Integrative Placental Multi-Omics Analysis Reveals Perturbed Pathways and Potential Prognostic Biomarkers in Gestational Hypertension.

BACKGROUND: Gestational hypertension (GH) is a severe complication that occurs after 20 weeks of pregnancy; however, its molecular mechanisms are not yet fully understood. OBJECTIVE: Through this case-control discovery phase study, we aimed to find disease-specific candidate placental microRNAs (miRNAs) and metabolite markers for differentiating GH by integrating next-generation sequencing and metabolomics multi-omics analysis of placenta. Using small RNA sequencing and metabolomics of placental tissues of healthy pregnant (HP, n = 24) and GH subjects (n = 20), the transcriptome and metabolome were characterized in both groups. RESULTS: The study identified a total of 44 downregulated placental miRNAs which includes three novel, three mature and 38 precursor miRNAs. Six miRNAs including three mature (hsa-miR-181a-5p, hsa-miR-498-5p, and hsa-miR-26b-5p) and three novel (NC_000016.10_1061, NC_000005.10_475, and NC_000001.11_53) were considered for final target prediction and functional annotation. Integrative analysis of differentially expressed miRNAs and metabolites yielded five pathways such as purine, glutathione, glycerophospholipid, inositol phosphate and ß-alanine to be significantly perturbed in GH. We present fourteen genes (LPCAT1, LPCAT2, DGKH, PISD, GPAT2, PTEN, SACM1L, PGM2, AMPD3, AK7, AK3, CNDP1, IDH2, and ODC1) and eight metabolites (xanthosine, xanthine, spermine, glycine, CDP-Choline, glyceraldehyde 3-phosphate, ß-alanine, and histidine) with potential to distinguish GH and HP. CONCLUSION: The differential expression of miRNAs, their target genes, altered metabolites and metabolic pathways in GH patients were identified for the first time in our study. Further, the altered miRNAs and metabolites were integrated to build their inter-connectivity network. The findings obtained from our study may be used as a valuable source to further unravel the molecular pathways associated with GH and also for the evaluation of prognostic markers.

Machine learning-based protein signatures for differentiating hypertensive disorders of pregnancy.

Hypertensive disorders of pregnancy (HDP) result in major maternal and fetal complications. Our study aimed to find a panel of protein markers to identify HDP by applying machine-learning models. The study was conducted on a total of 133 samples, divided into four groups, healthy pregnancy (HP, n = 42), gestational hypertension (GH, n = 67), preeclampsia (PE, n = 9), and ante-partum eclampsia (APE, n = 15). Thirty circulatory protein markers were measured using Luminex multiplex immunoassay and ELISA. Significant markers were screened for potential predictive markers by both statistical and machine-learning approaches. Statistical analysis found seven markers such as sFlt-1, PlGF, endothelin-1(ET-1), basic-FGF, IL-4, eotaxin and RANTES to be altered significantly in disease groups compared to healthy pregnant. Support vector machine (SVM) learning model classified GH and HP with 11 markers (eotaxin, GM-CSF, IL-4, IL-6, IL-13, MCP-1, MIP-1α, MIP-1ß, RANTES, ET-1, sFlt-1) and HDP with 13 markers (eotaxin, G-CSF, GM-CSF, IFN-gamma, IL-4, IL-5, IL-6, IL-13, MCP-1, MIP-1ß, RANTES, ET-1, sFlt-1). While logistic regression (LR) model classified PE with 13 markers (basic FGF, IL-1ß, IL-1ra, IL-7, IL-9, MIP-1ß, RANTES, TNF-alpha, nitric oxide, superoxide dismutase, ET-1, PlGF, sFlt-1) and APE by 12 markers (eotaxin, basic-FGF, G-CSF, GM-CSF, IL-1ß, IL-5, IL-8, IL-13, IL-17, PDGF-BB, RANTES, PlGF). These markers may be used to diagnose the progression of healthy pregnant to a hypertensive state. Future longitudinal studies with large number of samples are needed to validate these findings.

Integrated metabolomics and machine learning approach to predict hypertensive disorders of pregnancy.

