Deficiency in the omega-3 lysolipid transporter Mfsd2a leads to aberrant oligodendrocyte lineage development and hypomyelination.

Patients with autosomal recessive microcephaly 15 caused by deficiency in the sodium-dependent lysophosphatidylcholine (LPC) transporter major facilitator superfamily domain-containing 2a (Mfsd2a) present with both microcephaly and hypomyelination, suggesting an important role for LPC uptake by oligodendrocytes in the process of myelination. Here we demonstrate that Mfsd2a is specifically expressed in oligodendrocyte precursor cells (OPCs) and is critical for oligodendrocyte development. Single-cell sequencing of the oligodendrocyte lineage revealed that OPCs from OPC-specific Mfsd2a-KO mice (2aOKO mice) underwent precocious differentiation into immature oligodendrocytes and impaired maturation into myelinating oligodendrocytes, correlating with postnatal brain hypomyelination. 2aOKO mice did not exhibit microcephaly, a finding consistent with the notion that microcephaly is the consequence of an absence of LPC uptake at the blood-brain barrier rather than a deficiency in OPCs. Lipidomic analysis showed that OPCs and iOLs from 2aOKO mice had significantly decreased levels of phospholipids containing omega-3 fatty acids, with a corresponding increase in unsaturated fatty acids, the latter being products of de novo synthesis governed by Srebp-1. RNA-Seq indicated activation of the Srebp-1 pathway and defective expression of regulators of oligodendrocyte development. Taken together, these findings indicate that the transport of LPCs by Mfsd2a in OPCs is important for maintaining OPC state to regulate postnatal brain myelination.

DHEA on Sexual Function in Sheehan Syndrome: A Randomized Double-Blind Placebo-Controlled Crossover Trial.

CONTEXT: The majority of women with Sheehan syndrome (SS) suffer from sexual dysfunction. Severe androgen deficiency is a major contributory factor. Dehydroepiandrosterone (DHEA) supplementation has been reported to have variable efficacious in improving female sexual dysfunction (FSD) in several trials but studies using DHEA in SS are not available. OBJECTIVE: We aimed to study the use of DHEA supplementation in patients with SS. METHODS: In this crossover trial, 28 participants with SS (age 39.7 ±â€…8.6 years) were divided into 2 groups (using block randomization) who received DHEA supplements (25 mg twice daily) or matched placebo sequentially for 3 months each. Female Sexual Functioning Index (FSFI) score and serum DHEA sulfate (DHEAS) were measured at baseline and after completion of each phase. Glycemic parameters, lipid profile, and liver enzymes were also measured to assess metabolic side effects. RESULTS: There was significant improvement in FSFI score from baseline to end of the study in the DHEA group compared with the placebo group (P = 0.006). Mean FSFI score and most of the individual domains of female sexual dysfunction (FSD) improved with DHEA significantly in both groups (P = 0.001 for each group with DHEA). In those who received DHEA first followed by placebo, FSFI declined significantly after placebo (P = 0.041) but remained at an acceptable level of sexual functioning. Serum DHEAS increased significantly with DHEA treatment. No significant changes in glycemic index, lipid profile, and liver enzymes were noted with DHEA treatment. CONCLUSION: A short duration of DHEA supplementation in women with SS with FSD is efficacious and safe.

Satisfaction of patients with diabetic kidney disease with traditional chinese medicine physician visits.

Background: Patient-centred care is an important part of quality healthcare and patient satisfaction has been shown to be associated with improved clinical outcomes. We aim to explore the satisfaction of patients with diabetic kidney disease (DKD) with their visits to the TCM physician and its association with patients' socio-economic characteristics. Methods: A questionnaire survey was conducted among patients aged >21 years with DKD. Participants' demographic, socioeconomic characteristics and satisfaction scores measured with the self-administered Medical Interview Satisfaction Scale (MISS) were collected after they visited the TCM physician. MISS is a 26-item questionnaire consisting of three domains - cognitive, affective and behavioural which was developed to assess patient satisfaction with medical consultation. Independent samples t-test and one-way analysis of variance (ANOVA) were used to analyse the data. Results: 137 participants completed the questionnaires and were included in the analysis. The mean satisfaction score was 3.1 out of 5, with the cognitive domain being significantly higher compared to the affective and behavioural domains. The mean satisfaction score of the cognitive domain differed significantly among participants staying in different types of housing and those with previous TCM encounters. The mean satisfaction score of the behavioural domain differed significantly among participants of different ethnicities. The mean satisfaction scores of all the domains were also significantly different among participants with different duration of follow-up with their TCM physicians. Conclusion: We found that ethnicity, types of housing, previous TCM experience and the duration of follow-up with the TCM physician may affect the satisfaction scores of patients with DKD.

