Genetic basis for variation in plasma IL-18 levels in persons with chronic hepatitis C virus and human immunodeficiency virus-1 infections.

Inflammasomes are multi-protein complexes integrating pathogen-triggered signaling leading to the generation of pro-inflammatory cytokines including interleukin-18 (IL-18). Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections are associated with elevated IL-18, suggesting inflammasome activation. However, there is marked person-to-person variation in the inflammasome response to HCV and HIV. We hypothesized that host genetics may explain this variation. To test this, we analyzed the associations of plasma IL-18 levels and polymorphisms in 10 genes in the inflammasome cascade. About 1538 participants with active HIV and/or HCV infection in three ancestry groups are included. Samples were genotyped using the Illumina Omni 1-quad and Omni 2.5 arrays. Linear regression analyses were performed to test the association of variants with log IL-18 including HCV and HIV infection status, and HIV RNA in each ancestry group and then meta-analyzed. Eleven highly correlated single-nucleotide polymorphisms (r2=0.98-1) in the IL-18-BCO2 region were significantly associated with log IL-18; each T allele of rs80011693 confers a decrease of 0.06 log pg ml-1 of IL-18 after adjusting for covariates (rs80011693; rs111311302 ß=-0.06, P-value=2.7 × 10-4). In conclusion, genetic variation in IL-18 is associated with IL-18 production in response to HIV and HCV infection, and may explain variability in the inflammatory outcomes of chronic viral infections.

Human leucocyte antigen class I and II imputation in a multiracial population.

Human leucocyte antigen (HLA) genes play a central role in response to pathogens and in autoimmunity. Research to understand the effects of HLA genes on health has been limited because HLA genotyping protocols are labour intensive and expensive. Recently, algorithms to impute HLA genotype data using genome-wide association study (GWAS) data have been published. However, imputation accuracy for most of these algorithms was based primarily on training data sets of European ancestry individuals. We considered performance of two HLA-dedicated imputation algorithms - SNP2HLA and HIBAG - in a multiracial population of n = 1587 women with HLA genotyping data by gold standard methods. We first compared accuracy - defined as the percentage of correctly predicted alleles - of HLA-B and HLA-C imputation using SNP2HLA and HIBAG using a breakdown of the data set into an 80% training group and a 20% testing group. Estimates of accuracy for HIBAG were either the same or better than those for SNP2HLA. We then conducted a more thorough test of HIBAG imputation accuracy using five independent 10-fold cross-validation procedures with delineation of ancestry groups using ancestry informative markers. Overall accuracy for HIBAG was 89%. Accuracy by HLA gene was 93% for HLA-A, 84% for HLA-B, 94% for HLA-C, 83% for HLA-DQA1, 91% for HLA-DQB1 and 88% for HLA-DRB1. Accuracy was highest in the African ancestry group (the largest group) and lowest in the Hispanic group (the smallest group). Despite suboptimal imputation accuracy for some HLA gene/ancestry group combinations, the HIBAG algorithm has the advantage of providing posterior estimates of accuracy which enable the investigator to analyse subsets of the population with high predicted (e.g. >95%) imputation accuracy.

Association among vitamin D, oral candidiasis, and calprotectinemia in HIV.

Vitamin D deficiency is associated with negative health outcomes, including infections. Vitamin D modulates inflammation and down-regulates the expression of calprotectin, a molecule which influences neutrophil functions and which has been linked to oral candidiasis (OC), the most prevalent oral lesion in human immunodeficiency virus (HIV). We hypothesized a positive association between vitamin D deficiency and OC, and that this effect was partially modulated by calprotectinemia. Plasma calprotectin and serum 25 (OH) vitamin D levels were measured in stored samples from 84 HIV-seropositive Chicago women enrolled in the Oral Substudy of the Women's Interagency HIV Study (WIHS). OC and vitamin D deficiency were diagnosed in, respectively, 14 (16.7%) and 46 (54.8%) of those studied. Vitamin D deficiency was positively associated with OC (p = 0.011) and with higher calprotectinemia (p = 0.019) in univariate analysis. After adjustment for CD4, HIV viral load, HIV treatment, and tobacco and heroin/methadone use, vitamin D deficiency remained a significant predictor of OC (OR 5.66; 95% confidence interval 1.01-31.71). This association weakened after adjustment for calprotectinemia, supporting a role for calprotectinemia as a moderator of this effect. These findings support studies to examine the effect of vitamin D status on calprotectinemia, neutrophil functions, and opportunistic mucosal infections in HIV.

