Ag2O nanoparticle-catalyzed substrate-controlled regioselectivities: direct access to 3-ylidenephthalides and isocoumarins

Herein, we disclose the first example of an efficient, silver oxide nanoparticle-catalyzed, direct regioselective synthesis of 3-ylidenephthalides 11–16 and isocoumarins 17–20via sonogashira type coupling followed by substrate-controlled 5-exo-dig or 6-endo-dig cyclization reaction, respectively. This one pot coupling involves reaction of substituted 2-halobenzoic acid with meta/para-substituted and ortho-substituted terminal alkynes, which proceeded in a regioselective manner resulting in the formation of 3-ylidenephthalides or isocoumarins, respectively, in excellent yields (up to 95%) with complete Z-selectivity. This protocol features relatively broad substrate scope, mild conditions, operational simplicity, and is favourable with aromatic/alicyclic terminal alkynes. The competition experiments and gram-scale synthesis further highlight the importance and versatility of the methodology. The proposed mechanistic pathways illustrate that the regioselectivity is substantially being controlled by the substituent(s) present on the acetylenic phenyl ring.

We report the first example of an efficient, Ag₂O nanoparticle-catalyzed, direct regioselective synthesis of 3-ylidenephthalides and isocoumarins via Sonogashira type coupling followed by substrate-controlled 5-exo-dig or 6-endo-dig cyclization reaction, respectively.     

An elaborative NMR based plasma metabolomics study revealed metabolic derangements in patients with mild cognitive impairment: a study on north Indian population

Metabolic Brain Disease - Mild cognitive impairment (MCI) is transition phase between cognitive decline and dementia. The current study aims to investigate altered metabolic pattern in plasma of...     

Estrogen activates mitogen-activated protein kinase in native, nontransfected CHO-K1, COS-7, and RAT2 fibroblast cell lines

CHO-K1, COS-7, and Rat2 fibroblast cell lines are generally believed to be devoid of estrogen receptors (ERs) and have been widely used to study the functions of ER-alpha and ER-beta after transfection of their cDNAs. Numerous studies have demonstrated that transfected ER-alpha or ER-beta mediates estradiol-induced activation of multiple signaling pathways, including the MAPK/ERK pathways. We report here for the first time that both 17alpha-estradiol and 17beta-estradiol elicit activation of MAPK/ERK in native, nontransfected CHO-K1, COS-7, and Rat2 fibroblast cell lines. We further report that, contrary to the generally held belief, these cell lines are not unresponsive to estradiol in their native, nontransfected state, and that this estrogen responsiveness is associated with estrogen binding. Using multiple ER antibodies, we failed to find ER-alpha or ER-beta isoforms or even ER-X. In view of these findings, researchers, using such cells as models to investigate mechanisms of estrogen action, must always take into account the existence of endogenous estrogen binding proteins other than ER-alpha, ER-beta, or ER-X.     

Frequent occurrence of hypogonadotropic hypogonadism in type 2 diabetes

Type 2 diabetes is associated with lower total testosterone (T) levels in cross-sectional studies. However, it is not known whether the defect is primary or secondary. We investigated the prevalence of hypogonadism in type 2 diabetes by measuring serum total T, free T (FT), SHBG, LH, FSH, and prolactin (PRL) in 103 type 2 diabetes patients. FT was measured by equilibrium dialysis. FT was also calculated by using T and SHBG (cFT). Hypogonadism was defined as low FT or cFT. The mean age was 54.7 +/- 1.1 yr, mean body mass index (BMI) was 33.4 +/- 0.8 kg/m(2), and mean HbA1c was 8.4 +/- 0.2%. The mean T was 12.19 +/- 0.50 nmol/liter (351.7 +/- 14.4 ng/dl), SHBG was 27.89 +/- 1.65 nmol/liter, and FT was 0.250 +/- 0.014 nmol/liter. Thirty-three percent of patients were hypogonadal. LH and FSH levels were significantly lower in the hypogonadal group compared with patients with normal FT levels (3.15 +/- 0.26 vs. 3.91 +/- 0.24 mIU/ml for LH and 4.25 +/- 0.45 vs. 5.53 +/- 0.40 mIU/ml for FSH; P < 0.05). There was a significant inverse correlation of BMI with FT (r = -0.382; P < 0.01) and T (r = -0.327; P < 0.01). SHBG correlated inversely with BMI (r = -0.267; P < 0.05) but positively with age (r = 0.538; P < 0.001) and T (r = 0.574; P < 0.001). FT correlated strongly with cFT (r = 0.919; P < 0.001) but not with SHBG. LH levels correlated positively with FT (r = 0.287; P < 0.05). We conclude that hypogonadotropic hypogonadism occurs commonly in type 2 diabetes.     

