Fetal-derived adrenomedullin mediates the innate immune milieu of the placenta

The remodeling of maternal uterine spiral arteries (SAs) is an essential process for ensuring low-resistance, high-capacitance blood flow to the growing fetus. Failure of SAs to remodel is causally associated with preeclampsia, a common and life-threatening complication of pregnancy that is harmful to both mother and fetus. Here, using both loss-of-function and gain-of-function genetic mouse models, we show that expression of the pregnancy-related peptide adrenomedullin (AM) by fetal trophoblast cells is necessary and sufficient to promote appropriate recruitment and activation of maternal uterine NK (uNK) cells to the placenta and ultimately facilitate remodeling of maternal SAs. Placentas that lacked either AM or its receptor exhibited reduced fetal vessel branching in the labyrinth, failed SA remodeling and reendothelialization, and markedly reduced numbers of maternal uNK cells. In contrast, overexpression of AM caused a reversal of these phenotypes with a concomitant increase in uNK cell content in vivo. Moreover, AM dose-dependently stimulated the secretion of numerous chemokines, cytokines, and MMPs from uNK cells, which in turn induced VSMC apoptosis. These data identify an essential function for fetal-derived factors in the maternal vascular adaptation to pregnancy and underscore the importance of exploring AM as a biomarker and therapeutic agent for preeclampsia.     

Perceived social support interacts with prenatal depression to predict birth outcomes

Prenatal depression has been linked to adverse reproductive outcomes including preterm labor and delivery, and low birth weight. Social support also has been linked to birth outcomes, and may buffer infants from the adverse impact of maternal depression. In this prospective study, 235 pregnant women completed questionnaires about depression and social support. Clinical interviews were administered to assess for DSM-IV axis I disorders. Following delivery, birth outcomes were obtained from medical records. Babies of depressed mothers weighed less, were born earlier and had lower Apgar scores than babies of nondepressed mothers. Depressed women had smaller social support networks and were less satisfied with support from social networks. We found no direct associations between perceived social support and birth weight. However, depressed women who rated their partners as less supportive had babies who were born earlier and had lower Apgar scores than depressed mothers with higher perceived partner support. Women’s perception of partner support appears to buffer infants of depressed mothers from potential adverse outcomes. These results are notable in light of the low-risk nature of our sample and point to the need for continued depression screening in pregnant women and a broader view of risk for adverse birth outcomes. The results also suggest a possible means of intervention that may ultimately lead to reductions in adverse birth outcomes.     

Testing the relation between dispositional optimism and conditioned pain modulation: does ethnicity matter?

Greater dispositional optimism has been related to less severe pain; however, whether optimism is associated with endogenous pain modulation has not yet been examined. The beneficial effects of dispositional optimism often vary according to cultural dynamics. Thus, assessing optimism–pain relationships across different ethnic groups is warranted. This study sought to examine the association between optimism and conditioned pain modulation (CPM), and test whether this association differs according to ethnicity. Optimism and CPM were assessed in a sample of healthy, ethnically diverse young adults. CPM was determined by comparing pressure pain thresholds obtained before and during exposure to a cold pressor task. All participants completed a validated measure of dispositional optimism. Greater reported optimism was significantly associated with enhanced CPM, and the strength of this association did not vary according to individuals’ ethnic background. These findings suggest that an optimistic disposition may potentiate endogenous pain inhibition.     

Late diagnosis of HIV infection: trends, prevalence, and characteristics of persons whose HIV diagnosis occurred within 12 months of developing AIDS

