Expression of transferrin receptor 2 in normal and neoplastic hematopoietic cells.

Iron is essential for cell proliferation, heme synthesis, and a variety of cellular metabolic processes. In most cells, transferrin receptor-mediated endocytosis is a major pathway for cellular iron uptake. Recently, transferrin receptor 2 (TfR2), another receptor for transferrin, was cloned. High levels of expression of TfR2 messenger RNA (mRNA) occur in the liver, as well as in HepG2 (a hepatoma cell line) and K562 (an erythroid leukemia cell line). In this study, TfR2 mRNA expression was analyzed in hematological cell lines, normal erythroid cells at various stages of differentiation, and leukemia and preleukemia cells. High levels of TfR2 expression occurred in all of the erythroid cell lines that were examined. Erythroid-specific expression of TfR2 protein in bone marrow cells was confirmed by immunohistochemical staining. Expression of TfR2 mRNA was high in normal CD34(+) erythroid precursor cells, and levels decreased during erythroid differentiation in vitro. Levels of expression of TfR2-alpha mRNA were significantly higher in erythroleukemia (M6) marrow samples than in nonmalignant control marrow samples. In addition, relatively higher levels of TfR2-alpha mRNA expression occurred in some samples of myelodysplastic syndrome that had erythroid hyperplasia in bone marrow, acute myelogenous leukemia M1, M2, and chronic myelogenous leukemia. Expression profiles of normal members of the erythroid lineage suggest that TfR2-alpha may be a useful marker of early erythroid precursor cells. The clinical significance of TfR2-alpha expression in leukemia cells remains to be determined.     

Methotrexate for immunosuppression in life-supporting pig-to-cynomolgus monkey renal xenotransplantation

Methotrexate (MTX) has been used successfully as an immunosuppressant in rodent xenotransplantation models, but the data generated so far with MTX in pig-to-baboon cardiac transplantation studies have been disappointing. The potential of this agent was consequently explored in a life-supporting pig-to-primate renal model using the cynomolgus monkey as the recipient species. Introductory in vitro and in vivo pharmacokinetic and pharmacodynamic studies with MTX were conducted in three cynomolgus monkeys. Subsequently, 10 cynomolgus monkey recipients of a life-supporting kidney from human decay-accelerating factor transgenic pigs were administered MTX intravenously according to three different regimens. All the animals also received cyclosporine A and steroids. In addition, mycophenolate sodium (MPS) was administered post-operatively in two of the three groups of transplanted animals. At clinically relevant concentrations, MTX is able in vitro to inhibit the mixed lymphocyte reactions (MLR) in cynomolgus monkeys. After intravenous administration, moreover, exposure of cynomolgus monkeys to MTX appeared to be higher than had been previously reported in baboons. Graft function was observed in the transplanted animals, which survived from 0 to 41 days. All but two animals revealed acute humoral rejection in the explanted graft and developed diarrhea. Diarrhea was the cause of euthanasia in five cases. It was unrelated to the administration of MPS and associated with severe histopathological signs of enteritis. This study demonstrates that the pharmacokinetic and pharmacodynamic profiles if MTX vary substantially between non-human primate species. In vitro, MTX has immunosuppressive properties in the cynomolgus monkey at clinically relevant concentrations. In vivo, MTX has a very narrow therapeutic window in cynomolgus monkeys, however, as it does in baboons. We conclude that MTX is scarcely effective as an immunosuppressant, be it for induction or maintenance, in pig-to-cynomolgus monkey renal xenotransplantation.     

