Gonadal Failure in a Male With 3-M Syndrome.

OMIM 273750 (3-M) syndrome is a rare cause of severe short stature with variable dysmorphic features caused by pathogenic variants in several genes including cullin7 gene (CUL7). Hypogonadism and hypospadias have been described in only a few males. We report a patient with CUL7 pathogenic variant who had bifid scrotum and perineal hypospadias at birth. He entered puberty spontaneously at age 12 years and appropriately completed pubertal development by 15 years. Subsequently, a regression of testicular volumes, increased gonadotropin levels, and reduced (although normal) testosterone levels were observed. This case highlights the importance of careful pubertal monitoring as pubertal dysfunction may be associated with 3-M syndrome.

Enhancing equity in access to automated insulin delivery systems in an ethnically and socioeconomically diverse group of children with type 1 diabetes.

INTRODUCTION: Manufacturer-supported didactic teaching programmes offer effective automated insulin delivery (AID) systems onboarding in children and young people (CYP) with type 1 diabetes (T1D). However, this approach has limited flexibility to accommodate the needs of families requiring additional support. RESEARCH DESIGN AND METHODS: Evaluate the efficacy of an inperson manufacturer-supported didactic teaching programme (Group A), in comparison to a flexible flipped learning approach delivered virtually or inperson (Group B). Retrospective analysis of CYP with T1D using continuous glucose monitoring (CGM), who were initiated on AID systems between 2021 and 2023. Compare CGM metrics from baseline to 90 days for both groups A and B. Additionally, compare the two groups for change in CGM metrics over the 90-day period (∆), patient demographics and onboarding time. RESULTS: Group A consisted of 74 CYP (53% male) with median age of 13.9 years and Group B 91 CYP (54% male) with median age of 12.7 years. From baseline to 90 days, Group A lowered mean (±SD) time above range (TAR, >10.0 mmol/L) from 47.6% (±15.0) to 33.2% (±15.0) (p<0.001), increased time in range (TIR, 3.9-10.0 mmol/L) from 50.4% (±14.0) to 64.7% (±10.2) (p<0.001). From baseline to 90 days, Group B lowered TAR from 51.3% (±15.1) to 34.5% (±11.3) (p<0.001) and increased TIR from 46.5% (±14.5) to 63.7% (±11.0) (p<0.001). There was no difference from baseline to 90 days for time below range (TBR, <3.9 mmol/L) for Group A and Group B. ∆ TAR, TIR and TBR for both groups were comparable. Group B consisted of CYP with higher socioeconomic deprivation, greater ethnic diversity and lower carer education achievement (p<0.05). The majority of Group B (n=79, 87%) chose virtual flipped learning, halving diabetes educator time and increasing onboarding cadence by fivefold. CONCLUSIONS: A flexible virtual flipped learning programme increases onboarding cadence and capacity to offer equitable AID system onboarding.

Simultaneous Determination of Fipronil, Permethrin and their Key Related Substances in a Topical Drug Product by a Single Stability Indicating High Performance Liquid Chromatography Method.

