Can the KG1 cell line be used as a model of dendritic cells and discriminate the sensitising potential of chemicals?

The KG1 myeloid leukaemia was used as source of dendritic cells (DC) to discriminate between respiratory and contact sensitising chemicals. A cocktail of cytokines was used to differentiate KG1 to dendritic like cells (termed dKG1) and the effects of nine chemicals (respiratory and contact sensitisers) and an irritant control on surface marker expression, 'antigen presenting' function and cytokine expression investigated. The stability of these chemicals when dissolved was characterised using MALDI ToF MS. A Hill plot model was used with the cellular viability data to quantify the lethal dose 50% (LD50) and a maximum sub toxic concentration of each chemical defined. Cytokine expression by the treated dKG1 was quantified using multiplex immunobead analysis. Whilst dKG1 cells were morphologically similar to DCs, expression of specific surface markers was not typical for DCs derived from healthy precursor cells. When the chemicals were applied at defined sub toxic doses no effects on dKG1 phenotype, function, or cytokine expression, attributable to the sensitisation properties were discriminated. However, dKG1 cells were much more sensitive to the toxic effects of these chemicals compared to the parent KG1 cells. Only 4 of the 9 chemicals tested were stable when dissolved indicating that the effect of sensitising chemicals on antigen presenting cells may be related to species other than the parent compound.

Disseminated nocardia cyriacigeorgica presenting as right lung abscess and skin nodule.

Nocardia species are ubiquitous in the environment and can be found worldwide. Direct inhalation remains the most commonly attributed route of infection with Nocardia asteroides complex, causing 50% of invasive infections. Improved molecular methods have identified a significant proportion of N. asteroides complex isolates to be Nocardia cyriacigeorgica. We report a case of a 58-year-old male working as a contractor in Bagram Air Force Base, Afghanistan, with disseminated N. cyriacigeorgica involving the lung, brain, and dermis. Diagnosis was facilitated by early identification of branched, filamentous bacteria using Fite and gram staining along secA DNA sequencing of clinical isolates. Our patient is the first confirmed case of N. cyriacigeorgica infection in Afghanistan.

Cutaneous malignancies among HIV-infected persons.

BACKGROUND: As the life expectancy of persons infected with human immunodeficiency virus (HIV) increases, cancers have become an important cause of morbidity and mortality. Although cutaneous cancers are the most common malignant neoplasms in the general population, little data exist among HIV-positive persons, especially regarding the impact of HIV-specific factors. METHODS: We evaluated the incidence rates and factors associated with the development of cutaneous malignancies among HIV-infected persons by examining data that were prospectively collected from a large HIV study that included 4490 participants (1986-2006). Poisson regression and Cox proportional hazards models were performed. RESULTS: Six percent of HIV-infected persons (n = 254) developed a cutaneous malignancy during 33 760 person-years of follow-up (mean, 7.5 years). Since the advent of highly active antiretroviral therapy (HAART), the incidence rates of cutaneous non-AIDS-defining cancers (NADCs), in particular basal cell carcinoma, have exceeded the rates of cutaneous AIDS-defining cancers such as Kaposi sarcoma. Factors associated with the development of cutaneous NADCs in the multivariate models included increasing age (hazard ratio [HR], 2.1; 95% confidence interval [CI], 1.7-2.6) and race. Compared with the white/non-Hispanic race, African Americans (HR, 0.03; 95% CI, 0.01-0.14) and other races (HR, 0.14; 95% CI, 0.03-0.57) had a lower risk of cutaneous NADCs. There were no significant associations between cutaneous NADCs and time-updated CD4 lymphocyte counts, HIV RNA levels, or receipt of HAART. CONCLUSIONS: At present, the most common cutaneous malignancies among HIV-infected persons are NADCs. Cutaneous NADCs do not appear to be significantly associated with immune function or HAART but rather are related to traditional factors such as aging and skin color.

The impact of nelfinavir exposure on cancer development among a large cohort of HIV-infected patients.

