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Phenolic compounds include a broad variety of antioxidant plant substances such as flavonoids that have in common an aromatic ring with one or more hydroxyl groups. Nutraceuticals and health food supplements are designed from flavonoids as well as pure phytochemicals, often in isolation. However, studies on synergistic and antagonistic effects of such compounds are relatively few. In the current study, dual combinations prepared from five phenolic compounds (flavonoid and non-flavonoid) including rutin hydrate, quercetin dihydrate, hydroquinone, kaempferol, and resveratrol were tested for their antioxidant activities using DPPH

Impairment of proteostasis network is one of the characteristic features of many age-related neurodegenerative disorders including autosomal dominantly inherited Huntington’s disease (HD). In HD, N-terminal portion of mutant huntingtin protein containing expanded polyglutamine repeats accumulates as inclusion bodies and leads to progressive deterioration of various cellular functioning including proteostasis network. Here we report that Withaferin A (a small bioactive molecule derived from Indian medicinal plant, Withania somnifera) partially rescues defective proteostasis by activating heat shock response (HSR) and delays the disease progression in a HD mouse model. Exposure of Withaferin A activates HSF1 and induces the expression of HSP70 chaperones in an in vitro cell culture system and also suppresses mutant huntingtin aggregation in a cellular model of HD. Withaferin A treatment to HD mice considerably increased their lifespan as well as restored progressive motor behavioral deficits and declined body weight. Biochemical studies confirmed the activation of HSR and global decrease in mutant huntingtin aggregates load accompanied with improvement of striatal function in Withaferin A-treated HD mouse brain. Withaferin A-treated HD mice also exhibit significant decrease in inflammatory processes as evident from the decreased microglial activation. These results indicate immense potential of Withaferin A for the treatment of HD and related neurodegenerative disorders involving protein misfolding and aggregation.

Impairment of proteostasis network is one of the characteristic features of many age-related neurodegenerative disorders including autosomal dominantly inherited Huntington’s disease (HD). In HD, N-terminal portion of mutant huntingtin protein containing expanded polyglutamine repeats accumulates as inclusion bodies and leads to progressive deterioration of various cellular functioning including proteostasis network. Here we report that Withaferin A (a small bioactive molecule derived from Indian medicinal plant, Withania somnifera) partially rescues defective proteostasis by activating heat shock response (HSR) and delay the disease progression in a HD mouse model. Exposure of Withaferin A activates HSF1 and induces the expression of HSP70 chaperones in an in vitro cell culture system and also suppresses mutant huntingtin aggregation in a cellular model of HD. Withaferin A treatment to HD mice considerably increased their lifespan as well as restored progressive motor behavioural deficits and declined body weight. Biochemical studies confirmed the activation of HSR and global decrease in mutant huntingtin aggregates load accompanied with improvement of striatal function in Withaferin A treated HD mice brain. Withaferin A treated HD mice also exhibit significant decrease in inflammatory processes as evident from the decreased microglial activation. These results indicate immense potential of Withaferin A for the treatment of HD and related neurodegenerative disorders involving protein misfolding and aggregation.

