Body mass index and infectious disease mortality in midlife in a cohort of 2.3 million adolescents.

BACKGROUND: Obesity was linked to altered immunity, but also to favorable outcomes among patients with infectious disease (ID) in some settings. We assessed the association between adolescent body mass index (BMI) and ID mortality. METHODS: BMI of 2 294 139 Israeli adolescents (60% men; age 17.4±0.3 years) was measured between 1967 and 2010. The outcome, obtained by linkage with official national records, was death due to ID as the underlying cause. Multivariable Cox proportional hazards models were applied. RESULTS: During 42 297 007 person-years of follow-up (median 18.4 years), there were 689 deaths from ID (mean age 44.1±10.5 years). Adjusted hazard ratios (HR) were 1.039 (1.011-1.068) and 1.146 (1.099-1.194) among men and women, respectively, per unit increment in BMI (P for sex interaction=4.4 × 10-5). Adjusted hazard ratios among men were 1.2 (1.0-1.5), 1.9 (1.4-2.5) and 2.5 (1.5-4.2) for those with high-normal BMI (22.0-24.9 kg m-2), overweight and obese, respectively, compared with the 18.5⩽BMI<22 kg m-2 reference group, and 1.7 (1.1-2.6), 2.6 (1.6-4.3) and 6.6 (3.3-13.1) among women, respectively. The increased risk among underweight (<18.5 kg m-2) boys was attenuated when the study sample was restricted to those with unimpaired health at baseline. A multivariable spline model indicated a minimum risk for total ID mortality at 20.7 and 18.0 kg m-2 for men and women, respectively, with significantly increased risk seen above adolescent BMI values of 23.6 and 24.0 kg m-2, respectively. The association with BMI was particularly evident for bacterial infections (predominantly sepsis), airways and central nervous system infections (63% of the ID deaths). CONCLUSIONS: Adolescent overweight and obesity were strongly associated with ID mortality, especially of bacterial origin and among women.

Completed suicide and suicide attempts in the Arab population in Israel.

Completed suicide and suicide attempts among four Arab groups defined by religious affiliation in Israel: Bedouins, Muslims (other than Bedouin), Christians and Druze were investigated using national databases of suicide (1999-2011), and suicide attempts (2004-2012). Age specific and age-adjusted rates and ratio of suicides to suicidal behavior were calculated, and compared with the total Israeli population rates. Age-adjusted suicide rates were lowest among the non-Bedouin Muslims, 2.5, followed in ascending order by Bedouins, 3.2, and Christian Arabs, 3.3 per 100,000 population, respectively. The highest rate was found among the Druze, 8.7, per 100,000 population, particularly for young males. The rates among the Arab groups were lower than for the total Israeli population, 7.9 per 100,000 population, except for the Druze. The pattern of suicide rates by gender, higher for males than females, was similar in all groups. The rates among the Arab Israelis were highest for the 15-24 year old age group, while in the total population the rates increased with age. Age-adjusted suicide attempt rates were higher amongst non-Bedouin Muslims, 84.8 per 100,000 population, followed by the Bedouin, 72.4; Druze. 64.9; and lowest among Christian Arabs, 58.6, all per 100,000 population. In the total Israeli population, the rate was even higher, 89.8 per 100,000 population. Suicide attempt rates were higher for women in all groups, except among the Druze. Rates were higher in most groups for ages 15-24. In this age group, the rates for female Muslims and Bedouins and for male Druze were higher than among the total population. Arab elderly had low rates of both suicide and suicide attempts. The ratio of suicides to suicide attempts increased with age for all groups, except for the Christian Arabs. It was markedly higher for the Druze, compared to 7.3 % for the total population for ages 15 and over. Findings highlight the importance of investigating the differential distribution of suicidal behavior by specific ethno-religious groups.

Discovery of antiandrogen activity of nonsteroidal scaffolds of marketed drugs.

Finding good drug leads de novo from large chemical libraries, real or virtual, is not an easy task. High-throughput screening is often plagued by low hit rates and many leads that are toxic or exhibit poor bioavailability. Exploiting the secondary activity of marketed drugs, on the other hand, may help in generating drug leads that can be optimized for the observed side-effect target, while maintaining acceptable bioavailability and toxicity profiles. Here, we describe an efficient computational methodology to discover leads to a protein target from safe marketed drugs. We applied an in silico "drug repurposing" procedure for identification of nonsteroidal antagonists against the human androgen receptor (AR), using multiple predicted models of an antagonist-bound receptor. The library of marketed oral drugs was then docked into the best-performing models, and the 11 selected compounds with the highest docking score were tested in vitro for AR binding and antagonism of dihydrotestosterone-induced AR transactivation. The phenothiazine derivatives acetophenazine, fluphenazine, and periciazine, used clinically as antipsychotic drugs, were identified as weak AR antagonists. This in vitro biological activity correlated well with endocrine side effects observed in individuals taking these medications. Further computational optimization of phenothiazines, combined with in vitro screening, led to the identification of a nonsteroidal antiandrogen with improved AR antagonism and marked reduction in affinity for dopaminergic and serotonergic receptors that are the primary target of phenothiazine antipsychotics.

