Publications

RATIONALE

Genetic variants in endothelial nitric oxide synthase gene (NOS3) leading to endothelial dysfunction may be predispose to the coronary slow-flow phenomenon (CSFP).

METHODS AND RESULTS

In this study, we examined the relationship between Glu298Asp (894G/T) and 4b/4a polymorphisms of NOS3 and CSFP. A total of 27 patients with CSFP but otherwise normal coronary arteries (mean age 50.4±8.2 years) and 200 controls with a normal coronary angiogram (mean age 53.1±8.6 years) were screened for Glu298Asp and 4b/4a polymorphisms by restriction fragment length polymorphism and PCR, respectively. Nitric oxide levels were determined using Griess' enzymatic method for an association with the polymorphisms. The genotype distribution of the Glu298Asp polymorphism differed significantly between the CSFP patients and controls (P=0.004). The dominant genetic model showed that GT+TT was significantly prevalent in patients in comparison with controls (P=0.014) and the T allele was significantly prevalent in patients (P=0.002). The genetic distribution of 4b/4a differed significantly for the heterozygous genotype ba (P=0.047). The overdominant genetic model re-established that the ba genotype was significantly prevalent in patients (P=0.044). Nitric oxide level was higher in patients than in controls, the values being 144.51±43.25 and 129.64±29.47 μmol/l, respectively (P>0.05). The genotypes of Glu298Asp showed a trend of association with nitric oxide levels, which decreased linearly in the order of GG, GT, and TT (P>0.05).

CONCLUSION

The Glu298Asp polymorphism of NOS3 associates with CSFP.

BACKGROUND

Prioritizing interventions for patients with syphilis who are part of large or interconnected sexual networks may be high yield for partner services, and identifying venues named by patients with syphilis who report high numbers of partners may help identify such networks. In this analysis, we explore differences between interviewed patients with early syphilis regarding where they met sex partners.

METHODS

With a cross-sectional design, we examined the distribution of total reported sex partners from male index patients with early syphilis interviewed through the San Francisco Department of Public Health partner services program and the self-reported venues named as places they met sex partners. Based on the median number of total partners among male cases of syphilis who named each venue, we categorized venues into 3 levels of partner frequency: high (>15 partners reported), medium (6-15 partners reported), and low (<6 partners reported). Interviewed patients with early syphilis were then classified into these venue categories, and sociodemographic and risk behaviors from electronic medical records and interviews were compared using χ tests.

RESULTS

In 2011, 433 male patients with early syphilis named 32 venues. One hundred forty-three (32.3%) patients were categorized as high, 226 (51.0%) as medium, and 74 (16.7%) as low partner frequency venue users. Patients with early syphilis who reported meeting partners at high partner frequency venues were generally older, more likely to be white, have a previous syphilis infection, use methamphetamines in the previous year, and be HIV infected (all P < 0.05) compared with those who reported meeting partners at medium-frequency and low-frequency venues.

CONCLUSIONS

Venues where partners are met may be an appropriate proxy for network membership. Targeting additional resources, outreach, and services to clients who attend high-frequency venues may have a positive impact on syphilis prevention efforts.

BACKGROUND

The relationship between anemia and undiagnosed tuberculosis (TB) in patients living with HIV in sub-Saharan Africa is incompletely defined. We assessed the prevalence of TB among those with HIV-related anemia and evaluated new means of rapid TB diagnosis.

METHODS

Blood hemoglobin levels were measured in unselected antiretroviral treatment-naive patients in Cape Town, South Africa, and anemia was classified according to World Health Organization criteria. All patients were screened for TB by testing paired sputum samples using liquid culture (reference standard), fluorescence microscopy, and Xpert MTB/RIF. Urine samples were tested for lipoarabinomannan (LAM) using the Determine TB-LAM diagnostic assay.

RESULTS

Of 602 adults screened, 485 had complete results. Normal hemoglobin levels were found in 44.5% (n = 216) of patients, and mild, moderate, or severe anemia were present in 24.9% (n = 121), 25.4% (n = 123) and 5.2% (n = 25) of patients, respectively. Culture-confirmed pulmonary TB was diagnosed in 8.8% (19/216) of those without anemia compared with 16.5% (20/121), 26.0% (32/123), and 40.0% (10/25) among those with mild, moderate, or severe anemia, respectively (P < 0.001). Anemia was a strong independent predictor of TB. The sensitivities of diagnostic assays were much higher among those with moderate/severe anemia compared with those with no/mild anemia using sputum microscopy (42.9% vs 15.4%), urine LAM (54.8% vs 0%), sputum microscopy plus urine LAM (71.4% vs 15.4%), and sputum Xpert (73.8% vs 41.0%) (P < 0.01 for all).

CONCLUSIONS

A very high prevalence of undiagnosed TB was found in patients with moderate or severe anemia. Such patients should be prioritized for routine microbiological investigation using rapid diagnostic assays.