BACKGROUND: The topical veterinary drug product containing fipronil and permethrin provides an effective repellent protection and high insecticidal efficacy for dogs. OBJECTIVE: The objective of this study was to develop a stability indicating high performance liquid chromatography (HPLC) method for simultaneous detection and quantification of fipronil, permethrin, their key degradation products and butylated hydroxytoluene (BHT) in a topical drug product. METHOD: The two active ingredients, their degradation products, and the antioxidant (BHT) were separated by a gradient elution on a Phenomenex Kinetex C18 column (150 × 3 mm, 2.6 µm particle size) maintained at 37 °C with H2O/acetonitrile/isopropyl alcohol/85% H3PO4 (65.5 + 32.5 + 4/0.0053, v/v/v/v) as mobile phase-A and acetonitrile (100%) as mobile phase-B. The flow rate was 0.9 mL/min and analytes were detected and quantified at 235 nm. RESULTS: Specificity of the method was demonstrated by adequate separation of fipronil, permethrin, their degradation products, and BHT in the forced degraded finished product. Linearity of the method was demonstrated in the range of 0.2% to 150% of target analytical concentration of both active ingredients and 50% to 150% for BHT. Excellent recoveries of fipronil, permethrin and BHT in placebo spiked active ingredient solutions in the linearity range showed sufficient accuracy of the method. LOQ and LOD of the method were determined to be 0.2% and 0.07% of the analytical concentration. A robustness study did not identify any critical parameter that adversely effected the separation and quantification. CONCLUSIONS: Here, we report the development and validation of a robust, stability indicating HPLC method for identification and assay of fipronil, permethrin, and BHT, including estimation of fipronil's and permethrin's degradation products in a topical drug product for dogs. HIGHLIGHTS: The new HPLC method permits the acquisition of data for all analytes of interest for a topical finished drug product containing fipronil, permethrin, and BHT.

The Effect of Exogenous Cadmium and Zinc Applications on Cadmium, Zinc and Essential Mineral Bioaccessibility in Three Lines of Rice That Differ in Grain Cadmium Accumulation.

Millions of people around the world rely on rice (Oryza sativa) for a significant portion of daily calories, but rice is a relatively poor source of essential micronutrients like iron and zinc. Rice has been shown to accumulate alarmingly high concentrations of toxic elements, such as cadmium. Cadmium in foods can lead to renal failure, bone mineral density loss, cancer, and significant neurotoxicological effects. Several strategies to limit cadmium and increase micronutrient density in staple food crops like rice have been explored, but even when cadmium concentrations are reduced by a management strategy, total cadmium levels in rice grain are an unreliable means of estimating human health risk because only a fraction of the minerals in grains are bioaccessible. The goal of this work was to assess the influence of cadmium and zinc supplied to plant roots on the bioaccessibility of cadmium and essential minerals from grains of three rice lines (GSOR 310546/low grain Cd, GSOR 311667/medium grain Cd, and GSOR 310428/high grain Cd) that differed in grain cadmium accumulation. Treatments consisted of 0 µM Cd + 2 µM Zn (c0z2), 1 µM Cd + 2 µM Zn (c1z2), or 1 µM Cd + 10 µM Zn (c1z10). Our results revealed that an increased grain cadmium concentration does not always correlate with increased cadmium bioaccessibility. Among the three rice lines tested, Cd bioaccessibility increased from 2.5% in grains from the c1z2 treatment to 17.7% in grains from the c1z10 treatment. Furthermore, Cd bioccessibility in the low-Cd-accumulating line was significantly higher than the high line in c1z10 treatment. Zinc bioaccessibility increased in the high-cadmium-accumulating line when cadmium was elevated in grains, and in the low-cadmium line when both cadmium and zinc were increased in the rice grains. Our results showed that both exogenous cadmium and elevated zinc treatments increased the bioaccessibility of other minerals from grains of the low- or high-grain cadmium lines of rice. Differences in mineral bioaccessibility were dependent on rice line. Calculations also showed that increased cadmium bioaccessibility correlated with increased risk of dietary exposure to consumers. Furthermore, our results suggest that zinc fertilization increased dietary exposure to cadmium in both high and low lines. This information can inform future experiments to analyze genotypic effects of mineral bioavailability from rice, with the goal of reducing cadmium absorption while simultaneously increasing zinc absorption from rice grains.

Factors affecting the support for physical activity in children and adolescents with type 1 diabetes mellitus: a national survey of health care professionals' perceptions.

