PEG1/MEST and IGF2 DNA methylation in CIN and in cervical cancer.

INTRODUCTION: Although most invasive cervical cancer (ICC) harbor <20 human papillomavirus (HPV) genotypes, use of HPV screening to predict ICC from HPV has low specificity, resulting in multiple and costly follow-up visits and overtreatment. We examined DNA methylation at regulatory regions of imprinted genes in relation to ICC and its precursor lesions to determine if methylation profiles are associated with progression of HPV-positive lesions to ICC. MATERIALS AND METHODS: We enrolled 148 controls, 38 CIN and 48 ICC cases at Kilimanjaro Christian Medical Centre from 2008 to 2009. HPV was genotyped by linear array and HIV-1 serostatus was tested by two rapid HIV tests. DNA methylation was measured by bisulfite pyrosequencing at regions regulating eight imprinted domains. Logistic regression models were used to estimate odd ratios. RESULTS: After adjusting for age, HPV infection, parity, hormonal contraceptive use, and HIV-1 serostatus, a 10 % decrease in methylation levels at an intragenic region of IGF2 was associated with higher risk of ICC (OR 2.00, 95 % CI 1.14-3.44) and cervical intraepithelial neoplasia (CIN) (OR 1.51, 95 % CI 1.00-2.50). Methylation levels at the H19 DMR and PEG1/MEST were also associated with ICC risk (OR 1.51, 95 % CI 0.90-2.53, and OR 1.44, 95 % CI 0.90-2.35, respectively). Restricting analyses to women >30 years further strengthened these associations. CONCLUSIONS: While the small sample size limits inference, these findings show that altered DNA methylation at imprinted domains including IGF2/H19 and PEG1/MEST may mediate the association between HPV and ICC risk.

Chest radiography for predicting the cause of febrile illness among inpatients in Moshi, Tanzania.

AIM: To describe chest radiographic abnormalities and assess their usefulness for predicting causes of fever in a resource-limited setting. MATERIALS AND METHODS: Febrile patients were enrolled in Moshi, Tanzania, and chest radiographs were evaluated by radiologists in Tanzania and the United States. Radiologists were blinded to the results of extensive laboratory evaluations to determine the cause of fever. RESULTS: Of 870 febrile patients, 515 (59.2%) had a chest radiograph available; including 268 (66.5%) of the adolescents and adults, the remainder were infants and children. One hundred and nineteen (44.4%) adults and 51 (20.6%) children were human immunodeficiency virus (HIV)-infected. Among adults, radiographic abnormalities were present in 139 (51.9%), including 77 (28.7%) with homogeneous and heterogeneous lung opacities, 26 (9.7%) with lung nodules, 25 (9.3%) with pleural effusion, 23 (8.6%) with cardiomegaly, and 13 (4.9%) with lymphadenopathy. Among children, radiographic abnormalities were present in 87 (35.2%), including 76 (30.8%) with homogeneous and heterogeneous lung opacities and six (2.4%) with lymphadenopathy. Among adolescents and adults, the presence of opacities was predictive of Streptococcus pneumoniae and Coxiella burnetii, whereas the presence of pulmonary nodules was predictive of Histoplasma capsulatum and Cryptococcus neoformans. CONCLUSIONS: Chest radiograph abnormalities among febrile inpatients are common in northern Tanzania. Chest radiography is a useful adjunct for establishing an aetiologic diagnosis of febrile illness and may provide useful information for patient management, in particular for pneumococcal disease, Q fever, and fungal infections.

Nest-site fidelity in parental male bluegill Lepomis macrochirus: spatial patterns and the influence of prior mating success.

A 4 year mark-recapture study examined the pattern of nesting site fidelity of parental-type male bluegill Lepomis macrochirus. The study results indicated that iteroparous male L. macrochirus choose new nest sites near their own previously used sites. The scale of site fidelity varied, but generally males choose to renest within shoreline areas rather than specific or exact nest locations (94% within-year, 86% among-years). Iteroparous males also displayed no preference to nest in proximity to neighbouring males from previous colonies to suggest social fidelity. Contrary to expectation, manipulating males' reproductive success had no significant effect on the pattern or scale of male reproductive site fidelity.