BACKGROUND: Hypertensive disorders of pregnancy account for 3% to 10% of maternal-fetal morbidity and mortality worldwide. This condition has been considered one of the leading causes of maternal deaths in developing countries, such as India. OBJECTIVE: This study aimed to discover hypertensive disorders of pregnancy-specific candidate urine metabolites as markers for hypertensive disorders of pregnancy by applying integrated metabolomics and machine learning approaches. STUDY DESIGN: The targeted urinary metabolomics study was conducted in 70 healthy pregnant controls and 133 pregnant patients having hypertension as cases. Hypertensive disorders of pregnancy-specific metabolites for disease prediction were further extracted using univariate and multivariate statistical analyses. For machine learning analysis, 80% of the data were used for training (79 for hypertensive disorders of pregnancy and 42 for healthy pregnancy) and validation (27 for hypertensive disorders of pregnancy and 14 for healthy pregnancy), and 20% of the data were used for test sets (27 for hypertensive disorders of pregnancy and 14 for healthy pregnancy). RESULTS: The statistical analysis using an unpaired t test revealed 44 differential metabolites. Pathway analysis showed mainly that purine and thiamine metabolism were altered in the group with hypertensive disorders of pregnancy compared with the healthy pregnancy group. The area under the receiver operating characteristic curves of the 5 most predominant metabolites were 0.98 (adenosine), 0.92 (adenosine monophosphate), 0.89 (deoxyadenosine), 0.81 (thiamine), and 0.81 (thiamine monophosphate). The best prediction accuracies were obtained using 2 machine learning models (95% for the gradient boost model and 98% for the decision tree) among the 5 used models. The machine learning models showed higher predictive performance for 3 metabolites (ie, thiamine monophosphate, adenosine monophosphate, and thiamine) among 5 metabolites. The combined accuracies of adenosine from all models were 98.6 in the training set and 95.6 in the test set. Moreover, the predictive performance of adenosine was higher than other metabolites. The relative feature importance of adenosine was also observed in the decision tree and the gradient boost model. CONCLUSION: Among other metabolites, adenosine and thiamine metabolites were found to differentiate participants with hypertensive disorders of pregnancy from participants with healthy pregnancies; hence, these metabolites can serve as a promising noninvasive marker for the detection of hypertensive disorders of pregnancy.

Exposure to endocrine-disrupting chemicals and risk of gestational hypertension and preeclampsia: A systematic review and meta-analysis.

Prenatal exposure to endocrine-disrupting chemicals has been linked to gestational hypertension (GH) and preeclampsia (PE). However, the results were conflicting and inconclusive. We conducted a systematic review and meta-analysis for an overview of these relationships. We searched PubMed, and Google Scholar for studies investigating bisphenol A, phthalates, and per or poly-fluoroalkyl substances and GH or PE. Pooled odds ratio (OR) with a 95% confidence interval (CI) were calculated for risk estimate using the generic inverse variance method. A total of 14 studies were included in the present analysis. The pooled results demonstrated that perfluorooctanoic acid (PFOA, OR:1.20, 95% CI: 1.04, 1.39), perfluoro octane sulfonic acid (PFOS, (OR:1.23, 95% CI: 1.10, 1.38), and perfluononanoic acid (PFNA, OR:1.20, 95% CI: 1.03, 1.40) were significantly associated with an increased risk of PE. There was no significant association observed with perfluoro hexane sulfonic acid (PFHxS), perfluoro decanoic acid (PFDA), perfluoro heptanoic acid (PFHpA), and perfluoro undecanoic acid (PFUnDA) and PE. For GH, a statistically significant positive association was found with PFOA (OR:1.18, 95% CI: 1.01, 1.39) and PFHxS (OR:1.15, 95% CI: 1.02, 1.29). Among various phthalates analysed only mono-ethyl phthalate (MEP, OR:1.37, 95% CI: 1.11, 1.70) showed an association with GH. From our analysis, bisphenol A exposure during pregnancy did not show a significant association with the risk of PE. Our findings indicated that exposure to PFASs such as PFOA, PFOS, and PFNA during pregnancy is associated with an increased risk of PE and PFOA and PFHxS with GH. We also found that MEP was associated with GH. Most of the results were unstable in sensitivity analysis. Since most of these associations have limited evidence, more research is needed to confirm these findings.

