Cochrane systematic reviews are useful to map research gaps for decreasing maternal mortality

ObjectivesTo use an “evidence-mapping” approach to assess the usefulness of Cochrane reviews in identifying research gaps in the maternal health.Study Design and SettingThe article describes the general mapping, prioritizing, reconciling, and updating approach: (1) identifying gaps in the maternal health research using published systematic reviews and formulating research questions, (2) prioritizing questions using Delphi method, (3) reconciling identified research priorities with the existing literature (i.e., searching of ongoing trials in trials registries), (4) updating the process. A comprehensive search of Cochrane systematic reviews published or updated from January 2006 to March 2011 was performed. We evaluated the “Implications for Research” section to identify gaps in the research.ResultsOur search strategy identified 695 references; 178 systematic reviews identifying at least one research gap were used. We formulated 319 research questions, which were classified into 11 different categories based on the direct and indirect causes of maternal mortality: postpartum hemorrhage, abortion, hypertensive disorders, infection/sepsis, caesarean section, diabetes, pregnancy prevention, preterm labor, other direct causes, indirect causes, and health policies and systems. Most research questions concerned the effectiveness of clinical interventions, including drugs (42.6%), nonpharmacologic interventions (16.3%), and health system (14.7%).ConclusionIt is possible to identify gaps in the maternal health research by using this approach.     

Comparative Pharmacology and Toxicology of Pharmaceuticals in the Environment: Diphenhydramine Protection of Diazinon Toxicity in Danio rerio but Not Daphnia magna

Pharmaceuticals and other contaminants of emerging concern present unique challenges to environmental risk assessment and management. Fortunately, mammalian pharmacology and toxicology safety data are more readily available for pharmaceuticals than other environmental contaminants. Identifying approaches to read-across such pharmaceutical safety information to non-target species represents a major research need to assess environmental hazards. Here, we tested a biological read-across hypothesis from emergency medicine with common aquatic invertebrate and vertebrate models. In mammals, the antihistamine diphenhydramine (DPH) confers protection from poisoning by acetylcholinesterase inhibition because DPH blocks the acetylcholine receptor. We employed standardized toxicity methods to examine individual and mixture toxicity of DPH and the acetylcholinesterase inhibitor diazinon (DZN) in Daphnia magna (an invertebrate) and Danio rerio (zebrafish, a vertebrate). Though the standardized Fish Embryo Toxicity method evaluates early life stage toxicity of zebrafish (0–3 days post fertilization, dpf), we further evaluated DPH, DZN, and their equipotent mixture during three development stages (0–3, 3–6, 7–10 dpf) in zebrafish embryos. Independent action and concentration addition mixture models and fish plasma modeling were used to assist interpretation of mixture toxicity experiments. Though our primary hypothesis was not confirmed in acute studies with Daphnia magna, DPH conferred a protective effect for acute DZN toxicity to zebrafish when DPH plasma levels were expected to be greater than mammalian therapeutic, but lower than acutely lethal, internal doses. We further observed that timing of developmental exposure influenced the magnitude of DZN and DPH toxicity to zebrafish, which suggests that future zebrafish toxicity studies with pharmaceuticals and pesticides should examine exposure during developmental stages.KEY WORDS: alternative toxicity test methods, biological read-across, comparative pharmacology and toxicology, mixture toxicology, pharmaceuticals in the environment     

Molecular characterization of methylmalonate semialdehyde dehydrogenase deficiency

Three patients have been reported with (putative) methylmalonic semialdehyde dehydrogenase (MMSDH) deficiency. The urine metabolic pattern was strikingly different in all, including -alanine, 3-hydroxypropionic acid, both isomers of 3-amino- and 3-hydroxyisobutyric acids in one and 3-hydroxyisobutyric and lactic acids in a second, and mild methylmalonic aciduria in a third patient. In an effort to clarify these disparate metabolite patterns, we completed the cDNA structure, and characterized the genomic structure of human MMSDH gene in order to undertake molecular analysis. Only the first patient had alterations in the MMSDH coding region, revealing homozygosity for a 1336G>A transversion, which leads to substitution of arginine for highly conserved glycine at amino acid 446. No abnormalities of the MMSDH cDNA were detected in the other patients. These data provide the first molecular characterization of an inborn error of metabolism specific to the L-valine catabolic pathway.     

Estrogen receptor alpha and endothelial nitric oxide synthase are organized into a functional signaling module in caveolae

Estrogen causes nitric oxide (NO)-dependent vasodilation due to estrogen receptor (ER) alpha-mediated, nongenomic activation of endothelial NO synthase (eNOS). The subcellular site of interaction between ERalpha and eNOS was determined in studies of isolated endothelial cell plasma membranes. Estradiol (E(2), 10(-8) mol/L) caused an increase in eNOS activity in plasma membranes in the absence of added calcium, calmodulin, or eNOS cofactors, which was blocked by ICI 182,780 and ERalpha antibody. Immunoidentification studies detected the same 67-kDa protein in endothelial cell nucleus, cytosol, and plasma membrane. Plasma membranes from COS-7 cells expressing eNOS and ERalpha displayed ER-mediated eNOS stimulation, whereas membranes from cells expressing eNOS alone or ERalpha plus a myristoylation-deficient mutant eNOS were insensitive. Fractionation of endothelial cell plasma membranes revealed ERalpha protein in caveolae, and E(2) caused stimulation of eNOS in isolated caveolae that was ER-dependent; noncaveolae membranes were insensitive. Acetylcholine and bradykinin also activated eNOS in isolated caveolae. Furthermore, the effect of E(2) on eNOS in caveolae was prevented by calcium chelation. Thus, a subpopulation of ERalpha is localized to endothelial cell caveolae where they are coupled to eNOS in a functional signaling module that may regulate the local calcium environment. The full text of this article is available at http://www.circresaha.org.     

