Preeclampsia as a Risk Factor for Diabetes: A Population-Based Cohort Study

Background

Women with preeclampsia (PEC) and gestational hypertension (GH) exhibit insulin resistance during pregnancy, independent of obesity and glucose intolerance. Our aim was to determine whether women with PEC or GH during pregnancy have an increased risk of developing diabetes after pregnancy, and whether the presence of PEC/GH in addition to gestational diabetes (GDM) increases the risk of future (postpartum) diabetes.

Methods and Findings

We performed a population-based, retrospective cohort study for 1,010,068 pregnant women who delivered in Ontario, Canada between April 1994 and March 2008. Women were categorized as having PEC alone (n = 22,933), GH alone (n = 27,605), GDM alone (n = 30,852), GDM+PEC (n = 1,476), GDM+GH (n = 2,100), or none of these conditions (n = 925,102). Our main outcome was a new diagnosis of diabetes postpartum in the following years, up until March 2011, based on new records in the Ontario Diabetes Database. The incidence rate of diabetes per 1,000 person-years was 6.47 for women with PEC and 5.26 for GH compared with 2.81 in women with neither of these conditions. In the multivariable analysis, both PEC alone (hazard ratio [HR] = 2.08; 95% CI 1.97–2.19) and GH alone (HR = 1.95; 95% CI 1.83–2.07) were risk factors for subsequent diabetes. Women with GDM alone were at elevated risk of developing diabetes postpartum (HR = 12.77; 95% CI 12.44–13.10); however, the co–presence of PEC or GH in addition to GDM further elevated this risk (HR = 15.75; 95% CI 14.52–17.07, and HR = 18.49; 95% CI 17.12–19.96, respectively). Data on obesity were not available.

Conclusions

Women with PEC/GH have a 2-fold increased risk of developing diabetes when followed up to 16.5 years after pregnancy, even in the absence of GDM. The presence of PEC/GH in the setting of GDM also raised the risk of diabetes significantly beyond that seen with GDM alone. A history of PEC/GH during pregnancy should alert clinicians to the need for preventative counseling and more vigilant screening for diabetes. Please see later in the article for the Editors'' Summary     

Design,synthesis, and evaluation of substituted nicotinamide adenine dinucleotide (NAD+) synthetase inhibitors as potential antitubercular agents

Nicotinamide adenine dinucleotide (NAD⁺) synthetase catalyzes the last step in NAD⁺ biosynthesis. Depletion of NAD⁺ is bactericidal for both active and dormant Mycobacterium tuberculosis (Mtb). By inhibiting NAD⁺ synthetase (NadE) from Mtb, we expect to eliminate NAD⁺ production which will result in cell death in both growing and nonreplicating Mtb. NadE inhibitors have been investigated against various pathogens, but few have been tested against Mtb. Here, we report on the expansion of a series of urea-sulfonamides, previously reported by Brouillette et al. Guided by docking studies, substituents on a terminal phenyl ring were varied to understand the structure–activity-relationships of substituents on this position. Compounds were tested as inhibitors of both recombinant Mtb NadE and Mtb whole cells. While the parent compound displayed very weak inhibition against Mtb NadE (IC₅₀ = 1000 µM), we observed up to a 10-fold enhancement in potency after optimization. Replacement of the 3,4-dichloro group on the phenyl ring of the parent compound with 4-nitro yielded 4f, the most potent compound of the series with an IC₅₀ value of 90 µM against Mtb NadE. Our modeling results show that these urea-sulfonamides potentially bind to the intramolecular ammonia tunnel, which transports ammonia from the glutaminase domain to the active site of the enzyme. This hypothesis is supported by data showing that, even when treated with potent inhibitors, NadE catalysis is restored when treated with exogenous ammonia. Most of these compounds also inhibited Mtb cell growth with MIC values of 19–100 µg/mL. These results improve our understanding of the SAR of the urea-sulfonamides, their mechanism of binding to the enzyme, and of Mtb NadE as a potential antitubercular drug target.     