BACKGROUND: Preclinical studies suggest that the antiretroviral agent, nelfinavir mesylate (NFV), may have antineoplastic properties. The relationship between NFV and cancer incidence among HIV-infected patients is unknown. METHODS: We evaluated the impact of NFV on cancer development in a large cohort of HIV-infected persons with 108 cancer events during 13,421 person-years of follow-up. Using multivariate time-updated Cox proportional hazard models, the risk of cancer among those receiving NFV were compared to those on non-NFV antiretroviral regimens. RESULTS: The risk of cancer among those receiving NFV was similar to those on non-NFV antiretroviral regimens (hazard ratio 1.0, 95% confidence interval 0.5, 1.7, P = 0.90). We also examined AIDS-defining and non-AIDS-defining cancers separately and found no significant associations between NFV use and cancer risk. Antiretroviral use, with or without a protease inhibitor (PI) component, was associated with a reduced risk of AIDS-defining cancers compared with no antiretroviral therapy; however, the risk of cancer was the same among those using PI or PI-sparing regimens. DISCUSSION: Despite reports that NFV may have tumoricidal activity, we found no significant relationship between NFV or PI use compared with other antiretrovirals and the risk of developing cancer among a large cohort of HIV-infected persons.

Is HIV becoming more virulent? Initial CD4 cell counts among HIV seroconverters during the course of the HIV epidemic: 1985-2007.

BACKGROUND: Whether human immunodeficiency virus (HIV) seroconverters have been presenting with progressively lower CD4 cell counts over the course of the HIV epidemic is controversial. Additional data on whether HIV might have become more virulent on a population level (measured by post-seroconversion CD4 cell counts) may provide important insights regarding HIV pathogenesis. METHODS: To determine whether post-seroconversion CD4 cell counts have changed over time, we evaluated 2174 HIV seroconverters as part of a large cohort study during the period 1985-2007. Participants were documented antiretroviral-naive HIV seroconverters who had a CD4 cell count measured within 6 months after receiving a diagnosis of HIV infection. Multiple linear regression models were used to assess trends in initial CD4 cell counts. RESULTS: The mean initial CD4 cell count decreased during the study period from 632 cells/mm(3) in 1985-1990 to 553 cells/mm(3) in 1991-1995, 493 cells/mm(3) in 1996-2001, and 514 cells/mm(3) in 2002-2007. During those periods, the percentages of seroconverters with an initial CD4 cell count <350 cells/mm(3) were 12%, 21%, 26%, and 25%, respectively. In the multiple linear model, the mean decrease in CD4 cell count from 1985-1990 was 65 cells/mm(3) in 1991-1995 (P < .001)), 107 cells/mm(3) in 1996-2001 (P < .001), and 102 cells/mm(3) in 2002-2007 (P < .001). Similar trends occurred with regard to CD4 cell percentage and total lymphocyte count. Similar decreases in initial CD4 cell counts were observed among African American and white persons during the epidemic. DISCUSSION: A significant decrease in initial CD4 cell counts among HIV seroconverters in the United States has occurred during the HIV epidemic. These data provide an important clinical correlate to suggestions that HIV may have adapted to the host, resulting in a more virulent infection.

Trends in the incidence of cancers among HIV-infected persons and the impact of antiretroviral therapy: a 20-year cohort study.

OBJECTIVE: To describe trends in incidence rates of AIDS-defining cancers (ADCs) and non-AIDS-defining cancers (NADCs) during the HIV epidemic and to evaluate predictors, including the impact of antiretroviral therapy, of cancer development. DESIGN: Retrospective analysis of a multicenter, prospective natural history study including 4498 HIV-infected US military beneficiaries with 33 486 person-years of follow-up. METHODS: Predictors evaluated included demographics, clinical data, time-updated CD4 cell counts, HIV viral loads, and antiretroviral history. Time periods were classified as early pre (1984-1990), late pre (1991-1995), early post (1996-2000), and late post (2001-2006) HAART eras. Cox proportional hazard models were used to evaluate the association of specific factors with cancer. RESULTS: Ten percent of HIV-infected persons developed cancer. ADC rates increased between the early and late pre-HAART eras (7.6 and 14.2 cases per 1000 person-years) and have since declined from 5.4 to 2.7 in the early and late HAART eras, respectively (P < 0.001). Rates of NADCs have risen over the four periods (2.9, 2.8, 4.2, 6.7, P = 0.0004). During the late HAART era, 71% of cancers were NADCs. Predictors for ADCs included low CD4 cell count, noncancer AIDS diagnosis, and lack of HAART. NADCs were predicted by increasing age and white race (due to skin cancers). CONCLUSION: Although the rate of ADCs continues to fall, the rate of NADCs is rising and now accounts for the majority of cancers in HIV-infected persons. The development of NADCs is associated with increasing age among HIV patients. HAART use is protective for ADCs, but did not significantly impact NADCs.