Microalbuminuria predicts overt proteinuria among patients with HIV infection.

BACKGROUND: This study examines the association between microalbuminuria and the development of proteinuria among HIV-infected persons. METHODS: A total of 948 subjects provided urine samples for albumin, protein and creatinine measurements semiannually. Microalbuminuria was defined as an albumin-to-creatinine ratio of >30 mg/g. Proteinuria was defined as a protein-to-creatinine ratio of > or =0.350 mg/mg. The progression from microalbuminuria to proteinuria was described. RESULTS: At baseline, 69.4% of the subjects had no detectable proteinuria, 20.2% had microalbuminuria, and 10.4% had proteinuria. Subjects with microalbuminuria and proteinuria were more likely to be black (P=0.02), have lower CD4 cell counts (P=0.02 comparing subjects without abnormal urine protein excretion to subjects with microalbuminuria; P=0.0001 comparing subjects with microalbuminuria to subjects with proteinuria), and have a higher HIV RNA level (P=0.08 and 0.04, respectively). Among 658 subjects with normal urine protein, 82.7% continued to have no abnormality, 14.3% developed microalbuminuria, and 3.0% developed proteinuria. Subjects without baseline proteinuria (i.e. either normal protein excretion or microalbuminuria) who developed proteinuria were more likely to have microalbuminuria (P=0.001), a lower CD4 cell count (P=0.06), and a higher plasma HIV RNA (P=0.03) than those who did not progress to proteinuria. In multivariate analysis, only microalbuminuria remained associated with the development of proteinuria (odds ratio 2.9; 95% confidence interval 1.5, 5.5; P=0.001). CONCLUSION: Microalbuminuria predicts the development of proteinuria among HIV-infected persons. Because proteinuria has been linked to poorer outcomes, strategies to affect microalbuminuria should be tested.

Missed opportunities for diagnosis of tuberculosis and human immunodeficiency virus co-infection in Moshi, Tanzania.

SETTING: A community-based voluntary counseling and testing (VCT) center in Moshi, Tanzania. OBJECTIVE: To compare rates of prior human immunodeficiency virus (HIV) testing among clients with and without previous tuberculosis (TB) treatment, and HIV seropositivity among those with and without current TB symptoms. DESIGN: Cross-sectional study of consecutive clients presenting for initial testing; sociodemographic and clinical data were collected via a structured questionnaire. HIV status was compared among clients with or without three or more TB-related symptoms: weight loss, fever, cough, hemoptysis or night sweats. RESULTS: Overall, 225 (3%) of 6583 VCT clients who responded to questions on previous TB treatment reported a history of TB, but only 34 (15%) reported previous HIV testing. This rate of HIV testing was not different from the rate among those clients without a history of TB (OR 0.77, P = 0.175). One hundred thirty-five (61%) clients with a history of TB were HIV-infected at VCT, compared with 17% of all clients. Of the total 6592 first-time testers who responded, 372 (6%) had at least three symptoms suggestive of TB at VCT. These symptoms were strongly associated with HIV seropositivity (OR 16.30, P < 0.001). CONCLUSION: Missed opportunities for HIV diagnosis at the time of TB treatment appear frequent in this population, underscoring the need for integration of TB and HIV diagnostic services.

Morbidity and mortality among a cohort of HIV-infected adults in a programme for community home-based care, in the Kilimanjaro Region of Tanzania (2003-2005).