BACKGROUND: Many children and adolescents with Type 1 Diabetes Mellitus (T1DM) don't meet the recommended levels of physical activity. Healthcare professionals (HCPs) have a key role in supporting and encouraging children and adolescents with T1DM to be physically active. This study aims to understand the perspectives of HCPs in relation to supporting physical activity and implementing guidelines relating to physical activity. METHODS: An online mixed methods survey was circulated to HCPs in pediatric diabetes units in England and Wales. Participants were asked about how they support physical activity in their clinic and their perceptions of barriers/enablers of providing physical activity support to children and adolescents with T1DM. Quantitative data were analysed descriptively. An deductive thematic approach was applied to the free text responses using the Capability Opportunity Motivation model of Behaviour (COM-B) as a framework. RESULTS: Responses were received from 114 individuals at 77 different pediatric diabetes units (45% of pediatric diabetes units in England and Wales). HCPs surveyed felt that the promotion of physical activity is important (90%) and advised patients to increase levels of physical activity (88%). 19% of the respondents felt they did not have sufficient knowledge to provide support. HCPs reported limited knowledge and confidence, time and resources as barriers to providing support. They also felt the current guidance was too complicated with few practical solutions. CONCLUSION: Pediatric HCPs need training and support to be able to encourage and support children and adolescents with T1D to be a physical activity. In addition, resources that provide simple and practical advice to manage glucose around exercise are needed.

2022 European Thyroid Association Guidelines for the management of pediatric thyroid nodules and differentiated thyroid carcinoma.

At present, no European recommendations for the management of pediatric thyroid nodules and differentiated thyroid carcinoma (DTC) exist. Differences in clinical, molecular, and pathological characteristics between pediatric and adult DTC emphasize the need for specific recommendations for the pediatric population. An expert panel was instituted by the executive committee of the European Thyroid Association including an international community of experts from a variety of disciplines including pediatric and adult endocrinology, pathology, endocrine surgery, nuclear medicine, clinical genetics, and oncology. The 2015 American Thyroid Association Pediatric Guideline was used as framework for the present guideline. Areas of discordance were identified, and clinical questions were formulated. The expert panel members discussed the evidence and formulated recommendations based on the latest evidence and expert opinion. Children with a thyroid nodule or DTC require expert care in an experienced center. The present guideline provides guidance for healthcare professionals to make well-considered decisions together with patients and parents regarding diagnosis, treatment, and follow-up of pediatric thyroid nodules and DTC.

Heterozygous CDC73 mutation causing hyperparathyroidism in children and adolescents: a report of 2 cases.

OBJECTIVES: Primary hyperparathyroidism (PHPT), whilst common in elderly populations, is rare in adolescents. Hereditary cases make up less than 10% of patients with PH. We report two patients with CDC73 mutation presenting in early adolescence. CASE PRESENTATION: Case 1: A 14-year-old patient was referred from an adolescent mental health unit with hypercalcaemia. Imaging revealed a parathyroid adenoma. Genetic testing of the patient showed a heterozygous deletion of CDC73. Case 2: A 10-year-old patient was admitted to the general paediatric ward with symptoms suggestive of hypercalcaemia. The patient was known to carry an autosomal dominant mutation of CDC73. Imaging of the parathyroid gland showed bilateral adenoma. CONCLUSIONS: We present two patients with CDC73 defects, who both presented with symptoms of hypercalcaemia. The cases highlight the difference in paediatric populations with PHPT who are often symptomatic at the time of diagnosis when compared to adult patients.

An effective and cost-saving structured education program teaching dynamic glucose management strategies to a socio-economically deprived cohort with type 1 diabetes in a VIRTUAL setting.