The role of selection bias in comparing cesarean birth rates between physician and midwifery management.

OBJECTIVE: The midwifery service at our hospital has been observed to have a 2% cesarean birth rate consistently over a 10-year period. There are substantial differences in labor management style between the midwives and physicians. We sought to test the hypothesis that the low cesarean birth rate on the midwifery service was the result of patient selection bias. METHODS: A randomized blinded clinical trial was conducted in which 492 low-risk patients were assigned to either physician or midwifery management. The provider responsible for labor management was unable to determine group assignment. Patients in the midwifery group were managed by previously established protocols, and outcome was attributed to the midwives even if the patients subsequently required transfer to physician management. Route of delivery was the primary outcome measurement. Continuous variables were analyzed using Student t test and discrete variables using chi 2. RESULTS: There were no demographic differences between the groups, and the admission pelvic examinations were the same. The patients assigned to the midwifery group had a 2.1% cesarean birth rate, whereas those assigned to physician management had a 0.4% rate. The higher rate of operative vaginal deliveries in the physician group was statistically significant. There were no differences in neonatal outcomes. The physician-managed group had significantly more episiotomies and third- and fourth-degree extensions. CONCLUSIONS: The 2% cesarean birth rate observed on the midwifery service appeared to be the result of patient selection bias. A low cesarean birth rate can be achieved by either physician or midwifery management in a selected low-risk population.     

Effects of chronic exercise and imipramine on mRNA for BDNF after olfactory bulbectomy in rat

We examined the effects of chronic activity wheel running and antidepressant treatment on brain-derived neurotrophic factor (BDNF) messenger RNA (mRNA) in multiple brain regions-hippocampal formation (HF), ventral tegmental area/substantia nigra (VTA/SN), nucleus accumbens (NAc), and piriform cortex (PFx)-after bilateral olfactory bulbectomy (OBX). Male, Long-Evans rats (n=72) underwent either sham or OBX surgery and were randomly divided into eight experimental groups in a 2 (sham vs. OBX) x 2 (sedentary vs. activity wheel)x2 (saline vs. imipramine) factorial design. Animals were killed after 21 days of treatment. Drug x exercise interaction effects were observed for HF (P=0.006-0.023) and VTA/SN (P=0.021); exercise increased BDNF mRNA in the saline treated animals but not in the imipramine treated animals. OBX did not affect BDNF mRNA in the HF or VTA/SN (P>0.05). BDNF mRNA levels in the PFx were not altered by exercise, drug, or OBX (P>0.05). These results suggest that the effect of exercise on BDNF mRNA extends beyond the HF to the mesolimbic ventral tegmental area and that the potentiation of BDNF mRNA by exercise and antidepressant pharmacotherapy, reported by other investigators, is time limited.     

Extracorporeal life support for posttraumatic acute respiratory distress syndrome at a children's medical center

Background: Primary traumatic injury was considered previously a contraindication for institution of extracorporeal life support because of high risk for persistent or new bleeding. Published experience in adults suggests that extracorporeal membrane oxygenation (ECMO) can successfully support trauma victims with pulmonary failure. The authors reviewed their experience with the use of ECMO in pediatric and adult trauma patients with acute respiratory distress syndrome (ARDS) at a children’s medical center.Methods: ECMO Center records from 1991 through 2001 (76 children, 8 adults) were reviewed to identify all patients with a primary or secondary ICD-9 diagnostic code of posttraumatic ARDS in addition to documented trauma.Results: Five children and 3 adults with traumatic injury and ARDS received ECMO support. Seven patients were injured in motor vehicle collisions; one patient suffered a gunshot wound to the chest. Patient ages ranged from 21 months to 29 years (pediatric median, 4 years; range, 21 months to 18 years). Four patients had pre-ECMO laparotomies, including 3 who required splenectomy. Four patients had liver lacerations, 3 had pulmonary contusions, and 1 had a renal contusion. Median ventilation before ECMO was 6 days (range, 2 to 10). Seven of 8 patients were placed on venovenous (VV) ECMO. Seven patients had significant bleeding on ECMO. Patients were treated with blood product replacement, epsilon-aminocaproic acid (EACA), and aprotinin infusions. Surgical intervention was not required for bleeding. Six patients received hemofiltration. Median time on ECMO was 653 hours (range, 190 to 921 hours). Six of 8 patients overall survived (75%). Four of 5 pediatric patients survived.Conclusions: Children and adults with severe posttraumatic ARDS can be treated successfully on VV extracorporeal support. Hemorrhage occurs frequently but is manageable.