Gabapentin-induced coma: A MR-spectrometry analysis

As for the majority of antiepileptic drugs, encephalopathy, manifested by transient somnolence, mood and motor disorders, is a possible side-effect. To our knowledge, there is little information about gabapentin-induced coma. We report a third case of gabapentin-induced coma where magnetic resonance-spectrometry was performed in diagnosis assessment.     

Regulation of COX-2 mediates acid-induced bone calcium efflux in vitro.

Chronic metabolic acidosis induces net Ca efflux from bone; this osteoclastic bone resorption is mediated by increased osteoblastic prostaglandin synthesis. Cyclooxygenase, the rate-limiting enzyme in prostaglandin synthesis, is present in both constitutive (COX-1) and inducible (COX-2) forms. We report here that acidosis increases both osteoblastic RNA and protein levels for COX-2 and that genetic deficiency or pharmacologic inhibition of COX-2 significantly reduces acid-induced Ca efflux from bone. INTRODUCTION: Incubation of neonatal mouse calvariae in medium simulating physiologic metabolic acidosis induces an increase in osteoblastic prostaglandin E2 (PGE2) release and net calcium (Ca) efflux from bone. Increased PGE2 is necessary for acid-induced bone resorption, because inhibition of cyclooxygenase activity with indomethacin significantly decreases not only PGE2 production but also Ca release. Cyclooxygenase is present in both constitutive (COX-1) and inducible (COX-2) forms. Because COX-2 activity has been implicated in several forms of pathological bone resorption, we tested the hypothesis that COX-2 is critical for acid-induced, cell-mediated bone Ca efflux. MATERIALS AND METHODS: To determine the effect of metabolic acidosis on COX-2 RNA and protein, primary cells isolated from neonatal CD-1 mouse calvariae were cultured in neutral (Ntl) or physiologically acidic medium (Met). RNA levels for COX-2 and COX-1 were measured by quantitative real-time PCR. Levels of COX-2 and COX-1 protein were measured by immunoblot analysis. To determine the effect of acidosis on bone Ca efflux in genetically deficient COX-2 mice, mice heterozygous for the COX-2 knockout (strain B6;129S7-Ptgs2(tm1Jed)/J) were used as breeders, and neonatal calvariae were cultured in Ntl or Met. To determine the effects of the specific COX-2 inhibitor, NS398, on acid-induced bone resorption, CD-1 calvariae were incubated in Ntl or Met with or without NS398 (1 microM). Medium PGE2 was assayed by ELISA. RESULTS: Incubation of mouse calvarial cells in Met significantly increased COX-2 RNA and protein levels without a change in COX-1. Increased COX-2 protein levels in response to Met were also observed in cultured calvariae. Acid-induced, cell-mediated Ca efflux from B6;129S7-Ptgs2(tm1Jed)/J calvariae was dependent on genotype. From 0 to 24 h, when physicochemical Ca efflux predominates, Met significantly increased net Ca efflux in all genotypes. After 24 h, when cell-mediated Ca efflux predominates, Met induced greater Ca efflux from (+/+) than from (+/-), and there was no increase from (-/-). In calvariae from CD-1 mice, NS398 significantly inhibited both the acid-induced increase in PGE2 and Ca release. CONCLUSIONS: The specific acid-induced increase in COX-2 RNA and protein levels and the dependency of the increased Ca efflux on COX-2 activity, as determined by both genetic deficiency and pharmacologic inhibition, show that COX-2 is critical for acid-induced, cell-mediated bone resorption.     

Enhanced chondrogenesis and Wnt signaling in PTH-treated fractures.

Studies have shown that systemic PTH treatment enhanced the rate of bone repair in rodent models. However, the mechanisms through which PTH affects bone repair have not been elucidated. In these studies we show that PTH primarily enhanced the earliest stages of endochondral bone repair by increasing chondrocyte recruitment and rate of differentiation. In coordination with these cellular events, we observed an increased level of canonical Wnt-signaling in PTH-treated bones at multiple time-points across the time-course of fracture repair, supporting the conclusion that PTH responses are at least in part mediated through Wnt signaling. INTRODUCTION: Since FDA approval of PTH [PTH(1-34); Forteo] as a treatment for osteoporosis, there has been interest in its use in other musculoskeletal conditions. Fracture repair is one area in which PTH may have a significant clinical impact. Multiple animal studies have shown that systemic PTH treatment of healing fractures increased both callus volume and return of mechanical competence in models of fracture healing. Whereas the potential for PTH has been established, the mechanism(s) by which PTH produces these effects remain elusive. MATERIALS AND METHODS: Closed femoral fractures were generated in 8-wk-old male C57Bl/6 mice followed by daily systemic injections of either saline (control) or 30 microg/kg PTH(1-34) for 14 days after fracture. Bones were harvested at days 2, 3, 5, 7, 10, 14, 21, and 28 after fracture and analyzed at the tissue level by radiography and histomorphometry and at the molecular and biochemical levels level by RNase protection assay (RPA), real-time PCR, and Western blot analysis. RESULTS: Quantitative muCT analysis showed that PTH treatment induced a larger callus cross-sectional area, length, and total volume compared with controls. Molecular analysis of the expression of extracellular matrix genes associated with chondrogenesis and osteogenesis showed that PTH treated fractures displayed a 3-fold greater increase in chondrogenesis relative to osteogenesis over the course of the repair process. In addition, chondrocyte hypertrophy occurred earlier in the PTH-treated callus tissues. Analysis of the expression of potential mediators of PTH actions showed that PTH treatment significantly induced the expression of Wnts 4, 5a, 5b, and 10b and increased levels of unphosphorylated, nuclear localized beta-catenin protein, a central feature of canonical Wnt signaling. CONCLUSIONS: These results showed that the PTH-mediated enhancement of fracture repair is primarily associated with an amplification of chondrocyte recruitment and maturation in the early fracture callus. Associated with these cellular effects, we observed an increase in canonical Wnt signaling supporting the conclusion that PTH effects on bone repair are mediated at least in part through the activation of Wnt-signaling pathways.     

Incremental versus maximum bite advancement during twin-block therapy: a randomized controlled clinical trial.

The aim of this study was to evaluate the effectiveness of incremental and maximum bite advancement during treatment of Class II Division 1 malocclusion with the Twin-block appliance in the permanent dentition. It was performed at 3 district general hospitals in the United Kingdom with 4 operators. Two hundred three patients, 10-14 years old, were randomized. Control patients had the initial bite taken edge-to-edge for appliance construction with a standard Twin-block. Experimental patients had 2 mm initial bite advancement and subsequent 2 mm advancements at 6 weekly intervals with a Twin-block appliance incorporating advancement screws. Data were collected at the start and the finish of Twin-block treatment. The use of incremental advancement of the Twin-block did not confer any advantages in terms of process and outcome of the treatment. However, patient compliance was influenced by operator and patient age. The duration of treatment was influenced by operator and initial overjet. Incremental bite advancement produced no advantages over maximum advancement.