OBJECTIVES: Compare the clinical and cost-effectiveness of an established face to face (F2F) structured education program to a new remote (VIRTUAL) program teaching dynamic glucose management (DynamicGM) to children and young people with type 1 diabetes (CYPD) using continuous glucose monitoring (CGM). To ascertain the most effective DynamicGM strategies predicting time in range (TIR) (3.9-10.0 mmol/L) and incorporating these into a user-friendly teaching aid. DESIGN AND METHODS: Effectiveness of the F2F and VIRTUAL programs were ascertained by comparing the mean change (Δ) from baseline to 6 months in HbA1c, TIR and severe hypoglycemia. Delivery cost for the two programs were evaluated. Factors predicting TIR in the combined cohort were determined and incorporated into a user-friendly infographic. RESULTS: First 50 graduates per group were evaluated. The mean difference in Δ HbA1c, Δ TIR and Δ episodes of severe hypoglycemia between VIRTUAL and F2F groups were 1.16 (p = 0.47), 0.76 (p = 0.78) and -0.06 (p = 0.61) respectively. Delivery cost per 50 CYPD for VIRTUAL and F2F were $5752 and $7020, respectively. The strongest predictors of TIR (n = 100) were short bursts of exercise (10-40 min) to lower hyperglycemia (p < 0.001), using trend arrow adjustment tools (p < 0.001) and adjusting pre-meal bolus timing based on trend arrows (p < 0.01). These strategies were translated into a GAME (Stop highs), SET (Stay in target), MATCH (Prevent lows) mnemonic. CONCLUSION: Teaching DynamicGM VIRTUALLY is just as effective as F2F delivery and cost saving. Short bursts of exercise and using CGM trend arrows to adjust insulin dose and timing improves TIR.

WFS1 protein expression correlates with clinical progression of optic atrophy in patients with Wolfram syndrome.

BACKGROUND: Wolfram syndrome (WFS) is a rare disorder characterised by childhood-onset diabetes mellitus and progressive optic atrophy. Most patients have variants in the WFS1 gene. We undertook functional studies of WFS1 variants and correlated these with WFS1 protein expression and phenotype. METHODS: 9 patients with a clinical diagnosis of WFS were studied with quantitative PCR for markers of endoplasmic reticulum (ER) stress and immunoblotting of fibroblast protein extracts for WFS1 protein expression. Luciferase reporter assay was used to assess ATF-6 dependent unfolded protein response (UPR) activation. RESULTS: 6 patients with compound heterozygous nonsense mutations in WFS1 had no detectable WFS1 protein expression; 3 patients with missense variants had 4%, 45% and 48% WFS1 protein expression. One of these also had an OPA1 mutation and was reclassified as autosomal dominant optic atrophy-plus syndrome. There were no correlations between ER stress marker mRNA and WFS1 protein expression. ERSE-luciferase reporter indicated activation of the ATF6 branch of UPR in two patients tested. Patients with partial WFS1 expression showed milder visual acuity impairment (asymptomatic or colour blind only), compared with those with absent expression (registered severe vision impaired) (p=0.04). These differences remained after adjusting for duration of optic atrophy. CONCLUSIONS: Patients with WFS who have partial WFS1 protein expression present with milder visual impairment. This suggests a protective effect of partial WFS1 protein expression on the severity and perhaps progression of vision impairment and that therapies to increase residual WFS1 protein expression may be beneficial.

ImprintSeq, a novel tool to interrogate DNA methylation at human imprinted regions and diagnose multilocus imprinting disturbance.

PURPOSE: Disruptions of genomic imprinting are associated with congenital imprinting disorders (CIDs) and other disease states, including cancer. CIDs are most often associated with altered methylation at imprinted differentially methylated regions (iDMRs). In some cases, multiple iDMRs are affected causing multilocus imprinting disturbances (MLIDs). The availability of accurate, quantitative, and scalable high-throughput methods to interrogate multiple iDMRs simultaneously would enhance clinical diagnostics and research. METHODS: We report the development of a custom targeted methylation sequencing panel that covered most relevant 63 iDMRs for CIDs and the detection of MLIDs. We tested it in 70 healthy controls and 147 individuals with CIDs. We distinguished loss and gain of methylation per differentially methylated region and classified high and moderate methylation alterations. RESULTS: Across a range of CIDs with a variety of molecular mechanisms, ImprintSeq performed at 98.4% sensitivity, 99.9% specificity, and 99.9% accuracy (when compared with previous diagnostic testing). ImprintSeq was highly sensitive for detecting MLIDs and enabled diagnostic criteria for MLID to be proposed. In a child with extreme MLID profile a probable genetic cause was identified. CONCLUSION: ImprintSeq provides a novel assay for clinical diagnostic and research studies of CIDs, MLIDs, and the role of disordered imprinting in human disease states.