Gastrointestinal stromal tumors with KIT mutations exhibit a remarkably homogeneous gene expression profile.

Gastrointestinal stromal tumors (GISTs), the most common mesenchymal tumors of the digestive tract, are believed to arise from the interstitial cells of Cajal. GISTs are characterized by mutations in the proto-oncogene KIT that lead to constitutive activation of its tyrosine kinase activity. The tyrosine kinase inhibitor STI571, active against the BCR-ABL fusion protein in chronic myeloid leukemia, was recently shown to be highly effective in GISTs. We used 13,826-element cDNA microarrays to define the expression patterns of 13 KIT mutation-positive GISTs and compared them with the expression profiles of a group of spindle cell tumors from locations outside the gastrointestinal tract. Our results showed a remarkably distinct and uniform expression profile for all of the GISTs. In particular, hierarchical clustering of a subset of 113 cDNAs placed all of the GIST samples into one branch, with a Pearson correlation >0.91. This homogeneity suggests that the molecular pathogenesis of a GIST results from expansion of a clone that has acquired an activating mutation in KIT without the extreme genetic instability found in the common epithelial cancers. The results provide insight into the histogenesis of GIST and the clinical behavior of this therapeutically responsive tumor.

Psychosocial factors among members of religious and secular kibbutzim.

Mortality in 11 secular kibbutzim between 1970 and 1985 was nearly twice that of 11 matched religious kibbutzim. A cross-sectional study was undertaken in 1991 in 10 of these settlements, 5 religious and 5 secular, to determine whether differences in risk factors could explain the unequal survival. These comprised physical, physiologic and biochemical measurements, health-relevant behaviors and psychosocial variables. This report addresses the psychosocial aspect of the study, which included assessment of sense of coherence, hostility, satisfaction with self, work-related stress, social supports and social contacts using self-administered questionnaires. The response rate among the sample of men and women, aged 35-64 years, was 76% (437 respondents, 208 men and 229 women). Analysis of variance and logistic regression (the latter comparing the upper or lower fourths of the distribution vs. the rest) were used. Religious kibbutz members reported a higher sense of coherence (odds ratio = 1.58, 95% CI 1.02 to 2.46) and a lower level of hostility (odds ratio = 0.49, 95% CI 0.33 to 0.75) than their secular counterparts. Findings for satisfaction with self and work-related stress were inconsistent; there were significant interactions between religious affiliation, sex and age. Younger women reported less satisfaction with self and higher work-related stress than the other age-sex groups in both types of kibbutz. There was no difference in social support or frequency of social contact between religious and secular kibbutzim. Voluntary work was more frequent among the religious kibbutzim. The findings are consistent with an interpretation that Jewish religious observance may enhance the formation of certain protective personality characteristics. Membership in a cohesive religious kibbutz community may increase host resistance to stressors and thereby promote overall well-being and a positive health status. This could reflect an interplay of individual and collective attributes of religion.

Postoperative pain following outpatient pediatric urologic surgery: a comparison of anesthetic techniques.

OBJECTIVES: To evaluate and compare the efficacy of caudal and local nerve blocks in preventing pain following outpatient pediatric urologic surgery. METHODS: Seventy-seven boys undergoing outpatient urologic surgery were randomized into one of three groups: general anesthesia alone, general anesthesia and caudal nerve block, or general anesthesia and local nerve block. Pain scores, frequency of medication, and total dosage of medication were recorded in the immediate postoperative period. Long-term pain and discomfort were measured using a 24-hour and 1-week questionnaire. RESULTS: The caudal and local groups had lower pain scores and significantly lower medication requirements than the control group in the short-term postoperative period. The caudal group had lower pain scores than the local group in all categories; however, the only significant difference was at 24 hours postoperatively. At 1 week postoperatively, the only difference among the three groups was a lower pain score in the caudal group compared with the control group. CONCLUSIONS: This study demonstrates that for outpatient pediatric urologic procedures, both caudal and local nerve blocks significantly reduce pain and medication given in the immediate postoperative period and indicates that caudal block may decrease pain for up to 1 week following surgery.