Hooman Mirzakhani

Vitamin D and the development of allergic disease: how important is it?

Vitamin D has known effects on lung development and the immune system that may be important in the development, severity, and course of allergic diseases (asthma, eczema, and food allergy). Vitamin D deficiency is prevalent worldwide and may partly explain the increases in asthma and allergic diseases that have occurred over the last 50–60 years. In this review, we explore past and current knowledge on the effect of vitamin D on lung development and immunomodulation and present the evidence of its role in allergic conditions. While there is growing observational and experimental evidence for the role of vitamin D, well‐designed and well‐powered clinical trials are needed to determine whether supplementation of vitamin D should be recommended in these disorders.

Early pregnancy vitamin D status and risk of preeclampsia

BACKGROUND Low vitamin D status in pregnancy was proposed as a risk factor of preeclampsia. METHODS We assessed the effect of vitamin D supplementation (4,400 vs. 400 IU/day), initiated early in pregnancy (10-18 weeks), on the development of preeclampsia. The effects of serum vitamin D (25-hydroxyvitamin D [25OHD]) levels on preeclampsia incidence at trial entry and in the third trimester (32-38 weeks) were studied. We also conducted a nested case-control study of 157 women to investigate peripheral blood vitamin D-associated gene expression profiles at 10 to 18 weeks in 47 participants who developed preeclampsia. RESULTS Of 881 women randomized, outcome data were available for 816, with 67 (8.2%) developing preeclampsia. There was no significant difference between treatment (N = 408) or control (N = 408) groups in the incidence of preeclampsia (8.08% vs. 8.33%, respectively; relative risk: 0.97; 95% CI, 0.61-1.53). However, in a cohort analysis and after adjustment for confounders, a significant effect of sufficient vitamin D status (25OHD ≥30 ng/ml) was observed in both early and late pregnancy compared with insufficient levels (25OHD <30 ng/ml) (adjusted odds ratio, 0.28; 95% CI, 0.10-0.96). Differential expression of 348 vitamin D-associated genes (158 upregulated) was found in peripheral blood of women who developed preeclampsia (FDR <0.05 in the Vitamin D Antenatal Asthma Reduction Trial [VDAART]; P < 0.05 in a replication cohort). Functional enrichment and network analyses of this vitamin D-associated gene set suggests several highly functional modules related to systematic inflammatory and immune responses, including some nodes with a high degree of connectivity. CONCLUSIONS Vitamin D supplementation initiated in weeks 10-18 of pregnancy did not reduce preeclampsia incidence in the intention-to-treat paradigm. However, vitamin D levels of 30 ng/ml or higher at trial entry and in late pregnancy were associated with a lower risk of preeclampsia. Differentially expressed vitamin D-associated transcriptomes implicated the emergence of an early pregnancy, distinctive immune response in women who went on to develop preeclampsia. TRIAL REGISTRATION ClinicalTrials.gov NCT00920621. FUNDING Quebec Breast Cancer Foundation and Genome Canada Innovation Network. This trial was funded by the National Heart, Lung, and Blood Institute. For details see Acknowledgments.

Muscle Weakness Predicts Pharyngeal Dysfunction and Symptomatic Aspiration in Long-term Ventilated Patients

Background:Prolonged mechanical ventilation is associated with muscle weakness, pharyngeal dysfunction, and symptomatic aspiration. The authors hypothesized that muscle strength measurements can be used to predict pharyngeal dysfunction (endoscopic evaluation–primary hypothesis), as well as symptomatic aspiration occurring during a 3-month follow-up period. Methods:Thirty long-term ventilated patients admitted in two intensive care units at Massachusetts General Hospital were included. The authors conducted a fiberoptic endoscopic evaluation of swallowing and measured muscle strength using medical research council score within 24 h of each fiberoptic endoscopic evaluation of swallowing. A medical research council score less than 48 was considered clinically meaningful muscle weakness. A retrospective chart review was conducted to identify symptomatic aspiration events. Results:Muscle weakness predicted pharyngeal dysfunction, defined as either valleculae and pyriform sinus residue scale of more than 1, or penetration aspiration scale of more than 1. Area under the curve of the receiver-operating curves for muscle strength (medical research council score) to predict pharyngeal, valleculae, and pyriform sinus residue scale of more than 1, penetration aspiration scale of more than 1, and symptomatic aspiration were 0.77 (95% CI, 0.63–0.97; P = 0.012), 0.79 (95% CI, 0.56–1; P = 0.02), and 0.74 (95% CI, 0.56–0.93; P = 0.02), respectively. Seventy percent of patients with muscle weakness showed symptomatic aspiration events. Muscle weakness was associated with an almost 10-fold increase in the symptomatic aspiration risk (odds ratio = 9.8; 95% CI, 1.6–60; P = 0.009). Conclusion:In critically ill patients, muscle weakness is an independent predictor of pharyngeal dysfunction and symptomatic aspiration. Manual muscle strength testing may help identify patients at risk of symptomatic aspiration.

