REPRESSOR OF UV-B PHOTOMORPHOGENESIS proteins target ABA INSENSITIVE 5 for degradation to promote early plant development.

REPRESSOR OF UV-B PHOTOMORPHOGENESIS 1 (RUP1) and RUP2 are WD-40 domain-containing proteins that have been extensively characterized for their role in UV-B signaling. However, the roles of the RUP proteins outside the canonical UV-signaling pathway are less known. Here, we identify that RUP1 and RUP2 play important roles in ABA signaling to regulate seed germination and early seedling development in Arabidopsis thaliana. Our protein interaction studies confirmed that RUP1 and RUP2 physically interact with ABA INSENSITIVE 5 (ABI5). In the presence of abscisic acid, rup1, rup2 and rup1rup2 exhibited reduced germination and seedling establishment compared to the wild type. Germination and seedling establishment in rup1rup2abi5-8 was similar to abi5-8, suggesting that RUP1 and RUP2 suppress ABA-mediated inhibition of germination and early seedling development in an ABI5-dependent manner. The DDB1-binding WD40 (DWD) protein RUP2 promoted the ubiquitination of ABI5 to regulate its degradation. ABI5, in turn, establishes a negative feedback loop to inhibit the expression of RUP1/RUP2. ABI5 also inhibited the direct binding of ELONGATED HYPOCOTYL 5 (HY5) to the promoters of RUP1 and RUP2 under ABA. This study highlights the coordinated action of RUP1, RUP2, ABI5, and HY5 in regulating early plant development.

Lateral preoptic area glutamate neurons relay nociceptive information to the ventral tegmental area.

The ventral tegmental area (VTA) has been proposed to play a role in pain, but the brain structures modulating VTA activity in response to nociceptive stimuli remain unclear. Here, we demonstrate that the lateral preoptic area (LPO) glutamate neurons relay nociceptive information to the VTA. These LPO glutamatergic neurons synapsing on VTA neurons respond to nociceptive stimulation and conditioned stimuli predicting nociceptive stimulation and also mediate aversion. In contrast, LPO GABA neurons synapsing in the VTA mediate reward. By ultrastructural quantitative synaptic analysis, ex vivo electrophysiology, and functional neuroanatomy we identify a complex circuitry between LPO glutamatergic and GABAergic neurons and VTA dopaminergic, GABAergic, and glutamatergic neurons. We conclude that LPO glutamatergic neurons play a causal role in the processing of nociceptive stimuli and in relaying information about nociceptive stimuli. The pathway from LPO glutamatergic neurons to the VTA represents an unpredicted interface between peripheral nociceptive information and the limbic system.

Motivating factors associated with choosing orthodontics for future prospects among newly passed out dental professionals in Maharashtra, India.

BACKGROUND: Choosing postgraduate subject as a future career is always tricky but there are factors associated which persuade the dental undergrads to choose the particular postgraduate course and orthodontics is one of them. Hence, the aim of present study was to determine motivating factors associated with choosing orthodontics for future prospects among newly passed out undergraduate dental professionals. MATERIALS AND METHODS: This was a cross-sectional descriptive questionnaire study. The present study is conducted among the freshly pass out dental professionals who had started their setup. The study was conducted in October-November 2019. The study was conducted among three cities of Maharashtra. Convenient sampling was used to select the samples. A close ended questionnaire was prepared. RESULTS: Majority of study participants {64 (45.39%)} belonged to age group 26-28 years. Females respondents {82 (58.15%)} were more than male study participants. Majority of dental professionals {71 (50.35%)} choose orthodontics dentofacial orthopedics as the specialty for future prospect. Most common reasons {16 (22.57%)} to choose orthodontics for future prospect by majority of respondents was "Can earn more money." Age was significantly (P = 005*) associated with money as reason to choose orthodontic as future prospect. Gender was significantly associated with family pressure (P = 0.01*) and love, interest, and passion for orthodontics (P = 0.01*). CONCLUSION: It was concluded that majority of dental professionals choose orthodontic as their preferred choice. Main reason for choosing orthodontics was monetary benefits followed by the reason that finds orthodontics intellectually and clinically challenging.

Epidemiology of Hypersensitivity Pneumonitis among an Insured Population in the United States: A Claims-based Cohort Analysis.