A score predicts failure of reperfusion after fibrinolytic therapy for acute myocardial infarction

Background A rapid, accurate, noninvasive means of predicting the likelihood of failure to achieve Thrombolysis In Myocardial Infarction (TIMI) grade 3 flow within 90 minutes after the start of fibrinolysis with streptokinase could help to identify patients who might benefit from additional therapies that aim to preserve myocytes. Methods We measured ST recovery, which was assessed as the sum of ST deviation on a 12-lead electrocardiogram, and blood levels of the myocardial proteins, troponin T, creatine kinase myocardial band (CK-MB), and myoglobin before and 60 minutes after commencing streptokinase infused for 30 to 60 minutes in 107 patients, who presented within 12 hours of symptom onset and underwent angiography at 90 minutes. Results At 90 minutes, 56% of patients (95% CI 46-66) had TIMI-3 flow. The baseline levels of troponin T, CK-MB, and myoglobin were more commonly below the discrimination values in patients with TIMI-3 flow than in patients without TIMI-3 flow (all P < .005). On multivariate analysis, the factors associated with failure to achieve TIMI-3 flow were ST recovery of <70% (P = .009), a 60-minute/baseline troponin T ratio of ≤5 (P = .0004), a baseline CK-MB level of >4 μg/L (P = .039), or a baseline myoglobin level of >85 μg/L (P = .048). Age and a history of myocardial infarction were added into the multivariate model, and a risk score was developed to predict the likelihood of failure to achieve TIMI-3 flow. A score of ≤2 excluded failure to achieve TIMI-3 flow with 96% accuracy, and a score of ≥7 predicted failure to achieve TIMI-3 flow with 90% accuracy. Conclusion Failure to achieve TIMI-3 flow in the infarct-related artery within 90 minutes after the start of fibrinolysis can be accurately predicted at approximately 60 minutes by a score incorporating clinical variables, ST recovery, and the 60-minute/baseline ratios of troponin T, CK-MB, and/or myoglobin levels. This score may facilitate triage of patients at 60 minutes after fibrinolysis to additional reperfusion therapies. (Am Heart J 2003;145:508-14.)     

The impact of a celebrity promotional campaign on the use of colon cancer screening: the Katie Couric effect

BACKGROUND: Public participation in many preventive health programs is suboptimal. While various interventions to increase participation have been studied, the impact of a celebrity spokesperson on cancer screening has not been rigorously examined. The objective of this study was to assess the impact of Katie Couric's March 2000 Today Show colorectal cancer awareness campaign on colonoscopy rates. METHODS: A population-based observational study was conducted using 2 different data sources: (1) The Clinical Outcomes Research Initiative (CORI) database-a voluntary consortium of 400 endoscopists who performed 95 000 colonoscopies from July 1998 to December 2000; and (2) 44 000 adult members of a managed care organization. Using change point analyses and linear regression models, we compared colonoscopy utilization rates before and after Ms Couric's March 2000 television series. RESULTS: The number of colonoscopies performed per CORI physician per month after Ms Couric's campaign increased significantly (15.0 per month before campaign; 18.1 after campaign; P<.001). After adjusting for temporal trends, a significantly higher postcampaign colonoscopy rate was sustained for 9 months. Analysis also demonstrated a trend toward an increase in the percentage of colonoscopies performed on women (43.4% before campaign; 47.4% after campaign; P =.054). Colonoscopy rates also increased significantly in the managed care organization after Ms Couric's campaign (1.3 per 1000 members per month before; 1.8 after; P<.001). CONCLUSIONS: Katie Couric's televised colon cancer awareness campaign was temporally associated with an increase in colonoscopy use in 2 different data sets. These findings suggest that a celebrity spokesperson can have a substantial impact on public participation in preventive care programs.     

National databases and rheumatology research II: the National Health and Nutrition Examination Surveys

Three National Health and Nutrition Examination Surveys were conducted in the United States between 1971 and 1994 to provide data on the nutritional and health status of the population and on specific target conditions. This article describes features of the surveys and provides examples of research on musculoskeletal disorders that used the survey data.