Neuromuscular blocking agents for electroconvulsive therapy: a systematic review

Electroconvulsive therapy (ECT) is the transcutaneous application of small electrical stimuli to the brain to induce generalised seizures for the treatment of selected psychiatric disorders. The clinical indications for ECT as an effective therapeutic modality have been considerably expanded since its introduction. Anaesthesia and neuromuscular blocking agents (NMBAs) are required to ensure patients’ safety during ECT. The optimal dose of muscle relaxant for ECT reduces muscle contractions without inducing complete paralysis. Slight residual motor convulsive activity is helpful in ascertaining that a seizure has occurred, while total paralysis prolongs the procedure unnecessarily. Suxamethonium is commonly used, but nondepolarising NMBAs are indicated in patients with certain comorbidities. In this review, we summarise current concepts of NMBA management for ECT.

The Role of Vitamin D in the Transcriptional Program of Human Pregnancy.

Background Patterns of gene expression of human pregnancy are poorly understood. In a trial of vitamin D supplementation in pregnant women, peripheral blood transcriptomes were measured longitudinally on 30 women and used to characterize gene co-expression networks. Objective Studies suggest that increased maternal Vitamin D levels may reduce the risk of asthma in early life, yet the underlying mechanisms have not been examined. In this study, we used a network-based approach to examine changes in gene expression profiles during the course of normal pregnancy and evaluated their association with maternal Vitamin D levels. Design The VDAART study is a randomized clinical trial of vitamin D supplementation in pregnancy for reduction of pediatric asthma risk. The trial enrolled 881 women at 10–18 weeks of gestation. Longitudinal gene expression measures were obtained on thirty pregnant women, using RNA isolated from peripheral blood samples obtained in the first and third trimesters. Differentially expressed genes were identified using significance of analysis of microarrays (SAM), and clustered using a weighted gene co-expression network analysis (WGCNA). Gene-set enrichment was performed to identify major biological pathways. Results Comparison of transcriptional profiles between first and third trimesters of pregnancy identified 5839 significantly differentially expressed genes (FDR<0.05). Weighted gene co-expression network analysis clustered these transcripts into 14 co-expression modules of which two showed significant correlation with maternal vitamin D levels. Pathway analysis of these two modules revealed genes enriched in immune defense pathways and extracellular matrix reorganization as well as genes enriched in notch signaling and transcription factor networks. Conclusion Our data show that gene expression profiles of healthy pregnant women change during the course of pregnancy and suggest that maternal Vitamin D levels influence transcriptional profiles. These alterations of the maternal transcriptome may contribute to fetal immune imprinting and reduce allergic sensitization in early life. Trial Registration clinicaltrials.gov NCT00920621

Minimum Effective Doses of Succinylcholine and Rocuronium During Electroconvulsive Therapy: A Prospective, Randomized, Crossover Trial.

BACKGROUND: Neuromuscular blockade is required to control excessive muscle contractions during electroconvulsive therapy (ECT). In a crossover, assessor-blinded, prospective randomized study, we studied the minimum effective dose (MED) of succinylcholine and rocuronium for ECT. The MED was the lowest dose to provide a predefined qualitative measure of acceptable control of muscle strength during induced convulsions. METHODS: Succinylcholine (0.8 mg kg−1) or rocuronium (0.4 mg kg−1) was randomly administered in 227 ECT sessions to 45 patients. The dose was incrementally increased or decreased by 10% based on 2 psychiatrists’ (blinded to treatment) assessment of “acceptable” or “not acceptable” control of evoked muscle contractions (sufficient versus insufficient or excessive paralysis). The neuromuscular transmission was monitored quantitatively until full recovery. RESULTS: In our study, the MEDs of succinylcholine and rocuronium to produce acceptable ECT conditions in 50% of patients (MED50ECT) were 0.85 mg kg−1 (95% confidence interval [CI], 0.77–0.94) and 0.41 mg kg−1 (95% CI, 0.36–0.46) and in 90% of patients (MED90ECT) were 1.06 mg kg−1 (95% CI, 1.0–1.27) and 0.57 mg kg−1 (95% CI, 0.5–0.6), respectively. Nadir twitch height for acceptable muscle activity was 0% (0–4) and 4% (0–30; P < 0.001), respectively, and the time to recovery of the neuromuscular transmission was 9.7 ± 3.5 and 19.5 ± 5.7 minutes, respectively. CONCLUSIONS: A twitch suppression of >90% is needed for control of motor contractions during ECT. The initial ECT dose of succinylcholine should be selected based on each patient’s preprocedural condition, ranging between 0.77 and 1.27 mg kg−1 to produce acceptable muscle blockade in 50% to 90% of patients. Rocuronium–neostigmine combination is a safe alternative if appropriately dosed (0.36–0.6 mg kg−1) and monitored.