Community home-based care (CHBC) plays an integral role in the care of HIV-infected patients living in resource-limited regions. A longitudinal cohort study has recently been conducted, in the Kilimanjaro Region of northern Tanzania, in order to identify the components of an effective CHBC programme. Structured questionnaires were administered to clients over two census rounds, one in October 2003-February 2004 and the other in January 2005-October 2005. In the second round, follow-up interviews were completed for 226 (87.9%) of the 257 clients included in the first round. The clients included in the first round had a median (range) age of 38 (20-66) years and 182 (75.2%) of them were female. Although only 27 (12.9%) of them were using antiretroviral therapy (ART) when first interviewed, 108 (44.6%) were taking trimethoprim-sulfamethoxazole (SXT) prophylaxis. By the time of the follow-up interviews, 102 (45.1%) of the clients included in the first round had died, giving a mortality of 51/100 person-years of observation. The primary cause of death for 87 (85.3%) of the clients who had died was respiratory and/or gastro-intestinal infection, and the most common contributory causes of death were malnutrition (81.4%) and anaemia (42.2%). On bivariable analysis, the following first-round conditions were found to be significantly associated with death by the second census round: weakness for >1 month [odds ratio (OR)=2.64; P=0.008]; oral thrush (OR=2.31; P=0.015); painful swallowing (OR=2.02; P=0.036); staying in bed for part of the day over most of the previous month (OR=1.94; P=0.017); fever for >1 month (OR=1.95; P=0.016); and severe bacterial infections (OR=1.80; P=0.036). The high mortality was associated with advanced, symptomatic HIV disease for which antiretroviral therapy was indicated. Clients who were in the advanced stages of HIV disease (as defined by the World Health Organization's criteria) in the first census round were significantly more likely to have died by the time of the second round than the other clients investigated (log-rank chi(2)=8.115; P=0.044). The high level of morbidity observed in this study, and the causes of mortality that were identified, emphasise the need for CHBC programmes to provide HIV-infected patients with improved access to basic resources such as SXT and isoniazid prophylaxis, clean water, oral rehydration therapy, and micronutrient supplementation, in addition to increased access to ART.

Altered innate immunity following spinal cord injury.

STUDY DESIGN: Cross-sectional, paired cohort study. OBJECTIVES: To replicate the finding of impaired immunocyte function following spinal cord injury (SCI). To determine whether cellular immune function in SCI subjects with decentralized sympathetic nervous system (SNS) (T6 and above) varies from SCI subjects with intact SNS (below T6). SETTING: University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark, NJ, USA. METHOD: In vitro immune assays: (1) natural killer (NK) cell cytotoxicity using a K562 target cell line in a 4-h chromium(51) release assay. The mean of three samples for each effector-to-target (E:F) ratio (25:1, 50:1, 100:1) was used in the analyses. (2) Cell enumeration was performed using commercially available antibodies and standard flow cytometry techniques. RESULTS: Participation of 36 SCI subjects and 36 individually age- and sex-matched healthy controls. SCI subjects were stratified into two groups, that is, neurologic level of injury (NLI) at T6 or above (26 subjects) and NLI below T6 (10 subjects). No statistically significant differences were identified between NLI T6 and above and NLI below T6 groups for the NK cytotoxicity assay. There was a statistically significant reduction in NK cell numbers in all subjects with SCI as compared to their paired controls. There was a statistically significant reduction in NK cell cytotoxicity in SCI subjects, relative to the controls for E:F ratio of 100:1 (F=6.18, d.f.=34, P=0.02). CONCLUSION: We replicated the finding of decreased NK cell number and cytotoxicity in SCI subjects. The mechanism behind these findings needs to be further investigated, with the long-term goal of developing therapeutic strategies to improve immune function.

Low sensitivity of T-cell based detection of tuberculosis among HIV co-infected Tanzanian in-patients.

OBJECTIVE: To evaluate the performance of QuantiFERON-TB GOLD (QFTG) in a resource-poor setting among patients with and without HIV infection. DESIGN: Cross-sectional study. SETTING: Two hospitals in Northern Tanzania. SUBJECTS: Eighty three adult male and female inpatients. INTERVENTION: All patients were screened for HIV infection and underwent tuberculin skin test (TST) and QFTG. RESULTS: Eighty-three subjects were enrolled, and 29 (35%) of 83 were HIV-infected. QFTG yielded indeterminate results in 12 (22%; 95% CI 12%-34%) of 54 HIV-uninfected and 13 (45%; 95% CI 26%-64%) of 29 HIV-infected subjects (p = 0.0323). Among those with smear-positive pulmonary tuberculosis, TST was positive in 40 (100%; 95% CI 91%-100%) of 40 HIV-uninfected subjects compared with seven (54%; 95% CI 25%-81%) of 13 HIV-infected subjects (p < 0.0001), and QFTG was positive in 28 (70%; 95% CI 53%-83%) of 40 HIV-uninfected subjects compared with three (23%; 95% CI 5%-54%) of 13 HIV-infected subjects (p = 0.0029). Among medical inpatients at risk for latent tuberculosis infection, TST was positive in seven (50%) of 14 HIV-uninfected patients and three (19%) of 16 HIV-infected patients (p = 0.0701) and QFTG was positive among two (14%) of 14 HIV-uninfected patients and three (19%) of 16 HIV-infected patients (p = 0.7437). CONCLUSIONS: The presence of HIV co-infection was associated with a significant reduction in sensitivity of both the TST (p < 0.0001) and QFTG (p = 0.0029) for the diagnosis of active M. tuberculosis infection. The high proportion of indeterminate QFTG and lack of sensitivity, particularly among HIV-infected patients, may limit its applicability in settings like Tanzania. Larger studies in resource-poor settings are required.

