Search

The ATPase subunit of DNA gyrase B is an attractive antibacterial target due to high conservation across bacteria and the essential role it plays in DNA replication. A novel class of pyrazolopyridone inhibitors was discovered by optimizing a fragment screening hit scaffold using structure guided design. These inhibitors show potent Gram-positive antibacterial activity and low resistance incidence against clinically important pathogens.

Antibacterials with a novel mechanism of action offer a great opportunity to combat widespread antimicrobial resistance. Bacterial DNA Gyrase is a clinically validated target. Through physiochemical property optimization of a pyrazolopyridone hit, a novel class of GyrB inhibitors were discovered. Guided by structure-based drug design, indazole derivatives with excellent enzymatic and antibacterial activity as well as great animal efficacy were discovered.

Objective: To investigate the psychometric and structural properties of the Five Facets Mindfulness Questionnaire (FFMQ) among meditators, to develop a short form, and to examine associations of mindfulness with mental health and the mechanisms of mindfulness., Methods: Two independent samples were used, a German (n = 891) and a Spanish (n = 393) meditator sample, practicing various meditation styles. Structural and psychometric properties of the FFMQ were investigated with multigroup confirmatory factor analysis and exploratory structural equation modeling. Associations with mental health and mechanisms of mindfulness were examined with path analysis., Results: The derived short form broadly matched a previous item selection in samples of non-meditators. Self-regulated Attention and Orientation to Experience governed the facets of mindfulness on a higher-order level. Higher-order factors of mindfulness and meditation experience were negatively associated with symptoms of depression and anxiety, and perceived stress. Decentering and nonattachment were the most salient mechanisms of mindfulness. Aspects of emotion regulation, bodily awareness, and nonattachment explained the effects of mindfulness on depression and anxiety., Conclusions: A two-component conceptualization for the FFMQ, and for the study of mindfulness as a psychological construct, is recommended for future research. Mechanisms of mindfulness need to be examined in intervention studies.

A positive family history of coronary heart disease alone confers an increased risk, which may be affected by untreated hypercholesterolemia. Dietary counseling is a first-line treatment approach. To determine whether nurse counseling can provide additional benefits over usual physician efforts to lower dietary fat in high-risk persons, 117 apparently healthy adult siblings of persons with premature coronary heart disease were counseled by a registered nurse using adapted national guidelines. Reductions in total fat, saturated fat, and cholesterol were significantly greater in the nurse group compared to those in the usual care group. Total fat intake decreased by 14 g in the nurse group, compared with an increase of 5 g in the usual care group (p=0.0001). Assignment to the nurse group was also a significant predictor of a greater reduction in the percentage of total fat calories (p=0.008). The authors conclude that a registered nurse may serve as a complement to usual care in efforts to lower dietary fat and cholesterol in high-risk families. (c)2001 CHF, Inc.

Objective: The authors tested the impact on cardiovascular risk profiles of African American women ages 40 years and older after one year of participation in one of three church-based nutrition and physical activity strategies: a standard behavioral group intervention, the standard intervention supplemented with spiritual strategies, or self-help strategies., Methods: Women were screened at baseline and after one year of participation. The authors analyzed intention-to-treat within group and between groups using a generalized estimating equations adjustment for intra-church clustering. Because spiritual strategies were added to the standard intervention by participants themselves, the results from both active groups were similar and, thus, combined for comparisons with the self-help group., Results: A total of 529 women from 16 churches enrolled. Intervention participants exhibited significant improvements in body weight (-1.1 lbs), waist circumference (-0.66 inches), systolic blood pressure (-1.6 mmHg), dietary energy (-117 kcal), dietary total fat (-8 g), and sodium intake (-145 mg). The self-help group did not. In the active intervention group, women in the top decile for weight loss at one year had even larger, clinically meaningful changes in risk outcomes (-19.8 lbs)., Conclusions: Intervention participants achieved clinically important improvements in cardiovascular disease risk profiles one year after program initiation, which did not occur in the self-help group. Church-based interventions can significantly benefit the cardiovascular health of African American women.

