Citations

AbstractHepatitis C virus (HCV) was found to replicate in monocytes/macrophages particularly in patients with human immunodeficiency virus type 1 (HIV-1) infection. This study was undertaken to determine whether HIV facilitates HCV infection of native human macrophages in vitro. Monocytes/macrophages were collected from healthy donors, infected with HIV M-tropic molecular clone, and then exposed to HCV-positive sera. Presence of positive and negative HCV RNA strands was determined with a novel strand-specific quantitative real-time reverse transcription–polymerase chain reaction (RT-PCR). Preceding as well as near-simultaneous infection with HIV made the macrophages more susceptible to infection with HCV; in particular, an HCV RNA–negative strand was detectable almost exclusively in the setting of concomitant HIV infection. Furthermore, HCV RNAload correlated with HIV replication level in the early stage of infection. The ratio of positive to negative strand in macrophages was lower than in control liver samples. HIV infection was also found to facilitate HCV replication in a Daudi B-cell line with engineered CD4 expression. It seems that HIV infection can facilitate replication of HCV in monocytes/macrophages either by rendering cells more susceptible to HCV infection or by increasing HCV replication. This could explain the presence of extrahepatic HCV replication in HIV-coinfected individuals.

ABSTRACTMice immunized with irradiatedOnchocerca volvulusthird-stage larvae developed protective immunity. Eosinophil levels were elevated in the parasite microenvironment at the time of larval killing, and measurements of total serum antibody levels revealed an increase in the immunoglobulin E (IgE) level in immunized mice. The goal of the present study was to identify the role of granulocytes and antibodies in the protective immune response to the larval stages ofO. volvulusin mice immunized with irradiated larvae. Immunity did not develop in mice if granulocytes, including both neutrophils and eosinophils, were eliminated, nor did it develop if only eosinophils were eliminated. Moreover, larvae were killed in naïve interleukin-5 transgenic mice, and the killing coincided with an increase in the number of eosinophils and the eosinophil peroxidase (EPO) level in the animals. To determine if EPO was required for protective immunity, mice that were genetically deficient in EPO were immunized, and there were no differences in the rates of parasite recovery in EPO-deficient mice and wild-type mice. Two mouse strains were used to study B-cell function; μMT mice lacked all mature B cells, and Xid mice had deficiencies in the B-1 cell population. Immunity did not develop in the μMT mice but did develop in the Xid mice. Finally, protective immunity was abolished in mice treated to eliminate IgE from the blood. We therefore concluded that IgE and eosinophils are required for adaptive protective immunity to larvalO. volvulusin mice.

Giant cell arteritis (GCA) is a granulomatous and occlusive vasculitis that causes blindness, stroke, and aortic aneurysm. CD4+ T cells are selectively activated in the adventitia of affected arteries. In human GCA artery–severe combined immunodeficiency (SCID) mouse chimeras, depletion of CD83+ dendritic cells (DCs) abrogated vasculitis, suggesting that DCs are critical antigen-presenting cells in GCA. Healthy medium-size arteries possessed an indigenous population of DCs at the adventitia–media border. Adoptive T cell transfer into temporal artery–SCID mouse chimeras demonstrated that DCs in healthy arteries were functionally immature, but gained T cell stimulatory capacity after injection of lipopolysaccharide. In patients with polymyalgia rheumatica (PMR), a subclinical variant of GCA, adventitial DCs were mature and produced the chemokines CCL19 and CCL21, but vasculitic infiltrates were lacking. Human histocompatibility leukocyte antigen class II–matched healthy arteries, PMR arteries, and GCA arteries were coimplanted into SCID mice. Immature DCs in healthy arteries failed to stimulate T cells, but DCs in PMR arteries could attract, retain, and activate T cells that originated from the GCA lesions. We propose that in situ maturation of DCs in the adventitia is an early event in the pathogenesis of GCA. Activation of adventitial DCs initiates and maintains T cell responses in the artery and breaks tissue tolerance in the perivascular space.

