No abstract

Glycogen storage diseases (GSDs) of the liver are devastating disorders presenting with fasting hypoglycemia as well as hepatic glycogen and lipid accumulation, which could lead to long-term liver damage. Diet control is frequently utilized to manage the potentially dangerous hypoglycemia, but there is currently no effective pharmacological treatment for preventing hepatomegaly and concurrent liver metabolic abnormalities, which could lead to fibrosis, cirrhosis, and hepatocellular adenoma or carcinoma. In this study, we demonstrate that inhibition of glycogen synthesis using an RNAi approach to silence hepatic Gys2 expression effectively prevents glycogen synthesis, glycogen accumulation, hepatomegaly, fibrosis, and nodule development in a mouse model of GSD III. Mechanistically, reduction of accumulated abnormally structured glycogen prevents proliferation of hepatocytes and activation of myofibroblasts as well as infiltration of mononuclear cells. Additionally, we show that silencing Gys2 expression reduces hepatic steatosis in a mouse model of GSD type Ia, where we hypothesize that the reduction of glycogen also reduces the production of excess glucose-6-phosphate and its subsequent diversion to lipid synthesis. Our results support therapeutic silencing of GYS2 expression to prevent glycogen and lipid accumulation, which mediate initial signals that subsequently trigger cascades of long-term liver injury in GSDs.

Summary A nulliparous woman presented with pre‐eclampsia at 39 weeks' gestation. A combined spinal‐epidural anaesthesia was employed for Caesarean section but the spinal component produced no discernible block, so the epidural was topped up with 20 ml ropivacaine 0.75% without problem and surgery was uneventful. A week after delivery she developed twitching of her legs and opisthotonus, that was initially thought to be eclampsia but was subsequently diagnosed as spinal myoclonus. She was treated with oral carbamazepine and diazepam, with improvement over the next 4 days, and discharged home a week later taking oral carbidopa and levodopa. Her symptoms resolved completely 6 months after the initial event.

Twelve patients with chronic renal failure (dialysis-dependent) and six with good renal function after renal transplantation received i.v. morphine-6-glucuronide (M6G) 30 micrograms kg-1 as part of a standardized anaesthetic technique for minor surgery. Continuous peritoneal dialysis was commenced 6 h after M6G administration in six of the dialysis-dependent patients. Serum was sampled for up to 12 h and analysed for morphine and M6G by high pressure liquid chromatography. Morphine was not detected. Mean (SD) derived pharmacokinetic variables for the three groups (transplant, renally impaired non-dialysed and renally impaired dialysed, respectively) were: elimination half-life 2.14 (0.69) h, 27.10 (15.8) h, 17.33 (4.6) h; clearance 96.0 (34.9) ml min-1, 10.57 (5.57) ml min-1, 14.3 (6.2) ml min-1; volume of distribution 0.19 (0.03) litre kg-1, 0.25 (0.06) litre kg-1, 0.27 (0.06) litre kg-1. The elimination half-life was shorter (P < 0.01) and the clearance greater (P < 0.01) for the transplanted group compared with the dialysed and non-dialysed groups. Peritoneal dialysis for the second 6 h after drug administration had little effect on M6G disposition as assessed by comparison with data obtained from the non-dialysed group.

Summary Tau pathobiology has emerged as a key component underlying Alzheimer's disease (AD) progression; however, human neuronal in vitro models have struggled to recapitulate tau phenomena observed in vivo . Here, we aimed to define the minimal requirements to achieve endogenous tau aggregation in functional neurons utilizing human induced pluripotent stem cell (hiPSC) technology. Optimized hiPSC-derived cortical neurons seeded with AD brain-derived competent tau species or recombinant tau fibrils displayed increases in insoluble, endogenous tau aggregates. Importantly, MAPT- wild type and MAPT- mutant hiPSC-neurons exhibited unique propensities for aggregation dependent on the seed strain rather than the repeat domain identity, suggesting that successful templating of the recipient tau may be driven by the unique conformation of the seed. The in vitro model presented here represents the first successful demonstration of combining human neurons, endogenous tau expression, and AD brain-derived competent tau species, offering a more physiologically relevant platform to study tau pathobiology.