A Semliki forest virus vector engineered to express IFNα induces efficient elimination of established tumors.

Semliki Forest virus (SFV) represents a promising gene therapy vector for tumor treatment, because it produces high levels of recombinant therapeutic proteins while inducing apoptosis in infected cells. In this study, we constructed a SFV vector expressing murine interferon alpha (IFNα). IFNα displays antitumor activity mainly by enhancing an antitumor immune response, as well as by a direct antiproliferative effect. In spite of the antiviral activity of IFNα, SFV-IFN could be produced in BHK cells at high titers. This vector was able to infect TC-1 cells, a tumor cell line expressing E6 and E7 proteins of human papillomavirus, leading to high production of IFNα both in vitro and in vivo. When injected into subcutaneous TC-1 tumors implanted in mice, SFV-IFN was able to induce an E7-specific cytotoxic T lymphocyte response, and to modify tumor infiltrating immune cells, reducing the percentage of T regulatory cells and activating myeloid cells. As a consequence, SFV-IFN was able to eradicate 58% of established tumors treated 21 days after implantation with long-term tumor-free survival and very low toxicity. SFV-IFN was also able to induce significant antitumor responses in a subcutaneous tumor model of murine colon adenocarcimoma. These data suggest that local production of IFNα by intratumoral injection of recombinant SFV-IFN could represent a potent new strategy to treat tumors in patients.

Angiotensin-converting enzyme inhibitor therapy for ventricular dysfunction in infants, children and adolescents: a review.

Angiotensin-converting enzyme (ACE) inhibitors have become an important part of the pharmacologic armamentarium in the battle against treatment of ventricular dysfunction. There have been a number of large controlled, randomized trials in adults with both asymptomatic and symptomatic ventricular dysfunction, which confirm the safety and efficacy of this category of drugs for the treatment of this potentially lethal condition. ACE inhibitors may be used to treat infants, children and adolescents with asymptomatic and symptomatic ventricular dysfunction as well. The data supporting their use in children is less complete than that concerning the treatment of adults. We review here the various causes of ventricular dysfunction and congestive heart failure (CHF) in infants, children, and adolescents; the data available regarding treatment of these conditions with ACE inhibitors, and the safety and efficacy of these drugs for the various conditions. The pharmacokinetics and proposed mechanisms of action of ACE inhibitors in children are reviewed, as are speculated long-term results of ACE inhibitor use in cohorts of growing children. Recommendations are made for future studies.

Nurse practitioners' effectiveness in NICU.

The effectiveness of Neonatal Nurse Practitioners (NNPs) in a Level III Neonatal Intensive Care Unit (NICU) was evaluated by using a retrospective medical records review. Two groups of infants received care in a Transitional Care Unit (TCU), one by house officers and the second cared for by NNPs. Medical diagnoses, lengths of stay, hospital charges, discharge/transfer disposition and hospital readmissions were studied. No differences were found in DRG codes, discharge disposition, hospital readmission or number of infants transferred from TCU to NICU because of deteriorating condition. Though the infants cared for by the NNPs had significantly lower birth weight and lower gestational age, they averaged 2.4 fewer days in the hospital and $3,491 less in total hospital charges than the group cared for by house officers. This study confirms that NNPs can provide care comparable to house officers in a Level III NICU and be more cost effective.

Pericardial effusion and tamponade as a result of percutaneous silastic catheter use.

Percutaneous Silastic catheters (PSCs) are used in premature infants to deliver total parenteral nutrition. We report two cases in which migration of the catheter into the right atrium resulted in rapid onset of shocklike symptoms. Pericardial effusion and tamponade were diagnosed by echocardiography. Subxiphoid pericardiocenteses were performed, with immediate clinical improvement. In both cases, fluid withdrawn from the pericardial space was analyzed to be hyperalimentation and intravenous fat emulsion. Pericardial effusion and tamponade should be suspected in any infant with a PSC line in place who develops sudden onset of shocklike symptoms.

Chemical and morphologic alterations of rabbit bone induced by adriamycin.

Long term, low dose administration of adriamycin (ADR) to young growing rabbits resulted in significant alterations in bone structure and chemistry. Morphologic changes were most pronounced at epiphyseal and metaphyseal areas of long bones. Epiphyseal cartilage plates were thin and there was derangement of growth zones. Areas of primary and secondary spongiosa were deficient in trabeculae, osteoblasts and osteoclasts. Analysis of femora, humeri and lumbar vertebrae from ADR-treated rabbits revealed increased water and fat content and significant decreases in bone density compared to age-matched controls. Cortices of long bones were roentgenographically thin and contained large irregular spaces evident microscopically. Evaluation of bone ash from ADR treated rabbits revealed significant increases in the percentage of calcium and phosphorus, although Ca/P ratios were not different from controls. Results of in vitro studies indicate that ADR binds readily to nondemineralized, but not demineralized, fresh cortical bone powder. The findings of decreased bone density, histopathologic alterations, and a paucity of osteogenic cells in ADR treated rabbits are interpreted as retardation of bone maturation. It is suggested that ADR affects adversely both the organic and inorganic fractions of bone. Due to its unique characteristics of cytostatic action, binding to metal cations and orange-red fluorescence, ADR is a novel chemical agent that may be useful in experimental bone studies.

Hypercalcemic VX-2 carcinoma in rabbits: a clinicopathologic study.

Rabbits receiving intramuscular injections of VX-2 carcinoma cells in biceps femoris muscles developed rapidly progressive neoplastic growths at 14 to 21 days associated with a significant hypercalcemia. The biologic behavior of the VX-2 carcinoma was characterized by local infiltration and metastases to regional lymph nodes and lungs. No metastases to skeletal tissues were evident. Femora from intramuscularly injected rabbits had varying degrees of osteophytosis and lysis evident roentgenographically. Histopathologic evaluation of femoral sections revealed periosteal new bone growth, cortical osteolysis, endosteal new bone growth, and in a few long term rabbits, pathologic fractures. Bone lesions were evident histologically in the vicinity of neoplastic growth (i.e., femora, tibiae) but not at distant sites (i.e., humeri and vertebrae). Mineral analyses of VX-2 carcinoma tissues and kidneys from VX-2-bearing rabbits revealed concentrations of calcium 83 and 3 times greater, respectively, than those of skeletal muscle and kidneys from controls. These findings correlated well with histochemical evidence of excessive amounts of calcium in sections of kidneys and VX-2 carcinoma tissues. Rabbits receiving intraperitoneal injections of VX-2 carcinoma cells did not develop hypercalcemia despite an extensive, progressive neoplastic burden with metastases to abdominal and thoracic viscera. Roentgenographic, histopathologic, and physiochemical analyses of selected bones from these rabbits revealed no significant alterations. These findings indicate that VX-2 carcinoma cells need to be in close proximity to skeletal tissues in order to induce hypercalcemia. The development of a significant hypercalcemia in intramuscularly injected rabbits precedes the invasion of osseous tissues by VX-2 carcinoma cells. Therefore, it appears that VX-2 carcinoma cells have the ability to alter skeletal morphology and physiochemistry through a dual humoral/cellular mechanism. The clinicopathologic characteristics of the VX-2 carcinoma in the rabbit suggest that the neoplasm is a good experimental model to study osseous-mediated hypercalcemia of malignancy.