Pregestational diabetes alters cardiac structure and function of neonatal rats through developmental plasticity.

Pregestational diabetes (PGDM) leads to developmental impairment, especially cardiac dysfunction, in their offspring. The hyperglycemic microenvironment inside the uterus alters the cardiac plasticity characterized by electrical and structural remodeling of the heart. The altered expression of several transcription factors due to hyperglycemia during fetal development might be responsible for molecular defects and phenotypic changes in the heart. The molecular mechanism of the developmental defects in the heart due to PGDM remains unclear. To understand the molecular defects in the 2-days old neonatal rats, streptozotocin-induced diabetic female rats were bred with healthy male rats. We collected 2-day-old hearts from the neonates and identified the molecular basis for phenotypic changes. Neonates from diabetic mothers showed altered electrocardiography and echocardiography parameters. Transcriptomic profiling of the RNA-seq data revealed that several altered genes were associated with heart development, myocardial fibrosis, cardiac conduction, and cell proliferation. Histopathology data showed the presence of focal cardiac fibrosis and increased cell proliferation in neonates from diabetic mothers. Thus, our results provide a comprehensive map of the cellular events and molecular pathways perturbed in the neonatal heart during PGDM. All of the molecular and structural changes lead to developmental plasticity in neonatal rat hearts and develop cardiac anomalies in their early life.

Comparative efficacy and safety of oral nifedipine with other antihypertensive medications in the management of hypertensive disorders of pregnancy: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Hypertensive disorders of pregnancy are the most frequently occurring medical condition during pregnancy, resulting in fetal and/or maternal morbidity and mortality. This meta-analysis compared the efficacy and safety of nifedipine with other antihypertensive medications used in hypertensive disorders of pregnancy. METHODOLOGY: A comprehensive search was performed using PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), and Google Scholar. The meta-analysis was carried out using Review Manager Software, and the pooled effect estimate was generated as standardized mean difference and odds ratio with 95% confidence interval and two-sided P -value. RESULTS: The meta-analysis was comprised of 22 randomized control trials with 2595 participants. It was found that meantime and number of doses required to achieve target blood pressure were lower in the nifedipine group ( P  < 0.05). Even though it is statistically insignificant, fetal APGAR (Appearance, Pulse, Grimace, Activity, and Respiration) scores less than seven favors nifedipine intervention. Furthermore, none of the fetal or maternal secondary outcomes were found significant. CONCLUSION: Nifedipine was found to be more effective than other antihypertensive medications to reduce blood pressure, particularly in patients with severe hypertension. However, future clinical studies, including real-world data are necessary to establish the safety profile of nifedipine concerning the fetal outcomes in hypertensive pregnant women.

Implications of endocrine-disrupting chemicals on polycystic ovarian syndrome: A comprehensive review.

Polycystic ovarian syndrome (PCOS) is a complex multifactorial disorder of unknown pathogenesis in which genetic and environmental factors contribute synergistically to its phenotypic expressions. Endocrine-disrupting chemicals (EDCs), a group of widespread pollutants freely available in the environment and consumer products, can interfere with normal endocrine signals. Extensive evidence has shown that EDCs, environmental contributors to PCOS, can frequently induce ovarian and metabolic abnormalities at low doses. The current research on environmental EDCs suggests that there may be link between EDC exposure and PCOS, which calls for more human bio-monitoring of EDCs using highly sophisticated analytical techniques for the identification and quantification and to discover the underlying pathophysiology of the disease. This review briefly elaborated on the general etiology of PCOS and listed various epidemiological and experimental data from human and animal studies correlating EDCs and PCOS. This review also provides insights into various analytical tools and sample preparation techniques for biomonitoring studies for PCOS risk assessment. Furthermore, we highlight the role of metabolomics in disease-specific biomarker discovery and its use in clinical practice. It also suggests the way forward to integrate biomonitoring studies and metabolomics to underpin the role of EDCs in PCOS pathophysiology.