RATIONALE: Hypersensitivity pneumonitis is a complex lung disease resulting from repeated inhalation of a variety of antigens. Limited data exist regarding its epidemiology. OBJECTIVES: To describe the trends in the annual incidence and prevalence of hypersensitivity pneumonitis in the United States. METHODS: We developed novel claims-based coding algorithms to identify hypersensitivity pneumonitis, chronic hypersensitivity pneumonitis, and fibrotic hypersensitivity pneumonitis cases using the 2004 to 2013 MarketScan Commercial and Medicare Supplemental healthcare claims databases. Algorithm validity and reliability were assessed with clinical data from National Jewish Health. We calculated yearly cumulative incidence and prevalence overall and by age. For the subgroup with vital status, Kaplan-Meier methods were used to analyze survival stratified by evidence of fibrosis. RESULTS: We identified 7,498 cases that met our hypersensitivity pneumonitis definition over the 10-year study period, including 3,902 with chronic hypersensitivity pneumonitis and 1,852 with fibrotic hypersensitivity pneumonitis. On the basis of the clinical-radiological adjudication of the validation sample, 38 cases (95%) were confirmed as hypersensitivity pneumonitis. The mean age was 52 years, and 58% were women. The 1-year prevalence rates for hypersensitivity pneumonitis ranged from 1.67 to 2.71 per 100,000 persons, and 1-year cumulative incidence rates ranged from 1.28 to 1.94 per 100,000 persons. The prevalence increased with age, ranging from 0.95 per 100,000 among 0- to 9-year-olds to 11.2 per 100,000 among those aged 65 years and older. Between 56 and 68% of hypersensitivity pneumonitis cases in each year were classified as chronic hypersensitivity pneumonitis (prevalence, 0.91-1.70 per 100,000 persons; cumulative incidence, 0.63-1.08 per 100,000 persons). Fewer had fibrotic hypersensitivity pneumonitis (prevalence, 0.41-0.80 per 100,000 persons; cumulative incidence: 0.29-0.43 per 100,000 persons). Most cases (74%) were classified as unspecified hypersensitivity pneumonitis. Older age, male sex, and fibrosis were associated with higher mortality rates in unadjusted analyses. CONCLUSIONS: Using U.S. administrative claims-based data, we developed an algorithm with a high sensitivity and specificity for hypersensitivity pneumonitis. Between 2004 and 2013, hypersensitivity pneumonitis was more common among women and those older than 65 years. Most cases were classified as chronic hypersensitivity pneumonitis. Approximately one-fourth met our criteria for fibrotic hypersensitivity pneumonitis, which was associated with a higher mortality rate.

Comparing Healthcare Utilization and Costs Among Medicaid-Insured Patients with Chronic Noncancer Pain with and without Opioid-Induced Constipation: A Retrospective Analysis.

BACKGROUND: Constipation is a common adverse effect of opioid use and has been associated with increased healthcare utilization and costs among patients receiving opioids for pain management. OBJECTIVE: To compare the healthcare utilization and costs of Medicaid patients with chronic noncancer pain with and without constipation who were receiving opioids. METHODS: This retrospective, claims-based study was conducted using data from the Truven Health MarketScan Medicaid Multi-State database. Patients with no evidence of cancer who initiated opioid therapy between January 1, 2009, and June 30, 2013, were eligible for the study. Patients had to have continuous enrollment in the database in the 6 months before and 12 months after opioid initiation, with no evidence of substance abuse or functional or inflammatory bowel disease. Medical and pharmacy claims during the 12 months after opioid initiation were evaluated for a diagnosis of constipation or for prescription or over-the-counter medications indicative of constipation. All-cause healthcare utilization and costs were measured over the same period and were compared between propensity score-matched cohorts of patients with evidence of constipation and patients without constipation. RESULTS: Of the 25,744 patients meeting the study inclusion criteria, 2716 (10.5%) had evidence of constipation. After 1:1 propensity score matching, the 2 cohorts had similar demographic and clinical characteristics (ie, mean age, 47 years; 26%-27% male). During the 12-month follow-up period, healthcare utilization was more frequent among patients with constipation, including inpatient admissions and emergency department visits, than in the matched patients without constipation. The total all-cause mean healthcare costs were substantially higher among the patients with constipation ($28,234; 95% confidence interval [CI], $24,307-$32,160) than in the patients without constipation ($13,709; 95% CI, $12,618-$14,801), with a median cost difference of $4166 per patient (P <.001). CONCLUSION: Among Medicaid enrollees who receive opioids for chronic noncancer pain, constipation is associated with increased all-cause healthcare utilization and costs.

The Clinical and Economic Benefits of Co-Testing Versus Primary HPV Testing for Cervical Cancer Screening: A Modeling Analysis.

