Autosomal dominant hypocalcemia (ADH) type 1 and 2 are disorders of calcium homeostasis caused by gain of function variants. The calcium-sensing receptor (CaSR) is a class C GPCR that responds to elevated extracellular calcium (Ca²⁺ _o) by inhibiting parathyroid hormone (PTH) secretion and promoting renal excretion of Ca²⁺ and other salts to restore physiologically normal Ca²⁺ _o concentrations. CaSR negative allosteric modulators (NAMs) transiently raise PTH levels in individuals with ADH1, restoring Ca²⁺ _o concentration to a physiological normal range. Herein we disclose the discovery of a chemoreactive NAM (ATF936-NCS, 4) for the CaSR that (i) is wash-resistant indicative of irreversible receptor binding and (ii) stimulates prolonged PTH release in vivo. This 'first-in-class' chemical probe will provide invaluable insight towards the development of longer acting NAMs for the treatment of ADH.

BACKGROUND: In 2012, the Alaska Section of Epidemiology investigated personnel potentially exposed to a Brucella suis isolate as it transited through three laboratories. METHODS: We summarize the first implementation of the United States Centers for Disease Control and Prevention 2013 revised recommendations for monitoring such exposures: (1) risk classification; (2) antimicrobial postexposure prophylaxis; (3) serologic monitoring; and (4) symptom surveillance. RESULTS: Over 30 people were assessed for exposure and subsequently monitored for development of illness. No cases of laboratory-associated brucellosis occurred. Changes were made to gaps in laboratory biosafety practices that had been identified in the investigation. CONCLUSION: Achieving full compliance for the precise schedule of serologic monitoring was challenging and resource intensive for the laboratory performing testing. More refined exposure assessments could inform decision making for follow-up to maximize likelihood of detecting persons at risk while not overtaxing resources.
Alaska ; Appointments and Schedules ; Brucella suis ; Brucellosis* ; Centers for Disease Control and Prevention (U.S.) ; Classification ; Compliance ; Decision Making ; Epidemiology ; Follow-Up Studies ; Humans