Sara M. Debanne

Patients with Alzheimer's disease have reduced activities in midlife compared with healthy control-group members

The development of Alzheimers disease (AD) later in life may be reflective of environmental factors operating over the course of a lifetime. Educational and occupational attainments have been found to be protective against the development of the disease but participation in activities has received little attention. In a case-control study, we collected questionnaire data about 26 nonoccupational activities from ages 20 to 60. Participants included 193 people with probable or possible AD and 358 healthy control-group members. Activity patterns for intellectual, passive, and physical activities were classified by using an adaptation of a published scale in terms of “diversity” (total number of activities), “intensity” (hours per month), and “percentage intensity” (percentage of total activity hours devoted to each activity category). The control group was more active during midlife than the case group was for all three activity categories, even after controlling for age, gender, income adequacy, and education. The odds ratio for AD in those performing less than the mean value of activities was 3.85 (95% confidence interval: 2.65–5.58, P < 0.001). The increase in time devoted to intellectual activities from early adulthood (20–39) to middle adulthood (40–60) was associated with a significant decrease in the probability of membership in the case group. We conclude that diversity of activities and intensity of intellectual activities were reduced in patients with AD as compared with the control group. These findings may be because inactivity is a risk factor for the disease or because inactivity is a reflection of very early subclinical effects of the disease, or both.

Angiotensin-receptor blockade and risk of cancer: meta-analysis of randomised controlled trials

BACKGROUND Angiotensin-receptor blockers (ARBs) are a widely used drug class approved for treatment of hypertension, heart failure, diabetic nephropathy, and, recently, for cardiovascular risk reduction. Experimental studies implicate the renin-angiotensin system, particularly angiotensin II type-1 and type-2 receptors, in the regulation of cell proliferation, angiogenesis, and tumour progression. We assessed whether ARBs affect cancer occurrence with a meta-analysis of randomised controlled trials of these drugs. METHODS We searched Medline, Scopus (including Embase), Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and the US Food and Drug Administration website for studies published before November, 2009, that included any of the seven currently available ARBs. Randomised controlled trials with an ARB given in at least one group, with a follow-up of at least 1 year, and that enrolled at least 100 patients were included. New-cancer data were available for 61,590 patients from five trials. Data on common types of solid organ cancers were available for 68,402 patients from five trials, and data on cancer deaths were available for 93,515 patients from eight trials. FINDINGS Telmisartan was the study drug in 30,014 (85.7%) patients who received ARBs as part of the trials with new cancer data. Patients randomly assigned to receive ARBs had a significantly increased risk of new cancer occurrence compared with patients in control groups (7.2%vs 6.0%, risk ratio [RR] 1.08, 95% CI 1.01-1.15; p=0.016). When analysis was limited to trials where cancer was a prespecified endpoint, the RR was 1.11 (95% CI 1.04-1.18, p=0.001). Among specific solid organ cancers examined, only new lung-cancer occurrence was significantly higher in patients randomly assigned to receive ARBs than in those assigned to receive control (0.9%vs 0.7%, RR 1.25, 1.05-1.49; p=0.01). No statistically significant difference in cancer deaths was observed (1.8%vs 1.6%, RR 1.07, 0.97-1.18; p=0.183). INTERPRETATION This meta-analysis of randomised controlled trials suggests that ARBs are associated with a modestly increased risk of new cancer diagnosis. Given the limited data, it is not possible to draw conclusions about the exact risk of cancer associated with each particular drug. These findings warrant further investigation.

Significant Determinants of Susceptibility to Alcohol Teratogenicity

Typically, the rate of abusive drinking during pregnancy considerably exceeds the rates of fetal alcohol syndrome (FAS) and alcohol-related birth defects, suggesting that other factors may modify the impact of alcohol on the developing organism. Data in the literature supporting this susceptibility hypothesis are sparse. In this paper, two studies in different samples, using different analytic strategies to examine susceptibility to different adverse outcomes are presented. Among 176 pregnancies in which lowered birth weight for gestational age was detected as an effect attributable to frequent beer drinking, 27 infants weighted less than 2,700 grams and 149 weighed more. Using discriminant analysis to contrast these groups, lowered birth weight for gestational age was associated with black race and lower maternal weight and weight gain. The effects of these factors were additive with that of persistent alcohol exposure; no interactions were detected, but pregnancies with risks in addition to alcohol were more likely to yield growth-retarded infants. In a second study, pregnancies resulting in 25 FAS cases were contrasted with 50 controls. A four-factor model accounted for nearly two-thirds of the explainable variance in the occurrence of FAS. Adjusted for frequency of maternal drinking, chronic alcohol problems and parity, there was a sevenfold increase in risk for FAS among black infants. The findings from both studies are consistent with the susceptibility hypothesis and have potentially important implications for public health and clinical approaches to prevention, as well as for future research.