Picture exchange communication system as a behavior modification technique for oral health assessment in autistic children.

OBJECTIVE: The aim of this study was to establish a modality for behavioral intervention for dental management in autistic children using Picture Exchange Communication System (PECS). STUDY DESIGN: A prospective interventional study was carried out on 30 autistic children in the age range of 4-18 years diagnosed with mild to moderate grades of autism to evaluate the effectiveness of PECS in improving oral health over a period of 6 months. RESULTS: PECS Phases showed a gradual rise from first to third visit, which was statistically highly significant (p < 0.001). Oral Hygiene Index-Simplified (OHI-S) scores improved significantly from first visit and second visit. Definitely substantial correlation was seen between PECS and OHI-S. CONCLUSION: Gradual decrease was observed in OHI-S scores over a period of 6 months, indicating an improvement in the oral hygiene status of autistic children. Gradual progress in Phases of PECS proved to increase cognitive ability of autistic children towards understanding the dental setup related PECS cards.

Effect of Saliva Contamination on Shear Bond Strength of Self-etch Adhesive System to Dentin: An In Vitro Study.

AIM AND OBJECTIVE: This study aimed to evaluate the outcome of saliva contamination on shear bond strength (SBS) of a self-etch adhesive system to dentin. MATERIALS AND METHODS: A total of 60 premolars were selected. Occlusal surfaces of the teeth were severed off. Three groups of 20 teeth in each were formed after the samples were randomly divided. Group I: Not subjected to any contamination (control group). Group II: Contamination with saliva occurred before coating the teeth with a self-etch adhesive system. Group III: Contamination with saliva occurred after coating the teeth with a self-etch adhesive system. After the contamination, the composite was placed with the help of a Teflon tube. Under the universal testing machine, the SBS of these samples was then tested. RESULTS: The data obtained after testing were analyzed using SPSS software. Statistical difference was seen between all the three groups. Group II projected the least SBS. CONCLUSION: Contamination with saliva has a deleterious effect on the SBS. Contamination that occurs before the application of adhesive systems has shown considerably reduced SBS. CLINICAL SIGNIFICANCE: This study successfully established that saliva contamination acts as a major factor in reducing the SBS of the bonding agent. Hence, in clinical situations, it is necessary to ensure sufficient steps are taken to eliminate or reduce the chances of contamination with saliva to aid in the success of the restoration. HOW TO CITE THIS ARTICLE: Chaudhari RR, Srivastava HR, Raisingani D, et al. Effect of Saliva Contamination on Shear Bond Strength of Self-etch Adhesive System to Dentin: An In Vitro Study. Int J Clin Pediatr Dent 2021;14(4):443-446.

Chrysin mitigated obesity by regulating energy intake and expenditure in rats.