Sociodemographic and clinical characteristics of clients presenting for HIV voluntary counselling and testing in Moshi, Tanzania.

HIV voluntary counselling and testing (VCT) reduces high-risk sexual behaviour. Factors associated with HIV infection in VCT clients have not been well characterized in northern Tanzania. We prospectively surveyed 813 VCT clients in Moshi, Tanzania. Clients were administered a questionnaire on sociodemographic characteristics, sexual behaviour, and health status. Blood was taken for rapid HIV antibody testing. Factors associated with HIV seropositivity were identified using multivariate logistic regression analysis. Of 813 clients, the seroprevalence was 16.7%. The strongest associations with seropositivity were reporting diarrhoea (odds ratio [OR] 10.4, 95% confidence interval [CI] 3.6-29.9), an ill sexual partner (OR 6.3, 95% CI 3.0-12.9), or being a woman (OR 3.5, 95% CI 2.0-6.3). In a separate regression, the number of symptoms also predicted HIV infection (OR 2.1, 95% CI 1.6-2.6). VCT clients who tested positive had more HIV-related symptoms suggesting presentation at a later stage of HIV infection.

HIV-associated morbidity, mortality and diagnostic testing opportunities among inpatients at a referral hospital in northern Tanzania.

Hospitalized patients with HIV infection are among the most likely to benefit from the expanding availability of anti-retroviral therapy in sub-Saharan Africa. Between 1990 and 2000, 3667 people known to be HIV-infected were admitted to Kilimanjaro Christian Medical Centre (KCMC) in Moshi, northen Tanzania. The level of inpatient mortality among these patients varied from 15%-21%, and the proportion of the HIV-infected patients admitted who were female increased significantly, from 45% at the start of the study period to 52% at the end (P <0.001). When the medical records for 1683 of the HIV-infected patients who had been admitted between 1996 and 2001 were reviewed, the most prevalent diagnoses on admission were found to be pulmonary tuberculosis (21%), malaria (14%) and gastro-enteritis/diarrhoea (12%) among the adults, and non-tubercular pulmonary infection (21%), pulmonary tuberculosis (19%) and gastro-enteritis/diarrhoea (12%) among the children. The crude odds ratios (OR) for inpatient death were greatest for adults presenting with meningitis [OR=3.7; 95% confidence interval (CI)=2.1-6.7], septicaemia (OR=2.9; CI=1.2-7.3) or renal disease (OR=2.6; CI=1.2-5.7), and mortality was higher for men than for women (OR=1.4; CI=1.1-1.8). A single-day, point-prevalence survey in September 2001, among the KCMC's inpatients, identified HIV infection in 21% of those surveyed, many (44%) of the patients found positive being previously unaware of their infection. HIV infection remains a major cause of hospitalization and mortality in Moshi. A policy of routine testing would increase the number of HIV infections detected, allowing improvements in case management and in the prevention of infection.

Protease inhibitors are associated with a slowed progression of HIV-related renal diseases.