Circulatory hepcidin levels association with gestational diabetes mellitus: a meta-analysis of observational studies.

OBJECTIVES: Hepcidin is linked to glucose metabolism in women with gestational diabetes mellitus (GDM). This systematic review and meta-analysis was conducted to determine the association between hepcidin levels and GDM. A literature search was performed using different databases to identify potential studies investigating hepcidin association in GDM patients. The effect sizes were calculated based on the standardized mean difference (SMD) and Fisher's Z value with a 95% confidence interval (CI). KEY FINDINGS: Out of 827 articles, only 7 case-control studies satisfied the inclusion and exclusion criteria. The pooled SMD of circulatory hepcidin levels in GDM patients was considerably higher than normal pregnant women (SMD = 1.69; 95% CI, 0.86 to 2.53; P < 0.0001). This study also observed that hepcidin levels were positively correlated with ferritin levels (r = 0.264; Z = 0.27; P < 0.0001). Furthermore, a subgroup analysis of serum and plasma groups revealed significantly higher hepcidin levels in serum (SMD = 2.12; 95% CI, 0.44 to3.79; P = 0.001) than in the plasma group (SMD = 1.28; 95% CI, 0.32 to 2.2; I2 = 96%). SUMMARY: Our findings suggest that hepcidin levels may be elevated in GDM patients, making it a viable marker for GDM diagnosis, and regular monitoring of its levels could be helpful in aiding clinical decisions.

Levels of parabens and bisphenols in personal care products and urinary concentrations in Indian young adult women: Implications for human exposure and health risk assessment.

Limited information is available about the levels of exposure of paraben and bisphenols emerging from personal care products (PCPs) use in Indian women and the risk associated with it. In this study, liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to determine the concentrations of six parabens (methyl-, ethyl-, propyl-, butyl, benzyl-, and heptyl-parabens) and 8 bisphenols (Bisphenol A, B, F, P, S, Z, AP, and AF) in PCPs samples (n = 114) obtained from Indian market and in the urine samples of young adult females (n = 52). The concentrations measured in PCPs and urine samples were used to determine the estimated daily intake. The mean concentrations of 6 parabens and 8 bisphenols in PCPs ranged from 38.3 to 2.38 × 105 ng/g and 2.71-148 ng/g, respectively. In urine samples analysed, the mean concentrations of 6 parabens and 8 bisphenols ranged from 0.007 to 293 ng/mL and 0.10-10.8 ng/mL, respectively. There was no significant correlation of EDCs with age, BMI and waist-to-hip ratio (WHR), but significant correlations (p < 0.05) were observed between urinary paraben and bisphenol concentrations. A statistically significant difference (p < 0.05) exists between the BMI and WHR groups by bisphenol concentrations. Estimated daily intake and exposure risks for parabens and bisphenols revealed no possible concerns for Indian young adult females. Hitherto, this is the first study to show that Indian young adult females were exposed to parabens and bisphenols. This study provides evidence on PCPs usage contribute to the urinary concentrations of EDCs.

Estimation of parabens and bisphenols in maternal products and urinary concentrations in Indian pregnant women: daily intake and health risk assessment.

The presence of parabens and bisphenols in maternal products and usage during pregnancy have raised serious concern about their possible harm to pregnant women. The concentrations of six parabens and eight bisphenols were quantified by high-performance liquid chromatography-tandem mass spectrometry in the samples of commercially available herbal-based ayurvedic maternal products and urine of healthy pregnant women from Assam, India. Methyl paraben (MP) and bisphenol AF (BPAF) were found to be more dominant in the maternal products, whereas MP, bisphenol A (BPA), and BPAF were dominant in urine samples of healthy pregnant women. The sum of the mean concentrations of all forms of parabens and bisphenols in maternal products were 48,308.50 ng/g and 542.42 ng/g, respectively, and urine 101.33 ng/mL and 23.42 ng/mL, respectively. The estimated daily intake (EDI) of total parabens and bisphenols in maternal products were 7378.02 and 19.78 ng/kg body weight/day, respectively. EDI of total parabens and bisphenols from urinary concentrations were 690.12 and 111.33 µg/kg body weight/day, respectively. The concentrations of butyl (BP) and heptyl (HP) parabens have a significant positive correlation with birth weight. The hazard quotient (HQ) value of MP, EP, and BPA was less than 1, and margin of exposure (MOE) identified potential risk associated with propyl paraben. Results from Monte-Carlo risk assessment analysis did not exceed the acceptable daily intake (ADI). Our results showed that higher concentrations of parabens and bisphenols are present in maternal products and the urine of healthy pregnant women. Hence maternal products containing bisphenols and parabens should be used cautiously during pregnancy to avoid maternal and fetal complications.

