Visualization of atherosclerosis as detected by coronary artery calcium and carotid intima-media thickness reveals significant atherosclerosis in a cross-sectional study of psoriasis patients in a tertiary care center.

BACKGROUND: Psoriasis is a chronic inflammatory disease of the skin and joints that may also have systemic inflammatory effects, including the development of cardiovascular disease (CVD). Multiple epidemiologic studies have demonstrated increased rates of CVD in psoriasis patients, although a causal link has not been established. A growing body of evidence suggests that sub-clinical systemic inflammation may develop in psoriasis patients, even from a young age. We aimed to evaluate the prevalence of atherosclerosis and identify specific clinical risk factors associated with early vascular inflammation. METHODS: We conducted a cross-sectional study of a tertiary care cohort of psoriasis patients using coronary artery calcium (CAC) score and carotid intima-media thickness (CIMT) to detect atherosclerosis, along with high sensitivity C-reactive protein (hsCRP) to measure inflammation. Psoriasis patients and controls were recruited from our tertiary care dermatology clinic. Presence of atherosclerosis was defined using validated numeric values within CAC and CIMT imaging. Descriptive data comparing groups was analyzed using Welch's t test and Pearson Chi square tests. Logistic regression was used to analyze clinical factors associated with atherosclerosis, and linear regression to evaluate the relationship between psoriasis and hsCRP. RESULTS: 296 patients were enrolled, with 283 (207 psoriatic and 76 controls) having all data for the hsCRP and atherosclerosis analysis. Atherosclerosis was found in 67.6 % of psoriasis subjects versus 52.6 % of controls; Psoriasis patients were found to have a 2.67-fold higher odds of having atherosclerosis compared to controls [95 % CI (1.2, 5.92); p = 0.016], after adjusting for age, gender, race, BMI, smoking, HDL and hsCRP. In addition, a non-significant trend was found between HsCRP and psoriasis severity, as measured by PASI, PGA, or BSA, again after adjusting for confounders. CONCLUSIONS: A tertiary care cohort of psoriasis patients have a high prevalence of early atherosclerosis, increased hsCRP, and psoriasis remains a risk factor for the presence of atherosclerosis even after adjustment of key confounding clinical factors. Psoriasis may contribute to an accelerated systemic inflammatory cascade resulting in increased risk of CVD and CV events.

Lipoprotein-associated phospholipase A2 and cardiovascular disease risk in HIV infection.

OBJECTIVES: HIV-infected patients on antiretroviral therapy (ART) have an increased cardiovascular disease (CVD) risk as a result of heightened inflammation and immune activation, despite at times having normal lipids and few traditional risk factors. Biomarkers are needed to identify such patients before a clinical event. Lipoprotein-associated phospholipase A2 (Lp-PLA2 ) predicts CVD events in the general population. This study investigated the relationship between Lp-PLA2 and markers of CVD risk, systemic inflammation, immune activation, and coagulation in HIV infection. METHODS: One hundred subjects on stable ART with normal fasting low-density lipoprotein (LDL) cholesterol were enrolled in the study. Plasma Lp-PLA2 concentrations were measured by enzyme-linked immunosorbent assay (ELISA; > 200 ng/mL was considered high CVD risk). Subclinical atherosclerosis, endothelial function, inflammation, immune activation and fasting lipids were also evaluated. RESULTS: The median age of the patients was 47 years and 77% were male. Median (range) Lp-PLA2 was 209 (71-402) ng/mL. Fifty-seven per cent of patients had Lp-PLA2 concentrations > 200 ng/mL. Lp-PLA2 was positively correlated with soluble markers of inflammation or immune activation (tumour necrosis factor receptor-II, intercellular and vascular cellular adhesion molecules, and CD14; all R = 0.3; P < 0.01), and negatively correlated with coagulation markers (D-dimer and fibrinogen; both R = -0.2; P < 0.04). Lp-PLA2 was not correlated with lipids, coronary artery calcium score, or flow-mediated vasodilation, but trended towards a significant correlation with carotid intima-media thickness (R = 0.2; P = 0.05). CONCLUSIONS: In this population with stable ART and normal LDL cholesterol, Lp-PLA2 was in the high CVD risk category in the majority of subjects. Lp-PLA2 appears to be associated with inflammation/immune activation, but also with anti-thrombotic effects. Lp-PLA2 may represent a valuable early biomarker of CVD risk in HIV infection before subclinical atherosclerosis can be detected.