AIMS: While angiotensin-con-verting enzyme inhibitors and zidovudine may improve the course of the most common HIV-related renal disease, HIV-associated nephropathy (HIVAN), the effect of anti-retroviral combination therapy on this and other HIV-related renal diseases has not been assessed. This study describes the clinical course of HIV-related renal diseases and the effect of protease inhibitors on their progression. METHODS: This retrospective cohort study reviews the clinical course of 19 patients with a clinical or biopsy-proven diagnosis of HIVAN or other HIV-related renal diseases. Groups progressing and not progressing to ESRD were compared using longitudinal analyses to assess the association between creatinine clearance and clinical and therapeutic factors. RESULTS: The cohort consisted of 16 African-Americans, 2 Caucasians and 1 Native American. Their modes of HIV infection were intravenous drug use (7), a history of men having sex with men (3) and heterosexual behavior (5). Patients were followed for a median of 16.6 months. Seven patients reached ESRD. Loss of creatinine clearance over time did not differ among genders, races, or patients with different modes of HIV infection. Longitudinal analyses demonstrated an association between protease inhibitors and prednisone and a slower decline in creatinine clearance in multivariable models (p = 0.04 and 0.003, respectively). CONCLUSIONS: The epidemiology and clinical course of HIV-related renal diseases is more heterogeneous than previously described. This study suggests a benefit to the use of protease inhibitors and prednisone on the progression of these nephropathies.

Addressing the challenges of adherence.

Adherence to antiretroviral therapy is a crucial determinant of treatment success. Studies have unequivocally demonstrated the close association between adherence and plasma HIV RNA levels, CD4 cell counts, and mortality in patients with HIV infection and disease. Adherence levels of > or =95% are required to maintain virologic suppression. However, actual adherence rates are often far lower; most studies show that 40% to 60% of patients are <90% adherent. Adherence also tends to decrease over time. Patients offer a range of reasons for nonadherence, but the most frequently cited one is simply that they forget; other reasons include being away from home, being busy, or experiencing a change in daily routine. Additional barriers to adherence include psychiatric disorders, such as depression or substance use, uncertainty about the effectiveness of treatment and the consequences of poor adherence, regimen complexity, and treatment side effects. Several strategies can be employed in the effort to support patients' adherence, and all members of the multidisciplinary team should ideally employ these strategies in combination. Efforts should be made to educate and motivate patients, simplify treatment regimens and tailor them to individual lifestyles, prepare for and manage side effects, and address the concrete issues that may be a barrier to adherence. Recruiting an adherence monitor, providing memory aids to medication taking, and anticipating course corrections can also help patients achieve the adherence rates needed for successful treatment of HIV infection and disease.

Structured antiretroviral treatment interruptions in chronically HIV-1-infected subjects.

The risks and benefits of structured treatment interruption (STI) in HIV-1-infected subjects are not fully understood. A pilot study was performed to compare STI with continuous highly active antiretroviral therapy (HAART) in chronic HIV-1-infected subjects with HIV-1 plasma RNA levels (VL) <400 copies per ml and CD4(+) T cells >400 per microl. CD4(+) T cells, VL, HIV-1-specific neutralizing antibodies, and IFN-gamma-producing HIV-1-specific CD8(+) and CD4(+) T cells were measured in all subjects. STIs of 1-month duration separated by 1 month of HAART, before a final 3-month STI, resulted in augmented CD8(+) T cell responses in all eight STI subjects (P = 0.003), maintained while on HAART up to 22 weeks after STI, and augmented neutralization titers to autologous HIV-1 isolate in one of eight subjects. However, significant decline of CD4(+) T cell count from pre-STI level, and VL rebound to pre-HAART baseline, occurred during STI (P = 0.001 and 0.34, respectively). CD4(+) T cell counts were regained on return to HAART. Control subjects (n = 4) maintained VL <400 copies per ml and stable CD4(+) T cell counts, and showed no enhancement of antiviral CD8(+) T cell responses. Despite increases in antiviral immunity, no control of VL was observed. Future studies of STI should proceed with caution.

Primary care for patients infected with human immunodeficiency virus: a randomized controlled trial.