Comparative efficacy of topical aloe vera and low-level laser therapy in the management of oral lichen planus: a randomized clinical trial.

This randomized clinical trial aimed to compare the efficacy of topical aloe vera with low-level laser therapy in patients with oral lichen planus (OLP). A randomized, parallel arm, single-blind study comprising of 60 patients with OLP was randomly divided into two groups. Group A was given topical aloe vera extract gel applied thrice daily for 2 months, and group B was given low-level laser therapy (LLLT) at 980 nm twice weekly for 2 months. Both groups were followed up for 9 months. Patients were assessed for various parameters according to the Escudier scale at baseline, after treatment at 9 months. Results were assessed using the McNemar-Bowker test and the Mann-Whitney U test. Both individual groups showed significant (p < 0.05) results at the end of the treatment period (0-2 months) and the follow-up period (2-7 months). Intergroup comparison showed significant results in the laser group (reduction of VAS by 44.1%, site score by 24.6%, and activity score by 50%) as compared with the aloe vera group (reduction of VAS by 26.7%, site score by 9.2%, and the activity score by 26%) in the treatment period. In the follow-up period, both groups showed insignificant differences in comparison to each other. Within the limitations of the study, LLLT was more effective as compared with topical aloe vera in managing oral lichen planus during the active treatment time, while both were equally effective during the follow-up period. The clinical study was registered under the Clinical Trials Registry India with the registration number CTRI/2018/04/013147.

FURIN Inhibition Reduces Vascular Remodeling and Atherosclerotic Lesion Progression in Mice.

Objective- Atherosclerotic coronary artery disease is the leading cause of death worldwide, and current treatment options are insufficient. Using systems-level network cluster analyses on a large coronary artery disease case-control cohort, we previously identified PCSK3 (proprotein convertase subtilisin/kexin family member 3; FURIN) as a member of several coronary artery disease-associated pathways. Thus, our objective is to determine the role of FURIN in atherosclerosis. Approach and Results- In vitro, FURIN inhibitor treatment resulted in reduced monocyte migration and reduced macrophage and vascular endothelial cell inflammatory and cytokine gene expression. In vivo, administration of an irreversible inhibitor of FURIN, α-1-PDX (α1-antitrypsin Portland), to hyperlipidemic Ldlr-/- mice resulted in lower atherosclerotic lesion area and a specific reduction in severe lesions. Significantly lower lesional macrophage and collagen area, as well as systemic inflammatory markers, were observed. MMP2 (matrix metallopeptidase 2), an effector of endothelial function and atherosclerotic lesion progression, and a FURIN substrate was significantly reduced in the aorta of inhibitor-treated mice. To determine FURIN's role in vascular endothelial function, we administered α-1-PDX to Apoe-/- mice harboring a wire injury in the common carotid artery. We observed significantly decreased carotid intimal thickness and lower plaque cellularity, smooth muscle cell, macrophage, and inflammatory marker content, suggesting protection against vascular remodeling. Overexpression of FURIN in this model resulted in a significant 67% increase in intimal plaque thickness, confirming that FURIN levels directly correlate with atherosclerosis. Conclusions- We show that systemic inhibition of FURIN in mice decreases vascular remodeling and atherosclerosis. FURIN-mediated modulation of MMP2 activity may contribute to the atheroprotection observed in these mice.

Comparison of therapeutic response of lycopene and curcumin in oral submucous fibrosis: A randomized controlled trial.

