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.     

Some observations on the faecal carriage of mesophilic Aeromonas species in cows and pigs

Replicate faecal samples from healthy individual pigs and cows were examined for the presence of Aeromonas sp. over a 12-month period. Aeromonads were found to be minor components of the faecal flora, only 8.8% of 520 samples from pigs and 4.6% of 481 samples from cows proving positive. Isolation rates in both groups of animals were seasonal. A hydrophila (62% of the isolates) was the predominant species in cows, followed by A. caviae (32%) and A. sobria (15%). This pattern was also recorded in the natural waters that the animals drank from during the period when the faecal carriage rate was at its highest. In pigs, A. caviae (59%) was more common than A. hydrophila (41%). A. sobria was not found in any of the pig-associated samples. It seems that cattle acquire their faecal aeromonads from drinking water. The source of the organisms in pigs is less clear.     

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.     

RETROPERITONEAL SCHWANNOMA: A CASE SERIES AND REVIEW

Schwannomas account for only a small percentage of retroperitoneal tumours. Presentation is typically varied and non-specific and pre-operative diagnosis is difficult. Herein are described five cases of retroperitoneal schwannoma. Presentation was varied, ranging from abdominal pain, abdominal mass, obstructed labour or an incidental finding. All patients had either an abdominal computed tomography scan and/or ultrasound performed. Pre-operative biopsy either by fine needle aspiration (in one patient) or core biopsy in two patients was unhelpful. In four patients with smaller tumours, complete excision was possible with no apparent long-term morbidity and no clinical evidence of recurrent tumour with follow up from 3.5 months to 11 years. For the largest tumour, complete surgical excision was not attempted as it would have entailed significant morbidity.     

Flow dynamics through spinal needles

We examined the flow pattern produced when liquid dye was actively injected into a fluid medium at various flows through five different commonly used spinal needles. At all flows, the Whitacre-type needles produced a directional stream exiting at an angle from the longitudinal axis. At intermediate rates the stream developed tracks which disappeared at faster rates. The Quincke needle always produced an undeviated stream of dye and did not form tracks at any flow rate. When a perspex plate (representing the spinal cord) was interposed in front of the needle, the dispersion of dye was always unidirectional from the Whitacre needle and bidirectional from the Quincke needle. The dye adhered to the surface of the plate as a concentrated film at slow rates and at faster rates it dispersed turbulently for both types of needle.     

Socio-cognitive skills as a determinant of life satisfaction in aged persons.

The purpose of this study was to explore the viability of a revised model of elderly life satisfaction, specifically evaluating the contribution of socio-cognitive skills. The role of such skills in relation to life satisfaction among aged persons has not been explored in research to date. Pilot data gathered from 60 community-living aged individuals indicated that numerous variables (e.g., subjective/objective health, education, financial satisfaction, role participation, subjective integration) significantly correlated with life satisfaction. However, the combined effects of two variables, persons' feelings of loneliness and isolation from their families and a measure of socio-cognitive skill, accounted for 49 percent of the variability in elderly life satisfaction. The effects of each on life satisfaction were unique however. Implications of these data and possible interventions for increasing elderly persons' life satisfaction are discussed.     

Validation of the survey of work styles: a profile measure of the type A behaviour pattern

The present study compares the Type A classification accuracy of the Jenkins Activity Survey (JAS), The Framingham Type A Scale, and a new Type A behaviour pattern (TABP) measure. The Survey of Work Styles (SWS), a self-report measure of the TABP, was developed using a construct approach to scale construction. It consists of six content scales. Impatience, Anger, Work Involvement, Time Urgency, Job Dissatisfaction and Competitiveness. In addition to the six content scales, a seventh scale, Scale A, is comprised of items empirically selected to relate to the Rosenman Structured Interview. In the present study the SWS was found to be significantly related to both the JAS, and the Framingham Type A Scale in a sample of 163 business managers. Median reliability of the SWS subscales was 0.82, and for the total scale 0.90. Discriminant function analysis using cross validational jackknifing procedures resulted in a classification accuracy of 83% of the Type A managers in relation to the Structured Interview. Classification using the SWS was found to correlate significantly higher with the Structured Interview than did either classification with the JAS or with the Framingham Type A Scale. Modal profile analysis yielded three independent bipolar typal dimensions, indicating that a single dimension or classification of the TABP represents an oversimplification of a complex behaviour pattern. These results support the reconceptualization of the TABP in terms of distinct facets and profile patterns.