Spatio-Temporal Distribution and Ecological Preferences of Coexisting Hydropsychid Species (Trichoptera) in Two Mediterranean River Basins (S Spain)

The hydropsychids of two Mediterranean river basins in southern Spain (Guadaira and Guadalete) were investigated from January 1988 to January 1989. The distribution of hydropsychids along an environmental gradient related to altitude varied depending on species. Two distinct species assemblages were observed. one located in the lower altitude sites (the “downstream assemblage” comprising Hydropsyche pictetorum, Hydropsyche exocellata and Cheumatopsyche lepida) and the other in the upper-most areas (the “upstream assemblage” comprising Hydropsyche punica, Hydropsyche infernalis, Hydropsyche instabilis), which displayed a statistically significant preference for this type of habitat. Finally, H. pictetorum, selected the lowest sites. From a temporal point of view most species displayed a high variability in density dynamics between sites, suggesting a strong plasticity in life-cycle phenology.     

Fine mapping of the Autosomal Dominant Split Hand/Split Foot Locus on Chromosome 7, Band q21.3-q22.1

Split hand/split foot (SHFD) is a human developmental defect characterized by missing digits, fusion of remaining digits, and a deep median cleft in the hands and feet. Cytogenetic studies of deletions and translocations associated with this disorder have indicated that an autosomal dominant split hand/split foot locus (gene SHFD1) maps to 7q21-q22. To characterize the SHFD1 locus, somatic cell hybrid lines were constructed from cytogenetically abnormal individuals with SHFD. Molecular analysis resulted in the localization of 93 DNA markers to one of 10 intervals surrounding the SHFD1 locus. The translocation breakpoints in four SHFD patients were encompassed by the smallest region of overlap among the SHFD-associated deletions. The order of DNA markers in the SHFD1 critical region has been defined as PON–D7S812–SHFD1–D7S811–ASNS. One DNA marker, D7S811, detected altered restriction enzyme fragments in three patients with translocations when examined by pulsed-field gel electro-phoresis (PFGE). These data map SHFD1, a gene that is crucial for human limb differentiation, to a small interval in the q21.3-q22.1 region of human chromosome 7.     

Sex differences and similarities in the neuroendocrine regulation of social behavior in an African cichlid fish

An individual's position in a social hierarchy profoundly affects behavior and physiology through interactions with community members, yet little is known about how the brain contributes to status differences between and within the social states or sexes. We aimed to determine sex-specific attributes of social status by comparing circulating sex steroid hormones and neural gene expression of sex steroid receptors in dominant and subordinate male and female Astatotilapia burtoni, a highly social African cichlid fish. We found that testosterone and 17β-estradiol levels are higher in males regardless of status and dominant individuals regardless of sex. Progesterone was found to be higher in dominant individuals regardless of sex. Based on pharmacological manipulations in males and females, progesterone appears to be a common mechanism for promoting courtship in dominant individuals. We also examined expression of androgen receptors, estrogen receptor α, and the progesterone receptor in five brain regions that are important for social behavior. Most of the differences in brain sex steroid receptor expression were due to sex rather than status. Our results suggest that the parvocellular preoptic area is a core region for mediating sex differences through androgen and estrogen receptor expression, whereas the progesterone receptor may mediate sex and status behaviors in the putative homologs of the nucleus accumbens and ventromedial hypothalamus. Overall our results suggest sex differences and similarities in the regulation of social dominance by gonadal hormones and their receptors in the brain.     