OBJECTIVES: To evaluate and compare the therapeutic response of lycopene and curcumin with placebo in patients suffering from oral submucous fibrosis (OSMF) and to correlate the habit variables of smoked and smokeless tobacco products in OSMF. METHODS: A randomized placebo-controlled parallel clinical study was conducted on ninety OSMF patients, who were divided into three treatment groups using computer-generated randomization. Group A patients (n = 30) were given curcumin tablet (300 mg) twice daily, Group B patients (n = 30) received lycopene capsules (8 mg) twice daily, and for Group C (n = 30), placebo capsules were given once daily for a period of six months. Both the participant and outcome assessor were blinded. Pre- and post-treatment comparison of mouth opening, burning sensation, tongue protrusion, and cheek flexibility was analyzed at periodic follow-up of 9 months. RESULTS: The overall improvement in mouth opening, burning sensation, tongue protrusion, and cheek flexibility was 3.9 ± 4.9 mm, 4.8 ± 2.6, 5.0 ± 7.2 mm, & 0.36 ± 0.71 mm, respectively, for curcumin and 4.1 ± 4.2 mm, 5.0 ± 2.3, 2.4 ± 3.5 mm, & 0.66 ± 0.80 mm, respectively, for lycopene with the p value <0.05. CONCLUSION: Statistically significant improvement in clinical findings was observed in both curcumin and lycopene treatment groups in comparison with placebo. However, the therapeutic efficacy of curcumin and lycopene was found to be almost equal in OSMF patients.

The effect of Bacopa monnieri on gene expression levels in SH-SY5Y human neuroblastoma cells.

Bacopa monnieri is a plant used as a nootropic in Ayurveda, a 5000-year-old system of traditional Indian medicine. Although both animal and clinical studies supported its role as a memory enhancer, the molecular and cellular mechanism underlying Bacopa's nootropic action are not understood. In this study, we used deep sequencing (RNA-Seq) to identify the transcriptome changes upon Bacopa treatment on SH-SY5Y human neuroblastoma cells. We identified several genes whose expression levels were regulated by Bacopa. Biostatistical analysis of the RNA-Seq data identified biological pathways and molecular functions that were regulated by Bacopa, including regulation of mRNA translation and transmembrane transport, responses to oxidative stress and protein misfolding. Pathway analysis using the Ingenuity platform suggested that Bacopa may protect against brain damage and improve brain development. These newly identified molecular and cellular determinants may contribute to the nootropic action of Bacopa and open up a new direction of investigation into its mechanism of action.

Quercetin and Green Tea Extract Supplementation Downregulates Genes Related to Tissue Inflammatory Responses to a 12-Week High Fat-Diet in Mice.

Quercetin (Q) and green tea extract (E) are reported to counter insulin resistance and inflammation and favorably alter fat metabolism. We investigated whether a mixture of E + Q (EQ) could synergistically influence metabolic and inflammation endpoints in a high-fat diet (HFD) fed to mice. Male C57BL/6 mice (n = 40) were put on HFD (fat = 60%kcal) for 12 weeks and randomly assigned to Q (25 mg/kg of body weight (BW)/day), E (3 mg of epigallocatechin gallate/kg BW/day), EQ, or control groups for four weeks. At 16 weeks, insulin sensitivity was measured via the glucose tolerance test (GTT), followed by area-under-the-curve (AUC) estimations. Plasma cytokines and quercetin were also measured, along with whole genome transcriptome analysis and real-time polymerase chain reaction (qPCR) on adipose, liver, and skeletal muscle tissues. Univariate analyses were conducted via analysis of variance (ANOVA), and whole-genome expression profiles were examined via gene set enrichment. At 16 weeks, plasma quercetin levels were higher in Q and EQ groups vs. the control and E groups (p < 0.05). Plasma cytokines were similar among groups (p > 0.05). AUC estimations for GTT was 14% lower for Q vs. E (p = 0.0311), but non-significant from control (p = 0.0809). Genes for cholesterol metabolism and immune and inflammatory response were downregulated in Q and EQ groups vs. control in adipose tissue and soleus muscle tissue. These data support an anti-inflammatory role for Q and EQ, a result best captured when measured with tissue gene downregulation in comparison to changes in plasma cytokine levels.

Oxidative stress in hypothyroid patients and the role of antioxidant supplementation.