OBJECTIVE: To measure the impact of a teaching intervention and to compare process and outcomes of care for HIV-infected patients randomly assigned to a general medicine clinic (GMC) or an infectious disease clinic (IDC) for primary care. DESIGN: Prospective, randomized, controlled trial. SETTING: University hospital in Durham, NC. PATIENTS: Two hundred fourteen consecutive HIV-infected patients presenting for primary care. INTERVENTION: Physicians at the GMC received HIV-related training and evidence-based practice guidelines. MEASUREMENTS: Utilization of services, health-related quality of life, preventive and screening measures, and antiretroviral use for one year. RESULTS: At baseline GMC patients were more likely to be African American (85% vs 71%; P =.03) and had lower baseline CD4+ cell counts than IDC patients (262 +/- 269 vs 329 +/- 275; P =.05). A similar and high proportion of patients in both groups received appropriate preventive care services including Pneumocystis carinii pneumonia (PCP) prophylaxis, pneumococcal vaccination, and antiretroviral therapy. Screening for TB was more frequent in GMC (89% vs 68%; P =.001). In the year following randomization, GMC patients made more visits to the emergency department than IDC patients (1.6 +/- 3.0 vs 0.7 +/- 1.5; P =.05). Hospital use was higher for GMC patients with average length of stay 7.8 +/- 6.3 days compared to 5.7 +/- 3.8 days for IDC patients (P =.01). In analyses, which adjust for potential baseline imbalances, these differences remained. CONCLUSIONS: Targeted education in GMC achieved similar provision of primary care for GMC patients, yet use of health care services was higher for this group. The delivery of adequate primary care is necessary but not sufficient to produce changes in health care utilization.

Overview of the effectiveness of triple combination therapy in antiretroviral-naive HIV-1 infected adults.

AIM: To estimate the effectiveness of triple combination therapy in antiretroviral-naive adults. METHODS: A systematic overview of results from clinical trials involving triple combination therapy with dual nucleoside reverse transcriptase inhibitors (NRTI) and: a protease inhibitor (PI triple); a non-nucleoside reverse transcriptase inhibitor (NNRTI triple); or a third NRTI (triple NUC). Data from 23 clinical trials involving 31 independent treatment groups, 19 unique antiretroviral regimens, and 3257 enrolled patients were included in this study. RESULTS: Median log(10) baseline plasma HIV RNA and CD4 cell count over all trials averaged 4.69 (49,329 copies/ml) and 375 x 10(6) cells/l, respectively. The overall estimated percentage of patients with plasma HIV RNA < or = 400 copies/ml at 24 weeks was 64% [95% confidence interval (CI), 60 to 67%]. The percentages of patients with plasma HIV RNA < or = 50 copies/ml at 48 weeks by drug class were: PI triple, 46% (95% CI, 41 to 52%); NNRTI triple, 51% (95% CI, 43 to 59%); triple NUC, 45% (95% CI, 36 to 54%). The CD4 cell count increase over all trials at 24 and 48 weeks averaged +123 x 10(6) cells/l (95% CI, 111 x 10(6) to 135 x 10(6) cells/l) and +160 x 10(6) cells/l (95% CI, 146 x 10(6) to 175 x 10(6) cells/l), respectively and did not differ between drug classes. In multivariable regression analysis, neither baseline plasma HIV RNA level and CD4 cell count nor treatment regimen predicted plasma HIV RNA < or = 50 copies/ml at week 48. However, pill count was significantly negatively associated with plasma HIV RNA < or = 50 copies/ml at week 48 (P = 0.0085). CONCLUSIONS: The results suggest that three drug regimens containing two NRTI with a PI, a NNRTI, or a third NRTI may provide comparable activity, and practical issues such as daily pill burden should be considered when choosing a treatment regimen.

Immune function in healthy inner-city children.

The importance of investigating immunity in healthy children has been underscored in the last few years by studies of the immune pathology of childhood illnesses, including human immunodeficiency virus. This study reports both ennumerative and functional immune measures in healthy inner city children. A total of 152 of 207 children studied were completely heathy at the time of venipuncture and were included in this study. Laboratory immune batteries were completed (or begun) the same day as venipuncture. Relationships between age, gender, ethnicity, and immunity were then analyzed. We found that gender predicted both the absolute number and the percentage of T cells and helper cells and the percentage of natural killer cells. Total leukocyte counts and percentages of lymphocytes and granulocytes were related to ethnicity, as was the response to mitogen stimulation (concanavalin A and pokeweed mitogen) and phagocytic ability. In conclusion, age, gender, and ethnicity factors were found to contribute to differences in various immune measures in children and require further investigation.