There is limited data on prevalence of PD-L1 expression in papillary thyroid cancer (PTC). Anti- PD-L1 therapy is now being trialled for head and neck cancers including thyroid cancer. Whether presence of PD-L1 staining in PTC might result in a better response to anti-PD-L1 therapy is uncertain. We evaluated the frequency of tumoral PD-L1 expression using standard antibody (SP263) and clinicopathologic factors including mutation status - BRAF, NRAS, KRAS using OncoFocus Mass Array System in an Australian PTC cohort with low or high risk of recurrence /treatment response as per 2015 ATA guidelines. The cohort had 128 patients; 66% were females; 40% had both multifocal and bilateral PTC; 47% had low recurrence risk, of whom 92% had excellent treatment response; 34% had high recurrence risk, of whom 37% had structural incomplete treatment response. There was nil (0%) PD-L1 staining in 59%, 1% staining in 20%, 5-10% staining in 11%, >10% staining in rest of the cohort; 30%, 40% and 70% staining was seen in 2% each. PD-L1 in immune cells was positive in 62%. There was no significant association between PD-L1 tumour status and age, gender, size of tumour, multifocality, bilaterality, both multifocality and bilaterality, lymphovascular invasion, perineural invasion, extrathyroidal extension (ETE), histological variants, risk stratification, treatment response, metastases or mutation status. Among PD-L1 negative vs positive patients, BRAFV600E was present in 64.9% vs 67.5%, NRAS in 8.8% vs 0% and nil mutation in 26 % vs 33 % p=0.15. The staining thresholds were chosen according to existing literature. When analysed according to the percentage of PD-L1 staining (0%, 1-10% and >=10% thresholds), there was no significant association between PD-L1 staining category and other features, except for ETE (35% vs 65% vs 27%; p=0.007), a relationship that remained significant in a multivariable-adjusted model (OR 9.9, p=0.04). PD-L1 staining thresholds of =5% were significantly associated with the size of tumour (24.7±15.4 vs 33.3±21.8; p=0.02) and histological variants (57 % vs 61% for classic variants and 27% vs 11% for follicular variants, p=0.03). This is the first study to our knowledge that analysed PD-L1 staining based on the risk stratification categories. The majority of PTC showed negative or low staining intensity for PD-L1 expression. There was no significant association between PD-L1 staining, clinicopathologic characteristics and mutation status of the PTC. Relatively less ETE was seen in the group that showed >=10% and also >=5% PD-L1 staining as compared to the group that showed 1%

The study of miRNAs in PTC has shown that these molecules can help in the diagnosis, prognosis and also as therapeutic candidates [1]. miRNAs are known to be differentially expressed in PTC compared to non-cancerous tissue and a few studies have shown association with some clinico-pathological features. However, little is known regarding their expression in relation to risk of disease progression. In this study, we examined the expression of miRNAs in patients diagnosed with PTC in association with risk of disease recurrence and/or persistence. Patients were classified by three endocrinologists to either high (H) or low (L) risk according to ATA Risk Stratification. PTC tissue was micro-dissected from Formalin Fixed Paraffin Embedded (FFPE) tissue for analysis. OPenArray analysis showed that 21 miRNAs were differentially expressed in H-L groups (n=4/grp). qRT-PCR was used to confirm these differences in a larger cohort of PTC (H=46; L=58). This comparison also included comparisons between cancer and normal tissue and investigation of miRNAs known to be differentially expressed (i.e miRNAs 222, 221 and 146b). All analysis was performed in Rstudio using ΔΔCt relative to expression of miR-16 which was not altered by PTC. By qRT-PCR, only 3 of the 21 miRNAs identified by OpenArray analysis, were differentially expressed in H vs L risk (each P In this study, we identified 3 miRNAs with potential utility for the stratification of patients into those with H or L risk disease recurrence/persistence. As the current ATA 3-tiered system used is still a reflection of the continuum of risk that patients have, whether these 3 miRNAs may have the utility to further stratify those in the intermediate group remains to be investigated. Reference: 1. Ramírez-Moya, J. and P. Santisteban, miRNA-Directed Regulation of the Main Signaling Pathways in Thyroid Cancer. Frontiers in Endocrinology, 2019. 10: p. 430.

Angelman syndrome (AS) is a neurodevelopmental disorder categorized by severe disability in intellectual functions and affected by the loss of function of maternally inherited UBE3A gene. Mice deficient for the maternal Ube3a recapitulates many distinguishing behavioral features of the AS and is used as a typical model system to understand the disease pathogenic mechanism. Here, we first show a significant increase in HDAC1 and HDAC2 activities in AS mice brain from as early as embryonic day 16(E16). In depth study further reveals that the deficiency of Ube3a leads to transcriptional up-regulation of both HDAC1 and HDAC2. Restoration of HDAC1 and HDAC2 activities (as evident from the increased acetylation of histones H3 and H4) using simvastatin significantly improves the cognitive deficit and social interaction behavior in AS mice. Simvastatin treatment also restores the reduced level of BDNF in AS mice brain. Finally, we demonstrate that the treatment of simvastatin to primary cortical neuronal culture prepared from AS mice embryo also rescues altered acetylation of histones H3 and H4 and the level of BDNF. These results suggest that simvastatin could be a promising drug for the treatment of AS.