CONTEXT: The available data concerning oxidant stress and antioxidant capacity in hypothyroidism are scanty and inconclusive. While some authors suggest that tissues may be protected from oxidant damage because of a hypometabolic state in hypothyroidism, others report increased oxidative stress in hypothyroidism. Selenium acts as a cofactor for the thyroid hormone (TH) deiodinases that activate and then deactivate various THs and their metabolites. Selenium may inhibit thyroid autoimmunity. AIMS: The study was designed, first, to study the impact of oxidative stress in patients of primary hypothyroidism due to autoimmune thyroiditis, by estimation of serum malondialdehyde (MDA) as a biomarker of oxidative stress. Second, to study the change in MDA level pre- and post-L-thyroxine treatment. Finally, to look into the possible role of selenium supplementation on oxidative stress in autoimmune hypothyroidism. SUBJECTS AND METHODS: Patients attending endocrine outpatient department (OPD) services of IPGMER and SSKM hospital were considered for the study. Sixty treatment-naive adult patients (age > 18 years) with hypothyroidism were included in the study. The patients were divided into two groups, each comprised thirty patients. One group was treated with L-thyroxine and placebo (Group A). The other group received L-thyroxine replacement along with selenium (100 mcg twice a day) as antioxidant supplementation (Group B). The patients were blinded about selenium and placebo. The study duration for both groups was 6 months. The starting dose of L-thyroxine was 1.6 mcg/kg body weight free thyroxine (FT4), and thyroid-stimulating hormone (TSH) was repeated after 12 weeks. L-thyroxine dose adjustments were done if needed. MDA was assessed at the beginning and at the end of the study, i.e., after 6 months of treatment. The control cohort was composed of thirty healthy adults. Only overt hypothyroidism (OH) cases were included in the study. STATISTICAL ANALYSIS USED: Normality of data was determined using Anderson-Darling test, Shapiro-Wilk test, and QQ plot. P values were calculated using ANOVA and post hoc Bonferroni tests for normally distributed data. Correlation analysis was carried out using Pearson correlation test. P < 0.05 considered to be statistically significant. RESULTS: After treatment in Group A patients, FT4 showed a significant increment while TSH value decreased. MDA level reduced after treatment, (P < 0.001). After treatment in Group B patients, FT4 showed increment while TSH value decreased (P < 0.05). After treatment, there was a drop in estimated MDA level (P < 0.001). MDA level shows a significant drop in both groups after treatment. In Group B, there is more decline in the MDA percentage but did not reach statistical significance. By performing repeated measure MANOVA, no significant difference was found in the MDA levels between the two groups. MDA reduction when expressed as percentage showed reduction of 39.5% in patients of Group A. Similarly, Group B patients showed a percentage reduction of 45.4%. CONCLUSIONS: Oxidative stress compounds hypothyroidism. Hypothyroidism is a state of increased oxidative stress. In this study, biomarker, MDA level is high in treatment-naive primary hypothyroid patients. After treatment with L-thyroxine, the stress marker is reduced to a significant extent. MDA can be used as a useful biomarker to measure and monitor oxidative stress. The role of the addition of antioxidant in the form of selenium remained inconclusive.

A Mixed Flavonoid-Fish Oil Supplement Induces Immune-Enhancing and Anti-Inflammatory Transcriptomic Changes in Adult Obese and Overweight Women-A Randomized Controlled Trial.

Flavonoids and fish oils have anti-inflammatory and immune-modulating influences. The purpose of this study was to determine if a mixed flavonoid-fish oil supplement (Q-Mix; 1000 mg quercetin, 400 mg isoquercetin, 120 mg epigallocatechin (EGCG) from green tea extract, 400 mg n3-PUFAs (omega-3 polyunsaturated fatty acid) (220 mg eicosapentaenoic acid (EPA) and 180 mg docosahexaenoic acid (DHA)) from fish oil, 1000 mg vitamin C, 40 mg niacinamide, and 800 µg folic acid) would reduce complications associated with obesity; that is, reduce inflammatory and oxidative stress markers and alter genomic profiles in overweight women. Overweight and obese women (n = 48; age = 40-70 years) were assigned to Q-Mix or placebo groups using randomized double-blinded placebo-controlled procedures. Overnight fasted blood samples were collected at 0 and 10 weeks and analyzed for cytokines, C-reactive protein (CRP), F2-isoprostanes, and whole-blood-derived mRNA, which was assessed using Affymetrix HuGene-1_1 ST arrays. Statistical analysis included two-way ANOVA models for blood analytes and gene expression and pathway and network enrichment methods for gene expression. Plasma levels increased with Q-Mix supplementation by 388% for quercetin, 95% for EPA, 18% for DHA, and 20% for docosapentaenoic acid (DPA). Q-Mix did not alter plasma levels for CRP (p = 0.268), F2-isoprostanes (p = 0.273), and cytokines (p > 0.05). Gene set enrichment analysis revealed upregulation of pathways in Q-Mix vs. placebo related to interferon-induced antiviral mechanism (false discovery rate, FDR < 0.001). Overrepresentation analysis further disclosed an inhibition of phagocytosis-related inflammatory pathways in Q-Mix vs. placebo. Thus, a 10-week Q-Mix supplementation elicited a significant rise in plasma quercetin, EPA, DHA, and DPA, as well as stimulated an antiviral and inflammation whole-blood transcriptomic response in overweight women.