BACKGROUND: Consensus United States cervical cancer screening guidelines recommend use of combination Pap plus human papillomavirus (HPV) testing for women aged 30 to 65 years. An HPV test was approved by the Food and Drug Administration in 2014 for primary cervical cancer screening in women age 25 years and older. Here, we present the results of clinical-economic comparisons of Pap plus HPV mRNA testing including genotyping for HPV 16/18 (co-testing) versus DNA-based primary HPV testing with HPV 16/18 genotyping and reflex cytology (HPV primary) for cervical cancer screening. METHODS: A health state transition (Markov) model with 1-year cycling was developed using epidemiologic, clinical, and economic data from healthcare databases and published literature. A hypothetical cohort of one million women receiving triennial cervical cancer screening was simulated from ages 30 to 70 years. Screening strategies compared HPV primary to co-testing. Outcomes included total and incremental differences in costs, invasive cervical cancer (ICC) cases, ICC deaths, number of colposcopies, and quality-adjusted life years for cost-effectiveness calculations. Comprehensive sensitivity analyses were performed. RESULTS: In a simulation cohort of one million 30-year-old women modeled up to age 70 years, the model predicted that screening with HPV primary testing instead of co-testing could lead to as many as 2,141 more ICC cases and 2,041 more ICC deaths. In the simulation, co-testing demonstrated a greater number of lifetime quality-adjusted life years (22,334) and yielded $39.0 million in savings compared with HPV primary, thereby conferring greater effectiveness at lower cost. CONCLUSIONS: Model results demonstrate that co-testing has the potential to provide improved clinical and economic outcomes when compared with HPV primary. While actual cost and outcome data are evaluated, these findings are relevant to U.S. healthcare payers and women's health policy advocates seeking cost-effective cervical cancer screening technologies.

Hepatoprotective Effect of Cissus quadrangularis Stem Extract Against Rifampicin-induced Hepatotoxicity in Rats.

The study was designed to investigate the hepatoprotective activity of methanol extract of Cissus quadrangularis against rifampicin-induced hepatotoxicity in rats.The coarse powder of the shade dried stem of Cissus quadrangularis was subjected to successive extraction in a Soxhlet apparatus using solvents petroleum ether (60-80°) and methanol. Liver damage was induced in Wistar rats by administering rifampicin (54 mg/kg, p.o.) once daily for 30 days. Methanol extract of Cissus quadrangularis (500 mg/kg, p.o) was administered 1 h prior to the administration of rifampicin (54 mg/kg, p.o.) once daily for 30 days. Silymarin (50 mg/kg p.o) used as reference drug. Elevated levels of aspartate transaminase, alanine transaminase, alkaline posphatase and bilirubin following rifampicin induction were significantly lowered due to pretreatment with methanol extract of Cissus quadrangularis. Rifampicin administration significantly increased lipid peroxidation and decreased antioxidant activities like reduced glutathione, superoxide dismutas and catalase. Pretreatment of rats with methanol extract of Cissus quadrangularis significantly decreased lipid peroxidation and increased the antioxidant activities. Histology of the liver section of the animals treated with the methanol extract of Cissus quadrangularis further confirms the hepatoprotective activity. The results of the present study indicated the hepatoprotective effect of methanol extract of Cissus quadrangularis which might be ascribable to its antioxidant property due to the presence of ß-carotene.

Evolution of a physiological pH 6.8 bicarbonate buffer system: application to the dissolution testing of enteric coated products.

The use of compendial pH 6.8 phosphate buffer to assess dissolution of enteric coated products gives rise to poor in vitro-in vivo correlations because of the inadequacy of the buffer to resemble small intestinal fluids. A more representative and physiological medium, pH 6.8 bicarbonate buffer, was developed to evaluate the dissolution behaviour of enteric coatings. The bicarbonate system was evolved from pH7.4 Hanks balanced salt solution to produce a pH 6.8 bicarbonate buffer (modified Hanks buffer, mHanks), which resembles the ionic composition and buffer capacity of intestinal milieu. Prednisolone tablets were coated with a range of enteric polymers: hypromellose phthalate (HP-50 and HP-55), cellulose acetate phthalate (CAP), hypromellose acetate succinate (HPMCAS-LF and HPMCAS-MF), methacrylic acid copolymers (EUDRAGIT® L100-55, EUDRAGIT® L30D-55 and EUDRAGIT® L100) and polyvinyl acetate phthalate (PVAP). Dissolution of coated tablets was carried out using USP-II apparatus in 0.1M HCl for 2h followed by pH 6.8 phosphate buffer or pH 6.8 mHanks bicarbonate buffer. In pH 6.8 phosphate buffer, the various enteric polymer coated products displayed rapid and comparable dissolution profiles. In pH 6.8 mHanks buffer, drug release was delayed and marked differences were observed between the various coated tablets, which is comparable to the delayed disintegration times reported in the literature for enteric coated products in the human small intestine. In summary, the use of pH 6.8 physiological bicarbonate buffer (mHanks) provides more realistic and discriminative in vitro release assessment of enteric coated formulations compared to compendial phosphate buffer.