Objective: The present study was carried out to assess the in vitro anthelmintic activity of Abutilon theophrasti stem extracts. Methods: Simple maceration was employed for extraction. Solvents such as methanol, water, and hexane were used. Egg hatch test (EHT) and larval motility test were employed to check the anthelmintic activity of crude extracts. Concentrations of 500, 250, 125, 62.5, and 31.25 mg/ml were made. Levamisole and distilled water served as control, respectively. Results: All selected extracts displayed concentration-dependent inhibition except aqueous extracts. At higher concentration (500 mg/ml), stem extracts (methanol, aqueous, and ethanol) showed 74.39%, 72.5 and 70.03% of efficacy in EHT, respectively (p≤0.05). Meanwhile, inhibition of larval motility was seen higher with inhibition percentage of 79.79, 75.65, and 71.28 by methanolic, aqueous, and hexane extracts, respectively (p≤ 0.05). Conclusion: The presents study suggests active principles having anthelmintic efficacy in Abutilon theopharsti stem.

PTC and melanoma are known to harbour common mutations, but this has not been extensively investigated. Targeted therapies for BRAF and PD-L1 have been used for melanoma and there are ongoing clinical trials for use of PD-L1 inhibitors in PTC but its utility is uncertain. Additionally, many of these patients have multiple cancers, so, whether they have a tumour predisposition syndrome is also unclear. Both germline and somatic mutations in BRCA1-associated protein 1 (BAP1) are associated with a wide spectrum of tumours. We hypothesized that a common genetic link may be present in our cohort of patients who have both PTC and melanoma. The aim of this study was to elucidate molecular genetics, specifically BRAF, NRAS, KRAS, KIT using OncoFocus Mass Array System as well as expression of PD-L1 and BAP1, using a standard antibody (SP263) and C-4 respectively, in an Australian cohort with concurrent PTC and melanoma. In our cohort of 21 patients (43% females, all Caucasian), melanoma was diagnosed about 8 years prior to PTC (50.3 ± 18.3 vs. 58.6 ± 12.8 years). The most common mutation was BRAFV600E seen in 88% of PTC, followed by NRAS mutation in 12% of PTC. Majority of the PTC (68%) stained negative for PD-L1. There was no significant association between PD-L1 tumour status and clinicopathologic outcomes. Interestingly, majority of multifocal, bilateral and both bilateral and multifocal PTC were PD-L1 negative (85%,69% and 69% respectively, P25%, a much higher degree of staining compared to PTC group. Among 7 patients where data were available for both tissues, concordant mutations were found in only 2 patients (both BRAFV600E). In addition, 11 of the 21 patients had at least one other cancer apart from PTC and melanoma. Nine of the 11 patients who had more than one cancer were BRAF positive. BAP1 staining was retained in the majority of PTCs and melanoma tissues, indicating no loss of BAP1 protein. PTC and melanoma both share molecular markers including BRAF, NRAS, PD-L1 as shown in our cohort. This is the largest study describing the mutation status of both PTC and melanoma. It is also the only study describing the PD-L1 and BAP1 expression in PTC and melanoma. BRAFV600E was the most common mutation. Majority of the PTC and melanoma stained negative for PD-L1. BAP1 expression was retained in both either PTC and melanoma tissues thus making presence of BAP1 tumour predisposition syndrome unlikely.

Sporadic Creutzfeldt-Jakob disease (sCJD), the most common human prion disease, is transmissible through iatrogenic routes due to abundant infectious prions [misfolded forms of the prion protein (PrPSc)] in the central nervous system (CNS). Some epidemiological studies have associated sCJD risk with non-CNS surgeries. We explored the potential prion seeding activity and infectivity of skin from sCJD patients. Autopsy or biopsy skin samples from 38 patients [21 sCJD, 2 variant CJD (vCJD), and 15 non-CJD] were analyzed by Western blotting and real-time quaking-induced conversion (RT-QuIC) for PrPSc. Skin samples from two patients were further examined for prion infectivity by bioassay using two lines of humanized transgenic mice. Western blotting revealed dermal PrPSc in one of five deceased sCJD patients and one of two vCJD patients. However, the more sensitive RT-QuIC assay detected prion seeding activity in skin from all 23 CJD decedents but not in skin from any non-CJD control individuals (with other neurological conditions or other diseases) during blinded testing. Although sCJD patient skin contained ~103- to 105-fold lower prion seeding activity than did sCJD patient brain tissue, all 12 mice from two transgenic mouse lines inoculated with sCJD skin homogenates from two sCJD patients succumbed to prion disease within 564 days after inoculation. Our study demonstrates that the skin of sCJD patients contains both prion seeding activity and infectivity, which raises concerns about the potential for iatrogenic sCJD transmission via skin.