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

OBJECTIVES: 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). METHODS: Baseline mean common carotid artery (CCA) intima-media thickness (IMT) and carotid plaque (IMT > 1.5 cm) were evaluated in the first 60 subjects enrolled in the Stopping Atherosclerosis and Treating Unhealthy Bone with Rosuvastatin in HIV (SATURN-HIV) trial. All subjects were adults on stable ART with evidence of heightened T-cell activation (CD8(+)CD38(+)HLA-DR(+) ≥ 19%) or increased inflammation (high-sensitivity C-reactive protein ≥ 2 mg/L). All had fasting low-density lipoprotein (LDL) cholesterol ≤ 130 mg/dL. RESULTS: Seventy-eight per cent of patients were men and 65% were African-American. Median (interquartile range) age and CD4 count were 47 (43, 52) years and 648 (511, 857) cells/µL, respectively. All had HIV-1 RNA < 400 HIV-1 RNA copies/mL. Mean CCA-IMT was correlated with log-transformed CD8(+)CD38(+)HLA-DR(+) percentage (r = 0.326; P = 0.043), and concentrations of interleukin-6 (r = 0.283; P = 0.028), soluble vascular cell adhesion molecule (sVCAM; r = 0.434; P = 0.004), tumour necrosis factor-α receptor-I (TNFR-I; r = 0.591; P < 0.0001) and fibrinogen (r = 0.257; P = 0.047). After adjustment for traditional cardiovascular disease (CVD) risk factors, the association with TNFR-I (P = 0.007) and fibrinogen (P = 0.033) remained significant. Subjects with plaque (n = 22; 37%) were older [mean (standard deviation) 51 (7.7) vs. 43 (9.4) years, respectively; P = 0.002], and had a higher CD8(+)CD38(+)HLA-DR(+) percentage [median (interquartile range) 31% (24, 41%) vs. 23% (20, 29%), respectively; P = 0.046] and a higher sVCAM concentration [mean (standard deviation) 737 (159) vs. 592 (160) ng/mL, respectively; P = 0.008] compared with those without plaque. Pro-inflammatory monocyte subsets and serum markers of monocyte activation (soluble CD163 and soluble CD14) were not associated with CCA-IMT or plaque. CONCLUSIONS: Participants in SATURN-HIV have a high level of inflammation and immune activation that is associated with subclinical vascular disease despite low serum LDL cholesterol.

Time to detection of Mycobacterium tuberculosis as an alternative to quantitative cultures.

Testing new drugs is critical to improving the treatment of tuberculosis. Quantitative cultures of Mycobacterium tuberculosis on solid media have been used in Phase 1 and 2 trials, but are time and resource intensive. Time to detection (TTD) of growth of M. tuberculosis in automated liquid culture systems is an alternative. TTD has been shown to correlate with CFU in quantitative cultures, and is faster and simpler to perform. We compared TTD in the BACTEC 460 liquid culture system with CFU in a clinical trial that included 110 subjects. Comparing all sputum cultures collected between baseline and 2 months we found a strong negative correlation between log(10) CFU and TTD (rho = -0.91). In addition, when TTD at baseline was compared with 1 and 2 month sputum culture positivity, subjects whose cultures were negative after 1 and 2 months had a significantly longer median baseline TTD compared with subjects whose cultures were positive at 1 and 2 months (5 vs. 3 days and 3 vs. 2 days, respectively). TTD compares closely with CFU and represents a faster, simpler alternative to quantitative cultures.

Sputum Mycobacterium tuberculosis mRNA as a marker of bacteriologic clearance in response to antituberculosis therapy.

mRNA is a marker of cell viability. Quantifying Mycobacterium tuberculosis mRNA in sputum is a promising tool for monitoring response to antituberculosis therapy and evaluating the efficacy of individual drugs. mRNA levels were measured in sputum specimens from patients with tuberculosis (TB) receiving monotherapy in an early bactericidal activity study of fluoroquinolones and in those receiving a standard rifampin-based regimen in an interleukin-2 (IL-2) trial. In the early bactericidal activity study, sputum for quantitative culture and mRNA analysis was collected for 2 days before and daily during 7 days of study drug administration. In the IL-2 trial, sputum was collected for quantitative culture, Bactec 460 liquid culture, and mRNA analysis throughout the intensive treatment phase. RNA was isolated from digested sputum and tested in quantitative reverse transcription-PCR assays for several gene targets. mRNA for the glyoxylate cycle enzyme isocitrate lyase declined at similar rates in patients receiving isoniazid, gatifloxicin, levofloxacin, and moxifloxacin monotherapy. Isocitrate lyase mRNA correlated highly with CFU in sputum prior to therapy and during 7 days of monotherapy in all treatment arms. Isocitrate lyase mRNA was detectable in sputum of culture-positive TB patients receiving a rifampin-based regimen for 1 month. At 2 months, sputum for isocitrate mRNA correlated more closely with growth in liquid culture than did growth on solid culture medium. Data suggest that isocitrate lyase mRNA is a reliable marker of M. tuberculosis viability.

Early and extended early bactericidal activity of levofloxacin, gatifloxacin and moxifloxacin in pulmonary tuberculosis.