Analysis of CO<Subscript>2</Subscript> monitoring data demonstrates poor ventilation rates in Albanian schools during the cold season

Poor ventilation in schools is associated with accumulation of indoor-generated pollutants, which is associated with “stuffy” air, elevated risk of infectious diseases and impaired learning outcomes. This survey in Albania was conducted as part of WHO’s efforts to facilitate assessments of indoor air quality and other environmental factors in schools in the European Region. The survey was conducted in 36 classrooms in 12 middle schools (eight urban and four rural) from December 2011 through March 2012. In each school, carbon dioxide (CO₂) was continuously measured in three classrooms during one school week. Ventilation rates during classes were estimated using the build-up and steady-state mass balance equations utilizing CO₂ concentration data, classroom occupancy and classroom volume. All 12 schools had gravimetric ventilation systems. Heating systems were absent or not operational in most schools. Average classroom temperatures during lessons varied from 9.1 to 14.4 °C (median 11.7 °C) with lower temperature associated with poorer ventilation. Weekly average CO₂ levels during classes ranged from 1286 to 5546 ppm (median 2776 ppm) while average ventilation rates ranged from 0.8 to 3.6 (median 1.8) litres per second per person. Classrooms with indoor combustion heaters had higher indoor temperature, lower CO₂ levels and higher levels of carbon monoxide (CO). WHO guidelines on 1- and 8-h CO exposure levels were exceeded in one classroom. Classroom CO₂ levels were substantially above and ventilation rates below existing national and international guidelines. Detrimental impacts of poor ventilation on health and learning outcomes are likely to be substantial in Albanian schools during the cold season. Indoor temperature in most classrooms was below the commonly recommended levels.     

New treatment strategies for HIV-positive cancer patients undergoing antiblastic chemotherapy

Introduction: The introduction of Highly Active Antiretroviral Therapy (HAART) into clinical practice has dramatically changed the outcome of HIV-infected patients by prolonging their survival. The increase in life expectancy has led to an increased risk of non-AIDS-related mortality and morbidity, including cardiovascular diseases, neurocognitive diseases, neuroendocrine dysfunctions and cancer.

Areas covered: The GICAT (Italian Cooperation Group on AIDS and Tumors) has demonstrated that patients who receive a multidisciplinary approach with the combination of anticancer agents (AC) and HAART can achieve better responses and survival rates than patients who receive AC alone. The first obstacle for the oncologist to plan treatment for cancer HIV-patients is the preliminary evaluation of drug-drug interactions between AC and HAART. Recent progress in pharmacogenomics could provide a new approach for personalized treatments. The rationale of this review is to summarize the existing data on the impact of HAART on the clinical management of cancer patients with HIV/AIDS and DDIs between antiretrovirals and AC. In addition, to maximize the efficacy of both concomitant therapy and to minimize the risk of DDIs, a currently useful list of pharmacogenomic markers of key metabolic enzymes is provided.

Expert opinion: In this scenario, the importance of cooperation between oncologists and other health specialists (i.e., infectivologists, pharmacists, genetics and lab specialists) must not be underestimated in the management of these patients with the aim of planning an individual treatment strategy.     

Saccular trilobed aneurysm of azygos anterior cerebral artery

Multiple saccular or giant aneurysms of azygos anteriorcerebral artery(AACA) at the distal segments A2-A5 are very rarely reported. Distal anterior cerebral artery(DACA) aneurysms represent approximately 2%-7% of all cerebral aneurysms. We present the case of an Albanian 62-year-old male, admitted at our service after sudden onset of severe headache and vomiting. Computerized tomography(CT) of the head showed hemorrhage in the front of corpus callosum. CT angiography followed by digitally subtracted angiography(DSA) documented a large necked aneurysm with three lobes at the origin of calloso-marginal artery and a single DACA, also known as AACA. A frontal parasagittal craniotomy was performed. Obliteration of the aneurysm was done only by separate clipping of each three lobes at the respective neck. Postoperative DSA demonstrated complete exclusion of the aneurysm and a regular flow of AACA. The patient recovered uneventfully. Despite it is a rare occurrence, an aneurysm of distal segments of anterior cerebral artery A2-A5, concomitant to AACA should be studied with DSA. In the era of embolization, conserving good microsurgical skills is fundamental for dealing with multilobar cerebral aneurysms, associated with rare anatomical variations.