BACKGROUND AND AIM: Chrysin is a flavonoid found in plant extracts from Passiflora species, honey and propolis. It has demonstrated anti-adipogenic activity in vitro but there are no studies substantiating the anti-obesity activity of chrysin in vivo. EXPERIMENTAL PROCEDURE: The pancreatic lipase (PL) inhibitory potential of chrysin was determined by preliminary in silico screening and further confirmed by in vitro PL inhibitory assay and oral fat tolerance test (OFTT). The effect of chrysin on acute feed intake and sucrose preference test was determined in normal rats. Obesity was induced by feeding of high fructose diet (HFD) to the rats. The rats were divided into six groups: normal control, HFD control, orlistat and three doses of chrysin (25, 50 and 100 mg/kg body weight). Body weight, body mass index (BMI), abdominal circumference/thoracic circumference (AC/TC) ratio, calorie intake, adiposity index, fecal cholesterol, locomotor activity and histopathology of the adipose tissue of the rats were evaluated. RESULTS: Chrysin showed good affinity to PL with competitive type of inhibition. It significantly reduced serum triglycerides in OFTT. Chrysin also significantly reduced acute feed intake and sucrose preference in rats. Chrysin significantly decreased the body weight, BMI, AC/TC ratio, adiposity index, calorie intake while it significantly increased the fecal cholesterol and locomotor activity of the rats. Chrysin was found to reduce the size of the adipocytes when compared to the HFD control group. CONCLUSION: Thus, chrysin exerted anti-obesity effect by inhibiting PL, reducing sucrose preference, reducing calorie intake and increasing the locomotor activity of rats.

UPLC-QTof-MSE Metabolomics Reveals Changes in Leaf Primary and Secondary Metabolism of Hop (Humulus lupulus L.) Plants under Drought Stress.

The hop (Humulus lupulus L.) is an important specialty crop used in beer production. Untargeted UPLC-QTof-MSE metabolomics was used to determine metabolite changes in the leaves of hop plants under varying degrees of drought stress. Principal component analysis revealed that drought treatments produced qualitatively distinct changes in the overall chemical composition of three out of four genotypes tested (i.e., Cascade, Sultana, and a wild var. neomexicanus accession but not Aurora), although differences among treatments were smaller than differences among genotypes. A total of 14 compounds consistently increased or decreased in response to drought stress, and this effect was generally progressive as the severity of drought increased. A total of 10 of these marker compounds were tentatively identified as follows: five glycerolipids, glutaric acid, pheophorbide A, abscisic acid, roseoside, and dihydromyricetin. Some of the observed metabolite changes likely occur across all plants under drought conditions, while others may be specific to hops or to the type of drought treatments performed.

The Interaction of Innate and Adaptive Immunity and Stabilization of Mast Cell Activation in Management of Infusion Related Reactions in Patients with Fabry Disease.

Fabry disease (FD) is an X-linked lysosomal disorder caused by mutations in GLA gene resulting in lack of or faulty α-galactosidase A (α-GalA) enzyme. Enzyme replacement therapy (ERT) with recombinant human α-GalA enzyme (agalsidase) is the standard treatment option for FD. Infusion-related reactions (IRRs), with symptoms ranging from rigors, to fever, pain, vomiting, angioedema and diarrhea, are often seen due to immune response against the exogenous enzyme. To elucidate the mechanisms causing the IRRs in FD, eight patients who developed IRRs were investigated. All, except one, tested negative for agalsidase-specific IgE and had normal tryptase levels. Circulating dendritic cells were drastically reduced during IRRs, suggesting possible sequestration to the sites of inflammation. An increase in NK cells and a decrease in T cells were also observed. Cytokines IL-4, IL-8 and TNF-α showed a significant increase, indicating nonspecific degranulation of mast cells. All IRRs were managed successfully using a combination of standard premedications and mast cell stabilizers without any interruption of therapy. Taken together, the results indicate crosstalk between immune cells resulting in IgE-independent mast-cell-specific allergic inflammation. Mast cell stabilizers could be used to control IRRs and for safe reintroduction of agalsidase in patients previously treated with ERT.

Potential of neutrophil to lymphocyte ratio in predicting sustained remission in rheumatoid arthritis compared to other immune activation markers.