OBJECTIVE: To evaluate the early bactericidal activity (EBA) of the new fluoroquinolones levofloxacin, gatifloxacin and moxifloxacin in patients with pulmonary tuberculosis (PTB). DESIGN: Randomized, open-label trial. Forty adults with newly diagnosed smear-positive PTB (10 per arm) were assigned to receive isoniazid (INH) 300 mg, levofloxacin 1000 mg, gatifloxacin 400 mg, or moxifloxacin 400 mg daily for 7 days. Sputum for quantitative culture was collected for 2 days before and daily during 7 days of monotherapy. Bactericidal activity was estimated by measuring the decline in bacilli during the first 2 days (EBA 0-2) and last 5 days of monotherapy (extended EBA, EBA 2-7). Laboratory staff were blinded to treatment assignment. RESULTS: The EBA 0-2 of INH (0.67 log10 cfu/ml/day) was greater than that of moxifloxacin and gatifloxacin (0.33 and 0.35 log10 cfu/ml/day, respectively), but not of levofloxacin 1000 mg daily (0.45 log10 cfu/ml/day) (P = 0.14). Bactericidal activity between days 2 and 7 was similar for all three fluoroquinolones. In a pooled comparison, the EBA 2-7 of the fluoroquinolones was greater than for INH. CONCLUSION: Moxifloxacin, gatifloxacin, and high-dose levofloxacin have excellent EBA, only slightly less than for INH, and greater extended EBA. These drugs warrant further study in the treatment of drug-susceptible TB.

Tuberculosis infection among health care workers in Kampala, Uganda.

Nosocomial tuberculosis (TB) is a serious problem in sub-Saharan Africa due to the absence of protective measures for health care workers (HCWs). To determine the prevalence of TB infection among HCWs in Kampala, Uganda, a cross-sectional study was conducted between June and August 2001. A tuberculin skin test (TST) survey was conducted among 396 HCWs from three hospitals within Kampala, The prevalence of TST > or = 10 mm was 57%. Age and department of employment were associated with TST > or = 10 mm, while occupation and BCG status were not. Health care workers in Kampala, Uganda, have a high prevalence of latent TB infection.

Plasma homocysteine, vitamin B12 and folate in Alzheimer's patients and healthy Arabs in Israel.

High plasma homocysteine (tHcy) is a risk factor for cardiovascular disease and stroke and Alzheimer's disease (AD). An inverse relationship has been reported between tHcy and plasma B12 and folate levels. Seventy-nine AD patients and 156 controls from three Arab villages in northern Israel participated. Plasma tHcy, B12 and folate levels were determined. Data were analyzed using univariate statistical tests and logistical regression with confounders. tHcy was significantly higher in AD patients (20.6+/-8.7 micromol/l) than in controls (16.4+/-6.5 micromol/l) (p=0.03) after correction for year of birth, gender and smoking status. Plasma B12 (322.9+/-136.0/350.5+/-175.3 pmol/l) and plasma folate (4.5+/-3.8/4.9+/-2.6 nmol/l) levels did not differ significantly between AD patients and controls. Subjects in the highest tHcy tertile or in the lowest B12 and folate tertiles did not have greater risk to develop AD. In this population residing in Arab villages in northern Israel, tHcy levels were significantly higher among AD patients than in controls. Plasma B12 and folate levels were lower among cases but were not significant. There was not a significant association between plasma tHcy, B12 and folate levels in controls or AD patients. High levels of tHcy may suggest the need for folate and vitamin B12 supplementation in this population.

A re-examination of the potential impact of preventive therapy on the public health problem of tuberculosis in contemporary sub-Saharan Africa.

BACKGROUND: To estimate the effect size of tuberculosis preventive therapy (PT) on the public health problem of tuberculosis in contemporary sub-Saharan Africa. METHODS: A compartmental flow model that considers high levels of tuberculosis and human immunodeficiency virus (HIV) infection in contemporary sub-Saharan Africa was used to assess the impact of PT on the prevalence of tuberculosis and tuberculosis-associated mortality. RESULTS: Model implementation shows that giving PT to 25% of HIV-positive individuals with latent tuberculosis infection (LTBI) leads to a 3.9% reduction in the prevalence of tuberculosis in 10 years and a 5.1% reduction in 20 years. This intervention also prevents a cumulative total of 3.0% of tuberculosis-associated deaths in a decade and 5.5% in two decades. Doubling PT coverage to 50% approximately doubles the effect size, suggesting a linear relationship within the 20-year period. The effect size is slightly sensitive to changes in level of HIV transmission, level of tuberculosis transmission, and level of case detection and treatment cure rates in the population. CONCLUSIONS: Contrary to suggestions by previous authors that PT can significantly reduce the public health problem of tuberculosis in sub-Saharan Africa, this model-based analysis suggests that the impact of PT on tuberculosis in the population is likely to be small.

