Inhibition of c-Jun N-terminal Kinase Signaling Pathway Alleviates Lipopolysaccharide-induced Acute Respiratory Distress Syndrome in Rats.

BACKGROUND: An acute respiratory distress syndrome (ARDS) is still one of the major challenges in critically ill patients. This study aimed to investigate the effect of inhibiting c-Jun N-terminal kinase (JNK) on ARDS in a lipopolysaccharide (LPS)-induced ARDS rat model. METHODS: Thirty-six rats were randomized into three groups: control, LPS, and LPS + JNK inhibitor. Rats were sacrificed 8 h after LPS treatment. The lung edema was observed by measuring the wet-to-dry weight (W/D) ratio of the lung. The severity of pulmonary inflammation was observed by measuring myeloperoxidase (MPO) activity of lung tissue. Moreover, the neutrophils in bronchoalveolar lavage fluid (BALF) were counted to observe the airway inflammation. In addition, lung collagen accumulation was quantified by Sircol Collagen Assay. At the same time, the pulmonary histologic examination was performed, and lung injury score was achieved in all three groups. RESULTS: MPO activity in lung tissue was found increased in rats treated with LPS comparing with that in control (1.26 ± 0.15 U in LPS vs. 0.77 ± 0.27 U in control, P < 0.05). Inhibiting JNK attenuated LPS-induced MPO activity upregulation (0.52 ± 0.12 U in LPS + JNK inhibitor vs. 1.26 ± 0.15 U in LPS, P < 0.05). Neutrophils in BALF were also found to be increased with LPS treatment, and inhibiting JNK attenuated LPS-induced neutrophils increase in BALF (255.0 ± 164.4 in LPS vs. 53 (44.5-103) in control vs. 127.0 ± 44.3 in LPS + JNK inhibitor, P < 0.05). At the same time, the lung injury score showed a reduction in LPS + JNK inhibitor group comparing with that in LPS group (13.42 ± 4.82 vs. 7.00 ± 1.83, P = 0.001). However, the lung W/D ratio and the collagen in BALF did not show any differences between LPS and LPS + JNK inhibitor group. CONCLUSIONS: Inhibiting JNK alleviated LPS-induced acute lung inflammation and had no effects on pulmonary edema and fibrosis. JNK inhibitor might be a potential therapeutic medication in ARDS, in the context of reducing lung inflammatory.

Absence of circadian rhythms of preterm premature rupture of membranes and preterm placental abruption.

PURPOSE: Data regarding circadian rhythm in the onset of spontaneous preterm premature rupture of membranes (PROM) and placental abruption (PA) cases are conflicting. We modeled the time of onset of preterm PROM and PA cases and examined if the circadian profiles varied based on the gestational age at delivery. METHODS: We used parametric and nonparametric methods, including trigonometric regression in the framework of generalized linear models, to test the presence of circadian rhythms in the time of onset of preterm PROM and PA cases among 395 women who delivered a singleton between 2009 and 2010 in Lima, Peru. RESULTS: We found a diurnal circadian pattern, with a morning peak at 07:32 AM (95% confidence interval, 05:46 AM­09:18 AM) among moderate preterm PROM cases (P value < .001), and some evidence of a diurnal circadian periodicity among PA cases in term infants (P value = .067). However, we did not find evidence of circadian rhythms in the time of onset of extremely or very preterm PROM (P value = .259) and preterm PA (P value = .224). CONCLUSIONS: The circadian rhythms of the time of onset of preterm PROM and PA cases varied based on gestational weeks at delivery. Although circadian rhythms were presented among moderate preterm PROM and term PA cases, there was no evidence of circadian rhythms among preterm PA and very or extremely preterm PROM cases, underlying other mechanisms associated with the time of onset.

Association of serum vitamin D with symptoms of depression and anxiety in early pregnancy.

UNLABELLED: Abstract Objective: To evaluate associations between early pregnancy 25-hydroxyvitamin D (25[OH]D) concentrations and antepartum depression and anxiety symptoms and potential modifiers thereof. MATERIALS AND METHODS: In a pregnancy cohort (N=498), we examined cross-sectional associations of early pregnancy (mean=15.4 weeks gestation) serum 25[OH]D concentrations and depression and anxiety symptoms. Symptoms were measured using Depression, Anxiety, and Stress Scales (DASS-21) and Patient Health Questionnaire Depression Module (PHQ-9) instruments. Regression models were fit and effect modification by prepregnancy body mass index and leisure-time physical activity (LTPA) were assessed using interaction terms and stratified analyses. RESULTS AND DISCUSSION: Mean 25[OH]D concentration was 34.4 ng/mL. Approximately 12% had "moderate" anxiety (score ≥ 10) and depression (score ≥ 10) symptoms by DASS-21 Anxiety and PHQ-9 instruments, respectively. A 1 ng/mL lower 25[OH]D was associated with 0.043 and 0.040 higher DASS-21 Anxiety and PHQ-9 Scores (p-values=0.052 and 0.029, respectively). Participants in the lowest quartile of 25[OH]D (<28.9 ng/mL) had 1.11 higher PHQ-9 scores than those in the highest quartile (≥ 39.5 ng/mL, p<0.05). However, associations were attenuated and statistically insignificant in fully adjusted models. Inverse associations of 25[OH]D with depression symptoms were significant among participants who reported no LTPA, but not among women who reported any LTPA (interaction p=0.018). CONCLUSIONS: Our study provides modest evidence for inverse cross-sectional associations of early pregnancy maternal vitamin D concentrations with antepartum depression symptoms. We also observed that these associations may be modified by physical activity.