A case of oncogenic osteomalacia due to occult nasal sinus tumor.

This paper shows a case of oncogenic osteomalacia in a 35-year-old man who presented with a 2-year history of generalized pain and progressive weakness of lower limbs, eventually became bed bound. At admission he had severe hip pain resulting from atraumatic femoral neck fractures. Laboratory investigations revealed hypophosphatemia, hyperphosphaturia, normocalcemia, elevated alkaline phosphatase, and normal serum levels of parathormone and 25-hydroxyvitamin D. Serum FGF-23 was elevated. Imaging showed osteoporosis and insufficiency fractures of the femoral neck. Whole body functional imaging failed to reveal any areas of increased activity. However, on computed tomography (CT) and magnetic resonance (MR) imaging, a tumor was discovered at left nasal cavity. The patient was treated with phosphate supplements and vitamin D, but his hypophosphatemia persisted. The tumor was surgically removed. Histologically, the tumor was diagnosed as variant of a sinonasal hemangiopericytoma-like tumor. After surgery, his symptoms were relieved and biochemical parameters normalized.

Lead-free ZnSnO3/MWCNTs-based self-poled flexible hybrid nanogenerator for piezoelectric power generation.

A high-performance flexible piezoelectric hybrid nanogenerator (HNG) based on lead-free perovskite zinc stannate (ZnSnO3) nanocubes and polydimethylsiloxane (PDMS) composite with multiwall carbon nanotubes (MWCNTs) as supplement filling material is demonstrated. Even without any electrical poling treatment, the HNG possesses an open-circuit voltage of 40 V and a short-circuit current of 0.4 µA, respectively, under repeated human finger impact. It has been demonstrated that the output volume power density of 10.8 µW cm(-3) from a HNG can drive several colour light emitting diodes (LEDs) and a charge capacitor that powers up a calculator, indicating an effective means of energy harvesting power source with high energy conversion efficiency (∼1.17%) for portable electronic devices.

Primary hyperparathyroidism masquerading as rickets: diagnostic challenge and treatment outcomes.

Primary hyperparathyroidism (PHPT) is extremely uncommon among children and is more likely to be associated with genetic syndromes, multiglandular involvement, and more severe symptoms. Rickets can very rarely be the presenting feature of PHPT in children. Rickets was diagnosed in a 12-year-old girl presenting with short stature, genu valgum, eversion deformity at the ankle joints, and flat feet. Radiograms showed generalized osteopenia, widening of the distal ends of the long bones along with splaying, cupping and fraying. Biochemical evaluation revealed low serum calcium (7.8 mg/dL), low phosphorus (1.4 mg/dL), vitamin-D deficiency [25-hydroxy-vitamin-D (25(OH)D): 8.7 ng/mL], and elevated intact parathyroid hormone (PTH, 811 pg/mL). Re-evaluation due to lack of clinical improvement following vitamin-D and calcium supplementation revealed hypercalcemia 11.9 mg/dL, normal 25(OH)D 41 ng/mL, persistence of elevated PTH 632 pg/mL. A 99mTc-sestamibi scan showed increased uptake at the lower pole of the right lobe of the thyroid. A right inferior parathyroidectomy was performed. Histopathology revealed chief cell type parathyroid adenoma. Last evaluated 4 months after surgery, the bone pains and proximal weakness had resolved, with significant improvement in the patient's quality of life. Rickets in the setting of PHPT often masks the classical phenotype of PHPT. In a child with rickets, lack of improvement following vitamin-D supplementation, hypercalcemia at presentation or following vitamin-D supplementation are warning signs which necessitate further evaluation to rule out PHPT.