Plasma total homocysteine levels, dietary vitamin B6 and folate intake in AD and healthy aging.

PURPOSE: To study the association between Alzheimer s disease (AD) and plasma total homocysteine (tHcy), dietary folate and vitamin B6. METHODS: 64 AD patients were matched by gender, age, and smoking status to 64 healthy controls. tHcy was determined using an automated immunoassay. Dietary patterns for three age periods (20-39, 40-59, and 60 + yrs) were assessed using a questionnaire adapted from the Block Health Habits and History Questionnaire. Respondents (cases by proxy) reported food frequencies, which were translated into estimated daily nutrient intakes. APOE genotype, cognitive performance (CDR, MMSE), blood lipids, and albumin were obtained for patients and controls. RESULTS: tHcy did not differ significantly between controls (11.5 +/- 3.7 mmol/L) and AD patients (12.3 +/- 4.3 mmol/L)(p=0.25). tHcy levels were not related in AD patients or controls to education, CDR, MMSE, blood lipids, albumin or ApoE genotype (p>0.15). There was a negative correlation between plasma tHcy and triglyceride levels in AD patients (p=0.023), but not in controls. AD patients consumed significantly less dietary vitamin B6 (p=0.05) and folate (p=0.001) after age 60 than controls. CONCLUSIONS: Although plasma tHcy levels were higher in cases than controls, this difference was not significant. tHcy levels were not related to cognitive status. Plasma tHcy was inversely correlated with triglyceride levels in AD patients but not in controls.

On the use of surrogate respondents for controls in a case-control study of Alzheimer's disease.

OBJECTIVE: To examine the presence and extent of bias introduced by using surrogate respondents for healthy controls in a case-control study of Alzheimer's disease (AD). DESIGN: Comparative study of matched responses to questionnaire ascertaining lifestyle issues. SETTING: University Hospitals/Case Western Reserve University Alzheimer Center. PARTICIPANTS: Controls (n = 50) were identified through the Research Registry. Surrogates (n = 50) were their healthy relatives or friends. MEASUREMENTS: Answers in the areas of demographic and occupational history, smoking habits, medical history, dietary intake, and leisure and work activities were recorded. The analysis was based on methods for paired data. Continuous variables were analyzed, focusing on paired differences between self and surrogate responses. RESULTS: For occupations and exposures, over 80% of the surrogates agreed with the subjects on over 80% of the questions. On smoking history, over 90% of the surrogates agreed with the subjects on over 70% of the questions. On leisure and work activities, over 70% of the surrogates agreed with the subjects on over 50% of the questions. There was less agreement regarding medical history. For continuous variables, most paired t-tests of zero mean difference between self and surrogate responses resulted in nonrejection of this hypothesis. Computed mean differences were not always positive or always negative. CONCLUSION: We did not find systematic under- or overreporting by the surrogates of the controls. Therefore, if there are biases in the responses of surrogates of the AD cases in our case-control study, they would not be canceled out by using surrogates for the controls.

Infection and disease among household contacts of patients with multidrug-resistant tuberculosis.

SETTING: Urban public teaching and referral hospital in Espirito Santo, Brazil. OBJECTIVE: To assess whether rates of infection and progression to active tuberculosis (TB) differed between household contacts of patients with multidrug-resistant (MDR) and drug susceptible (DS) pulmonary tuberculosis. DESIGN: Household contacts were assessed for evidence of TB infection and disease by purified protein derivative (PPD) skin testing, physical examination, chest X-ray, and sputum smear and culture. RESULTS: Among 133 close contacts of patients with MDR-TB, 44% were PPD-positive (> or =10 mm) compared to 37% of 231 contacts of the DS-TB cases (P = 0.18, chi2 test, OR 1.2, 95%CI 0.8-2). In a multivariate logistic regression analysis, after allowance for between-household variation in PPD responses, PPD positivity among household contacts of patients with MDR-TB remained comparable to PPD positivity in contacts of patients with DS-TB (OR 2.1, 95%CI 0.7-6.5). Respectively six (4%) and 11 (4%) contacts of the MDR- and DS-TB cases were found to have active TB at the time of initial evaluation or during follow-up (P = 0.78, chi2 test). Five of six contacts of MDR-TB cases and nine of nine contacts of DS-TB cases who developed TB, and for whom drug susceptibility test results were available, had the same bacterial susceptibility profiles as their index cases. DNA fingerprinting analysis of Mycobacterium tuberculosis isolates was identical between household contacts with active TB and the index MDR or DS-TB case for all 14 pairs compared. CONCLUSION: Our data suggest that the prevalence of tuberculous infection and progression to active TB among household contacts exposed to DS and MDR-TB cases is comparable, despite a longer duration of exposure of contacts to the index case in patients with MDR-TB.