Telemedicine via satellite to support offshore oil platforms.

On any one day, approximately 15,000-28,000 oil industry personnel are employed in the North Sea oil and gas industry. First aid in this remote environment is provided by non-medical staff on the rigs. Remote specialist advice via videoconferencing should improve the quality of offshore health care and reduce avoidable medical evacuations. Satellite communications and videoconferencing equipment was installed on the 'Alwyn North' oil platform, with medical advice provided via a call centre in Milan. Over a nine-month period, trial telemedicine links were conducted approximately twice per week. The three onshore physicians were very satisfied on each occasion with communications and diagnostic data image quality, including the ultrasound screening carried out by the rig provider. Remote specialist advice via videoconferencing should reduce unnecessary and/or untimely patient evacuation to hospital or onshore for medical assessment.

A low-cost decision support network for electrocardiograph transmission from oil rigs in the North Sea.

A telemedicine service consisting of electrocardiogram (ECG) interpretation and advice on the management of chest pain offshore was offered to oil rig installations in the North Sea. A total of 14 subscribing oil rigs were supplied with thrombolytic drugs and rig paramedics were trained in their delivery. Electrocardiographs could be recorded using a standard ECG machine and then digitized using a scanner for transmission as an email attachment. Several oil companies invested in ECG equipment which allowed direct recording of the patient's ECG in electronic form for transmission by email. Uptake of the telemedicine service was very rapid. The majority of rig medics found the system very easy to use. During a 36-month study period from August 2004, 47 cases of chest pain were dealt with by telemedicine. Of these 47 cases, only six patients (13%) were airlifted to shore. The 41 remaining ECGs did not to have acute changes requiring immediate evacuation. The use of email for ECG transmission proved to be highly effective in managing chest pain offshore.

Fatal pulmonary Mycobacterium abscessus infection in a patient using etanercept.

A case of fatal pulmonary Mycobacterium abscessus infection in a 56-year-old man is reported. The patient had a longstanding history of seropositive, nodular rheumatoid arthritis with severe joint manifestations that had been treated with a regimen of prednisone, leflunomide, and etanercept. He presented to our facility with complaint of productive cough, persistent fevers, pleuritic chest discomfort, and dyspnea at rest. The patient was admitted to hospital, placed in isolation, a left-sided chest tube was inserted (left pneumothorax identified), and sputum acid-fast bacteria stains and cultures were obtained. Fluorochrome stains demonstrated numerous acid-fast bacteria, and M. abscessus was recovered from the culture media. He was treated with a regimen of amikacin, cefoxitin, and clarithromycin. He initially responded well, and was discharged home with this regimen. He remained afebrile with decreased cough and sputum production until 15 days after discharge when he was again admitted to hospital, with acute onset dyspnea and right-sided chest discomfort (right pneumothorax identified). He ultimately expired, due to overwhelming pulmonary infection, 20 days after readmission to hospital. Autopsy revealed acid fast bacilli in the setting of numerous, bilateral, necrotic, granulomatous, cavitary pulmonary lesions. Based on its mechanism of action, we propose an association between the use of etanercept, a tumor necrosis factor alpha (TNF-alpha) inhibitor, and this case of fatal pulmonary mycobacterial infection. We recommend that physicians exercise cautious clinical judgment when initiating etanercept therapy in persons with underlying lung disease, especially in communities in which mycobacterial organisms are highly prevalent. We also advise physicians to maintain a high level of vigilance for late onset granulomatous infection in persons using etanercept.