Cretinism revisited.

OBJECTIVE: Cretinism is a condition of severely stunted physical and mental growth due to untreated congenital hypothyroidism. It has been largely eliminated in the developed world, though we still continue to see cases in India. CASE REPORT: A 22-year-old male was brought to our Endocrine clinic by his brother due to his "not growing up". The patient was 83 cm in height (SDS - 16.98) and weighed 13.9 kg (<3(rd) percentile). He had dull look, puffy face with thick lips, macroglossia, and umbilical hernia. There was sexual infancy with prepubertal testes (<3 ml). He could sit without support, but could not stand, or walk without support and could only talk in monosyllables. He was born full term by normal vaginal delivery, and cried immediately after birth. The developmental milestones were delayed, and not achieved till date. He is the eldest of seven siblings, rest six of whom have no complaints. An X-ray of hand was done showing bone age of less than 1 year. A thyroid profile showed TSH >150 IU/ml, free T4 and T3 below the assay range. Ultrasound of neck showed absent thyroid tissue in neck. Iodine-131 uptake scan was consistent with thyroid aplasia. Diagnosis was myxematous cretinism due to thyroid aplasia was made, and patient was started on thyroxine supplementation. CONCLUSION: This case represents the most severe form of untreated congenital hypothyroidism presenting as severely stunted physical and mental growth with delayed bone and sexual maturation.

Idiopathic hypoparathyroidism and systemic sclerosis: An association likely missed.

Hypoparathyroidism in systemic sclerosis is extremely rare with only a single case reported till date. Idiopathic hypoparathyroidism with systemic sclerosis was diagnosed in a 59-year-old gentleman who had presented with recurrent seizures, instability of gait, skin thickening and tightening over both legs and forearms, and arthritis. Examination was significant for positive Trousseau sign and cerebellar ataxia. Evaluation revealed bilateral symmetrical cerebellar and basal ganglia calcification, sensorineural deafness, low serum calcium, elevated serum phosphorus, normal magnesium, normal vitamin D, low plasma parathyroid hormone, high titer of thyroid peroxidase antibody, positive centromere pattern antinuclear antibody, strongly positive anti-topoisomerase-1 (Scl-70) antibody, nonvisualization of parathyroids on neck ultrasonography and skin biopsy suggestive of hyperkeratosis, increased collagen in dermis, and perivascular lymphomononuclear cell infiltration compatible with scleroderma. Last evaluated 10 months after the diagnosis, his ataxia had improved, he remained seizure-free, Trousseau sign was negative, and he had low-normal calcium calcium with calcium carbonate and calcitriol supplementation and switch from phenytoin to valproate. Further studies are warranted to study the use of serum calcium as a screening test for hypoparathyroidism in patients with systemic sclerosis.

The relative transcription index: a gene expression based metric for prioritization of drug candidates.

Efficient compound selection remains a key challenge in drug discovery today. The goal is to identify developable drug candidates early in the screening process while simultaneously flagging compounds with off-target effects indicative of liabilities or alternate indications. This goal overlaps but is distinct from the goal of toxicogenomics which is focused primarily on identifying toxicity signatures of lead candidates in key tissues. We propose a framework where global changes in gene expression levels in response to compounds can be used as an objective metric for early compound prioritization. We call this metric the Relative Transcription Index (RTI). RTI is a measure of the relative activity of compounds as ascertained by their effects on transcription at a genome-wide level. Compounds with a low RTI affect the expression of only a few genes whereas compounds with a high RTI affect the expression of a large number of genes. This information is useful for differentiating compounds that, based on phenotypic assays alone, may appear to be equally efficacious. Since compounds with high RTI are more likely to display off-target effects, the RTI metric, if implemented early in the screening process, can become a valuable tool for compound selection. The utility of the RTI metric is demonstrated by its application to two different gene expression datasets--one involving modulators of the liver X receptor (LXR) and the other concerning antibacterial compounds belonging to diverse mechanistic classes.