Effect of tuberculosis on the survival of women infected with human immunodeficiency virus.

Evidence regarding the effect of tuberculosis (TB) disease on progression of human immunodeficiency virus (HIV) disease is inconclusive. The authors estimated the effect of time-varying incident TB on time to acquired immunodeficiency syndrome (AIDS)-related mortality using a joint marginal structural Cox model. Between 1995 and 2002, 1,412 HIV type 1 (HIV-1)-infected women enrolled in the Women's Interagency HIV Study were followed for a median of 6 years. Twenty-nine women incurred incident TB, and 222 died of AIDS-related causes. Accounting for age, CD4 cell count, HIV-1 RNA level, serum albumin level, and non-TB AIDS at study entry, as well as for time-varying CD4 cell count, CD4 cell count nadir, HIV-1 RNA level, peak HIV-1 RNA level, serum albumin level, HIV-related symptoms, non-TB AIDS, anti-Pneumocystis jiroveci prophylaxis, antiretroviral therapy, and household income, the hazard ratio for AIDS-related death comparing time after incident TB with time before incident TB was 4.0 (95% confidence interval (CI): 1.2, 14). The effect of incident TB on mortality was similar among highly active antiretroviral therapy (HAART)-exposed women (hazard ratio = 4.3, 95% CI: 0.9, 22) and non-HAART-exposed women (hazard ratio = 3.9, 95% CI: 0.9, 17; interaction p = 0.91). Although results were imprecise because few women incurred TB, irrespective of HAART exposure, incident TB increases the hazard of AIDS-related death among HIV-infected women.

Incident hepatitis C virus in women with human immunodeficiency virus infection.

Individuals infected with human immunodeficiency virus type 1 (HIV-1) are frequently coinfected with hepatitis C virus (HCV). Acute HCV infection is often asymptomatic and poorly understood. We conducted a historical prospective study of HCV antibody and viremia in plasma samples obtained during 1994-1999 from a cohort of initially HIV-1-infected, HCV-uninfected women and from HIV-1-HCV-uninfected women. Twenty-two (1.5%) of 1517 experienced seroconversion. Of these, 14 (64%) truly acquired a new infection as assessed by enzyme immunoassay response and new-onset viremia. The incidence rate in HIV-1-infected women was 2.7 cases per 1000 person-years; it was 3.3 cases per 1000 person-years in HIV-1-seronegative women (relative risk, 1.21; P=.75). Acquisition of HCV was associated with any history of drug use (P<.01). Five of 12 viremic, seroconverting individuals cleared viremia. Incident HCV infection among HIV-1-infected and HIV-1-uninfected women was low. It was linked to drug use and commonly resolved.

Association of vitamin A deficiency with cervical squamous intraepithelial lesions in human immunodeficiency virus-infected women.

To explore the relationship between vitamin A (retinol) deficiency and cervical squamous intraepithelial lesions (SILs) in human immunodeficiency virus (HIV)-infected women, we measured serum retinol concentrations in 1314 women enrolled in the Women's Interagency HIV Study and correlated the results with concurrent cervical cytology. At the baseline visit, 204 (15.5%) of the 1314 patients had retinol concentrations consistent with deficiency (<1.05 micromol/L). Analysis of Papanicolaou smears showed SILs in 216 (16.4%) of 1314 women. Cervical SILs were found to be associated with retinol concentrations <1.05 micromol/L (multivariate odds ratio [OR], 1.63; P=.04) in a multivariate model, which included human papillomavirus (HPV) status and markers of nutritional status and HIV disease stage. In the subset of women with genital HPV (n=774), a multivariate analysis again revealed a significant independent association between retinol <1.05 micromol/L and cervical SILs (multivariate OR, 1.75; P=.02). Our findings suggest that retinol deficiency may contribute to the development of cervical SILs in HIV-infected women.

Evaluation of a new color vision test: "color vision testing made easy".