Immunologic profile of human immunodeficiency virus-infected patients during viral remission and relapse on antiretroviral therapy.

A dissociation between plasma human immunodeficiency virus (HIV) RNA levels and CD4(+) cell counts has been reported in patients experiencing viral relapse while receiving antiretroviral therapy. This study compared patients with stable CD4(+) lymphocytes during viral relapse while receiving treatment with patients who had sustained virus suppression. Plasma HIV RNA levels, lymphocyte immunophenotyping, and T cell receptor excision circle (TREC) levels were measured. Naive CD4(+) lymphocyte phenotype and TREC levels were not significantly different in patients with virus suppression or in those who had relapsed. However, CD8(+) lymphocyte activation, including the number and percentage of activated cells and CD38 antibody-binding capacity, was significantly elevated during viral relapse, compared with that in suppressed patients. By multivariable regression analyses, CD8(+) and CD4(+) lymphocyte activation were associated significantly with increasing plasma HIV RNA levels.

Thymopoiesis in HIV-infected adults after highly active antiretroviral therapy.

The thymus of HIV-seropositive patients can enlarge as CD4+ T cell counts increase on highly active anti-retroviral therapy (HAART). This may indicate development of new T cells or represent mature peripheral T cells recirculating to the thymus. To define the etiology of the enlargement, the thymuses of two HIV-infected individuals on HAART were biopsied. For more than 3 years before initiation of HAART, both patients (38 and 41 years of age) had documented CD4+ T lymphopenia. Peripheral blood samples were obtained to assess circulating CD4+ CD45RA+ CD62L+ T cells, which were thought to have recently developed in the thymus. Peripheral blood T cells from both patients and thymocytes from the second patient were also tested for levels of DNA episomes formed during T cell receptor gene rearrangement (T cell receptor rearrangement excision circles, TRECs). With HAART, peripheral blood CD4+ T cell counts increased from approximately 60/mm(3) to 552/mm(3) and 750/mm(3) for patients 1 and 2, respectively. Thymic biopsies from both patients showed normal thymus histology with active thymopoiesis. Percentages of peripheral blood CD4+ CD45RA+ CD62L+ T cells and quantitation of T cell TRECs also reflected active thymopoiesis in both patients. Thus, in these two HIV-seropositive adults examined after initiation of HAART, thymic enlargement represented active thymopoiesis. Thymopoiesis in adult AIDS patients may contribute to immune reconstitution even after prolonged CD4+ T lymphopenia.

The isolation of FOS-1, a gene encoding a putative two-component histidine kinase from Aspergillus fumigatus.

In fungi, two-component histidine kinases are involved in response mechanisms to extracellular changes in osmolarity, resistance to dicarboximide fungicides, and cell-wall assembly. In the human opportunistic fungus, Candida albicans, each of the three histidine kinases plays a role in virulence. Here, we identify, for the first time, a gene, FOS-1, from the human pathogenic fungus Aspergillus fumigatus that predicts a protein with homology to two-component histidine kinases. The predicted FOS-1 protein is highly homologous to bacterial and other fungal histidine kinases in several functional domains, but is divergent at the amino- and carboxy-termini. A mutant lacking the FOS-1 locus, DeltaFOS-1, did not exhibit a detectable defect in either hyphal growth or morphology when grown on solid or liquid medium. However, in liquid medium, conidiophore development of the DeltaFOS-1 mutant was delayed. Compared to wild type, the DeltaFOS-1 strain was neither osmotically sensitive nor sensitive or resistant to a number of nondicarboximide antifungal drugs, but was highly resistant to dicarboximide fungicides and resistant to novozym 234, suggesting that FOS-1p may play a role in the regulation of cell-wall assembly.

Meningococcemia in a patient coinfected with hepatitis C virus and HIV.

We describe the first reported case of meningococcemia in a patient coinfected with hepatitis C virus and HIV. Hypocomplementemia secondary to hepatic dysfunction may have enhanced the patient's susceptibility to meningococcal infection.