Comparative analysis of FV vectors with human α- or ß-globin gene regulatory elements for the correction of ß-thalassemia.

ß-Globin locus control region (LCR) sequences have been widely used for the regulated expression of the human ß-globin gene in therapeutic viral vectors. In this study, we compare the expression of the human ß-globin gene from either the HS2/HS3 ß-globin LCR or the HS40 regulatory element from the α-globin locus in the context of foamy virus (FV) vectors for the genetic correction of ß-thalassemia. Both regulatory elements expressed comparable levels of human ß-globin in a murine erythroleukemic line, whereas in murine hematopoietic stem cells the HS40.ß vector proved more efficient in ß-globin expression and correction of the ß-thalassemia phenotype. Following transplantation in the Hbb(th3/+) mouse model, the expression efficiency by the two vectors was similar, whereas the HS40.ß vector achieved relatively more stable transgene expression. In addition, in an ex vivo assay using CD34+ cells from thalassemic patients, both vectors achieved significant human ß-globin expression and restoration of the thalassemic phenotype as evidenced by enhanced erythropoiesis and decreased apoptosis. Our data suggest that FV vectors with the α-globin HS40 element can be used as alternative but equally efficient vehicles for human ß-globin gene expression for the genetic correction of ß-thalassemia.

Formal adult infectious disease specialist consultations in the outpatient setting at a comprehensive cancer center (1998-2008): diverse and impactful.

PURPOSE: The literature on the impact of infectious disease (ID) consulations in the outpatient treatment of cancer is scarce. METHODS: The medical records of consecutive adult patients with cancer formally evaluated by two board-certified ID specialists in an outpatient setting at our institution over a 10-year period (1998-2008) were reviewed retrospectively. The patients' demographics, referring departments, purposes for consultation, ID specialist recommendations, and overall impact of consultations on outcome were analyzed. RESULTS: We identified 598 patients who underwent ID specialist consultations. Most of them had solid tumors (53%), predominantly breast cancer, whereas non-Hodgkin's lymphoma was the most common hematologic malignancy. Almost half of the patients (45%) had active malignancies, but few of them were severely neutropenic (8%) or had been receiving high doses of corticosteroids (17%). The most frequent requests for consultation were culture or serologic test (15%), and treatment of cellulitis and/or surgical wound infections (14%). Of 337 isolated pathogens, the most prevalent were methicillin-resistant Staphylococcus aureus (13%) and Pseudomonas aeruginosa (8%), as well as atypical mycobacteria (16%) and Aspergillus species (11%). ID specialists provided alternative diagnoses in 53% of the cases, including identification of a different infection (46%), a noninfectious etiology (29%), colonization (16%), and drug-related toxic effects (9%). Overall, we deemed the contribution of the ID specialist to be significant in 62% of the consultations. CONCLUSIONS: ID specialists contribute significantly to the outpatient care of individuals with cancer.

Voriconazole-associated zygomycosis: a significant consequence of evolving antifungal prophylaxis and immunosuppression practices?

Mucormycosis (zygomycosis) is an uncommon infection that afflicts severely immunocompromised patients and those with poorly controlled diabetes mellitus. A recent increase in the incidence of mucormycosis at many transplant centres has been linked to the introduction and widespread use of voriconazole prophylaxis in these high-risk populations. However, it is not known if this association reflects a true epidemiological link or represents a marker of changing immunosuppression occurring in parallel with the evolution of transplant practices and immunosuppression strategies.