Teriparatide increases bone formation in modeling and remodeling osteons and enhances IGF-II immunoreactivity in postmenopausal women with osteoporosis.

Transiliac bone biopsies were obtained from 55 women treated with teriparatide or placebo for 12-24 months. We report direct evidence that modeling bone formation at quiescent surfaces was present only in teriparatide-treated patients and bone formation at remodeling sites was higher with teriparatide than placebo. INTRODUCTION: Recombinant teriparatide [human PTH(1-34)], a bone formation agent for the treatment of osteoporosis when given once daily subcutaneously, increases biochemical markers of bone turnover and activation frequency in histomorphometry studies. MATERIALS AND METHODS: We studied the mechanisms underlying this bone-forming action of teriparatide at the basic multicellular unit by the appearance of cement lines, a method used to directly classify surfaces as modeling or remodeling osteons, and by the immunolocalization of IGF-I and IGF-II. Transiliac bone biopsies were obtained from 55 postmenopausal women treated with teriparatide 20 or 40 microg or placebo for 12-24 months (median, 19.8 months) in the Fracture Prevention Trial. RESULTS: A dose-dependent relationship was observed in modeling and mixed remodeling/modeling trabecular hemiosteons. Trabecular and endosteal hemiosteon mean wall thicknesses were significantly higher in both teriparatide groups than in placebo. There was a dose-dependent relationship in IGF-II immunoreactive staining at all bone envelopes studied. The greater local IGF-II presence after treatment with teriparatide may play a key role in stimulating bone formation. CONCLUSIONS: Direct evidence is presented that 12-24 months of teriparatide treatment induced modeling bone formation at quiescent surfaces and resulted in greater bone formation at remodeling sites, relative to placebo.     

Tumorigenicity study in Syrian hamsters fed areca nut together with nitrite

In order to evaluate the effect of concurrent administrationof areca nut and sodium nitrite, a long-term feeding study wasconducted with 120 Syrian hamsters. The animals were dividedinto four treatment groups, each consisting of 15 males and15 females, and received 2 g/kg diet of sodium nitrite (groupI), 20 g/kg diet of powdered areca nut (group II), 2 g/kg dietof sodium nitrite plus 20 g/kg diet of areca nut (group III)or powdered diet only (group IV) throughout their lifetime.Urine samples from all groups were analysed for N-nitrosonipecoticacid (NNIP), a major urinary metabolite of areca-nut-derivednitrosamines. NNIP was only detected in the urine of hamstersfed nitrite plus areca nut (concentration: 1.9±0.9 ng/mlurine), indicating that areca nut alkaloids underwent in vivonitrosation to form arecanut-specific nitrosamines. The totaltumour response was not significantly elevated in groups IIand III. Hamsters of group III had a markedly, but also insignificantlyhigher frequency of malignant tumours than those of the othergroups, with a statistically significant increase in malignantlymphomas in the males. Although limited by the low number ofanimals per group, these results indicate that exposure to nitritetogether with areca nut constituents appears to enhance therisk of developing malignancies.     

Synaptically evoked membrane potential oscillations induced by substance P in lamprey motor neurons.

Short-lasting application (10 min) of tachykinin neuropeptides evokes long-lasting (>24 h) modulation of N-methyl-D-aspartate (NMDA)-evoked locomotor network activity in the lamprey spinal cord. In this study, the net effects of the tachykinin substance P on the isolated spinal cord have been examined by recording from motor neurons in the absence of NMDA and ongoing network activity. Brief bath application of substance P (30 s to 2 min) induced irregular membrane potential oscillations in motor neurons. These oscillations consisted of depolarizing and hyperpolarizing phases and were associated with phasic ventral-root activity. The oscillations were blocked by the tachykinin antagonist spantide II. They were also blocked by tetrodotoxin (TTX), suggesting that they were not dependent on intrinsic membrane properties of the motor neurons but were synaptically mediated. Substance P could also have a direct effect, however, because a membrane potential depolarization persisted in the presence of TTX. Protein kinase agonists and antagonists were used to investigate the intracellular pathways through which substance P acted. The oscillations were blocked by the selective protein kinase C (PKC) antagonist chelerythrine. However, the TTX-resistant membrane potential depolarization was not significantly affected by blocking PKC. The protein kinase A and G antagonist H8 did not affect either the oscillations or the direct TTX-resistant membrane potential depolarization. The glutamate receptor antagonist kynurenic acid abolished the substance-P-evoked oscillations, suggesting that they were dependent on glutamate release. The oscillations were abolished or reduced by the AMPA/kainate receptor antagonist 6-cyano-7-nitroquinoxalene-2,3-dione but were only reduced by the NMDA receptor antagonist D-AP5. The oscillations were thus mediated by glutamatergic inputs with a greater dependence on non-NMDA receptors. Blocking glycinergic inputs with strychnine resulted in large depolarizing plateaus and bursts of spikes. The glutamatergic and glycinergic inputs underlying the oscillations are apparently evoked through direct and indirect excitatory effects on inhibitory and excitatory premotor interneurons. Substance P thus has a distributed excitatory effect in the spinal cord. While it can activate premotor networks, this activation alone is not able to evoke a coordinated behaviorally relevant motor output.     

How Cluster Headache is Explained as an Intracavernous Inflammatory Process Lesioning Sympathetic Fibers

SYNOPSIS
A large body of evidence points to an inflammatory process in the cavernous sinus and tributary veins as being primarily responsible for cluster headaches. The inflammation obliterates the venous outflow from the cavernous sinus on one side and injures the through-running sympathetic fibers to the eye, upper eye lid, forehead skin, and the intracranial internal carotid artery and its branches. The active period ends when the inflammation is suppressed and the sympathetic fibers partially or fully recover. Evidence is presented that the symptoms suggestive of an enhanced parasympathetic activity during attacks may alternatively be explained as local pain fiber activation or a stasis in the outflow from the cavernous sinus. Vasodilator agents like nitroglycerin induce an attack by enhancing the venous load on the cavernous sinus. Constriction of the proximal intracranial internal carotid artery, spontaneously induced by tressful pain activation of the perivascular sympathetic nerves, or by exogenous administration of serotonin 1 D-like receptor agonists or oxygen, terminates the venous load and thus the pain and associated symptoms.     

A double-blind combination study of clonazepam with sertraline in obsessive-compulsive disorder.

This double blind, randomized, parallel, placebo-controlled study investigates whether clonazepam accelerates and/ or increases the overall response in patients with obsessive compulsive disorder (OCD) who are treated with sertraline. Thirty-seven patients were randomized with 20 in the sertraline and clonazepam group and 17 in the sertraline and placebo groups. Male and female outpatients, age 18-65 years, met criteria for a primary diagnosis of obsessive compulsive disorder according to DSM-IV, as determined by the structured clinical MINI interview. Appropriate safety and efficacy parameters were measured throughout the study. The determination of efficacy was based primarily on changes from baseline to the last observation taken through week 12. Analysis revealed no significant difference between groups at endpoint on the main scale.