Early and Extended Early Bactericidal Activity of Linezolid in Pulmonary Tuberculosis

RATIONALE Linezolid, the first oxazolidinone approved for clinical use, has effective in vitro and promising in vivo activity against Mycobacterium tuberculosis. OBJECTIVES To evaluate the early and extended early bactericidal activity of linezolid in patients with pulmonary tuberculosis. METHODS Randomized open label trial. Thirty patients with newly diagnosed smear-positive pulmonary tuberculosis (10 per arm) were assigned to receive isoniazid (300 mg daily) and linezolid (600 mg twice daily or 600 mg once daily) for 7 days. Sputum for quantitative culture was collected for 2 days before and then daily during 7 days of study drug administration. Bactericidal activity was estimated by measuring the decline in bacilli during the first 2 days (early bactericidal activity) and the last 5 days of study drug administration (extended early bactericidal activity). MEASUREMENTS AND MAIN RESULTS The mean early bactericidal activity of isoniazid (0.67 log10 cfu/ml/d) was greater than that of linezolid twice and once daily (0.26 and 0.18 log10 cfu/ml/d, respectively). The extended early bactericidal activity of linezolid between Days 2 and 7 was minimal. CONCLUSIONS Linezolid has modest early bactericidal activity against rapidly dividing tubercle bacilli in patients with cavitary pulmonary tuberculosis during the first 2 days of administration, but little extended early bactericidal activity. Clinical trial registered with www.clinicaltrials.gov (NCT00396084).

Shortening Treatment in Adults with Noncavitary Tuberculosis and 2-Month Culture Conversion

RATIONALE Cavitary disease and delayed culture conversion have been associated with relapse. Combining patient characteristics and measures of bacteriologic response might allow treatment shortening with current drugs in some patients. OBJECTIVES To assess whether treatment could be shortened from 6 to 4 months in patients with noncavitary tuberculosis whose sputum cultures converted to negative after 2 months. METHODS This study was a randomized, open-label equivalence trial. HIV-uninfected adults with noncavitary tuberculosis were treated daily with isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months, followed by 2 months of isoniazid and rifampin. After 4 months, patients with drug-susceptible TB whose sputum cultures on solid media were negative after 8 weeks of treatment were randomly assigned to continue treatment for 2 more months or to stop treatment. Patients were followed for relapse for 30 months after beginning treatment. MEASUREMENTS AND MAIN RESULTS Enrollment was stopped by the safety monitoring committee after 394 patients were enrolled due to apparent increased risk for relapse in the 4-month arm. A total of 370 patients were eligible for per protocol analysis. Thirteen patients in the 4-month arm relapsed, compared with three subjects in the 6-month arm (7.0 vs. 1.6%; risk difference, 0.054; 95% confidence interval with Hauck-Anderson correction, 0.01-0.10). CONCLUSION Shortening treatment from 6 to 4 months in adults with noncavitary disease and culture conversion after 2 months using current drugs resulted in a greater relapse rate. The combination of noncavitary disease and 2-month culture conversion was insufficient to identify patients with decreased risk for relapse.

Smoking and increased severity of hepatic fibrosis in primary biliary cirrhosis: A cross validated retrospective assessment

An epidemiological association between cigarette smoking and primary biliary cirrhosis (PBC) has been demonstrated. Our aim was to determine the relationship between smoking and severity of liver fibrosis at presentation in patients with PBC. All patients with PBC seen at the three major teaching hospitals of Case Western Reserve University between October 1998 and December 2005 were identified. Data obtained at the time of the first evaluation leading to the PBC diagnosis on 97 patients were collected. The cumulative number of cigarette packs smoked per year (pack‐years) was calculated. Advanced histological disease was defined as Ludwig stages 3 or 4. Analyses were performed to determine associations between advanced histological disease, smoking and other variables related to liver fibrosis. Smoking history was more common (P = .0008) in patients with advanced histological disease at presentation compared to those with early disease. Among smokers, mean lifetime tobacco consumption was higher (P = .04) in cases with advanced histological disease at presentation (30 pack‐years) compared to cases with early disease (17 pack‐years). Logistic regression demonstrated a significant association between a lifetime tobacco consumption of ≥10 pack‐years and advanced histological disease at presentation (OR = 13.3). The association remained significant after adjusting for age, gender, and alcohol intake. The validity of these results was corroborated by cross‐validation in an independent confirmatory set of 172 patients with PBC. In conclusion, smoking may accelerate the progression of PBC. This could be induced by exposure to chemicals in cigarette smoke. (HEPATOLOGY 2006;44:1564–1571.)

Markers of inflammation and CD8 T-cell activation, but not monocyte activation, are associated with subclinical carotid artery disease in HIV-infected individuals.

The aim of the study was to explore the relationships between lymphocyte and monocyte activation, inflammation, and subclinical vascular disease among HIV‐1‐infected patients on antiretroviral therapy (ART).