BACKGROUND: Persons diagnosed late in the course of HIV infection may be unknowingly transmitting infection and once diagnosed may have worse outcomes and greater medical expenses. METHODS: Persons diagnosed with AIDS in San Francisco between 2001 and 2005 were included. Late testers were persons diagnosed with HIV 12 months or less before their AIDS diagnosis. Prevalence trends, demographic and risk correlates, and predictors of late testing were measured. RESULTS: Among 2139 persons included, 830 (38.8%) were late testers. The prevalence of late testing was stable between 2001 and 2005. Late testing was more likely among persons <30 years old (Odds ratio [OR]: 1.99, 95% confidence interval [CI]: 1.4, 2.8), heterosexuals (OR: 1.88, 95% CI: 1.1, 3.1), persons without a reported risk (OR: 2.88, 95% CI: 1.7, 5.0), persons with private insurance (OR: 1.82, 95% CI: 1.4, 2.4), no insurance (OR: 1.83, 95% CI: 1.4, 2.4), born outside of the United States (OR: 1.64, 95% CI: 1.2, 2.2), and whose initial AIDS diagnosis was an opportunistic infection (OR: 2.24, 95% CI: 1.8, 2.8). CONCLUSIONS: A large proportion of persons with AIDS have tested late in the course of HIV infection and this proportion has not declined in recent years. Routine testing in medical settings, and use of rapid oral-fluid testing in traditional and nontraditional settings may increase early HIV diagnosis.     

JAB1 determines the response of rheumatoid arthritis synovial fibroblasts to tumor necrosis factor-alpha

Fibroblast-like synoviocytes (FLSs) of patients with rheumatoid arthritis (RA FLSs) exhibit prosurvival, rather than apoptotic, response to tumor necrosis factor (TNF)-alpha stimulation. Here, we show that JAB1 is a critical regulator of the TNF-alpha-mediated anti-apo-ptosis pathways in RA FLSs. We found that knockdown of JAB1 using small interfering (si)RNA led to restoration of the TNF-alpha-induced apoptosis response, reduction of nuclear factor-kappaB activity, delayed degradation of IkappaB-alpha, and inhibited phosphorylation of JNK. Analysis of the interactions of JAB1 by reciprocal co-immunoprecipitations and confocal microscopy revealed that JAB1 interacts with TNF receptor-associated-factor 2 (TRAF2). The generation of the anti-apoptotic signal on binding of TNF-alpha to the TNF receptor (TNFR)1 has been shown to be associated with the recruitment of TRAF2 to the TNFR1 in a process that requires ubiquitination of TRAF2 with lysine-63-linked polyubiquitin chains. We found that TNF-alpha stimulation of JAB1 siRNA-transfected RA FLSs failed to stimulate ubiquitination of TRAF2. Thus, we conclude that JAB1-regulated ubiquitination of TRAF2 is a novel mechanism whereby TNF-alpha can induce anti-apoptosis signaling and production of matrix metalloproteinases through activation of nuclear factor-kappaB and JNK in RA FLSs.     

Comparing therapies for postmenopausal osteoporosis prevention and treatment

OBJECTIVE: To review the literature concerning the efficacy of calcium, hormone replacement therapy (HRT), bisphosphonates, selective estrogen receptor modulators, and calcitonin in the prevention and treatment of postmenopausal osteoporosis. DATA SOURCES: Articles were identified through searches of the MEDLINE (1966-July 2002), EMBASE (1980-July 2002), and International Pharmaceutical Abstracts (1970-July 2002) databases using the key words osteoporosis, postmenopausal, fracture, calcium, vitamin D, hormone replacement therapy, bisphosphonates, alendronate, risedronate, raloxifene, and calcitonin. Additional references were located through review of the bibliographies of the articles cited. Searches were not limited by time restriction, language, or human subject. STUDY SELECTION AND DATA EXTRACTION: Experimental and observational studies of the use of calcium and antiresorptive therapies for the prevention and treatment of postmenopausal osteoporosis were selected. Articles evaluating bone mineral density (BMD) or fracture efficacy were included in this review. DATA SYNTHESIS: HRT, bisphosphonates, raloxifene, and calcitonin have demonstrated stabilization of and improvement in BMD. Randomized clinical trials have shown fracture risk reduction with bisphosphonates, raloxifene, HRT, calcium, and calcitonin. The largest risk reductions have been reported with use of bisphosphonates in several trials. CONCLUSIONS: Several therapeutic options with well-documented improvements in BMD and reductions in fracture risk are available to women for the prevention and treatment of postmenopausal osteoporosis.