Assessment of gastrointestinal pH, fluid and lymphoid tissue in the guinea pig, rabbit and pig, and implications for their use in drug development.

Laboratory animals are often used in drug delivery and research. However, basic information about their gastrointestinal pH, fluid volume, and lymphoid tissue is not completely known. We have investigated these post-mortem in healthy guinea pigs, rabbits and pigs, to assess their suitability for pre-clinical studies by comparing the results with reported human literature. The mean gastric pH (fed ad libitum) was 2.9 and 4.4 in guinea pig and pig, respectively. In contrast, a very low pH (1.6) was recorded in the rabbits. The small intestinal pH was found in the range of 6.4-7.4 in the guinea pigs and rabbits, whereas lower pH (6.1-6.7) was recorded in the pig, which may have consequences for ionisable or pH responsive systems when tested in pig. A relatively lower pH than in the small intestine was found in the caecum (6.0-6.4) and colon (6.1-6.6) of the guinea pig, rabbit and the pig. The water content in the gastrointestinal tract of guinea pig, rabbit and pig was 51g, 153g and 1546g, respectively. When normalized to the body weight, the guinea pig, had larger amounts of water compared to the rabbit and the pig (guinea pig>rabbit>pig); in contrast, a reverse order was found when normalized to per unit length of the gut (guinea pig

Alcoholic leaf extract of Plectranthus amboinicus regulates carbohydrate metabolism in alloxan-induced diabetic rats.

OBJECTIVE: The present investigation was undertaken to explore the possible mechanisms of Plectranthus amboinicus leaf extract in alloxan-induced diabetic rats. MATERIALS AND METHODS: Control and alloxan-induced diabetic albino rats received different treatments; orally control (vehicle), 200 mg/kg and 400 mg/kg of ethanol extract of Plectranthus amboinicus (PAEE) and 600 µg/kg of glibenclamide (standard) for 15 days. At the end of the experiment, the animals were sacrificed and enzyme activities of carbohydrate metabolism were measured in the liver. RESULTS: Diabetic control rats showed a significant elevation (P < 0.001) in fasting blood glucose on successive days of the experiment as compared with their basal values, which was maintained over a period of 2 weeks. Daily oral treatment with PAEE showed a significant reduction (P < 0.001) in the blood glucose levels on successive days of the experiment as compared with their basal values. The most pronounced antihyperglycemic effect was obtained with the dose of 400 mg/kg. PAEE shows a dose-dependent reduction in gluconeogenic enzymes like glucose-6-phosphatase and fructose-1,6-disphosphatase. After 15 days of treatment with PAEE, glycolytic enzymes like phosphoglucoisomerase resulted in a significant increase with a concomitant significant decrease in the activities of aldolase. On the other hand, glucose-6-phosphate dehydrogenase was significantly improved in diabetic rats on administration of PAEE; the 400 mg/kg dose of PAEE elicited a more potent effect compared with the 200 mg/kg dose. CONCLUSION: The results obtained in this study provide evidence of the antidiabetic activity of PAEE, mediated through the regulation of carbohydrate metabolic enzyme activities.

Evaluation of hepatoprotective activity of Cissus quadrangularis stem extract against isoniazid-induced liver damage in rats.

OBJECTIVE: The study was designed to investigate the hepatoprotective activity of methanol extract of Cissus quadrangularis (CQ) against isoniazid-induced hepatotoxicity in rats. MATERIALS AND METHODS: The successive petroleum ether (60-80°C) and methanol extracts of C. quadrangularis were used. Hepatic damage was induced in Wistar rats by administering isoniazid (54 mg/kg, p.o.) once daily for 30 days. Simultaneously, CQ (500 mg/kg p.o) was administered 1 h prior to the administration of isoniazid (54 mg/kg, p.o.) once daily for 30 days. Silymarin (50 mg/kg p.o) was used as a reference drug. RESULTS: Elevated levels of aspartate transaminase, alanine transaminase, alkaline posphatase, and bilirubin following isoniazid administration were significantly lowered due to pretreatment with CQ. Isoniazid administration significantly increased lipid peroxidation (LPO) and decreased antioxidant activities such as reduced glutathione, superoxide dismutase, and catalase. Pretreatment of rats with CQ significantly decreased LPO and increased the antioxidant activities. CONCLUSION: The results of this study indicated that the hepatoprotective effect of CQ might be attributed to its antioxidant property.