Background: The Pl(A2) polymorphism of GPIIIa has been associated with unstable coronary syndromes in some studies, but the association has remained debated. None of the previous studies have focused on families at high risk. Risk factors tend to cluster within kindreds with high prevalence of premature coronary heart disease (CHD). Therefore, a heightened prevalence of the Pl(A2) polymorphism among siblings of patients with CHD would support the hypothesis that Pl(A2) is linked, directly or indirectly, to CHD., Objectives: To measure the prevalence of the Pl(A2) polymorphism among siblings of patients with CHD before the age of 60 years and to seek an association between the Pl(A2) polymorphism and established atherosclerotic and thrombogenic risk factors., Methods: From January 1994 to April 1996, we genotyped 116 asymptomatic siblings (60 Caucasians, 56 Afro-Caribbeans) of patients with CHD manifestations before the age of 60 years for the Pl(A) polymorphism (also called HPA-1). A control cohort was used for comparison, consisting of individuals that were matched for race and geographic area but were free of CHD (n = 268, 168 Caucasians and 100 Afro-Caribbeans). In addition, we have characterized the sibling cohort for other atherogenic and thrombogenic risk factors., Results: The prevalence of Pl(A2)-positive individuals (Pl(A2)[+], Pl(A1/A2) heterozygotes plus Pl(A2/A2) homozygotes) in the sibling cohort was high: 41.4%. When analyzed separately, the prevalence of Pl(A2)(+) siblings was 53.3% among Caucasians and 28.6% among Afro-Caribbeans. There was no association between Pl(A2) and other established atherogenic or thrombogenic risk factors. Interestingly, the clustering of other risk factors was lesser among Pl(A2)(+) siblings than their Pl(A1) counterparts., Conclusions: This study supports the hypothesis that the prevalence of Pl(A2)(+) individuals is high in kindreds with premature CHD. Hence, like the established risk factors that tend to cluster in families with premature CHD and contribute strongly to the accelerated atherosclerotic process affecting these individuals, the Pl(A2) polymorphism of GPIIIa may represent an inherited risk that promotes the thromboembolic complications of CHD. That these asymptomatic Pl(A2)(+) siblings had overall less established risk factors than their Pl(A1) counterparts might represent an explanation for why they remained asymptomatic despite their Pl(A2) positivity.

To determine the extent to which the Fifth Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure (JNC-V) guidelines were implemented in high-risk families with premature coronary heart disease, we examined the prevalence of hypertension and associated coronary risk factors in asymptomatic siblings of persons with documented premature coronary disease (<60 years of age). A total of 859 apparently healthy siblings (51% male, 19% African American) were screened for coronary risk factors. Siblings were classified as normotensive or hypertensive (BP > or = 140/90 and/or current antihypertensive pharmacotherapy). The prevalence of hypertension, awareness, treatment, and control among siblings was compared with published national estimates from the third National Health and Nutrition Examination Survey. The prevalence of hypertension in siblings was 44%. Among all hypertensives, only 60% were aware of being hypertensive, 45% were being treated, and 16% were under control. A high prevalence of other coronary risk factors was found among hypertensive siblings: 72% were hypercholesterolemic; 61% were obese; 29% were current smokers; 82% were consuming >30% of calories from fat; and only 14% were participating in vigorous physical activity three or more times per week. Comparisons with the national reference population revealed siblings to have a significantly higher prevalence of hypertension, along with significantly lower levels of awareness, treatment, and control. These findings demonstrate the intersection of multiple risk factors among hypertensive siblings and emphasize the need for more aggressive screening and treatment in this easily identifiable high-risk population.

Background: Exercise testing, even when combined with radionuclide perfusion imaging, does not accurately predict future clinical coronary heart disease (CHD) in low-risk asymptomatic populations. We hypothesized that these tests would perform better in a higher-risk population with a high prevalence of occult CHD. Siblings of persons with premature CHD represent such a group in whom it would be advantageous to identify affected individuals before the occurrence of clinically manifest CHD., Methods and Results: Exercise thallium scintigraphy was performed in 264 asymptomatic individuals less than 60 years of age who had a sibling with documented CHD before age 60. Despite an average age of only 46 years at the time of screening, 19 of 264 siblings developed clinical CHD (sudden death in 1, myocardial infarction in 10, coronary revascularization in 8) over a mean of 6.2 years (range, 1 to 9 years) of follow-up. Abnormal thallium scans were observed in 29% of men and 9% of women, while abnormal exercise ECGs occurred in 12% and 5% respectively. Of men >/= 45 years of age, 45% had an abnormal exercise ECG, thallium scan, or both. In contrast, only 3% of women < 45 years of age had an abnormal test result. Although abnormal exercise ECGs and thallium scans were both predictive of future clinical CHD, the thallium scan was associated with a higher relative risk. After adjustment for age, sex, and exercise ECG results, the relative risk of developing clinical CHD was 4.7 for an abnormal scan. Siblings with a concordant abnormal exercise ECG and thallium scan had a relative risk of 14.5. These siblings were all men > 45 years of age at the time of screening and had a strikingly high incidence of CHD (6 of 12, 50%)., Conclusions: Exercise thallium scintigraphy appears to be useful in the risk assessment of asymptomatic siblings of patients with premature CHD, particularly in male siblings who are 45 years of age or older.