Prostaglandins (PGs) are multifunctional regulators of bone metabolism that stimulate both bone resorption and formation. PGs have been implicated in bone resorption associated with inflammation and metastatic bone disease and also in bone formation associated with fracture healing and heterotopic ossification. Recent studies identified roles for inducible cyclooxygenase-2 (COX-2) and PGE2 receptors in these processes. Although the effects of PGs have been most often associated with cAMP production and PKA activation, PGs can engage an extensive G-protein signaling network. Further analysis of COX-2 and PG receptors and their downstream G-protein signaling in bone could provide us with important clues to the regulation of skeletal cell growth in both health and disease.

The fate of double-stranded RNA (dsRNA) in the cell depends on both its length and location . The expression of dsRNA in the nucleus leads to several distinct consequences. First, the promiscuous deamination of adenosines to inosines by dsRNA-specific adenosine deaminase (ADAR) can lead to the nuclear retention of edited transcripts . Second, dsRNAs might induce heterochromatic gene silencing through an RNAi-related mechanism . Is RNA editing also connected to heterochromatin? We report that members of the conserved Vigilin class of proteins have a high affinity for inosine-containing RNAs. In agreement with other work , we find that these proteins localize to heterochromatin and that mutation or depletion of the Drosophila Vigilin, DDP1, leads to altered nuclear morphology and defects in heterochromatin and chromosome segregation. Furthermore, nuclear Vigilin is found in complexes containing not only the editing enzyme ADAR1 but also RNA helicase A and Ku86/70. In the presence of RNA, the Vigilin complex recruits the DNA-PKcs enzyme, which appears to phosphorylate a discrete set of targets, some or all of which are known to participate in chromatin silencing. These results are consistent with a mechanistic link between components of the DNA-repair machinery and RNA-mediated gene silencing.

Oxidative stress has been implicated as an important mechanism of vascular endothelial dysfunction induced by aging. Previous studies suggested that tetrahydrobiopterin (BH 4), an essential cofactor of endothelial NO synthase, could be a molecular target for oxidation. We tested the hypothesis that oxidative stress, in particular oxidation of BH 4, may contribute to attenuation of endothelium-dependent relaxation in aged mice. Vasomotor function of isolated carotid arteries was studied using a video dimension analyzer. Vascular levels of BH 4 and its oxidation products were measured via HPLC. In aged mice (age, 95 Ϯ 2 wk), endothelium-dependent relaxation to ACh (10 Ϫ5 to 10 Ϫ9 M) as well as endothelium-independent relaxation to the NO donor diethylammo-Ϫ5 to 10 Ϫ9 M) were significantly reduced compared with relaxation detected in young mice (age, 23 Ϯ 0.5 wk). Incubation of aged mouse carotid arteries with the cell-permeable SOD mimetic Mn(III)tetra(4-benzoic acid)porphyrin chloride normalized relaxation to ACh and DEA-NONOate. Furthermore, production of superoxide anion in aorta and serum levels of amyloid P component, which is the murine analog of C-reactive protein, was increased in old mice. In aorta, neither the concentration of BH 4 nor the ratio of reduced BH4 to the oxidation products were different between young and aged mice. Our results demonstrate that in mice, aging impairs relaxation mediated by NO most likely by increased formation of superoxide anion. Oxidation of BH 4 does not appear to be an important mechanism underlying vasomotor dysfunction in aged mouse arteries. endothelial dysfunction; nitric oxide; superoxide anion; reactive oxygen species; C-reactive protein AGING IS A RISK FACTOR for vascular disease; however, the role of aging, either as a process or as the result of longer exposure to other risks, is not well defined (16,17). In murine vascular tissue, the age-dependent changes in vasomotor function have not been characterized. Studies on rats have shown impairment of endothelium-dependent relaxation due to increased production of superoxide anions, but the source of the superoxide anions has also not been characterized (16,30). Reactive oxygen species (ROS) have been implicated in endothelial dysfunction associated with aging, hypertension, hypercholesteremia, diabetes, and cigarette smoking (3). ROS can interfere with endothelium-dependent relaxation particularly by the scavenging of NO by superoxide anion (O 2 Ϫ ⅐; Refs. 1, 3, 34).

Objective Antipsychotic medications are used by increasing numbers of women of reproductive age. The safety of these medications during pregnancy has not been well-described. We undertook a systematic review and meta-analysis of the adverse obstetric and neonatal outcomes associated with exposure to antipsychotics during pregnancy. Data Sources PubMed, Reprotox, and ClinicalTrials.gov were searched to identify potential studies for inclusion. Methods of Study Selection Case-control or cohort studies estimating adverse birth outcomes associated with antipsychotic exposure during pregnancy were included. Pooled odds ratios (OR) were used for dichotomous outcomes and weighted mean differences (WMD) were used for infant birth weight and gestational age. Thirteen cohort studies, including 6,289 antipsychotic-exposed and 1,618,039 unexposed pregnancies were included. Tabulation, Integration, and Results Antipsychotic exposure was associated with an increased risk of major malformations (Absolute Risk Difference = 0.03, 95% confidence interval [CI] 0.00 – 0.05, p=0.04, Z = 2.06), heart defects (Absolute Risk Difference =0.01, 95% CI 0.00 – 0.01, p<0.001, Z = 3.44), preterm delivery (Absolute Risk Difference = 0.05, 95% CI 0.03 – 0.08, p<0.001, Z = 4.10), small-for-gestational-age births (Absolute Risk Difference = 0.05, 95% CI 0.02 – 0.09, p = 0.006, Z = 2.74), elective termination (Absolute Risk Difference = 0.09, 95% CI 0.05 – 0.13, p<0.001, Z = 4.69) and decreased birth weight (WMD=−57.89g, 95%CI −103.69g – −12.10g, p=0.01). There was no significant difference in the risk of major malformations (test for subgroup differences: χ2 = 0.07, df = 1, p = 0.79) between typical (OR = 1.55, 95% CI 1.21 – 1.99, p = 0.006) and atypical (OR = 1.39, 95% CI 0.66 – 2.93, p = 0.38) antipsychotic medications. Antipsychotic exposure was not associated with risk of large for gestational age births, stillbirth, and spontaneous abortion. Although antipsychotic exposure during pregnancy was associated with increased risk of adverse obstetric and neonatal outcomes, this association does not necessarily imply causation. This analysis was limited by the small number of included studies and limited adjustment in studies for possible confounders. Conclusion Women requiring antipsychotic treatment during pregnancy appear at higher risk of adverse birth outcomes, regardless of causation, and may benefit from close monitoring and minimization of other potential risk factors during pregnancy.

No abstract