PURPOSE: A new pseudoisochromatic color plate test, "Color Vision Testing Made Easy" (CVTMET) has recently been introduced. Said to be designed for all age groups, including pre-school children, it uses the identification of simple shapes and objects to detect red-green color deficiencies. We evaluated the CVTMET to determine if the test is suitable for color vision screening of young children. METHODS: Forty-one adults predetermined to be color normal (n = 20) or to have hereditary red-green color deficiency (n = 21), served as subjects. A battery of color vision tests including the Ishihara, Panel D-15, and the anomaloscope were used for diagnosis and color deficiency classification. Subjects were then tested with Part I and Part II of the CVTMET test and results were compared to the Ishihara, Panel D-15, and anomaloscope. In addition, the CVTMET was used to screen for color vision deficiency in 152 kindergarten children 5 to 7 years of age. RESULTS: The pass/fail results for the adult subjects were the same for Parts I and II and compared favorably with the anomaloscope. There were no false positives (100% specificity) and only a few (2 of 21) false negatives (90.5% sensitivity). The two color-deficient subjects who passed the CVTMET had the mildest color deficiencies (simple deuteranomaly) and also passed the Ishihara test. Testability of kindergarten children was found to be 100%. Color vision deficiency occurred in 5.06% of the boys, which is about the same frequency found in older boys of similar ethnic background. CONCLUSION: This preliminary study indicates that the CVTMET appears to be an excellent screening instrument for red-green color deficiency in adults and has been shown to be useful for examining color vision in children 5 to 7 years of age.

Use of DNA fingerprinting to assess tuberculosis infection control.

BACKGROUND: DNA fingerprinting establishes the genetic relatedness of Mycobacterium tuberculosis isolates and has become a powerful tool in tuberculosis epidemiology. OBJECTIVE: To use DNA fingerprinting to assess the efficacy of current tuberculosis infection-control practices. DESIGN: Retrospective molecular and descriptive epidemiologic study. SETTING: A 700-bed urban public hospital that follows the Centers for Disease Control and Prevention (CDC) guidelines for tuberculosis infection control. PATIENTS: 183 patients who had positive cultures for M. tuberculosis from 1 April 1995 to 31 March 1996. RESULTS: 173 of 183 M. tuberculosis isolates from the study period underwent DNA fingerprinting. Fingerprinting revealed that five isolates represented false-positive cultures and that 91 (54%) of the remaining 168 isolates were in 15 DNA fingerprinting clusters, which ranged in size from 2 to 29 isolates. Risk factors for clustering were birth in the United States, African-American ethnicity, homelessness, substance abuse, and male sex. Retrospective epidemiologic analysis of inpatient and outpatient visits by the 91 patients who had clustered isolates revealed only one possible instance of patient-to-patient transmission. CONCLUSIONS: The DNA fingerprinting of all M. tuberculosis isolates from a 1-year period revealed one possible instance of nosocomial transmission and five false-positive M. tuberculosis cultures. However, these results did not lead to changes in infection-control practices or in clinical care. The study findings do not support the use of DNA fingerprinting for nosocomial tuberculosis surveillance, but they suggest that compliance with the CDC tuberculosis infection-control guidelines may control patient-to-patient transmission in high-risk urban hospitals.

The use of tetanus toxoid to elucidate the delayed-type hypersensitivity response in an older, immunized population.

Tuberculin reactivity decreases with age despite epidemiologic evidence that the elderly are more likely to have been infected. Whether this phenomenon is due to lack of antigenic stimulus or host inability to mount a delayed type hypersensitivity (DTH) response is unclear. In order to determine if the DTH response to tetanus toxoid in an exposed population is a useful tool to understand the phenomenon of lack of tuberculin reactivity in the remotely exposed elderly, a trial of skin testing was undertaken. Seventy-seven residents of a Veterans Affairs domiciliary were skin-tested using solutions of tetanus toxoid, candida and mumps skin test antigen. The 35 subjects who had negative reaction to the tetanus skin test were randomized into two groups: one which received tetanus vaccination before repeat skin testing and one which did not. Positive skin test reactions occurred in 42 patients to tetanus toxoid, 44 to mumps and 37 to candida. Of the 35 randomized, 27 were available for repeat skin tests. None reacted to the repeat tetanus skin test although 5 reacted to other antigens to which they had previously been nonreactive. Tetanus toxoid was equal to other antigens in its ability to elicit a DTH response originally; however antigenic stimulation with vaccination did not elicit positive skin test in nonreactors. Lack of DTH response to tetanus toxoid in recently vaccinated patients implies that nonresponse was secondary to host factors rather than lack of antigenic stimulation.

Evaluation of Kojima-Matsubara color vision test plates: validity in young children.