Maternal plasma advanced glycation end products concentrations in response to oral 50-gram glucose load in mid-pregnancy: a pilot study.

BACKGROUND: Accumulating evidence documents the initiation of diverse physiologic and biochemical responses subsequent to an oral glucose load. OBJECTIVES: We sought to evaluate the extent to which acute hyperglycemia, resulting from a 50-gram glucose load, contributes to changes in maternal plasma concentrations of advanced glycation end products (AGEs), a heterogeneous group of molecules formed from the non-enzymatic reaction of reducing sugars with free amino groups of proteins, lipids, and nucleic acids. METHODS: Blood specimens were collected from each participant in mid-pregnancy using standard procedures before and after a 50-gram oral glucose load. Maternal plasma methylglyoxal (MG), pentosidine and N(epsilon)-(carboxymethyl)lysine (CML) (free and bound) were measured by HPLC-MS/MS method. Non-parametric methods were employed for statistical analysis. RESULTS AND CONCLUSIONS: Median plasma MG increased 1.27 fold as a result of acute hyperglycemia. Median bound CML concentrations were elevated 21% in post-load plasma samples as compared with pre-load samples, while median free pentosidine concentrations were 51% lower (both p-values < 0.05). Future studies of larger populations and longer periods of follow-up are warranted to investigate the consequences of acute and chronic hyperglycemia on placental function and fetal development.

[The protective effects of inhibition of c-Jun N-terminal kinase signal pathway on the intestinal barrier in rats with endotoxemia].

OBJECTIVE: To examine the protective effects of inhibition of c-jun N-terminal kinase (JNK) stress signal pathway on the injured barrier in endotoxemic rats. METHODS: Twenty-four male Sprague Dwaley (SD) rats were randomly divided into control group, endotoxemia model group and JNK inhibitor group (n=8 each) to receive administration of: 1 normal saline 2 ml/kg + PPCES 2.5 ml/kg [vehicle of JNK inhibitor (SP600125), control group]; 2 lipopolysaccharide (LPS) 10 mg/kg + PPCES 2.5 ml/kg (endotoxemia model group); 3 LPS 10 mg/kg + JNK inhibitor (SP600125) 10 mg/kg (JNK inhibitor group). The activity and survival rate of the rats were recorded. Ileum tissue samples were collected 12 hours after drug administration for pathological examination. Blood samples were collected at the same time for determination of concentration of D-lactate by enzyme linked immunosorbent assay (ELISA). RESULTS: Rats in control group were active normally, and there was no death. Pathological examination showed there was edema of ileal mucosa, and shortening of villus and inflammatory cell infiltration in model group as compared with control group. JNK inhibitor greatly ameliorated the lesions compared with model group. The concentration of D-lactate (µg/L) in model group was significantly higher than that in control group. (943.8 ± 439.6 vs 227.9 ± 130.0, P<.05). JNK inhibitor could decrease the plasma D-lactate concentration (637.4 ± 114.4 vs 943.8 ± 439.6, P<.05). CONCLUSION: Inhibition of the JNK stress signal pathway could attenuate the intestinal barrier injury in endotoxemic rats.

Maternal plasma protein profiles in response to oral 50-gram glucose load in mid-pregnancy: a pilot study.

Accumulating evidence documents the initiation of diverse physiologic and biochemical response subsequent to an oral glucose load. However, significant gaps in knowledge exist in the understanding of consequences of glucose load during pregnancy, a state of insulin resistance. Using high dimensional protein arrays, we conducted a pilot proof-of-concept and feasibility study to investigate profiles of 120 plasma proteins in pre- and post- 50-gram oral glucose challenge samples. Participants (N = 10) were selected from among women enrolled in a pregnancy cohort. Differences in plasma protein concentrations between pre- and post-glucose load challenge samples were evaluated using Student's T-test (paired) and mean fold change comparisons. Multiple testing adjusted p-values (i.e., false discovery rate q values) were computed using Benjamini-Hochberg (BH) corrections. Plasma haptoglobulin, epidermal growth factor, hemoglobin, thrombospondin-1, and S100 protein concentrations were two to five fold higher in post-glucose load compared with pre-glucose load samples (all q-values <0.05). Among women aged >31 years (above median), post-load S100 protein was elevated 9.92-fold above pre-load concentrations, while it was elevated 4.10-fold among women aged <31 years (below median). Similarly, among women with post-load glucose concentrations <101mg/dl (below median), S100 was elevated 8.26-fold while it was elevated 3.28 fold among women with post-load glucose concentrations >101mg/dl (above median). Our study findings suggest that post-glucose load changes in plasma biomarkers represent a diverse set of cellular responses including receptor for advanced glycation end products (RAGE), inflammation, oxidative stress and adipogenesis, during mid-pregnancy. Future studies of larger populations and longer periods of follow-up are warranted.