Vitamin D prenatal programming of childhood metabolomics profiles at age 3 y

Background: Vitamin D deficiency is implicated in a range of common complex diseases that may be prevented by gestational vitamin D repletion. Understanding the metabolic mechanisms related to in utero vitamin D exposure may therefore shed light on complex disease susceptibility.Objective: The goal was to analyze the programming role of in utero vitamin D exposure on childrens metabolomics profiles.Design: First, unsupervised clustering was done with plasma metabolomics profiles from a case-control subset of 245 children aged 3 y with and without asthma from the Vitamin D Antenatal Asthma Reduction Trial (VDAART), in which pregnant women were randomly assigned to vitamin D supplementation or placebo. Thereafter, we analyzed the influence of maternal pre- and postsupplement vitamin D concentrations on cluster membership. Finally, we used the metabolites driving the clustering of children to identify the dominant metabolic pathways that were influential in each cluster.Results: We identified 3 clusters of children characterized by 1) high concentrations of fatty acids and amines and low maternal postsupplement vitamin D (mean ± SD; 27.5 ± 11.0 ng/mL), 2) high concentrations of amines, moderate concentrations of fatty acids, and normal maternal postsupplement vitamin D (34.0 ± 14.1 ng/mL), and 3) low concentrations of fatty acids, amines, and normal maternal postsupplement vitamin D (35.2 ± 15.9 ng/mL). Adjusting for sample storage time, maternal age and education, and both child asthma and vitamin D concentration at age 3 y did not modify the association between maternal postsupplement vitamin D and cluster membership (P = 0.0014). Maternal presupplement vitamin D did not influence cluster membership, whereas the combination of pre- and postsupplement concentrations did (P = 0.03).Conclusions: Young children can be clustered into distinct biologically meaningful groups by their metabolomics profiles. The clusters differed in concentrations of inflammatory mediators, and cluster membership was influenced by in utero vitamin D exposure, suggesting a prenatal programming role of vitamin D on the childs metabolome. This trial was registered at clinicaltrials.gov as NCT00920621.

Current state of the art in management of vascular complications after pediatric liver transplantation

Vascular complications by compromising the blood flow to the allograft can have significant and sometimes life‐threatening consequences after pediatric liver transplantation. High level of suspicion and aggressive utilization of diagnostic modalities can lead to early diagnosis and salvage of the allograft. This review will summarize the current trends in management of vascular complications after pediatric liver transplantation.

Integration of metabolomic and transcriptomic networks in pregnant women reveals biological pathways and predictive signatures associated with preeclampsia

IntroductionPreeclampsia is a leading cause of maternal and fetal mortality worldwide, yet its exact pathogenesis remains elusive.ObjectivesThis study, nested within the Vitamin D Antenatal Asthma Reduction Trial (VDAART), aimed to develop integrated omics models of preeclampsia that have utility in both prediction and in the elucidation of underlying biological mechanisms.MethodsMetabolomic profiling was performed on first trimester plasma samples of 47 pregnant women from VDAART who subsequently developed preeclampsia and 62 controls with healthy pregnancies, using liquid-chromatography tandem mass-spectrometry. Metabolomic profiles were generated based on logistic regression models and assessed using Received Operator Characteristic Curve analysis. These profiles were compared to profiles from generated using third trimester samples. The first trimester metabolite profile was then integrated with a pre-existing transcriptomic profile using network methods.ResultsIn total, 72 (0.9%) metabolite features were associated (p < 0.01) with preeclampsia after adjustment for maternal age, race, and gestational age. These features had moderate to good discriminatory ability; in ROC curve analyses a summary score based on these features displayed an area under the curve (AUC) of 0.794 (95%CI 0.700, 0.888). This profile retained the ability to distinguish preeclamptic from healthy pregnancies in the third trimester [AUC: 0.762 (95% CI 0.663, 0.860)]. Additionally, metabolite set enrichment analysis identified common pathways, including glycerophospholipid metabolism, at the two time-points. Integration with the transcriptomic signature refined these results suggesting a particular role for lipid imbalance, immune function and the circulatory system.ConclusionsThese findings suggest it is possible to develop a predictive metabolomic profile of preeclampsia. This profile is characterized by changes in lipid and amino acid metabolism and dysregulation of immune response and can be refined through interaction with transcriptomic data. However validation in larger and more diverse populations is required.

Increased expression of nuclear factor of activated T cells 1 drives IL-9-mediated allergic asthma.

To the Editor: Nuclear factor of activated T cells (NFAT) is a family of transcription factors activated by dephosphorylation mediated by Ca-activated calcineurin. NFAT coordinates different aspects of T-cell development and activation of T, B, natural killer, and mast cells and is the target of the immunosuppressive drug cyclosporin A. We reported recently that targeted deletion of NFATc1 in T cells resulted in inhibition of TH2 and TH17 differentiation. 2