Regulations of mitoNEET by the key redox homeostasis molecule glutathione.

Human mitoNEET (mNT) and CISD2 are two NEET proteins characterized by an atypical [2Fe-2S] cluster coordination involving three cysteines and one histidine. They act as redox switches with an active state linked to the oxidation of their cluster. In the present study, we show that reduced glutathione but also free thiol-containing molecules such as ß-mercaptoethanol can induce a loss of the mNT cluster under aerobic conditions, while CISD2 cluster appears more resistant. This disassembly occurs through a radical-based mechanism as previously observed with the bacterial SoxR. Interestingly, adding cysteine prevents glutathione-induced cluster loss. At low pH, glutathione can bind mNT in the vicinity of the cluster. These results suggest a potential new regulation mechanism of mNT activity by glutathione, an essential actor of the intracellular redox state.

Childhood adversity, prenatal depression, and maternal inflammation across pregnancy.

Background: To examine whether change in neutrophil-lymphocyte ratio, a marker of systemic inflammation, differs by childhood adversity and prenatal depression. Methods: Prenatal complete blood count data were used to calculate neutrophil-lymphocyte ratio in first and third trimesters. The Adverse Childhood Experiences scale measured childhood adversity, and the Patient Health Questionnaire-9 measured depression. This is a secondary analysis of a study of predictors of risk for sleep-disordered breathing. Results: Participants were 98 pregnant women, mean age 30 years (SD = 5), mean body mass index of 35 kg/m2 (SD = 7), 61% identified as white, and 28% identified as Hispanic. Women who reported childhood sexual abuse history displayed greater increase in neutrophil-lymphocyte ratio over pregnancy relative to women without childhood sexual abuse. Change in neutrophil-lymphocyte ratio across pregnancy did not differ by prenatal depression. Conclusion: Experiences of sexual abuse in childhood may impact markers of systemic inflammation in pregnancy.

Determination of the Absolute Molar Mass of [Fe-S]-Containing Proteins Using Size Exclusion Chromatography-Multi-Angle Light Scattering (SEC-MALS).

Size Exclusion Chromatography coupled with Multi-Angle Light Scattering (SEC-MALS) is a technique that determines the absolute molar mass (molecular weight) of macromolecules in solution, such as proteins or polymers, by detecting their light scattering intensity. Because SEC-MALS does not rely on the assumption of the globular state of the analyte and the calibration of standards, the molar mass can be obtained for proteins of any shape, as well as for intrinsically disordered proteins and aggregates. Yet, corrections need to be made for samples that absorb light at the wavelength of the MALS laser, such as iron-sulfur [Fe-S] cluster-containing proteins. We analyze several examples of [2Fe-2S] and [4Fe-4S] cluster-containing proteins, for which various corrections were applied to determine the absolute molar mass of both the apo- and holo-forms. Importantly, the determination of the absolute molar mass of the [2Fe-2S]-containing holo-NEET proteins allowed us to ascertain a change in the oligomerization state upon cluster binding and, thus, to highlight one essential function of the cluster.

New Insights of the NEET Protein CISD2 Reveals Distinct Features Compared to Its Close Mitochondrial Homolog mitoNEET.

Human CISD2 and mitoNEET are two NEET proteins anchored in the endoplasmic reticulum and mitochondria membranes respectively, with an Fe-S containing domain stretching out in the cytosol. Their cytosolic domains are close in sequence and structure. In the present study, combining cellular and biochemical approaches, we compared both proteins in order to possibly identify specific roles and mechanisms of action in the cell. We show that both proteins exhibit a high intrinsic stability and a sensitivity of their cluster to oxygen. In contrast, they differ in according to expression profiles in tissues and intracellular half-life. The stability of their Fe-S cluster and its ability to be transferred in vitro are affected differently by pH variations in a physiological and pathological range for cytosolic pH. Finally, we question a possible role for CISD2 in cellular Fe-S cluster trafficking. In conclusion, our work highlights unexpected major differences in the cellular and biochemical features between these two structurally close NEET proteins.

Maternal History of Adverse Childhood Experiences and Ambulatory Blood Pressure in Pregnancy.

