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Objectives: The aim of this study was to repurpose a drug for the treatment of bipolar depression. Methods: A gene expression signature representing the overall transcriptomic effects of a cocktail of drugs widely prescribed to treat bipolar disorder was generated using human neuronal‐like (NT2‐N) cells. A compound library of 960 approved, off‐patent drugs were then screened to identify those drugs that affect transcription most similar to the effects of the bipolar depression drug cocktail. For mechanistic studies, peripheral blood mononuclear cells were obtained from a healthy subject and reprogrammed into induced pluripotent stem cells, which were then differentiated into co‐cultured neurons and astrocytes. Efficacy studies were conducted in two animal models of depressive‐like behaviours (Flinders Sensitive Line rats and social isolation with chronic restraint stress rats). Results: The screen identified trimetazidine as a potential drug for repurposing. Trimetazidine alters metabolic processes to increase ATP production, which is thought to be deficient in bipolar depression. We showed that trimetazidine increased mitochondrial respiration in cultured human neuronal‐like cells. Transcriptomic analysis in induced pluripotent stem cell‐derived neuron/astrocyte co‐cultures suggested additional mechanisms of action via the focal adhesion and MAPK signalling pathways. In two different rodent models of depressive‐like behaviours, trimetazidine exhibited antidepressant‐like activity with reduced anhedonia and reduced immobility in the forced swim test. Conclusion: Collectively our data support the repurposing of trimetazidine for the treatment of bipolar depression. [ABSTRACT FROM AUTHOR]

Background Kawasaki disease (KD) is an acute systemic vasculitis which predominantly occurs in childhood but rarely in adulthood. Diagnosis relies on the presence of typical clinical features; however, patients may present atypically, increasing the challenge of timely diagnosis for physicians. Case summary We report a case of a 40-year-old male presenting with persistent fever, rash, and unilateral neck swelling. Initial investigations were suggestive of necrotizing lymphadenitis, with a presumed infective aetiology. However, extensive microbiology and immunological investigations remained negative. Cardiac injury was evident with elevated troponin T and NT-proBNP; however, left ventricular systolic function was normal. After 4 days, clinical features consistent with KD were noted and the results of a lymph node biopsy supported this diagnosis. Despite timely treatment with intravenous immunoglobulins (IVIG) and high-dose aspirin, follow-up computed tomography (CT) coronary angiography demonstrated two sequential aneurysms (max 6 mm) in the right coronary artery, plus one small subtle aneurysm in the proximal left anterior descending artery (4 mm). Discussion Diagnosis of adult KD remains challenging, as symptoms often present sequentially over time rather than simultaneously and many of the clinical features necessary for diagnosis share commonality with other infectious disease processes. [ABSTRACT FROM AUTHOR]

A deficiency in hydrogen sulfide has been implicated in the development and progression of diabetic chronic kidney disease. The purpose of this study was to determine the effect of diabetes on the H2S system in early-stage diabetic kidney disease. We characterised gene and protein expression profile of the enzymes that regulate H2S production and degradation, and H2S production capacity, in the kidney from 10-week-old C57BL6Jdb/db mice (n = 6), in age-matched heterozygous controls (n = 7), and in primary endothelial cells (HUVECs) exposed to high glucose. In db/db mice, renal H2S levels were significantly reduced (P = 0.009). Protein expression of the H2S production enzymes was differentially affected by diabetes: cystathionine β-synthase (CBS) was significantly lower in both db/db mice and high glucose-treated HUVECs (P < 0.0001; P = 0.0318) whereas 3-mercatopyruvate sulfurtransferase (3-MST) expression was higher in the db/db kidney (P < 0.0001), yet lower in the HUVECs (P = 0.0001). Diabetes had no effect on the expression of cystathionine γ-lyase (CSE) in the db/db kidney (P = ns) but was associated with reduced expression in the HUVECs (P = 0.0004). Protein expression of degradation enzyme sulfide quinone reductase (SQOR) was significantly higher in db/db kidney (P = 0.048) and lower in the high glucose-treated HUVECs (P = 0.008). Immunofluorescence studies revealed differential localisation of the H2S enzymes in the kidney, including both tubular and vascular localisation, suggestive of functionally distinct actions in the kidney. The results of this study provide foundational knowledge for future research looking at the H2S system in both kidney physiology and the aetiology of chronic diabetic kidney disease. [ABSTRACT FROM AUTHOR]