The effect of Gymnema sylvestre supplementation on glycemic control in type 2 diabetes patients: A systematic review and meta-analysis.

This systematic review and meta-analysis aims to find the effect of Gymnema sylvestre (GS) supplementation on glycemic control in type-2 diabetes mellitus (T2DM). PubMed, Cochrane library, Google Scholar, and Science Direct were searched from inception to June 2020 to identify the studies that reported GS supplementation on glycemic parameters. Standardized mean difference (SMD) was calculated by comparing the post-intervention data with baseline data. SMDs with 95% confidence intervals (CIs) were pooled using a random-effects model. Our meta-analysis consisting of 10 studies with a total of 419 participants showed that GS supplementation significantly reduces fasting blood glucose (FBG) (SMD 1.57 mg/dl, 95% CI 2.22 to -0.93, p < .0001, I2 90%), postprandial blood glucose (PPBG) (SMD 1.04 mg/dl, 95% CI 1.53 to -0.54, p < .0001, I2 80%), and glycated haemoglobin (HbA1c) (SMD 3.91, 95% CI 7.35 to -0.16%, p < .0001, I2 99%) compared to baseline. Further, our study also found that GS significantly reduces triglycerides (SMD 1.81 mg/dl, 95% CI 2.95 to -0.66, p < .0001, I2 : 96%), and total cholesterol (SMD 4.10 mg/dl, 95% CI 7.21 to -0.99, p < .0001, I2 : 98%) compared to baseline. Our study shows that GS supplementation is effective in improving glycemic control and reducing lipid levels in T2DM patients and suggests that such supplementation might be used as an effective therapy for the management of T2DM and its associated complications to an extent.

Transporter-mediated drug-drug interactions: advancement in models, analytical tools, and regulatory perspective.

Drug-drug interactions mediated by transporters are a serious clinical concern hence a tremendous amount of work has been done on the characterization of the transporter-mediated proteins in humans and animals. The underlying mechanism for the transporter-mediated drug-drug interaction is the induction or inhibition of the transporter which is involved in the cellular uptake and efflux of drugs. Transporter of the brain, liver, kidney, and intestine are major determinants that alter the absorption, distribution, metabolism, excretion profile of drugs, and considerably influence the pharmacokinetic profile of drugs. As a consequence, transporter proteins may affect the therapeutic activity and safety of drugs. However, mounting evidence suggests that many drugs change the activity and/or expression of the transporter protein. Accordingly, evaluation of drug interaction during the drug development process is an integral part of risk assessment and regulatory requirements. Therefore, this review will highlight the clinical significance of the transporter, their role in disease, possible cause underlying the drug-drug interactions using analytical tools, and update on the regulatory requirement. The recent in-silico approaches which emphasize the advancement in the discovery of drug-drug interactions are also highlighted in this review. Besides, we discuss several endogenous biomarkers that have shown to act as substrates for many transporters, which could be potent determinants to find the drug-drug interactions mediated by transporters. Transporter-mediated drug-drug interactions are taken into consideration in the drug approval process therefore we also provided the extrapolated decision trees from in-vitro to in-vivo, which may trigger the follow-up to clinical studies.

Neonatal lupus erythematosus presenting with rash, thrombocytopenia compounded by cytomegalovirus colonisation: a diagnostic dilemma.