OBJECTIVE: This study aimed to study the association between maternal history of childhood adversity and blood pressure in pregnancy. METHODS: A total of 127 pregnant women completed measures of adverse childhood experiences (ACE) and prenatal stress between June 2015 and April 2019. At 11 weeks' gestation (range, 6-17 weeks), we measured 24-hour ambulatory blood pressure. All women were considered to be at risk for pregnancy complications due to elevated body mass index and self-reporting snoring in pregnancy. RESULTS: Women were, on average, 30 years old (range, 19-40 years), and average (standard deviation) body mass index in this sample was 34 (7) kg/m (range, 27-55 kg/m). Higher ACE scores were associated with higher nighttime blood pressure (systolic blood pressure: ß = 0.23, p = .013; diastolic blood pressure: ß = 0.22, p = .028). There were no significant associations between the ACE score and daytime blood pressure. Women with four or more ACEs were more likely to display nocturnal blood pressure nondipping (odds ratio = 3.97, 95% confidence interval = 1.38-11.40). Associations between ACE and nocturnal blood pressure remained significant after adjusting for symptoms of prenatal stress. CONCLUSIONS: Results indicate that experiences of childhood adversity are associated with elevated nocturnal blood pressure and loss of a typical decline in blood pressure between day and night.

Exploring Fetal Sex as a Risk Factor for Sleep Disordered Breathing and Its Complications in Pregnancy.

Sleep disordered breathing (SDB) is a common, yet under-recognized and undertreated condition in pregnancy. Sleep disordered breathing is associated with pregnancy complications including preeclampsia, gestational diabetes, preterm birth, as well as severe maternal morbidity and mortality. The identification of risk factors for SDB in pregnancy may improve screening, diagnosis, and treatment of SDB prior to the onset of pregnancy complications. The goal of this study was to determine whether fetal sex increases risk of SDB in pregnancy. A cohort of singleton (N = 991) pregnant women were recruited within 24 to 48 hours of delivery and answered questions regarding SDB symptoms by questionnaire. Women who reported frequent loud snoring at least 3 times a week were considered to have SDB. Hospital records were reviewed to extract information on fetal sex and pregnancy complications including preeclampsia, pregnancy-induced hypertension, gestational diabetes, preterm delivery, and low birth weight. Women carrying male fetuses were significantly more likely to have SDB (ß = .37, P = .01, OR: 1.45 [95% CI: 1.09-1.94]). Fetal sex was associated with increased risk of hypertensive disorders of pregnancy (defined as preeclampsia and/or pregnancy-induced hypertension) among women with SDB in pregnancy (ß = .41, P = .02, OR: 1.51[95%CI:1.08-2.11]).Fetal sex did not increase risk of preterm birth, low birth weight, or gestational diabetes among women with SDB in pregnancy. Women carrying male fetuses were approximately 1.5 times more likely to report SDB in pregnancy compared to women carrying female fetuses, and women with pregnancy-onset SDB carrying male fetuses were 1.5 times more likely to have hypertensive disorders of pregnancy compared to women with SDB carrying female fetuses. Confirmation of fetal sex as a risk factor may, with other risk factors, play a role in identifying women at highest risk of SDB complications in pregnancy.

Anthropometric Measures and Prediction of Maternal Sleep-Disordered Breathing.

STUDY OBJECTIVES: Pregnant women are at risk for sleep-disordered breathing (SDB); however, screening methods in this dynamic population are not well studied. The aim of this study was to examine whether anthropometric measures can accurately predict SDB in pregnant women. METHODS: Pregnant women with snoring and overweight/obesity were recruited in the first trimester. Anthropometric measures were performed according to the International Standards for Anthropometric Assessment, including a seated neutral and extended neck Mallampati class. Home sleep apnea monitoring was performed using a level III device after completion of anthropometric assessment. SDB was defined as an apnea-hypopnea index ≥ 5 events/h of sleep. Pearson and Spearman tests examined correlations between various measures. Generalized linear models, sensitivity, specificity, and area under the curve as well as odds ratios were performed to test the model. RESULTS: A total of 129 participants were recruited, and 23 had SDB. Average gestational age was 10.6 ± 1.9 weeks. Due to concerns over multicollinearity, the final model included extended Mallampati class and upright neck circumference. Neck circumference was significantly higher in participants with Mallampati classes 2/3 and grade 4 compared to participants with Mallampati class 1 (P = .0005). Increasing neck circumference was associated with higher odds of SDB (P = .0022). In Mallampati class 1, odds ratio for SDB was 2.89 (1.19, 7.03) per unit increase in neck circumference. CONCLUSIONS: Modeling neck circumference while allowing for differences by Mallampati class showed a nearly threefold increase in the risk of SDB with increasing neck circumference in women with Mallampati class 1. Other potential sites of airway obstruction need to be investigated in future research.

Pulse transit time in pregnancy: a new way to diagnose and classify sleep disordered breathing?