Coordinated action of NSF and PKC regulates GABAB receptor signaling efficacy

The obligatory heterodimerization of the GABAB receptor (GBR) raises fundamental questions about molecular mechanisms controlling its signaling efficacy. Here, we show that NEM sensitive fusion (NSF) protein interacts directly with the GBR heterodimer both in rat brain synaptosomes and in CHO cells, forming a ternary complex that can be regulated by agonist stimulation. Inhibition of NSF binding with a peptide derived from GBR2 (TAT-Pep-27) did not affect basal signaling activity but almost completely abolished agonist-promoted GBR desensitization in both CHO cells and hippocampal slices. Taken with the role of PKC in the desensitization process, our observation that TAT-Pep-27 prevented both agonist-promoted recruitment of PKC and receptor phosphorylation suggests that NSF is a priming factor required for GBR desensitization. Given that GBR desensitization does not involve receptor internalization, the NSF/PKC coordinated action revealed herein suggests that NSF can regulate GPCR signalling efficacy independently of its role in membrane trafficking. The functional interaction between three bona fide regulators of neurotransmitter release, such as GBR, NSF and PKC, could shed new light on the modulation of presynaptic GBR action.     

Structure–Activity Relationship Studies on Derivatives of Eudesmanolides from Inula helenium as Toxicants against Aedes aegypti Larvae and Adults

An Aedes aegypti larval toxicity bioassay was performed on compounds representing many classes of natural compounds including polyacetylenes, phytosterols, flavonoids, sesquiterpenoids, and triterpenoids. Among these compounds, two eudesmanolides, alantolactone, and isoalantolactone showed larvicidal activities against Ae. aegypti and, therefore, were chosen for further structure–activity relationship study. In this study, structural modifications were performed on both alantolactone and isoalantolactone in an effort to understand the functional groups necessary for maintaining and/or increasing its activity, and to possibly lead to more effective insect‐control agents. All parent compounds and synthetic modification reaction products were evaluated for their toxic activities against Ae. aegypti larvae and adults. Structure modifications included epoxidations, reductions, catalytic hydrogenations, and Michael additions to the α,β‐unsaturated lactones. None of the synthetic isomers synthesized and screened against Ae. aegypti larvae were more active than isoalantolactone itself which had an LC₅₀ value of 10.0 μg/ml. This was not the case for analogs of alantolactone for which many of the analogs had larvicidal activities ranging from 12.4 to 69.9 μg/ml. In general, activity trends observed from Ae. aegypti larval screening were not consistent with observations from adulticidal screening. The propylamine Michael addition analog of alantolactone was the most active adulticide synthesized with an LC₅₀ value of 1.07 μg/mosquito. In addition, the crystal structures of both alantolactone and isoalantolactone were determined using CuK_α radiation, which allowed their absolute configurations to be determined based on resonant scattering of the light atoms.     

Ontogenetic changes in the diet of the sandbar shark, <Emphasis Type="Italic">Carcharhinus plumbeus</Emphasis>, in lower Chesapeake Bay and Virginia (USA) coastal waters

This study describes the diet of the sandbar shark, Carcharhinus plumbeus, highlighting differences in diet within various regions of the Virginia (USA) nursery area, as well as ontogenetic changes in diet. Stomach samples were obtained in 2001 and 2002 from 232 sharks caught by gillnets or longlines. Historical data from the Virginia Institute of Marine Science (VIMS) Shark Ecology Program were also analyzed. Ontogenetic changes in diet were evident, with crustacean prey decreasing in frequency with increasing shark size, and elasmobranch prey importance increasing with increasing shark size. Whereas previous research in Chincoteague Bay, VA showed the blue crab, Callinectes sapidus, was the dominant crustacean in sandbar shark diet, the mantis shrimp, Squilla empusa, dominated the crustacean portion of the diet in this study. Differences in diet of sharks were observed among locations within the study area. Small juveniles (≤80 cm precaudal length) in the lower Chesapeake Bay ate more fishes, whereas Eastern Shore juveniles ate more crustaceans. Crustacean prey items varied among locations along the Eastern Shore, with more portunid crabs consumed in waters near Wachapreague and more mantis shrimp consumed near Sand Shoal Inlet. Our study showed that Carcharhinus plumbeus is a generalist predator and is thus unlikely to strongly impact the population of any particular prey species, and in turn is not likely to be strongly affected by fluctuations in abundance of a single prey species.