Background & objectives: Cells and cell proportions may indicate the equilibrium status of the immune system. The present study was conducted to evaluate the role of cytokines and the immunocompetent cells as biomarkers of remission in rheumatoid arthritis (RA) patients intended to withdraw or reduce disease-modifying anti-rheumatic drug (DMARD) treatment. Methods: This prospective observational study involved newly diagnosed and treated RA patients who fulfilled 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) criteria. The patients were classified based on disease activity score (DAS)28-C-reactive protein (CRP)(3) score into remission (≤2.6) and treatment-naïve/active (>2.6) groups. Remission patients were followed up for six months and were reclassified into those in sustained remission (≤2.6) and relapse (>2.6) based on the DAS28-CRP(3) score. Various cytokines and cell surface markers were quantitated using whole blood samples, and the CD3+/CD19+ and FOXP3+/CD4+ ratios were calculated. The clinical, demographic, cytokine and cellular phenotype characteristics were compared between remission and treatment-naïve groups. The factors associated with sustained remission were verified. Results: Of the 72 patients, 52 were in remission and 20 were DMARD naïve and had active disease. Duration of illness, interleukin-6 (IL-6) and IL-10 were significantly different between remission and treatment naïve/active disease patients. Increased likelihood for achieving sustained remission was noted in RA patients with baseline NLR ≤2. Other demographic/clinical variables and cell phenotypes, namely age, gender, duration of illness, CD3+, CD4+, FOXP3+, CD19+, CD3+/CD19+, FOXP3+/CD4+ and cytokines - IL-6 and IL-10 were not associated with sustained remission. Interpretation & conclusions: The present preliminary study highlighted the potential of NLR in predicting sustained remission in RA patients with a cut-off <2. Further study with a large sample size should be done to confirm this finding.

Pregnancy Outcomes in Late Onset Pompe Disease.

There is limited data on pregnancy outcomes in Pompe Disease (PD) resulting from deficiency of the lysosomal enzyme acid alpha-glucosidase. Late-onset PD is characterized by progressive proximal muscle weakness and decline of respiratory function secondary to the involvement of the respiratory muscles. In a cohort of twenty-five females, the effects of both PD on the course of pregnancy and the effects of pregnancy on PD were investigated. Reproductive history, course of pregnancy, use of Enzyme replacement therapy (ERT), PD symptoms, and outcomes of each pregnancy were obtained through a questionnaire. Among 20 subjects that reported one or more pregnancies, one subject conceived while on ERT and continued therapy through two normal pregnancies with worsening of weakness during pregnancy and improvement postpartum. While fertility was not affected, pregnancy may worsen symptoms, or cause initial symptoms to arise. Complications with pregnancy or birth were not higher, except for an increase in the rate of stillbirths (3.8% compared to the national average of 0.2-0.7%). Given small sample size and possible bias of respondents being only women who have been pregnant, further data may be needed to better analyze the effects of pregnancy on PD, and the effects of ERT on pregnancy outcomes.

Effect of Substrate Reduction Therapy in Comparison to Enzyme Replacement Therapy on Immune Aspects and Bone Involvement in Gaucher Disease.

Gaucher disease (GD) is caused by mutations in the GBA gene, leading to deficient activity of the lysosomal enzyme glucocerebrosidase. Among all the symptoms across various organ systems, bone disease is a major concern as it causes high morbidity and reduces quality of life. Enzyme replacement therapy (ERT) is the most accepted treatment; however, there are still unmet needs. As an alternative, substrate reduction therapy (SRT) was developed using glucosylceramide synthase inhibitors. In the current study, the effects of ERT vs. SRT were compared, particularly the immunological and bone remodeling aspects. GD subjects were divided into three cohorts based on their treatment at initial visit: ERT, SRT, and untreated (UT). Immunophenotyping showed no significant immune cell alterations between the cohorts. Expression of RANK/RANKL/Osteoprotegerin pathway components on immune cells and the secreted markers of bone turnover were analyzed. In the ERT cohort, no significant changes were observed in RANK, RANKL or serum biomarkers. RANKL on T lymphocytes, Osteopontin and MIP-1ß decreased with SRT treatment indicating probable reduction in osteoclast activity. Other secreted factors, Osteocalcin and RANKL/Osteoprotegerin did not change with the treatment status. Insights from the study highlight personalized differences between subjects and possible use of RANK pathway components as markers for bone disease progression.

