The electronic health record Risk of Alzheimer's and Dementia Assessment Rule (eRADAR) Brain Health Trial: Protocol for an embedded, pragmatic clinical trial of a low-cost dementia detection algorithm.

BACKGROUND: About half of people living with dementia have not received a diagnosis, delaying access to treatment, education, and support. We previously developed a tool, eRADAR, which uses information in the electronic health record (EHR) to identify patients who may have undiagnosed dementia. This paper provides the protocol for an embedded, pragmatic clinical trial (ePCT) implementing eRADAR in two healthcare systems to determine whether an intervention using eRADAR increases dementia diagnosis rates and to examine the benefits and harms experienced by patients and other stakeholders. METHODS: We will conduct an ePCT within an integrated healthcare system and replicate it in an urban academic medical center. At primary care clinics serving about 27,000 patients age 65 and above, we will randomize primary care providers (PCPs) to have their patients with high eRADAR scores receive targeted outreach (intervention) or usual care. Intervention patients will be offered a "brain health" assessment visit with a clinical research interventionist mirroring existing roles within the healthcare systems. The interventionist will make follow-up recommendations to PCPs and offer support to newly-diagnosed patients. Patients with high eRADAR scores in both study arms will be followed to identify new diagnoses of dementia in the EHR (primary outcome). Secondary outcomes include healthcare utilization from the EHR and patient, family member and clinician satisfaction assessed through surveys and interviews. CONCLUSION: If this pragmatic trial is successful, the eRADAR tool and intervention could be adopted by other healthcare systems, potentially improving dementia detection, patient care and quality of life.

Comparative study of various processes used for removal of bitterness from kinnow pomace and kinnow pulp residue.

The current study was focused on new approaches for debittering of by-products like kinnow pomace and kinnow pulp residue by using various food grade mild chemical methods, such as alkali treatment, acid treatment, and solventogenesis. Whereas in the studied various chemical treatments, the solventogenesis method with acetone resulted in maximum extraction of naringin and limonene from kinnow pomace and pulp residue and showed high acceptability for food product development. The acetone treatment was further optimized by RSM for the maximum extraction of naringin and limonene. Under optimized conditions, the maximum amount of naringin and limonene extracted were found to be 8.955, 2.122 mg/g from kinnow pomace and 9.971, 3.838 mg/g from pulp residue, respectively. This process can not only result in the effective utilization of agro-industrial by-product but also provide a sustainable solution to the environmental pollution caused by kinnow juice industry.

Screening of Some Novel 4, 5 Disubstituted 1, 2, 4-Triazole-3-thiones for Anticonvulsant Activity.

OBJECTIVE: In the present study, we synthesized fifteen 4, 5-disubstituted 1, 2, 4-triazol- 3-thione derivatives and evaluated for anticonvulsant activity with neurotoxicity determination. METHODS: The synthesized compounds were characterized using FTIR, 1H-NMR and MS. The molecular docking study was also performed to study the interactions of compounds with LYS329 residue of gamma amino butyric acid aminotransferase (GABA-AT) using Autodock 4.2 software. The anticonvulsant activity was assessed by maximal electroshock (MES) test and subcutaneous pentylenetetrazol (scPTZ) tests. The neurotoxicity was assessed by rotarod ataxia test. RESULTS: In MES test, compounds 5a, 8a and 9a were found active at 100 mg/kg and five compounds were found active at 300 mg/kg dose after 1 hr of administration. After 4 hr of drug administration, only two compounds 8a and 9a exhibited protection at 100 mg/kg. In scPTZ test, three compounds 2a, 6a and 8a were found active at 100 mg/kg and 7a was active at 300 mg/kg after 1 hr of test drug administration. Most of the compounds were found active in MES test with 8a and 9a being the most active among all. In docking study, 2a was found to be best compound based on the binding energy of -6.5 kcal/mol and estimated inhibition constant of 17.2 µM. CONCLUSION: Majority of synthesized compounds were found active in MES test, whereas only few were found to possess anti scPTZ activity. Among all compounds, only 14a caused motor coordination impairment in rotarod ataxia test at 300 mg/kg 1 hr duration.