Neonatal lupus erythematosus (NLE) should be considered when a newborn develops atrioventricular heart block along with the presence of autoantibodies to Sjogren's syndrome autoantigens in the maternal serum. NLE can also present with features such as cutaneous lesions, hepatic dysfunction or haematological abnormalities. Differential diagnosis usually includes congenital infections as there is a significant overlap of symptoms with NLE. We report a case of NLE who had multiorgan involvement with macular erythematous skin lesions present at birth, and on investigation was found to have cytomegalovirus (CMV) infection. The diagnostic dilemma was whether to consider this infection as symptomatic or just colonisation. In the infant described, the absence of end organ damage specific to CMV infection (hearing loss, intracranial calcifications, retinitis, brain involvement) made a diagnosis of symptomatic CMV unlikely.

Successful management of airway hemangioma with propranolol.

Airway hemangiomas can be difficult to manage and cause anxiety in both the parents and the treating physician. Propranolol, a nonselective beta-blocker, has recently been used for treating proliferating infantile hemangiomas. We report successful management of a proliferating, large, mixed infantile hemangioma with subglottic extension in an Indian infant using oral propranolol in a dose of 2mg/kg/day without any side effects. Induction of early involution and freedom from the side effects of steroid therapy seem encouraging for using propranolol as a first line treatment modality in the management of troublesome hemangiomas.

Complete form of pachydermoperiostosis: a case report.

Pachydermoperiostosis is a primary form of hypertrophic osteoarthropathy, which presents with pachydermia, digital clubbing, and radiologic periostosis. Pachydermoperiostosis occurs owing to mutations of the gene encoding for 15-hydroxyprostaglandin dehydrogenase (15HPGD). Clinical manifestations of PDP are thought to relate to excessive collagen formation and dysregulation of matrix proteins because of fibroblastic hyperactivation. We present a very rare case of the complete form of pachydermoperiostosis in a young Indian male.

Generalized linear porokeratosis: a rare entity with excellent response to acitretin.

Linear porokeratosis is a rare disorder of keratinization that usually presents at birth. We report a 17-year-old male with generalized linear porokeratosis, a very rare variant of porokeratosis, with extensive involvement of the trunk and extremities along with nail and genital involvement. The patient was treated with oral acitretin with excellent clinical response.

Dorfman-Chanarin syndrome in two female siblings: a case report and discussion on approach and management.

UNLABELLED: Dorfman-Chanarin syndrome (DCS) is a very rare disorder of lipid metabolism that exhibits an autosomal recessive pattern of inheritance. Besides ichthyosis, systemic manifestations may be present. We report two female siblings with DCS who presented with non-bullous ichthyosiform erythroderma (NBIE). A peripheral blood smear demonstrated Jordan anomaly. This case emphasizes the need for peripheral blood smear screening in patients with congenital ichthyosis. CASE REPORT: A 2½-year-old female child and her 1-month-old sibling presented with generalized erythema and scaling, which was suggestive of NBIE. Hepatomegaly and ectropion were seen in the older sibling. A peripheral blood smear of both the patients revealed Jordan anomaly. Serum biochemistry revealed abnormal liver function tests, abnormal lipid profile, and elevated muscle-derived enzymes. A diagnosis of Dorfman-Chanarin syndrome was made in both the siblings. Screening for Jordan anomaly in the family members including the parents and maternal and paternal grandmothers was negative. CONCLUSION: The peculiarities in our case include the presence of this disorder in both female siblings along with alopecia in the younger sibling. Hyperlipidemia, noted in one of our cases, is also not a common association. Diagnosing DCS is fairly simple and a high index of suspicion may lead to higher rates of detection of this rare disorder.

CHILD syndrome with thrombocytosis and congenital dislocation of hip: A case report from India.

Congenital Hemidysplasia with Ichthyosiform Nevus and Limb Defects (CHILD) is a very rare entity inherited as an X-linked trait. The cutaneous lesions are characteristic and usually involve the right side of the body. We report a case of CHILD syndrome in an Indian child affecting the left side with various other associations not yet described in the literature, such as thrombocytosis and congenital dislocation of the hip. The rarity of the syndrome prompted us to report this case.