STUDY OBJECTIVES: There are significant discrepancies between the prevalence of snoring and that of objectively defined sleep disordered breathing among pregnant women, suggesting subtle airflow limitations that may not be captured by conventional scoring. This study examined the performance of pulse transit time, an indirect measure of arterial stiffness and sympathetic activation, in pregnancy. METHODS: Pregnant women with obesity and snoring and a group of controls without symptoms of sleep disordered breathing were recruited in the first trimester. Women underwent a level III in-laboratory sleep monitoring study including an electrocardiogram and pulse oximetry, and pulse transit time was measured. Sleep disordered breathing was defined as an apnea-hypopnea index at least five events per hour of sleep. Statistical analysis was performed using Spearman correlation, Fisher's exact t-test, and univariate analysis. RESULTS: Of the 222 women, 38 met criteria for sleep disordered breathing. Pulse transit time drops were very prevalent (95% of participants with snoring had > 5 drops per hour). Median apnea-hypopnea index was 0.7 (interquartile range [IQR]: 2.6) events per hour whereas median pulse transit time drop index was 20.70 (IQR: 35.90) events per hour. Pulse transit time index was significantly higher in snorers with apnea-hypopnea index less than five events per hours and participants with apnea-hypopnea index greater than five events per hour compared to controls. Examination of random epochs with pulse transit time drops showed that 95% of pulse transit time drops were associated with airflow limitation. CONCLUSIONS: Pulse transit time ascertains frequent events of sympathetic activation in at-risk women with and without sleep disordered breathing beyond conventional apneas and hypopneas. Pulse transit time may be an important addition to the identification of clinically significant sleep disordered breathing in pregnant women, and may identify more sleep disordered breathing than apnea-hypopnea index.

Snoring and markers of fetal and placental wellbeing.

INTRODUCTION: Snoring, the symptom of partial airway obstruction during sleep, is a common complaint during pregnancy and is associated with adverse perinatal outcomes. Mechanisms underlying this association have not been studied. We investigated the relationship between snoring in pregnancy and maternal serum markers of feto-placental wellbeing. METHODS: We conducted a secondary analysis of a cross sectional study designed to investigate perinatal outcomes of sleep-disordered breathing. Women admitted for delivery were systematically selected and answered a questionnaire about snoring using the Multivariable Apnea Prediction Index. Participants who had screening markers measured were included and divided into snorers and non -snorers. Markers measured included first and second trimester Down syndrome screening markers, reported as multiples of the median (MoM). An additional analysis was performed with snorers categorized as acute or chronic snorers based on duration of snoring in relation to pregnancy. RESULTS: While significant differences were noted in co-morbid maternal medical conditions between snorers and non-snorers, there were no significant differences in the neonatal outcomes assessed between the two groups. No significant differences were noted in any of the first trimester (PAPP-A) or second trimester (AFP, uE3, hCG, inhibin-A) markers between snorers and non-snorers, p > 0.25. In addition, no significant differences in marker levels were noted between acute and chronic snorers. CONCLUSION: Snoring is not associated with alterations in the markers of fetal or placental wellbeing tested here and suggests that there are alternative mechanisms underlying the association between snoring and adverse perinatal outcomes.

Colistin monotherapy v/s colistin combination therapy for treatment of Acinetobacter infections, a systematic review.

INTRODUCTION: Acinetobacter baumanii is currently responsible of many nosocomial life threatening infections, and growing multiple types of resistance mechanisms causing a great therapeutic challenge. Colistin has been used for the treatment of Acinetobacter infections after the emergence of resistant strains as an alternative and salvage therapy. Our study's aim is to compare the efficacy of colistin monotherapy versus colistin in combination therapy, its safety in terms of nephrotoxicity and potential resistance emergence. METHODOLOGY: Online electronic databases were searched for studies evaluating colistin in monotherapy compared to colistin in combination therapy. Seven studies met the inclusion criteria after eliminating duplicates according to a Prism flow chart. Endnote and Review Manager 5.3 softwares were used. RESULTS: we found that there is no significant difference in the mortality between the group treated with colistin alone compared to colistin in combination with other antibiotics (OR: 0. 87 95% CI= 0.62, 1.24 P=0.45), we also found no difference in terms of clinical cure or nephrotoxicity, however, microbiological eradication was found to be superior in the combination therapy group (OR: 1.88 95% CI = 1.13, 3.12 p = 0.01). CONCLUSION: Colistin is a safe and effective option in monotherapy as in combination therapy for the treatment of Acinetobacter baumanii infections. Larger RCTs are needed.