Interspecies comparative features of trichomes in Ocimum reveal insights for biosynthesis of specialized essential oil metabolites.

Ocimum species commonly referred to as "Tulsi" are well-known for their distinct medicinal and aromatic properties. The characteristic aroma of Ocimum species and cultivars is attributed to their specific combination of volatile phytochemicals mainly belonging to terpenoid and/or phenylpropanoid classes in their essential oils. The essential oil constituents are synthesized and sequestered in specialized epidermal secretory structures called as glandular trichomes. In this comparative study, inter- and intra-species diversity in structural attributes and profiles of expression of selected genes related to terpenoid and phenylpropanoid biosynthetic pathways have been investigated. This is performed to seek relationship of variations in the yield and phytochemical composition of the essential oils. Microscopic analysis of trichomes of O. basilicum, O. gratissimum, O. kilimandscharicum, and O. tenuiflorum (green and purple cultivars) revealed substantial variations in density, size, and relative proportions of peltate and capitate trichomes among them. The essential oil yield has been observed to be controlled by the population, dominance, and size of peltate and capitate glandular trichomes. The essential oil sequestration in leaf is controlled by the dominance of peltate glandular trichome size over its number and is also affected by the capitate glandular trichome size/number with variations in leaf area albeit at lower proportions. Comprehension and comparison of results of GC-MS analysis of essential oils showed that most of the Ocimum (O. basilicum, O. tenuiflorum, and O. gratissimum) species produce phenylpropanoids (eugenol, methyl chavicol) as major volatiles except O. kilimandscharicum, which is discrete in being monoterpenoid-rich species. Among the phenylpropanoid-enriched Ocimum (O. basilicum, O. gratissimum, O. tenuiflorum purple, O. tenuiflorum green) as well, terpenoids were important constituents in imparting characteristic aroma. Further, comparative abundance of transcripts of key genes of phenylpropanoid (PAL, C4H, 4CL, CAD, COMT, and ES) and terpenoid (DXS and HMGR) biosynthetic pathways was evaluated vis-à-vis volatile oil constituents. Transcript abundance demonstrated that richness of their essential oils with specific constituent(s) of a chemical group/subgroup was manifested by the predominant upregulation of phenylpropanoid/terpenoid pathway genes. The study provides trichomes as well as biosynthetic pathway-based knowledge for genetic improvement in Ocimum species for essential oil yield and quality.

Tamarixetin 3-O-ß-d-Glucopyranoside from Azadirachta indica Leaves: Gastroprotective Role through Inhibition of Matrix Metalloproteinase-9 Activity in Mice.

Neem (Azadirachta indica) is a well-known medicinal and insecticidal plant. Although previous studies have reported the antiulcer activity of neem leaf extract, the lead compound is still unidentified. The present study reports tamarixetin 3-O-ß-d-glucopyranoside (1) from a methanol extract of neem leaves and its gastroprotective activity in an animal model. Compound 1 showed significant protection against indomethacin-induced gastric ulceration in mice in a dose-dependent manner. Moreover, ex vivo and circular dichroism studies confirmed that 1 inhibited the enzyme matrix metalloproteinase-9 (MMP-9) activity with an IC50 value of ca. 50 µM. Molecular docking and dynamics showed the binding of 1 into the pocket of the active site of MMP-9, forming a coordination complex with the catalytic zinc, thus leading to inhibition of MMP-9 activity.

In-vitro antioxidant and anti-hyperlipidemic activities of Blumea eriantha DC.