The relationship between cadmium zinc and birth weight in pregnant women who smoke

It is universally accepted that smoking during pregnancy results in decreased infant birth weight. However, the mechanism for decreased birth weight is not completely understood. This study tested the hypothesis that the cadmium/zinc interaction in the maternal-fetal-placental unit of the mother who smokes could be related to birth weight. Thiocyanate was used as the index of smoking status and atomic absorption spectroscopy was used to determine trace elements. Results show that cord vein red blood cell zinc and maternal whole blood cadmium levels are significant predictors of infant birth weight when variance that is due to clinical factors and thiocyanate is controlled with stepwise multiple regression techniques (n = 202). Bivariate correlation techniques showed that the factors affecting birth weight were different in the smoking and nonsmoking groups. For example, in nonsmokers (n = 125), the cord vein red blood cell zinc level was positively related to birth weight. In smokers (n = 77), maternal whole blood cadmium, placental cadmium, and placental zinc levels were negatively related to birth weight; the ratio of placental zinc to placental cadmium and the cord vein red blood cell zinc level were positively related to birth weight. The results suggest that increased maternal cadmium and decreased cord vein red blood cell zinc levels in infants of smokers may be significant clinically since increased maternal whole blood cadmium and decreased cord vein red blood cell zinc levels are both significantly related to decreased birth weight.

Rosuvastatin reduces vascular inflammation and T-cell and monocyte activation in HIV-infected subjects on antiretroviral therapy.

Background:Despite suppressive antiretroviral therapy (ART), increased levels of immune activation persist in HIV-infected subjects. Statins have anti-inflammatory effects and may reduce immune activation in HIV disease. Methods:Stopping Atherosclerosis and Treating Unhealthy bone with RosuvastatiN in HIV (SATURN-HIV) is a randomized, double-blind placebo-controlled trial assessing the effect of rosuvastatin (10 mg daily) on markers of cardiovascular risk and immune activation in ART-treated patients. T-cell activation was measured by expression of CD38, HLA-DR, and PD1. Monocyte activation was measured with soluble markers (sCD14 and sCD163) and by enumeration of monocyte subpopulations and tissue factor expression. Markers of systemic and vascular inflammation and coagulation were also measured. SATURN-HIV is registered on clinicaltrials.gov (identifier: NCT01218802). Results:Rosuvastatin, compared with placebo, reduced sCD14 (−10.4% vs 0.5%, P = 0.006), lipoprotein-associated phospholipase A2 (−12.2% vs −1.7%, P = 0.0007), and IP-10 (−27.5 vs −8.2%, P = 0.03) levels after 48 weeks. The proportion of tissue factor-positive patrolling (CD14DimCD16+) monocytes was also reduced by rosuvastatin (−41.6%) compared with placebo (−18.8%, P = 0.005). There was also a greater decrease in the proportions of activated (CD38+HLA-DR+) T cells between the arms (−38.1% vs −17.8%, P = 0.009 for CD4+ cells, and −44.8% vs −27.4%, P = 0.003 for CD8+ cells). Conclusions:Forty-eight weeks of rosuvastatin treatment reduced significantly several markers of inflammation and lymphocyte and monocyte activation in ART-treated subjects.

Rosuvastatin Treatment Reduces Markers of Monocyte Activation in HIV-Infected Subjects on Antiretroviral Therapy

BACKGROUND Statins, or 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, have anti-inflammatory effects that are independent of their lipid-lowering properties. Despite suppressive antiretroviral therapy (ART), elevated levels of immune activation and inflammation often persist. METHODS The Stopping Atherosclerosis and Treating Unhealthy Bone With Rosuvastatin in HIV (SATURN-HIV) trial is a randomized, double-blind, placebo-controlled study, designed to investigate the effects of rosuvastatin (10 mg/daily) on markers of cardiovascular disease risk in ART-treated human immunodeficiency virus (HIV)-infected subjects. A preplanned analysis was to assess changes in markers of immune activation at week 24. Subjects with low-density lipoprotein cholesterol <130 mg/dL and heightened immune activation (%CD8(+)CD38(+)HLA-DR(+) ≥19%, or plasma high-sensitivity C-reactive protein ≥2 mg/L) were randomized to receive rosuvastatin or placebo. We measured plasma (soluble CD14 and CD163) and cellular markers of monocyte activation (proportions of monocyte subsets and tissue factor expression) and T-cell activation (expression of CD38, HLA-DR, and PD1). RESULTS After 24 weeks of rosuvastatin, we found significant decreases in plasma levels of soluble CD14 (-13.4% vs 1.2%, P = .002) and in proportions of tissue factor-positive patrolling (CD14(Dim)CD16(+)) monocytes (-38.8% vs -11.9%, P = .04) in rosuvastatin-treated vs placebo-treated subjects. These findings were independent of the lipid-lowering effect and the use of protease inhibitors. Rosuvastatin did not lead to any changes in levels of T-cell activation. CONCLUSIONS Rosuvastatin treatment effectively lowered markers of monocyte activation in HIV-infected subjects on antiretroviral therapy. CLINICAL TRIALS REGISTRATION NCT01218802.