AIM To investigate if glycaemic profiles and outcomes of patients with diabetes admitted for cardiothoracic surgery or acute coronary syndrome improved after implementation of a structured glycaemia management guideline. METHODS This is a retrospective before-and-after comparative analysis of outcomes for all consecutive cardiothoracic and acute coronary syndrome patients with diabetes (N = 375), who were admitted at our tertiary-care university-affiliated hospital during the preguideline period (July-December, 2013) and the postguideline period (July-December, 2014). RESULTS A total of 55 cardiothoracic and 136 acute coronary syndrome patients were enrolled in the before period, and 36 cardiothoracic and 148 acute coronary syndrome patients were enrolled in the after period. In the cardiothoracic group, comparing the before vs after period, mean BGL improved (9 vs 8.4 mmol/L, P = .045), but there were no significant differences in the readmission rate (18% vs 14%; P = .6), number of hypoglycaemic episodes (1 vs 1, P = .5) or in-hospital mortality (0% vs 5.6%; P = .08). In the acute coronary syndrome group, there were no significant pre-post differences in the mean BGL (9.4 vs 10.2 mmol/L, P = .14), readmission rate (10% vs 11%; P = .8), number of hypoglycaemic episodes (1 vs 1, P = 1.0) or in-hospital mortality (5% vs 7%; P = .4). Endocrinology referrals increased significantly during the after period. CONCLUSIONS Implementation of a structured guideline for glycaemia management on inpatient wards marginally improved glycaemic profiles in the cardiothoracic group but not in the acute coronary syndrome group.

Objective: To report a case of a giant retroperitoneal teratoma involving the adrenal gland associated with persistent postoperative adrenal insufficiency likely due to the secretion of corticotropin releasing hormone (CRH) and adrenocorticotropic hormone (ACTH) from the teratoma.Methods: We describe the presenting signs and symptoms, investigations, and pathologic features leading to the diagnosis and treatment options.Results: A 29-year-old male was found to have a large retroperitoneal mass arising near the right kidney and adrenal, encasing the dual renal arteries and causing right urinary tract obstruction on computed tomography imaging. Resection of the mass required right nephrectomy and median sternotomy. Microscopy demonstrated a mature teratoma arising from the retroperitoneum. The right adrenal gland was compressed and trapped in the edge of the mass. His postoperative course was complicated by unexpected persistent hypocortisolism requiring cortisol replacement. Subsequent immunostaining was positive for CRH and ACTH, suggesting that the teratoma was secreting CRH and ACTH.Conclusion: This is the first reported case of teratoma associated with CRH and ACTH secretion leading to postoperative adrenal insufficiency. Although extremely rare, the possibility of a teratoma secreting hormones should be kept in mind and appropriate evaluation is recommended pre- and postoperatively.ACTH = adrenocorticotropic hormone; AFP = alphafetoprotein; CRH = corticotropin releasing hormone; CT = computed tomography; RR = reference range

Age-related macular degeneration (AMD) is the leading cause of blindness in the elderly in the developed world. We conducted a genome-wide association study in a series of families enriched for AMD and completed a meta-analysis of this new data with results from reanalysis of an existing study of a late-stage case-control cohort. We tested the top findings for replication in 1896 cases and 1866 controls and identified two novel genetic protective factors for AMD. In addition to the complement factor H (CFH) (P=2.3 × 10⁻⁶⁴) and age-related maculopathy susceptibility 2 (ARMS2) (P=1.2 × 10⁻⁶⁰) loci, we observed a protective effect at rs429608, an intronic SNP in SKIV2L (P=5.3 × 10⁻¹⁵), a gene near the complement component 2 (C2)/complement factor B (BF) locus, that indicates the protective effect may be mediated by variants other than the C2/BF variants previously studied. Haplotype analysis at this locus identified three protective haplotypes defined by the rs429608 protective allele. We also identified a new potentially protective effect at rs2679798 in MYRIP (P=2.9 × 10⁻⁴), a gene involved in retinal pigment epithelium melanosome trafficking. Interestingly, MYRIP was initially identified in the family-based scan and was confirmed in the case-control set. From these efforts, we report the identification of two novel protective factors for AMD and confirm the previously known associations at CFH, ARMS2 and C3.