Background— Diabetes portends an adverse prognosis in patients undergoing percutaneous coronary intervention (PCI). Whether improvements in current clinical practice (stents, IIb/IIIa antagonists) have resulted in substantial improvement of these outcomes remains an issue. The aim of this study was to determine the influence of diabetes on 9-month outcomes of patients undergoing PCI in the current era. Methods and Results— The 11 482 patients enrolled in the Prevention of REStenosis with Tranilast and its Outcomes (PRESTO) Trial were stratified according to the presence (n=2694) or absence (n=8798) of diabetes. Diabetic patients were older; were more likely to be female; had a higher proportion of congestive failure, hypertension, prior CABG, and unstable angina; and had higher body mass index and lower ejection fraction than nondiabetic patients ( P <0.01 for all comparisons). The degree of multivessel disease was similar between the two groups. American College of Cardiology/American Heart Association type C lesions were more common in diabetic patients (17% versus 15%, P <0.01). Angiographic and procedural success rates and in-hospital events were similar between the two groups. The primary end point of death, myocardial infarction, or target vessel revascularization (TVR) was analyzed as time-to-first event within 9 months of the index PCI. After adjusting for certain baseline characteristics, diabetes was independently associated with death at 9 months (relative risk [RR], 1.87; 95% CI, 1.31 to 2.68, P <0.01) and with an increased likelihood of TVR (RR, 1.27; 95% CI, 1.14 to 1.42, P <0.01), as well as the composite end point of death/myocardial infarction/TVR (RR, 1.26; 95% CI, 1.13 to 1.40, P <0.01). Conclusions— Despite advances in interventional techniques, diabetes remains a significant independent predictor of adverse events in the intermediate term after PCI.

Purpose This review provides an update on the current understanding of the clinical cardiac tolerability of trastuzumab, a humanized monoclonal antibody effective in the treatment of patients with advanced breast cancer overexpressing or amplifying HER2. Methods and Results We produced a summary of currently available information regarding the incidence and natural history of trastuzumab-associated cardiac dysfunction. Data from new, prospective clinical studies that incorporate close cardiac monitoring and standardized follow-up in patients with either advanced or earlier stages of breast cancer are also presented, and hypotheses regarding potential mechanisms of trastuzumab-related cardiotoxicity are discussed. Patients treated with trastuzumab in the pivotal trials were found to have increased risk for cardiac dysfunction, mostly when used concurrent with anthracyclines. Recent trials have required more stringent and consistent cardiac monitoring criteria and excluded patients with abnormal cardiac function, pre-existing heart disease, and/or high cumulative doses of anthracyclines. Decreases of ejection fraction and a few cases of congestive heart failure (CHF) requiring medical therapy have been detected. Improvements in ejection fraction and the symptoms of CHF have been subsequently noted in a significant number of these patients. Conclusion Trastuzumab is associated with an increased risk of asymptomatic decreases in ejection fraction, and, in a small number of patients, CHF that is almost always responsive to medical management. This risk is greatest in patients receiving concurrent anthracyclines. More data are needed to help elucidate the pathophysiology of this syndrome.

Purpose Few options are available for pain relief in patients with bone metastases who fail standard treatments. We sought to determine the benefit of radiofrequency ablation (RFA) in providing pain relief for patients with refractory pain secondary to metastases involving bone. Patients and Methods Thirty-one US and 12 European patients with painful osteolytic metastases involving bone were treated with image-guided RFA using a multitip needle. Treated patients had ≥ 4/10 pain and had either failed or were poor candidates for standard treatments such as radiation or opioid analgesics. Using the Brief Pain Inventory–Short Form, worst pain intensity was the primary end point, with a 2-unit drop considered clinically significant. Results Forty-three patients were treated (median follow-up, 16 weeks). Before RFA, the mean score for worst pain was 7.9 (range, 4/10 to 10/10). Four, 12, and 24 weeks following treatment, worst pain decreased to 4.5 (P < .0001), 3.0 (P < .0001), and 1.4 (P = .0005), respectively. Ninety-five percent (41 of 43 patients) experienced a decrease in pain that was considered clinically significant. Opioid usage significantly decreased at weeks 8 and 12. Adverse events were seen in 3 patients and included (1) a second-degree skin burn at the grounding pad site, (2) transient bowel and bladder incontinence following treatment of a metastasis involving the sacrum, and (3) a fracture of the acetabulum following RFA of an acetabular lesion. Conclusion RFA of painful osteolytic metastases provides significant pain relief for cancer patients who have failed standard treatments.