Adeno-associated virus vector-mediated systemic delivery of IFN-beta combined with low-dose cyclophosphamide affects tumor regression in murine neuroblastoma models.

PURPOSE: Type I IFNs (IFN-alpha/beta) have shown significant antitumor activity in preclinical models but limited efficacy and significant toxicity in clinical trials. We hypothesized that the antitumor activity of type I IFNs could be enhanced by chronic, low-dose systemic delivery and sought to test this in murine neuroblastoma models. EXPERIMENTAL DESIGN: Continuous liver-generated expression of human IFN-beta (hINF-beta) was achieved through a gene therapy-mediated approach using adeno-associated virus vectors encoding hIFN-beta (AAV hINF-beta). Orthotopic localized retroperitoneal and disseminated models of neuroblastoma were established using three different xenografts. Immunohistochemical analysis and ELISA were used to evaluate the antiangiogenic effect of therapy. RESULTS: The development of both localized orthotopic (retroperitoneal) and disseminated neuroblastoma was prevented in all mice expressing hINF-beta. Continued growth of established retroperitoneal tumors, treated with AAV hINF-beta as monotherapy, was significantly restricted, and survival for mice with established, disseminated disease was significantly prolonged following administration of AAV hINF-beta. Analysis of treated tumors revealed a significant antiangiogenic effect. Mean intratumoral vessel density was diminished and expression of the angiogenic factors vascular endothelial growth factor and basic fibroblast growth factor were both decreased. Finally, combination therapy in which AAV hIFN-beta was used together with low-dose cyclophosphamide resulted in regression of both established retroperitoneal and disseminated disease. CONCLUSIONS: AAV-mediated delivery of hIFN-beta when used as monotherapy was able to restrict neuroblastoma growth due in part to inhibition of angiogenesis. When used in combination with conventional chemotherapy, AAV hIFN-beta was able to effect complete tumor regression.     

Designing new substance abuse treatment services for a competitive environment.

A multivariate analysis of the relationships between service attributes and physician perceptions was conducted as an approach to marketing substance abuse treatment services. The results of this attribute-perceptive-preference study indicate: the physician(s) on staff attribute makes the greatest contribution to perceived quality and efficiency; easy referral admission makes the largest contribution to accessibility perceptions; and providing feedback produces the greatest contribution to perceived continuity. The JCAH attributes neither adds to nor subtracts from the perceptions of any of the four perceptual attributes. Other findings indicate that perceived efficiency produces the greatest contribution to overall consumer preference. Quality perceptions make the second largest contribution to overall preference, followed by continuity and accessibility perceptions.     

Laboratory diagnosis in Ontario and the need for reform relative to the profession of chiropractic

The purpose of this paper is to provide an historical review of the progression of events within the jurisdiction of the province of Ontario related to the issue of laboratory diagnosis and the profession of chiropractic. The provisions of relevant legislation, task forces, Councils, reviews, consensus statements, Commissions and committees, are highlighted and discussed during respective time periods. Chiropractors had entitlement to order and perform laboratory tests until 1972 when a regulatory amendment, made without consultation with the chiropractic profession, precluded their continuing entitlement. Chiropractic patients require access to diagnostic laboratory services and equitable access to necessary laboratory services should be restored and preserved. This is consistent with the academic institutional accreditation standards of chiropractic education and the jurisdictional regulatory mechanisms of chiropractic practice and is consistent with both protecting and enhancing the public interest.     

A role for calcitonin gene-related peptide in protection against gastric ulceration.

OBJECTIVE: The goal of this investigation was to determine the role of calcitonin gene-related peptide (CGRP) in gastric mucosal resistance to ulceration. SUMMARY BACKGROUND DATA: CGRP is a 37-amino acid peptide found in the peripheral ends of afferent gastric neurons. CGRP is known to inhibit acid secretion, stimulate mucosal blood flow, and stimulate release of somatostatin. METHODS: The release of CGRP in response to intragastric and intra-arterial administration of capsaicin in the isolated, vascularly perfused rat stomach was measured by radioimmunoassay. The molecular forms of CGRP released were analyzed by gel filtration chromatography. The effect of intravenous CGRP or intragastric capsaicin on gastric ulceration induced by 100 mmol/L HCl and indomethacin was studied in intact and endogenous CGRP-depleted rats. RESULTS: Intra-arterial capsaicin (concentration range, 10(-7) to 10(-5) mol/L) stimulated a prompt and sustained release of immunoreactive CGRP, of which 84% coeluted with rat 1-37 CGRP I by gel filtration. Intragastric capsaicin (range, 10(-5) to 10(-4) mol/L) failed to release CGRP into the vascular perfusate. In intact rats, intragastric capsaicin (10(-6) mol/L) or intravenous CGRP I (10 micrograms/kg/hr) reduced the number and area of mucosal lesions caused by HCl and indomethacin compared with the findings in control rats. Rats depleted of endogenous CGRP were more susceptible to gastric ulceration than were normal rats. Intragastric capsaicin failed to protect the mucosa of CGRP-depleted rats, whereas exogenous intravenous CGRP was effective. CONCLUSIONS: These data support the hypothesis that CGRP released from gastric enteric neurons mediates gastric mucosal resistance to ulceration by noxious agents.     

The first t-test

The data with which Student illustrated the application of his famous distribution are examined from a number of aspects. Central to the discussion is the within-patient clinical trial at Kalamazoo whose results were published by Cushny and Peebles and misquoted by Student and Fisher. This trial is discussed from historical, pharmacological and statistical perspectives. Student's and Fisher's analyses and a more modern analysis by Preece are considered as is Cushny's and Peebles's interpretation. Brief biographies of the five physicians involved in running the trial are presented.     

Effects of polyethylene on macrophages

A system was developed to expose macrophages to polyethylene in vitro. Exposure of macrophages to these particles in isolation led to the release of tumor necrosis factor alpha and prostaglandin E₂. Exposure of macrophages in co-culture with osteoblasts to polyethylene particles increased the release of prostaglandin E₂ and also led to the release of interleukin-6. Incubation of radiolabelled calvariae with conditioned medium from macrophages exposed to polyethylene particles alone or to particles in co-culture with osteoblasts led to bone resorption reflected by release of ⁴⁵Ca. Incubation with pamidronate was effective in inhibiting resorption stimulated by conditioned medium from macrophages exposed to these particles alone or in co-culture with osteoblasts. This demonstrates that pamidronate, or other bisphosphonates, may be effective in inhibiting bone resorption at the implant/bone interface in association with the macrophage ressponse to particulate polyethylene. Further investigation into the possible use of pamidronate or other bisphosphonates in the treatment of aseptic loosening is warranted.