Background Anemia and micronutrient deficiencies are common among Indian schoolchildren. However, past studies have narrowly focused on only a few micronutrients and have not carefully evaluated the association between sociodemographic factors and nutritional status of schoolchildren. Objective To assess the nutritional status of schioolchildren in Himalayan villages of India and to determine the relationships between their nutritional status, intestinal helminth infection, and sociodemographic characteristics. Methods A random sample of 499 children 6 to 10 years of age from 20 public primary schools was selected. Household sociodemographic data and morbidity data on children were collected through interviews with their caretakers. Height and weight were measured, and venous blood was drawn for assessment of hemoglobin, serum ferritin, soluble transferrin receptor, retinol, zinc, folic acid, vitamin B12, and C-reactive protein. Stool samples were analyzed for parasitic infections. Results Underweight, stunting, and wasting were present in 60.9%, 56.1%, and 12.2% of schoolchildren, respectively. Anemia, iron-deficiency anemia, and low serum concentrations of ferritin, zinc, retinol, folate, and vitamin B12 were found in 36.7%, 10.2%, 24.1%, 57.1%, 56.1%, 67.9%, and 17.4% of the children, respectively. One-fifth of the children had intestinal parasites. Being underweight was associated with lower household wealth ( p < .05). Helminth infection was associated with stunting, anemia, and low serum retinol ( p < .05). Living at higher altitude was associated with low serum levels of ferritin, retinol, and vitamin B12. There were no associations between any sociodemographic variables and serum zinc or folate. Conclusions Growth impairment and micronutrient deficiencies are prevalent among schoolchildren in Himalayan villages of India.

Modern development has caused a lot of people attention about the deadly aspects of the industrial revolution, due to the fact that there is a lot of industrial corruption. आधुनिकविकासकाप्रतीकबनकरआईऔद्योगिकक्रांतिके घातकपहलुओं के बारेमेंबहुत कम लोगोंका ध्यानजापायाहैजानेकितनेलोगऔद्योगिकप्रदुषण के कारणतिल-तिलकरमरतेहैं।दिनांदिनप्रदुषितहोतेपर्यावरण के कारणसंक्रामकबीमारियाँ न सिर्फभारतमेंअपितुविश्व के अधिकांशदेशोंमें बढ़तीजारहीहै।भारतहीनहींसम्पणर््ूाविश्वमेंबीमारियोंका खतराहरदिन बढ़ रहाहै।

Complement factor H (CFH) is a key regulator of the alternative pathway of complement and its mutations have been associated with membranoproliferative glomerulonephritis type II, atypical hemolytic uremic syndrome and age-related macular degeneration (AMD), suggesting that alternative pathway dysregulation is a common pathogenetic feature of these ocular and renal conditions. In this study we tested the hypothesis that common CFH variants have a global role in renal function in the Australian population-based Blue Mountains Eye Study (BMES). We replicated the association of I62V with estimated glomerular filtration rate (GFR; P=0.017) and creatinine clearance (CRCL; P=0.015). The minor allele of I62V (G) was deleterious: adding one copy of the G allele decreased GFR/CRCL by approximately 0.98 ml min(-1) per 1.73 m(2) (95% confidence interval (CI): 0.97, 0.99). We also replicated the association of Y402H with AMD and provided an unbiased estimate of population attributable risk (PAR). The minor allele of Y402H (C) was deleterious: the odds ratio estimate of CC genotype compared to TT was 1.87 (95% CI: 1.44, 2.45). The PAR of the C allele was estimated as 0.22 (95% CI: 0.15, 0.28). In summary, in the BMES population we confirmed the association between I62V and renal function, as measured by the estimated GFR, plus the association of Y402H with both early- and late-stage AMD.