The management of latent tuberculosis infection (LTBI) most commonly consists of a nine-month course of isoniazid (INH) therapy and is complicated by low adherence and completion rates. The Latent Tuberculosis Initiative at the HAVEN Free Clinic was developed to provide LTBI treatment to an underserved, high-risk, foreign-born population. We conducted a retrospective chart review to evaluate the program. Of 39 patients enrolled, 26 (67%) successfully completed nine months of INH, eight (21%) discontinued, and five (12%) were lost to follow-up. Patients had a median of nine encounters during the course of treatment and mean self-reported medication adherence was 29/30 pills/month (96%). Median days-of-treatment was 273, 95, and 63 among completion, discontinuation, and lost to follow-up groups, respectively (p < .0001). There was one death in the program, related to a complication of a diagnostic procedure in a patient who had developed INH toxicity. These results are comparable to the most successful published programs (50-65% six-month completion rates), suggesting that student-run clinics serving high-risk populations may contribute to LTBI management and TB control efforts.

OBJECTIVE

Hostility is associated with adverse outcomes in patients with coronary heart disease (CHD). However, assessment tools used to evaluate hostility in epidemiological studies vary widely.

METHODS

We administered nine subscales of the Cook-Medley Hostility Scale (CMHS) to 656 outpatients with stable CHD between 2005 and 2007. We used Cox proportional hazards models to determine the association between each hostility subscales and all-cause mortality. We also performed an item analysis using logistic regression to determine the association between each CMHS item and all-cause mortality.

RESULTS

There were 136 deaths during 1364 person-years of follow-up. Four of nine CMHS subscales were predictive of mortality in age-adjusted analyses, but only one subscale (the seven-item Williams subscale) was predictive of mortality in multivariable analyses. After adjustment for age, sex, education, smoking, history of heart failure, diabetes, and high-density lipoprotein, each standard deviation increase in the Williams subscale was associated with a 20% increased mortality rate (hazard ratio = 1.20, 95% confidence interval = 1.00-1.43, p = .046), and participants with hostility scores in the highest quartile were twice as likely to die as those in the lowest quartile (hazard ratio = 2.00, 95% confidence interval = 1.10-3.65, p = .023).

CONCLUSIONS

Among nine variations of the CMHS that we evaluated, a seven-item version of the Williams subscale was the most strongly associated with mortality. Standardizing the assessment of hostility in future epidemiological studies may improve our understanding of the relationship between hostility and mortality in patients with CHD.

With advances in antiretroviral therapy (ART), individuals with human immunodeficiency virus (HIV) infection are living longer and increasingly die of non-HIV-related diseases, such as cardiovascular disease (CVD). Several observational studies suggest that HIV-infected patients on ART are at increased risk of CVD; however, the precise mechanisms underlying the association between HIV infection and CVD risk are uncertain. Atherosclerosis and arterial disease in HIV-infected individuals is a multifactorial process with several potential targets for research and therapeutic intervention. This paper critically reviews the contributions of imaging to our understanding of arterial disease, atherosclerosis, and CVD risk in HIV-infected individuals. In general, the findings of studies using carotid ultrasound, coronary computed tomographic angiography, and aortic positron emission tomography agree with those from observational studies of CVD events and suggest that HIV infection is associated with an increased risk of CVD. Observational studies of CVD outcomes and studies using carotid intima-media thickness suggest that there is a moderate increase in CVD risk related to HIV serostatus. Less can be said about the role of ART and specific ART therapies in CVD risk, mainly because imaging studies have had serious methodological limitations that diminish their generalizability. Brachial artery reactivity testing has been especially useful for elucidating the arterial pathophysiology of HIV infection and its treatments, as well as the arterial effects of interventions for treating HIV and dyslipidemia. Aortic positron emission tomography has been especially useful for evaluating arterial inflammation. Coronary artery calcium has not proven to be a useful marker of subclinical atherosclerosis in HIV-infected individuals. Imaging studies support the intriguing hypothesis that persistent inflammation and immune dysregulation contribute to increased CVD risk among treated and suppressed patients with HIV infection.

Autoimmunity occurs when T cells, B cells or both are inappropriately activated, resulting in damage to one or more organ systems. Normally, high-affinity self-reactive T and B cells are eliminated in the thymus and bone marrow through a process known as central immune tolerance. However, low-affinity self-reactive T and B cells escape central tolerance and enter the blood and tissues, where they are kept in check by complex and non-redundant peripheral tolerance mechanisms. Dysfunction or imbalance of the immune system can lead to autoimmunity, and thus elucidation of normal tolerance mechanisms has led to identification of therapeutic targets for treating autoimmune disease. In the past 15 years, a number of disease-modifying monoclonal antibodies and genetically engineered biologic agents targeting the immune system have been approved, notably for the treatment of rheumatoid arthritis, inflammatory bowel disease and psoriasis. Although these agents represent a major advance, effective therapy for other autoimmune conditions, such as type 1 diabetes, remain elusive and will likely require intervention aimed at multiple components of the immune system. To this end, approaches that manipulate cells ex vivo and harness their complex behaviors are being tested in preclinical and clinical settings. In addition, approved biologic agents are being examined in combination with one another and with cell-based therapies. Substantial development and regulatory hurdles must be overcome in order to successfully combine immunotherapeutic biologic agents. Nevertheless, such combinations might ultimately be necessary to control autoimmune disease manifestations and restore the tolerant state.