Objective. Inflammatory diseases often coincide with reduced bone mass. Mechanoresponsive osteocytes regulate bone mass by maintaining the balance between bone formation and resorption. Despite its biologic significance, the effect of inflammation on osteocyte mechanoresponsiveness is not understood. To fill this gap, we investigated whether the inflammatory cytokines tumor necrosis factor ␣ (TNF␣) and interleukin-1␤ (IL-1␤) modulate the osteocyte response to mechanical loading.Methods. MLO-Y4 osteocytes were incubated with TNF␣ (0.5-30 ng/ml) or IL-1␤ (0.1-10 ng/ml) for 30 minutes or 24 hours, or with calcium inhibitors for 30 minutes. Cells were subjected to mechanical loading by pulsatile fluid flow (mean ؎ amplitude 0.7 ؎ 0.3 Pa, 5 Hz), and the response was quantified by measuring nitric oxide (NO) production using Griess reagent and by measuring intracellular calcium concentration ([Ca 2؉ ] i ) using Fluo-4/AM. Focal adhesions and filamentous actin (F-actin) were visualized by immunostaining, and apoptosis was quantified by measuring caspase 3/7 activity. Cell-generated tractions were quantified using traction force microscopy, and cytoskeletal stiffness was quantified using optical magnetic twisting cytometry. ] i , and that IL-1␤ stimulates osteocyte apoptosis. Since both NO and osteocyte apoptosis affect osteoclasts, these findings provide a mechanism by which inflammatory cytokines might contribute to bone loss and consequently affect bone mass in rheumatoid arthritis. Results. Pulsatile fluid flow increased [Ca 2؉ ] i within seconds (in 13% of cells) and NO production within 5 minutes (4.7-fold). TNF␣ and IL-1␤ inhibitedThe most important task of the skeleton is to provide mechanical support in order to withstand the force of gravity, and to support muscle forces during movement. This mechanical performance is secured by the constant adaptation of bone mass to its mechanical loading environment. Adaptation of bone mass is brought about by the coordinated actions of boneresorbing osteoclasts and bone-forming osteoblasts,

The cystic kidney disease nephronophthisis (NPHP) is the commonest genetic cause of end-stage renal failure in young people and children. Histologically the disease is characterized by interstitial fibrosis, tubular atrophy with corticomedullary cyst development and disruption of the tubular basement membrane. Affected children present with polydipsia and polyuria, secondary to a urinary concentration defect, before these structural changes develop. Recently, molecular genetic advances have identified several genes mutated in NPHP, providing novel insights into its pathophysiology for the first time in decades. Here we review the normal physiological mechanisms of urinary concentration and explain, in the context of recent discoveries, the possible mechanisms underlying urinary concentration defects in patients with NPHP. The pattern of a ciliary and adherens junction subcellular localization of nephrocystin proteins is discussed. Recent animal models of cystic kidney disease and treatment with vasopressin V2 receptor antagonists are reviewed and a hypothesis regarding urinary concentration defects in NPHP is proposed. Understanding the cellular mechanisms underlying NPHP and other cystic kidney diseases will provide the rationale for therapeutic interventions in this disease. Early urinary concentration defects provide both a clue to clinical diagnosis of NPHP and potential therapeutic targets for pharmacological treatment of this condition.

ED is highly prevalent in patients on chronic PD. Increasing age and diabetes were associated with higher percentage of ED.

A disequilibrium between immunosuppressive Tregs and inflammatory IL-17–producing Th17 cells is a hallmark of autoimmune diseases, including multiple sclerosis (MS). However, the molecular mechanisms underlying the Treg and Th17 imbalance in CNS autoimmunity remain largely unclear. Identifying the factors that drive this imbalance is of high clinical interest. Here, we report a major disease-promoting role for microRNA-92a (miR-92a) in CNS autoimmunity. miR-92a was elevated in experimental autoimmune encephalomyelitis (EAE), and its loss attenuated EAE. Mechanistically, miR-92a mediated EAE susceptibility in a T cell–intrinsic manner by restricting Treg induction and suppressive capacity, while supporting Th17 responses, by directly repressing the transcription factor Foxo1. Although miR-92a did not directly alter Th1 differentiation, it appeared to indirectly promote Th1 cells by inhibiting Treg responses. Correspondingly, miR-92a inhibitor therapy ameliorated EAE by concomitantly boosting Treg responses and dampening inflammatory T cell responses. Analogous to our findings in mice, miR-92a was elevated in CD4 + T cells from patients with MS, and miR-92a silencing in patients’ T cells promoted Treg development but limited Th17 differentiation. Together, our results demonstrate that miR-92a drives CNS autoimmunity by sustaining the Treg/Th17 imbalance and implicate miR-92a as a potential therapeutic target for MS.

Hypocalcaemic tetany is a known complication of plasmapheresis. It has two causes. Intravenously administered 4.5% human albumin solution (HAS) has no calcium or magnesium, so the replacement of plasma with this fluid depletes these ions. The citrate in fresh frozen plasma (FFP) chelates divalent cations, so the exchange with this at the end reduces the proportion of calcium and magnesium that is ionised. We studied the effect of supplementing HAS with 2 mmol/l calcium chloride and 0.8 mmol/l magnesium sulphate on the changes in ionised and total calcium and magnesium concentrations throughout plasmapheresis. The supplements prevented the falls in these concentrations that is otherwise seen during the HAS infusion, and, thus, the transient fall in ionised calcium concentration induced by the citrate in the FFP was not so profound, reaching 0.92 instead of 0.78 mmol/l (P = 0.002). Supplementation with calcium and magnesium during HAS maintains their balance and prevents tetany during the FFP infusion.