Comparisons of causes of death and mortality rates among HIV-infected persons: analysis of the pre-, early, and late HAART (highly active antiretroviral therapy) eras.

METHODS: Comparisons of death-related variables during the 3 eras were performed. RESULTS: The number of deaths declined over the study period, with 987 deaths in the pre-HAART era, 159 deaths in the early HAART era (1997-1999), and 78 deaths in the late HAART era (2000-2003) (P < 0.01). The annual death rate peaked in 1995 (10.3 per 100 patients) and then declined to <2 deaths per 100 persons in the late HAART era (P < 0.01). The proportion of deaths attributable to infection decreased, but infection remained the leading cause of death in our cohort, followed by cancer. Of those who died, there was an increasing proportion of non-HIV-related deaths (32% vs. 9%; P < 0.01), including cardiac disease (22% vs. 8%; P < 0.01) and trauma (8% vs. 2%; P = 0.01) in the post-HAART versus pre-HAART era. Despite the absence of intravenous drug use and the low prevalence of hepatitis C coinfection in our cohort, an increasing proportion of deaths in the HAART era were attributable to liver disease, although the numbers are small. CONCLUSIONS: Despite increasing concerns regarding antiretroviral resistance, the death rate among HIV-infected persons in our cohort continues to decline. Our data show a lower death rate than that reported among many other US HIV-infected populations; this may be the result of open access to health care. A shift in the causes of death toward non-HIV-related causes suggests that a more comprehensive health care approach may be needed for optimal life expectancy; this may include enhanced screening for malignancy and heart disease as well as preventive measures for liver disease and accidents.

Incidence and risk factors for the occurrence of non-AIDS-defining cancers among human immunodeficiency virus-infected individuals.

BACKGROUND: The objective of this study was to determine the rates and predictors of non-AIDS-defining cancers (NADCs) among a cohort of human immunodeficiency virus (HIV)-infected individuals. METHODS: The authors conducted a retrospective study of 4144 HIV-infected individuals who had 26,916 person-years of follow-up and who had open access to medical care at 1 of the United States military HIV clinics during the years 1988-2003. Cancer incidence rates were race specific and were adjusted for age; these were compared with national rates using logistic regression to assess predictors of NADC development. RESULTS: One hundred thirty-three NADCs were diagnosed with a rate of 980 diagnoses per 100,000 person-years. The most frequent NADCs were skin carcinomas (basal cell and squamous cell), Hodgkin disease, and anal carcinoma. The results showed that there were higher rates of melanoma, basal and squamous cell skin carcinomas, anal carcinoma, prostate carcinoma, and Hodgkin disease among the HIV-infected cohort compared with age-adjusted rates for the general United States population. Predictors of NADCs included age older than 40 years (odds ratio [OR], 12.2; P < 0.001), Caucasian/non-Hispanic race (OR, 2.1; P < 0.001), longer duration of HIV infection (OR, 1.2; P < 0.001), and a history of opportunistic infection (OR, 2.5; P < 0.001). The use of highly active antiretroviral therapy (HAART) was associated with lower rates of NADCs (OR, 0.21; P < 0.001). A low CD4 nadir or CD4 count at diagnosis (< 200 cells/mL) was not predictive of NADCs. CONCLUSIONS: The most frequent NADCs were primary skin malignancies. Melanoma, basal and squamous cell skin carcinomas, anal carcinoma, prostate carcinoma, and Hodgkin disease occurred at higher rates among HIV-infected individuals. The implementation of screening programs for these malignancies should be considered. Most risk factors for the development of NADCs are nonmodifiable; however, the use of HAART appeared to be beneficial in protecting against the development of malignant disease.

Hemophagocytic lymphohistiocytosis: a rare cause of pancytopenia.

A 36-year-old man with fever and pancytopenia due to Hemophagocytic Lymphohistiocytosis is reported. The patient was started on the HLH-94 based treatment. Two weeks after the initiation of therapy the patient's pancytopenia had resolved and he was discharged to complete treatment as an outpatient. The initial clinical presentation, diagnostic criteria, pathophysiology and treatment will be discussed.