Phase I trial of doxorubicin-containing low temperature sensitive liposomes in spontaneous canine tumors.

PURPOSE: To determine the maximum tolerated dose, dose-limiting toxicities, and pharmacokinetic characteristics of doxorubicin encapsulated in a low temperature sensitive liposome (LTSL) when given concurrently with local hyperthermia to canine solid tumors. EXPERIMENTAL DESIGN: Privately owned dogs with solid tumors (carcinomas or sarcomas) were treated. The tumors did not involve bone and were located at sites amenable to local hyperthermia. LTSL-doxorubicin was given (0.7-1.0 mg/kg i.v.) over 30 minutes during local tumor hyperthermia in a standard phase I dose escalation study. Three treatments, given 3 weeks apart, were scheduled. Toxicity was monitored for an additional month. Pharmacokinetics were evaluated during the first treatment cycle. RESULTS: Twenty-one patients were enrolled: 18 with sarcomas and 3 with carcinomas. Grade 4 neutropenia and acute death secondary to liver failure, possibly drug related, were the dose-limiting toxicities. The maximum tolerated dose was 0.93 mg/kg. Other toxicities, with the possible exception of renal damage, were consistent with those observed following free doxorubicin administration. Of the 20 dogs that received > or = 2 doses of LTSL-doxorubicin, 12 had stable disease, and 6 had a partial response to treatment. Pharmacokinetic variables were more similar to those of free doxorubicin than the marketed liposomal product. Tumor drug concentrations at a dose of 1.0 mg/kg averaged 9.12 +/- 6.17 ng/mg tissue. CONCLUSION: LTSL-doxorubicin offers a novel approach to improving drug delivery to solid tumors. It was well tolerated and resulted in favorable response profiles in these patients. Additional evaluation in human patients is warranted.     

The vagal nerve as a link between the nervous and immune system in the instance of polymicrobial sepsis

Background The role of the vagal nerve in the autonomic nervous system is widely well known. Recently, an additional function was revealed serving as a connector between the nervous and immune system. This connection is called the “cholinergic inflammatory pathway.” Through stimulation of the acetylcholine receptors located upon the macrophages, the “unspecific” immune system can be directly influenced. Methods The vagal nerve was completely transected directly posterior to its passage through the diaphragm. The effect of complete vagotomy was analyzed using a murine model of polymicrobial peritonitis (colon ascendens stent peritonitis, CASP). Survival and clinical course of vagotomized or sham-operated mice were analyzed in the CASP model. Results After CASP surgery, vagotomy led to a significantly increased mortality (64.7%) in comparison to sham-vagotomized animals (34%). No difference in the bacterial load of various tissues (lung, liver, spleen, blood, lavage fluid, and kidney) from septic animals with or without vagotomy was observed. Vagotomized animals reveal elevated serum cytokine levels (TNF, IL-6, IL-10, and MCP-1) 20 h after the induction of polymicrobial peritonitis. Conclusion The vagal nerve is therefore an important modulator of the immune system. W. Kessler and T. Traeger contributed equally to this work Best of Forum Papers presented at the Annual Meeting of the German Society of Surgery, 2–5 May 2006, Berlin, Germany     

Cytomegalovirus induces T-cell independent apoptosis in brain during immunodeficiency.

BACKGROUND: Cytomegalovirus (CMV) is the most common opportunistic viral pathogen associated with HIV/AIDS or immunosuppressive therapy. Systemic pathology may be caused either through direct virus-mediated infection or by indirect mechanisms such as 'by-stander' apoptosis. CMV infection of the central nervous system (CNS) occurs late in disease progression and understanding of pathology in the brain is fundamental for selection of appropriate therapies. OBJECTIVES: Using a model of disseminated neurotropic CMV disease, these experiments are designed to identify cellular predilection of murine CMV (MCMV) within mature brain and to determine, if CMV induces apoptosis within CNS cells. STUDY DESIGN: Adult immunodeficient (SCID) and normal BALB/c mice were infected via the tail vein with 4.5 x 10(5)pfu recombinant MCMV expressing a green fluorescent protein reporter. Animals were perfused at various time periods from 3 to 35 days post inoculation and tissues were stained for MCMV, GFAP, NEU-N, MBP, TUNEL, and caspase-3. RESULTS: CMV infection within brain was observed in multiple, independent foci affecting several different cell types, including neurons, glial cells, meninges, ependymal cells, and cerebral vessels. Cellular changes included nuclear karyopyknosis and karyorrhexis, and associated meningitis, choroiditis, encephalitis, vasculitis, and necrosis. TUNEL and caspase-3 staining of brain-demonstrated apoptosis of nearby 'by-stander' meningial, glial, and neuronal cells, but only in immunodeficient mice lacking T- and B-lymphocytes. Generally, only large CMV infection foci were associated with apoptosis of non-infected adjacent cells. CONCLUSIONS: These results indicate that MCMV may cause both direct and indirect pathology to brain and that T-cell independent apoptosis of surrounding cells of the CNS may be an important mechanism of disease in the pathogenesis of neurotropic CMV.     