Two integrated and highly predictive functional analysis-based procedures for the classification of MSH6 variants in Lynch syndrome.

PURPOSE: Variants in the DNA mismatch repair (MMR) gene MSH6, identified in individuals suspected of Lynch syndrome, are difficult to classify owing to the low cancer penetrance of defects in that gene. This not only obfuscates personalized health care but also the development of a rapid and reliable classification procedure that does not require clinical data. METHODS: The complete in vitro MMR activity (CIMRA) assay was calibrated against clinically classified MSH6 variants and, employing Bayes' rule, integrated with computational predictions of pathogenicity. To enable the validation of this two-component classification procedure we have employed a genetic screen to generate a large set of inactivating Msh6 variants, as proxies for pathogenic variants. RESULTS: The genetic screen-derived variants established that the two-component classification procedure displays high sensitivities and specificities. Moreover, these inactivating variants enabled the direct reclassification of human variants of uncertain significance (VUS) as (likely) pathogenic. CONCLUSION: The two-component classification procedure and the genetic screens provide complementary approaches to rapidly and cost-effectively classify the large majority of human MSH6 variants. The approach followed here provides a template for the classification of variants in other disease-predisposing genes, facilitating the translation of personalized genomics into personalized health care.

Assessing the Effectiveness of Panchatikta Ghrita, a Classical Ayurvedic Formulation as Add-on Therapy to Vitamin D3 and Calcium Supplements in Patients with Osteopenia: A Randomized, Open-Labeled, Comparative, Controlled Clinical Study.

Objectives: To assess the change in the bone mineral density (BMD) score, bone-specific biomarkers (serum vitamin D3, tartrate-resistant acid phosphatase 5b [TRAP-5b], and osteocalcin), quality of life, Ayurvedic symptoms (Asthikshaya Lakshanas), and fracture risk assessment tool (FRAX) scores following treatment with Panchatikta Ghrita (PG), a classical herbal formulation as add-on therapy to calcium and vitamin D3 supplements. Study design: Randomized, open-labeled, comparative, controlled clinical study. Location: TN Medical College and BYL Nair Hospital, Mumbai, India. Study participants: Eighty adult patients, aged between 40 and 75 years, diagnosed to have osteopenia (BMD T-score between -1 and -2.5 in at least two of the three joints tested-lumbar spine L1-L4, left femur-neck, left forearm-radius total). Study intervention: Treatment group received two tablespoons of PG (10 mL in lukewarm milk) along with calcium and vitamin D3 supplements twice a day, whereas control group received only calcium and vitamin D3 supplements twice a day for a period of 12 months. Outcome measures: BMD, bone-specific biomarkers (vitamin D3, TRAP-5b, and osteocalcin), quality of life, Ayurvedic symptoms, and FRAX scores were evaluated before and at 6 and 12 months. Results: Eighty patients were enrolled; of which, 65 patients completed the study while 15 patients dropped out. Improvement in the BMD scores was observed at 6 and 12 months with the maximum benefit in the lumbar spine region. Significant improvement in the bone-specific biomarkers, namely serum vitamin D3 (p < 0.001), osteocalcin (p < 0.001), and TRAP-5b (p < 0.05), was observed in the PG-treated group compared with the standard treatment group. Improvement in the quality of life, Ayurvedic symptoms scores, and risk reduction in FRAX scores of major osteoporotic fracture risk and hip fracture risk was greater with PG, although not statistically significant. Conclusions: The study findings demonstrate that PG slows down the bone degeneration processes by its stabilizing effect on the bone-specific biomarkers, indicating its potential usefulness as preventive therapy in osteopenia. The positive improvement noted in this study needs to be confirmed in studies with a larger sample size and longer duration.