S-nitrosoglutathione reductase (GSNOR), or ADH5, is an enzyme in the alcohol dehydrogenase (ADH) family. It is unique when compared to other ADH enzymes in that primary short-chain alcohols are not its principle substrate. GSNOR metabolizes S-nitrosoglutathione (GSNO), S-hydroxymethylglutathione (the spontaneous adduct of formaldehyde and glutathione), and some alcohols. GSNOR modulates reactive nitric oxide (•NO) availability in the cell by catalyzing the breakdown of GSNO, and indirectly regulates S-nitrosothiols (RSNOs) through GSNO-mediated protein S-nitrosation. The dysregulation of GSNOR can significantly alter cellular homeostasis, leading to disease. GSNOR plays an important regulatory role in smooth muscle relaxation, immune function, inflammation, neuronal development, and cancer progression, among many other processes. In recent years, the therapeutic inhibition of GSNOR has been investigated to treat asthma, cystic fibrosis and interstitial lung disease (ILD). The direct action of •NO on cellular pathways, as well as the important regulatory role of protein S-nitrosation, are closely tied to GSNOR regulation and define this enzyme as an important therapeutic target.

Key Points Question Is altered fetal brain development in the setting of maternal psychological distress associated with infant neurodevelopment? Findings In this cohort study of 97 mother-infant dyads who underwent 184 fetal magnetic resonance imaging studies (87 participants with 2 fetal studies each) and infant neurodevelopmental testing at 18 months, prenatal maternal stress was negatively associated with infant cognitive outcome, and this association was mediated by fetal left hippocampal volume. The study also found that increased fetal cortical local gyrification index and sulcal depth under elevated prenatal maternal distress were associated with decreased infant social-emotional scores measured by Bayley Scales of Infant and Toddler Development and competence scores measured by Infant-Toddler Social and Emotional Assessment. Meaning These findings suggest that altered in vivo fetal brain development in the setting of elevated prenatal maternal psychological distress may be associated with adverse neurodevelopment.

Tocolytics show limited efficacy to prevent preterm delivery. In uterine smooth muscle cGMP accumulation following addition of nitric oxide (NO) has little effect on relaxation suggesting a role for protein S-nitrosation. In human myometrial tissues from women in labor at term (TL), or spontaneously in labor preterm (sPTL), direct stimulation of soluble guanylyl cyclase (sGC) fails to relax myometrium, while the same treatment relaxes vascular smooth muscle completely. Unlike term myometrium, effects of NO are not only blunted in sPTL, but global protein S-nitrosation is also diminished, suggesting a dysfunctional response to NO-mediated protein S-nitrosation. Examination of the enzymatic regulator of endogenous S-nitrosoglutathione availability, S-nitrosoglutathione reductase, reveals increased expression of the reductase in preterm myometrium associated with decreased total protein S-nitrosation. Blockade of S-nitrosoglutathione reductase relaxes sPTL tissue. Addition of NO donor to the actin motility assay attenuates force. Failure of sGC activation to mediate relaxation in sPTL tissues, together with the ability of NO to relax TL, but not sPTL myometrium, suggests a unique pathway for NO-mediated relaxation in myometrium. Our results suggest that examining the action of S-nitrosation on critical contraction associated proteins central to the regulation of uterine smooth muscle contraction can reveal new tocolytic targets.

The mechanisms governing maintenance of quiescence during pregnancy remain largely unknown. The current study characterizes a stretch-activated, tetraethylammoniuminsensitive K ϩ current in smooth muscle cells isolated from pregnant human myometrium. This study hypothesizes that these K ϩ currents can be attributed to TREK-1 and that upregulation of this channel during pregnancy assists with the maintenance of a negative cell membrane potential, conceivably contributing to uterine quiescence until full term. The results of this study demonstrate that, in pregnant human myometrial cells, outward currents at 80 mV increased from 4.8 Ϯ 1.5 to 19.4 Ϯ 7.5 pA/pF and from 3.0 Ϯ 0.8 to 11.8 Ϯ 2.7 pA/pF with application of arachidonic acid (AA) and NaHCO 3, respectively, causing intracellular acidification. Similarly, outward currents were inhibited following application of 10 M fluphenazine by 51.2 Ϯ 9.8% after activation by AA and by 73.9 Ϯ 4.2% after activation by NaHCO3. In human embryonic kidney (HEK-293) cells stably expressing TREK-1, outward currents at 80 mV increased from 91.0 Ϯ 23.8 to 247.5 Ϯ 73.3 pA/pF and from 34.8 Ϯ 8.9 to 218.6 Ϯ 45.0 pA/pF with application of AA and NaHCO3, respectively. Correspondingly, outward currents were inhibited 89.5 Ϯ 2.3% by 10 M fluphenazine following activation by AA and by 91.6 Ϯ 3.4% following activation by NaHCO3. Moreover, currents in human myometrial cells were activated by stretch and were reduced by transfection with small interfering RNA or extracellular acidification. Understanding gestational regulation of expression and gating of TREK-1 channels could be important in determining appropriate maintenance of uterine quiescence during pregnancy.

Background/objectives: Few studies of Chlamydia trachomatis incidence, especially among men, and most studies of C trachomatis in US military populations are cross sectional prevalence surveys. A population based retrospective cohort was used to determine risk factors for repeat diagnoses of genital C trachomatis infections among male and female soldiers with previous C trachomatis infections. Methods: All active duty soldiers diagnosed with C trachomatis genital infections between 1994 and 1998. Cohort members were passively followed until repeat diagnoses of C trachomatis infection, termination of army service, or the end of the study. Results: Among 11 771 soldiers with initial diagnoses of chlamydia, the crude rate of repeat diagnoses was 52.0 per 1000 person years. Women and men aged 20-24 were at greatest unadjusted risk of reinfection. After adjustment, women aged 20-24 and men aged 25-29 were at higher risk than their younger or older counterparts. Conclusions: Results of this study suggest that both male and female soldiers who are diagnosed with chlamydia infections have relatively high risks of reinfection through their 20s. (Sex Transm Inf 2001;77:33-36)