Stereophotogrammetric measurement of the nasolabial fold in repose: a study of age and posture-related changes

The nasolabial fold is a significant facial landmark. Its size, shape, and symmetry are important in facial reanimation surgery, while effacement is an important goal in rejuvenation surgery. However, quantitative data for the nasolabial fold volume (NLFV) and depth is still unavailable. We present a new method of measurement using 3D color speckle stereophotogrammetry and its application in the assessment of NLFV. The VECTRA-3D system was validated to determine its minimum resolution and accuracy. Normal volunteers aged 13–84 years (n = 87) were imaged in repose. Mother–daughter pairs (n = 15, aged 13–61) were imaged in the upright and supine positions. All data were processed using custom software and analyzed by linear regression and nonparametric tests as appropriate. NLFV varied from 0.0026 to 0.2306 ml. There was significant correlation between NLFV and age (r = 0.7269, p < 0.0001). Men had significantly higher NLFV than women across all ages. There was no significant difference between the left and right NLFV. NLFV altered significantly from upright to supine in all subjects (p = 0.0012). However, the mothers increased their NLFV by 32% from supine to upright postures, which was a greater change than observed in their daughters. We have demonstrated a rapid, objective, and non-invasive assessment tool for facial reanimation and rejuvenation surgery. We have quantified the effects of age and posture on NLFV, and the efficacy and longevity of rejuvenation procedures are currently under investigation.     

Study of the localization of radiopacities similar to calcified carotid atheroma by means of panoramic radiography.

OBJECTIVE: To determine the location in soft tissues of the calcifications, similar to calcified carotid atheromas, that can be observed radiographically in the cervical region in panoramic radiographs. STUDY DESIGN: In each anatomic cadaver specimen preserved in formol, consisting of the head and neck, radiopaque spheres (made from gutta-percha) were positioned in anatomic structures of the cervical region that can be sites of calcification. For each anatomic structure marked in this way, panoramic radiography was performed, consisting of 17 radiographs. The images obtained were analyzed by 24 examiners who indicated which radiographs, in their opinion, presented the radiopaque reference projected in the region of bifurcation of the carotid artery. Analysis of 2 proportions from agreement and disagreement was used to determine radiopacities that could be confused in panoramic radiographs with calcified atheromas in the carotid artery. RESULTS: The results showed that 75% (18) of the examiners correctly indicated the reference in the bifurcation of the carotid artery and 79.2% (19) indicated a triticeous cartilage as calcified atheroma of the carotid artery. CONCLUSIONS: Calcified atheromas of the carotid artery are not the only features that can produce radiopaque images lateral to the panoramic radiograph; the presence of calcification in the triticeous cartilage also can induce an erroneous diagnosis of calcified carotid atheroma.     

A pharmacokinetic comparison of cyclosporin oral solution and cyclosporin capsules in heart and lung transplant recipients

Pharmacokinetic profiles were obtained for 16 heart or lung recipients following the administration of identical doses of cyclosporin as oral solution and capsules on consecutive days. A comparison of pharmacokinetic parameters (AUC, C_max, C_min and t_max) showed that there were no significant differences between the two formulations except for the t_max, which was significantly longer for the capsules. The mean variation in day-to-day trough levels produced by the two different forms was 25.6%. A retrospective study was carried out of consecutive cyclosporin levels in patients at steady state on oral solution. The mean variation in day-to-day trough levels was 32.3%. This was not significantly different from the variation in consecutive trough levels seen in the oral solution/capsule comparison. This study shows that cyclosporin capsules can be substituted for oral solution without causing acute changes in cyclosporin blood levels, and that the pharmacokinetics of the two formulations are similar.This work was carried out in partial fulfillment of the requirements for the Master of Science Degree in Clinical Pharmacy, University of London     

Rural Hospital Nursing as an Elective*

A rural hospital elective in a diploma nursing program is described. A need and opportunity for this unique practicum was identified in a Canadian province where one-third of the acute care beds are in hospitals of under 100 beds, located primarily in towns outside of metropolitan areas. The six week course offers students 35 hours of classroom content focusing on rural health care concepts plus a 150 hour practicum in one of three participating hospitals. The course is seen as unique in that it focuses on rural health care and is offered within the context of a diploma nursing program. Vive student outcomes are identified: awareness of the differences between rural and urban health care; integration of knowledge and experience from previous nursing courses as it relates to the rural context; increasing understanding of how rural population groups affect health care delivery; awareness of rural employment opportunities; and, preparation for the graduate role. A shared vision and collaborative effort on the part of the School of Nursing, the rural hospitals and the host communities has been necessary to establish and maintain such a course.