PURPOSE: We examined a pseudoisochromatic color plate test by Kojima and Matsubara for young children which uses drawings of familiar objects rather than letters or numbers. First, we evaluated the test's efficacy as a color deficiency screener and its validity in classifying the types of color deficiencies by comparing its results with those from the Moreland anomaloscope. Second, we eliminated the chromatic factor and evaluated the functional ability of young children to perform the task by determining how many correct responses were obtained using modified black/white replicas of the test plates. METHODS: Part 1: Twenty color-normal and 13 color-deficient adults were diagnosed and classified with the Ishihara test, Panel D-15 test, and anomaloscope. Subjects were then tested with the Kojima-Matsubara test and result were compared with those from the anomaloscope. Part 2: Fifty children aged 3 to 7 years were tested with modified black/white test plate replicas. The number of correct responses for each plate was determined for five different age groups. RESULTS: Part 1: Among the 20 color-normal subjects, 18 read all 10 plates correctly and 2 subjects missed 1 of the 10. Only 1 of the 13 color-deficient subjects exhibited the expected responses for plates 2 to 6 (used for color deficiency screening). The color-deficient subjects' responses for plates 7 to 10, which are used to classify red-green defects, were varied and only the protanomalous subjects (n = 2) followed the expected response pattern. Part 2: Of the 10 black/white modified plates, only 2 were correctly identified by all 50 children. The other plates had a recognition rate that ranged from 32 to 98%. CONCLUSIONS: Because the response patterns given by most of the color-deficient adult subjects were different from those in the test manual, ambiguous results would occur if the Kojima-Matsubara test were used for color vision screening or the diagnosis of color deficiency. In addition, the difficulty that many of the young children exhibited in identifying the objects in the black/white replica plates suggests that there would be a large number of false positive errors (classifying a color normal as color deficient) when using this test in young children.

Nontuberculous mycobacterial infections.

The acquired immunodeficiency syndrome (AIDS) pandemic has led to greater understanding and respect for the pathogenic potential of non-tuberculous mycobacteria. Mycobacterium avium complex (MAC) has emerged as the most common systemic bacterial infection in AIDS, causing debilitating disseminated disease in late-stage HIV-infected patients. With the release of the macrolide antibiotics, clarithromycin and azithromycin, effective and well-tolerated therapeutic regimens for MAC have been developed which prolong survival and increase quality of life. The macrolides and rifabutin are also effective as preventive therapy for MAC in patients with AIDS. Mycobacterium kansasii, which causes pulmonary disease similar to tuberculosis as well as disseminated disease in AIDS, is treatable with isoniazid, rifampin and ethambutol. Clinical syndromes and therapeutic options for other non-tuberculous mycobacteria in AIDS are also reviewed.

Cholecystectomy in patients with AIDS: clinicopathologic correlations in 107 cases.

The etiologic and clinical features of cholecystisis in infection due to human immunodeficiency virus (HIV) were studies retrospectively. The charts and histopathologic specimens of 136 HIV-infected patients who underwent cholecystectomy between February 1987 and May 1993 at a large tertiary care center were reviewed. Opportunistic pathogens infecting the 107 patients with AIDS included microsporidia (eight cases-- Enterocytozoon bieneusi in six and Septata intestinalis in two); cytomegalovirus alone (six cases); Cryptosporidium alone (eight cases); cytomegalovirus plus Cryptosporidum (15 cases); and Pneumocystis carinii and Isospora belli (one case each). In addition, histopathologic changes characteristic of Kaposi's sarcoma were seen in one case. Thirty-eight patients with AIDS had acalculous cholecystitis for which no etiologic agent was found. Twenty-eight AIDS patients had cholelithiasis, six with coexistent opportunistic gallbladder infection. In the 107 AIDS patients, no specific symptom was found to be predictive of opportunistic infection of the gallbladder, but such infection was significantly associated with an abnormal abdominal ultrasound (P = .017) and with nonvisualization of the gallbladder by radionucleotide biliary scan (P < .001).

Physical change, time of day, and child characteristics as factors in poison injury.

In a study of 85 children under 6 y whose mothers called the poison center, information regarding the physical surroundings of the substance ingested at the time of the incident was obtained along with ratings of maternal stress and child behavior problems. In 51% of the incidents, the substance had recently been moved from a usual storage site or was in use at the time of the ingestion. Environmental changes occurred in 1/3 of those poisoned between 4 and 6 pm which was the 2-h period of the greatest incidence. Poisoning in children 1 and 2 y were more likely to have followed physical environmental change. Children with higher child behavior problem score were more likely to be poisoned in the morning.

Poisoning with the North American Jack O'Lantern mushroom, Omphalotus illudens.

Ingestion of Jack O'Lantern mushrooms by fourteen people led to vomiting in 8, diarrhea in 5, weakness in 2. Tiredness, the feeling of weakness and being cold occurred in 8. Recovery was complete within 18 hours.