Telomere length, pre-eclampsia, and gestational diabetes.

BACKGROUND: Telomere length is a marker of cumulative damage to the cell, and has been associated with cardiovascular disease, hypertension, and diabetes. FINDINGS: The association of telomere length with pre-eclampsia and gestational diabetes mellitus (GDM) was examined in a nested case-control study. Circulating leukocyte telomere length was measured by Quantitative-PCR. Mean and median telomere length among cases and controls was compared, and logistic regression was used to model the outcomes as a function of tertile telomere length, with control for effects of potential confounders. Mean telomere length in pre-eclampsia cases was 0.77 (SD 0.14), in GDM cases was 0.73 (SD 0.10), and in controls was 0.74 (SD 0.14). The adjusted odds ratio comparing the highest tertile to the lowest for pre-eclampsia was 0.92 (0.15-5.46), and for gestational diabetes was 0.65 (0.13-3.34). CONCLUSIONS: Further study is necessary to determine if telomere length is associated with these pregnancy complications.

Maternal pre-pregnancy overweight status and obesity as risk factors for cesarean delivery.

OBJECTIVE: To determine the extent to which, if at all, maternal pre-pregnancy adiposity and other anthropometric factors are related to risk of cesarean delivery. METHODS: This hospital-based prospective cohort study included 738 nulliparous women who initiated prenatal care prior to 16 weeks gestation. Participants provided information about their pre-pregnancy weight and height and other sociodemographic and reproductive covariates. Labor and delivery characteristics were obtained from maternal and infant medical records. Risk ratios (RR) and 95% CI were estimated by fitting generalized linear models. RESULTS: The proportion of cesarean deliveries in this population was 26%. Women who were overweight (BMI 25.00-29.99 kg/m2) were twice as likely to deliver their infants by cesarean section as lean women (BMI<20.00 kg/m2) (RR=2.09; 95% CI 1.27-3.42). Obese women (BMI>or=30.00 kg/m2) experienced a three-fold increase in risk of cesarean delivery when compared with this referent group (RR=3.05; 95% CI 1.80-5.18). The joint association between maternal pre-pregnancy overweight status and short stature was additive. When compared with tall (height>or=1.63 m), lean women, short (<1.63 m), overweight (BMI>or=25.00 kg/m2) women were nearly three times as likely to have a cesarean delivery (RR=2.79; 95% CI 1.72-4.52). CONCLUSION: Our findings suggest that nulliparous women who are overweight or obese prior to pregnancy, and particularly those who are also short, have an increased risk of delivering their infants by cesarean section.

Family history of hypertension and diabetes in relation to preeclampsia risk in Peruvian women.

In a case-control study of 169 preeclamptics and 201 controls, we assessed maternal parental history of chronic hypertension and diabetes in relation to preeclampsia risk among Peruvian women. Participants provided information on parental history of the two conditions and other covariates during postpartum interviews. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) adjusted for confounding by age, parity and prepregnancy adiposity. In this population, women were more likely to know the diabetes status of their parents than their hypertension status. Compared with women without a parental history of hypertension, women with a parental history of hypertension experienced a 20% increased risk of preeclampsia (OR = 1.2; 95% CI 0.7-2.2) that did not reach statistical significance. Women with a positive parental history for diabetes had a 3.4-fold increased risk of preeclampsia (95% CI 1.4-8.4). Women with a positive parental history of both hypertension and diabetes, as compared with those whose parents had neither condition, experienced a 4.6- fold increased risk of preeclampsia (OR = 4.6; 95% CI 0.9-23.0). Our results are generally consistent with the thesis that parental history of hypertension and diabetes reflects genetic and behavioral factors whereby women may be predisposed to an increased risk of preeclampsia.

History of abortion and subsequent risk of preeclampsia.

OBJECTIVE: To examine the effect of abortion type, number and timing on risk of preeclampsia in subsequent pregnancies. STUDY DESIGN: We conducted a hospital-based, case-control study in Seattle and Tacoma, Washington, between 1998 and 2001. Preeclampsia cases (n = 199) and controls (n = 383) provided detailed information regarding their pregnancy histories and other covariates, such as prepregnancy weight and adult height. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression. RESULTS: Multiparous women, both with a history of abortion and without, experienced decreases of 60% (adjusted OR = 0.40, 95% CI .23-.71) and 71% (adjusted OR = .29, 95% CI .16-.53), respectively, in risk of preeclampsia when compared to nulliparous women with no history of abortion. Type (spontaneous and/or induced), number and timing of prior abortion did not appear to influence the risk of preeclampsia among nulliparous women. CONCLUSION: These results confirm the work of others that multiparous women, both with and without a history of abortion, have a reduced risk of preeclampsia. However, much work remains with respect to exploring mechanistic hypotheses offering biologic explanations and examining possible confounding factors of this association, such as change in paternity and interpregnancy interval.