Alcoholic and water extracts of the stem and root of Blumea eriantha DC were prepared and evaluated for in-vitro antioxidant activity by methods like total reducing power, scavenging of us free radicals like as 1,2-diphenyl-2-picrylhydrazyl (DPPH), super oxide, nitric oxide, and hydrogen peroxide. The percentage scavenging effect of free radicals was compared with standard antioxidants like ascorbic acid and Butylated- hydroxyl anisole (BHA). Different extracts were also tested for anti-hyperlipidemic activity in triton WR-1339 (iso-octyl polyoxyethylene phenol)-induced hyperlipidemia in albino rats by determination of serum triglyceride like VLDL, LDL, HDL levels. Significant antioxidant activity was estimated in different methods, (p<0.01) for reducing power and (p<0.001) for scavenging DPPH, super oxide, nitric oxide, and hydrogen peroxide radicals. The different extracts having significant reduction (p<0.01) in cholesterol at 6 and 24 h and (p<0.05) at 48 h. There was significant reduction (p<0.01) in triglyceride level at 6, 24 and 48 h. There was significant increase (p<0.01) in HDL at 6, 24 and 48 h. From the VLDL was also significantly (p<0.05) reduced from 24 h and maximum reduction (p<0.01) results, it is clear that alcoholic and water extracts of Blumea eriantha DC can remarkably decrease plasma cholesterol, triglyceride, LDL, and VLDL and increase plasma HDL levels. In addition, the alcoholic and aqueous extracts have shown significant antioxidant activity.

Azelastine desensitization of transient receptor potential vanilloid 1: a potential mechanism explaining its therapeutic effect in nonallergic rhinitis.

BACKGROUND: Capsaicin, a prototypic transient receptor potential vanilloid 1 (TRPV1) agonist, has been shown to be more clinically effective in the treatment of nonallergic rhinitis (NAR) compared with other rhinitis subtypes. Azelastine has also been found to be clinically effective in the treatment of NAR but its mechanism(s) of action is still poorly elucidated. This study was designed to determine, using in vitro cell lines, whether topical therapies including azelastine have activity on TRPV1 ion channels similar to capsaicin. METHODS: The effects of capsaicin (1 µM), azelastine (30 µM), bepotastine (10 µM), olopatadine (10 µM), and fluticasone (200 µM) on TRPV1 channels using mice neuronal cells (Cath.a), as surrogates for submucosal sensory neurons, and human nasal epithelial cells (hNEC) were determined and compared. For azelastine, bepotastine, and capsaicin, which elicited an agonist effect on TRPV1, live cell [Ca(2+)] signaling in Cath.a cells and hNECs expressing TRPV1 were performed in the absence and presence of capsazepine at 10 µM (a TRPV1 antagonist) or using wild-type mouse embryonic fibroblasts (wtMEFs) that express TRPV1 ion channels and TRPV1 homozygous null mutant (TRPV1-/-) knockout MEF cells as controls to establish TRPV1 channel selectivity. As azelastine has previously been found clinically effective in NAR, additional experiments were performed to determine its ability to desensitize TRPV1 ion channels and its effect on regulating intracellular calcium homeostasis. RESULTS: Cath.a cells treated with azelastine, bepotastine, or capsaicin showed a significant increase in TRPV1-dependant (Ca(2+)) specific cytosolic fluorescence. Continuous treatment with azelastine or capsaicin resulted in desensitization of TRPV1 channels. In hNECs, azelastine stimulation resulted in Ca(2+) shifts from the cytosol to mitochondria and overexpression of hematopoietic cell-specific Lyn substrate 1-associated protein X1, which may thus be effective in cytosolic Ca(2+) homeostasis. CONCLUSION: Azelastine, similar to capsaicin, exhibits direct activity on TRPV1 ion channels that may represent a novel mechanistic pathway explaining its clinical efficacy in NAR.

Discovery of pyrazole carboxylic acids as potent inhibitors of rat long chain L-2-hydroxy acid oxidase.

Long chain L-2-hydroxy acid oxidase 2 (Hao2) is a peroxisomal enzyme expressed in the kidney and the liver. Hao2 was identified as a candidate gene for blood pressure (BP) quantitative trait locus (QTL) but the identity of its physiological substrate and its role in vivo remains largely unknown. To define a pharmacological role of this gene product, we report the development of selective inhibitors of Hao2. We identified pyrazole carboxylic acid hits 1 and 2 from screening of a compound library. Lead optimization of these hits led to the discovery of 15-XV and 15-XXXII as potent and selective inhibitors of rat Hao2. This report details the structure activity relationship of the pyrazole carboxylic acids as specific inhibitors of Hao2.