Discovery of a potent small-molecule antagonist of inhibitor of apoptosis (IAP) proteins and clinical candidate for the treatment of cancer (GDC-0152)

A series of compounds were designed and synthesized as antagonists of cIAP1/2, ML-IAP, and XIAP based on the N-terminus, AVPI, of mature Smac. Compound 1 (GDC-0152) has the best profile of these compounds; it binds to the XIAP BIR3 domain, the BIR domain of ML-IAP, and the BIR3 domains of cIAP1 and cIAP2 with K(i) values of 28, 14, 17, and 43 nM, respectively. These compounds promote degradation of cIAP1, induce activation of caspase-3/7, and lead to decreased viability of breast cancer cells without affecting normal mammary epithelial cells. Compound 1 inhibits tumor growth when dosed orally in the MDA-MB-231 breast cancer xenograft model. Compound 1 was advanced to human clinical trials, and it exhibited linear pharmacokinetics over the dose range (0.049 to 1.48 mg/kg) tested. Mean plasma clearance in humans was 9 ± 3 mL/min/kg, and the volume of distribution was 0.6 ± 0.2 L/kg.     

Mortality of Tuberculosis in Very Old People

OBJECTIVES: To describe the clinical characteristics and outcomes of tuberculosis (TB) in elderly people.
DESIGN: Observational analysis of a prospective cohort of adults with TB (1995–2004). A case–control study to determine attributable mortality to TB in very old people was done.
RESULTS: Of 319 patients with TB, 109 (34.2%) were aged 65 and older. The older group was more likely to have comorbidities (1.4% vs 0.4%; P <.001), extrapulmonary and disseminated TB (50.4% vs 26.1%; P <.001), toxicity (22% vs 9.8%; P =.006), and 30-day mortality (18.3% vs 1.6%; P <.001). When patients aged 65 to 79 were compared with those aged 80 and older, only differences in TB-related mortality were detected (9.8% vs 44.4%; P =.01). In the attributable mortality analysis, 30-day and 6-month mortality were higher in very old patients with TB than in controls without TB (41.7% vs 11.1%, P =.005; 45.8% and 19.4%, P =.01, respectively). No differences in mortality were shown when excluding patients with postmortem TB diagnosis or those who died within the first 72 hours of diagnosis.
CONCLUSION: Older people with TB had a higher frequency of atypical features, more adverse drug reactions, and greater TB-related mortality than younger people. Data suggest that very old patients with TB have higher mortality, but if diagnosed early and adequately treated, very old patients with TB do not have greater mortality than those without.     

Prevalence of Diabetic Complications in Rural Goa, India

Objective:

To determine the prevalence of diabetes mellitus (DM) and its associated diabetic complications in rural Goa, India.

Materials and Methods:

A community-based study was carried out in a rural setting in Goa, India. About 1,266 participants were selected by systematic random sampling. The participants were interviewed using a semi-structured questionnaire and were subjected to anthropometric, clinical evaluation and biochemical investigations. American Diabetes Association criteria were used to determine the prevalence of diabetes and standard operational definitions were used to define the diabetic complications. Data was analyzed using SPSS version 14.0 while chi-square and chi-square for trend were the tests used.

Results:

Among the total 1,266 study participants about 130 (10.3%) were diabetics. The prevalence of the associated diabetic complications were as follows viz. neuropathy (60%), CHD (32.3%) and cataract (20%), retinopathy (15.4%), peripheral vascular disease (11.5%) and cerebrovascular accidents (CVAs) (6.9%). A significant rising trend in the prevalence of all diabetic complications was observed with advancing duration of diabetes.

Conclusion:

The prevalence of DM and its associated complications was higher among the diabetic individuals in the rural setting of Goa, India. All the associated diabetic complications observed need to be addressed with appropriate prevention and control strategies.     

长期口服小剂量阿司匹林不能预防健康女性患2型糖尿病

慢性无临床症状的炎症与2型糖尿病的发生有关,流行病学资料认为这种关联在妇女表现得更为强烈。虽然小型临床研究显示短期口服大剂量阿司匹林具有明显的降糖效果,但是并没有随机试验直接评估临床可接受的剂量的阿司匹林预防糖尿病的效果。在美国一项随机、双盲、安慰剂-对照的女性健康研究（Women＇s Health Study）中,38716名45岁以上的且无临床糖尿病的健康女性随机口服小剂量的阿司匹林（n=19326）或安慰剂（n=19390）,     

Disseminated Histoplasmosis in a 13-year-old girl: a case report

Background

Disseminated histoplasmosis is a rare fungal infection and most documented cases are in immune-compromised individuals such as those with acquired immuno-deficiency syndrome.

Objective

To describe a case of disseminated histoplasmosis in an adolescent girl.

Method

We report a case of disseminated histoplasmosis in a 13-year-old adolescent girl. She was admitted for 16 days because of neck masses of 3 years duration, generalized body swelling of 3 months and reduction in urinary output of 2 months. She tested negative for human immunodeficiency virus antibodies.

Result

An autopsy was performed because a definitive diagnosis could not be made while the patient was still alive. The autopsy revealed central caseating areas in the lymph nodes and membranoproliferative glomerulonephritis. The periodic acid-Schiff staining technique for tissues showed viable yeast cells suggestive of histoplasmosis. Zeihl-Neelsen''s staining for mycobacteria tuberculosis was negative.

Conclusion

Undiagnosed case of disseminated histoplasmosis while the patient was alive is being reported in a 13-year-old girl. Disseminated histoplasmosis should be considered as a differential diagnosis of childhood chronic infections and malignancies as in Nigeria.