is associated with an increase in both short- and long-term morbidity and mortality, increased hospital length of stay, and greater health care costs. The pathophysiological mechanism associated with the development of CIN remains unknown. This narrative review summarizes the pathophysiology, risk factors, and current evidence for the prevention of CIN. DATA SOURCES: A MEDLINE literature search (2004-May 2014) was performed using search terms contrast-induced nephropathy and prevention. Additional references were identified from literature citations, review articles, and meta-analyses. STUDY SELECTION AND DATA EXTRACTION: Abstracts of English-language human clinical trials that examined therapies for the prevention of CIN were evaluated. Studies that did not investigate a preventative intervention for CIN were excluded. Emphasis was placed on recent publications. DATA SYNTHESIS: A multitude of therapies focused on the prevention of CIN have been investigated. Unfortunately, many of these studies have produced negative and/or inconsistent results. There is a paucity of adequately designed clinical studies evaluating strategies for the prevention of CIN. However, the best data supports use of preprocedural hydration with isotonic solution as the standard of care for prophylaxis. CONCLUSION: Given the poor prognosis associated with CIN, there is need for improved methods to prevent it. At present, the best tools to protect patients from unnecessary risk for CIN are careful assessment of renal function, judicious use of procedures that utilize contrast media, and adequate hydration with isotonic solution.

Improvement in appropriate utilization of recombinant human erythropoietin pre- and post-implementation of a required order form.

BACKGROUND: Erythropoietin stimulating agents (ESAs) are high-cost medications that have a significant impact on many pharmacy budgets. Recently, ESAs have received stronger safety warnings and reimbursement has been curtailed by third-party payers including the Centers for Medicare and Medicaid Services. For these reasons, many hospitals are developing strategies to optimize their use. A required order form with acceptable indications and dosing was implemented at an academic medical center in an attempt to improve dosing and appropriate utilization of ESAs. OBJECTIVE: To determine whether implementation of a required order form increased appropriate use and/or decreased total utilization of recombinant human erythropoietin (rHuEPO). METHODS: This was a retrospective cohort study of rHuEPO utilization for 4 months pre- and 6 months post-implementation (April 2008-January 2009). RESULTS: Implementation of a required order form for rHuEPO resulted in significantly fewer patients receiving inappropriate doses of rHuEPO (51.3% vs 19.2%, p < 0.001). The number of patients treated, adjusted to hospital census, was also reduced after implementation of the order form (0.003 vs 0.004 pts./average pt. days, p = 0.03). Annual spending for rHuEPO was reduced by 47% during 2008 despite an increased acquisition cost. CONCLUSIONS: Implementation of a required order form with evidence-based dosing recommendations can be an effective strategy to improve appropriate utilization of rHuEPO.

Structure of the TSC2 GAP Domain: Mechanistic Insight into Catalysis and Pathogenic Mutations.

The TSC complex is the cognate GTPase-activating protein (GAP) for the small GTPase Rheb and a crucial regulator of the mechanistic target of rapamycin complex 1 (mTORC1). Mutations in the TSC1 and TSC2 subunits of the complex cause tuberous sclerosis complex (TSC). We present the crystal structure of the catalytic asparagine-thumb GAP domain of TSC2. A model of the TSC2-Rheb complex and molecular dynamics simulations suggest that TSC2 Asn1643 and Rheb Tyr35 are key active site residues, while Rheb Arg15 and Asp65, previously proposed as catalytic residues, contribute to the TSC2-Rheb interface and indirectly aid catalysis. The TSC2 GAP domain is further stabilized by interactions with other TSC2 domains. We characterize TSC2 variants that partially affect TSC2 functionality and are associated with atypical symptoms in patients, suggesting that mutations in TSC1 and TSC2 might predispose to neurological and vascular disorders without fulfilling the clinical criteria for TSC.

Housing situation and healthcare for patients in a psychiatric centre in Berlin, Germany: a cross-sectional patient survey.

OBJECTIVE: To determine the housing situation among people seeking psychiatric treatment in relation to morbidity and service utilisation. DESIGN: Cross-sectional patient survey. SETTING: Psychiatric centre with a defined catchment area in Berlin, Germany, March-September 2016. PARTICIPANTS: 540 psychiatric inpatients including day clinics (43.2% of all admitted patients in the study period (n=1251)). MAIN OUTCOME MEASURES: Housing status 30 days prior the interview as well as influencing variables including service use, psychiatric morbidity and sociodemographic variables. RESULTS: In our survey, 327 participants (68.7%) currently rented or owned an own apartment; 62 (13.0%) reported to be homeless (living on the street or in shelters for homeless or refugees); 87 (18.3%) were accommodated in sociotherapeutic facilities. Participants without an own apartment were more likely to be male and younger and to have a lower level of education. Homeless participants were diagnosed with a substance use disorder significantly more often (74.2%). Psychotic disorders were the highest among homeless participants (29.0%). Concerning service use, we did neither find a lower utilisation of ambulatory services nor a higher utilisation of hospital-based care among homeless participants. CONCLUSIONS: Our findings underline the need for effective housing for people with mental illness. Despite many sociotherapeutic facilities, a concerning number of people with mental illness is living in homelessness. Especially early interventions addressing substance use might prevent future homelessness.