Several factors correlate with the risk of suicide in people taking antidepressants. After controlling for these factors, the risk of suicide was similar among the 10 study antidepressants. Overdose with antidepressants accounted for only 14% of the suicides.
Most agents that regulate osteoclast bone resorption exert their effects indirectly, through the osteoblast. Nitric oxide, which stimulates soluble guanylyl cyclase, has been reported to inhibit osteoclast bone resorption directly, by a cGMP-independent mechanism (1). In this report, we demonstrate that C-type natriuretic peptide (CNP), an activator of membrane-bound guanylyl cyclase, stimulates bone resorption by osteoclast-containing 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3)-stimulated mouse bone marrow cultures. Quantitative reverse transcription polymerase chain reaction assays and anti-CNP immunocytochemistry were used to demonstrate that CNP is expressed in mouse marrow cells cultured in the presence, but not the absence, of, 1,25-(OH)2D3. mRNA for guanylyl cyclase type B, the receptor for CNP, was expressed in cultures independent of 1,25-(OH)2D3. CNP (1 and 10 microM) elevated cGMP production in marrow cultures to 350 and 870%, respectively, of control values. 10 microM CNP increased osteoclast bone resorptive activity, measured by the resorption area on whale dentine wafers, or by the NH4Cl-inhibitable release of [3H]proline from radiolabeled bone chips, to 214 and 557% of control, respectively, without affecting osteoclast formation. Bone resorption by the marrow cultures was inhibited by 7F9.1, a monoclonal antibody raised against CNP, but not by control antibodies. These results indicate that CNP is a potent activator of osteoclast activity and may be a novel local regulator of bone remodeling.
A large primary-care computerized database was searched to determine the incidence and prevalence of epilepsy and epileptic seizures in old age compared with the general population. The prevalence of subjects with a diagnosis of epileptic seizures was higher in older age groups: 10.9/1000 for sexagenarians, 12.0 for septuagenarians and 13.1 for those over 80, compared with 9.0/1000 in the overall population. The overall prevalence in subjects aged over 60 was 11.8. Annual incidence rose even more sharply in old age: 76/100,000 for sexagenarians, 147 for septuagenarians, and 159 for those over 80, compared with an overall population incidence of 69/100,000. The overall incidence in subjects over 60 was 117. Of incident cases requiring treatment, 35.5% were over 60 years old. Our findings are in keeping with other recent epidemiological studies and in part reflect the age-associated increase in the prevalence of cerebrovascular disease. They have implications for the organization of services for elderly people, for the education of general practitioners and hospital doctors and for directing epilepsy research.
High concentrations of nitric oxide (NO) inhibit bone resorption by mature osteoclasts. We examined the effects of low NO concentrations on osteoclast formation in mouse bone marrow cultures. The NO releasers sodium nitroprusside (SNP) and S-nitroso-N-acetyl-DL-penicillamine inhibited the formation of multinucleated cells expressing tartrate-resistant acid phosphatase (a marker for osteoclasts) when administered during the last 3 days of 6-day cultures (differentiation stage) but not during the first 3 days (proliferation stage). SNP (1 microM) completely inhibited pit formation on dentine wafers when added to cultures during osteoclast formation, but 100 microM SNP was required to inhibit pitting by mature osteoclasts. Conversely, the NO synthase inhibitors aminoguanidine and nitro-L-arginine methyl ester both increased osteoclast formation. Inhibition of osteoclast formation by NO likely was guanosine 3',5'-cyclic monophosphate (cGMP) dependent, as SNP increased cGMP in marrow cultures, and 1 mM 8-bromo-cGMP or dibutyryl-cGMP reduced osteoclast formation when administered during the differentiation stage. The cGMP-specific type V phosphodiesterase inhibitor, zaprinast (M & B 22948) also inhibited osteoclast formation (half-maximal inhibitory constant, 100 microM) only when added during the differentiation stage. We conclude that the differentiation stage of osteoclast formation is inhibited by increases in cGMP levels elicited by NO.
ObjectiveTo estimate the frequency of cholestatic hepatitis of uncertain origin occurring among persons who had recently received flucloxacillin, a drug which has recently been reported as causing cholestatic hepatitis, and to compare this frequency with that related to oxytetracycline, a drug which has seldom been reported as causing this disorder. DesignA retrospective cohort study using data automatically recorded on general practitioners' office computers. SettingSome 600 general practices in the United Kingdom. Subjects132 087 people who received flucloxacillin and 145 844 people who received oxytetracycline. Main outcome measureClinically documented cholestatic hepatitis of uncertain origin diagnosed 1–45 days after a prescription for flucloxacillin, 46–90 days after a prescription for flucloxacillin and, for comparison, 1–45 days after a prescription for oxytetracycline. ResultsThere were 10 cases of cholestatic hepatitis of uncertain origin diagnosed within 45 days of receiving flucloxacillin that were either characteristic of or consistent with a syndrome recently described as being associated with this drug; there was one such case 46–90 days after a prescription for flucloxacillin; there were three such cases 1–45 days after a prescription for oxytetracycline. ConclusionFlucloxacillin is a likely cause of cholestatic hepatitis. The risk is estimated to be in the range of 7.6 per 100 000 users (95% confidence interval, 3.6–13.9).
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