Thiopentone inhibits beta-adrenergic responses in myocardial tissue

The purpose of this study was to determine the importance of inhibition of beta-adrenergic function in thiopentone-induced myocardial depression. Using an isolated, electrically stimulated rat left atria model, contractile dose-response curves to thiopentone (200 μM, 400 μM, 600 μM, 800 μM) were shifted to the right in preparations treated with 10^{− 3} M dibutyryl cyclic adenosine monophosphate (cAMP) compared with atria stimulated with 10^{− 6} M isoprenaline, demonstrating that inhibition of beta-adrenergic mechanisms by thiopentone is physiologically important. Depression by thiopentone was similar in atria treated with 10^{− 5} M forskolin compared with preparations stimulated with 10^{− 6} M isoprenaline, indicating that thiopentone does not block beta-adrenergic receptors. It is concluded that thiopentone depresses myocardial function by several mechanisms, one of which involves inhibition of the adenyl cyclase cascade. The adenyl cyclase enzyme is a likely site where thiopentone inhibits the system; however, other components of the cascade may also be involved. L’objectif de cette étude consiste à déterminer l’influence de l’inhibition de l’activité β-adrenergique sur la dépression myocardique induite par le thiopentone. A l’aide d’un modèle constitué d’une oreillette gauche de rat stimulée électriquement, la relation dose-effet du thiopentone sur la contractilité (200 μM, 400 μM, 600 μM, 800 μM) se déplace vers la droite dans des préparations traitées avec de l’adénosine monophosphorique cyclique (cAMP) 10^{− 3} M comparativement à des oreillettes stimulées avec de l’isoprénaline 10^{− 6} M, ce qui démontre que l’inhibition β-adrénergique provoquée par le thiopentone est physiologiquement importante. La dépression de l’oreillette provoquée par le thiopentone est identique à celle que produit la forskoline 10^{− 5} M comparativement à celle de l’isoprénaline 10^{− 6} M, ce qui indique que le thiopentone n’inhibe pas les récepteurs β-adrénergiques. Les auteurs concluent que le thiopentone déprime la fonction myocardique par plusieurs mécanismes qui impliquent l’inhibition de la cascade de l’adényl cyclase. L’inhibition du système se produit vraisemblablement au niveau de l’enzyme adényl cyclase; cependant, il est possible que d’autres éléments de la cascade de l’adényl cyclase soient impliqués.     

DNA diagnostics: goals and challenges

The exponential increase in the discovery of human disease genes over the past 10 years has transformed DNA diagnostics from a minor research-based activity to a major professional operation. Mutation testing and linkage analysis are now used to provide prenatal or postnatal diagnosis for a wide range of monogenic disorders, but robust automated procedures for scanning disease genes for mutations are not yet available. The discovery of genes which confer susceptibility to common disorders is likely to create demand for high throughput testing for specific mutations or clinically relevant polymorphisms. Widespread genetic testing must be supported by adequate genetic counselling and by education of healthcare professionals in order to ensure the appropriate application of this information for the benefit of patients and their families.     

A case of cerebral toxoplasmosis

A histopathologically proven case of cerebral toxoplasmosis in a young HIV positive patient has been presented. The clinical problems in management are highlighted.     

Inhibition of the type III epidermal growth factor receptor variant mutant receptor by dominant-negative EGFR-CD533 enhances malignant glioma cell radiosensitivity.

PURPOSE: The commonly expressed variant epidermal growth factor receptor (EGFR), the type III EGFR variant (EGFRvIII), functions as an oncoprotein promoting neoplastic transformation and tumorigenicity. The role of EGFRvIII in cellular responses to genotoxic stress, such as ionizing radiation, is only minimally defined. Thus, we have investigated EGFRvIII as a potential modulator of cellular radiation responses and explored the feasibility of adenovirus (Ad)-mediated expression of dominant-negative EGFR-CD533 as a gene therapeutic approach for inhibiting EGFRvIII function in vitro and in vivo. EXPERIMENTAL DESIGN AND RESULTS: EGFR-CD533 and EGFRvIII were expressed in vitro and in vivo in malignant U-373 MG glioma cells through transduction with an Ad vector, Ad-EGFR-CD533 and Ad-EGFRvIII, respectively. In vivo studies defined the importance of EGFRvIII as a modulator of radiation responses, demonstrating a 2.6-fold activation of EGFRvIII in U-373 malignant glioma tumors. Concomitant expression of EGFR-CD533 inhibited the radiation-induced activation of EGFRvIII in vitro and completely abolished the enhanced clonogenic survival conferred by EGFRvIII. The ability of EGFR-CD533 to inhibit EGFRvIII function was further confirmed in vivo through complete inhibition of EGFRvIII-mediated increased tumorigenicity and radiation-induced activation of EGFRvIII. Growth delay assays with U-373 xenograft tumors demonstrated that the expression of EGFR-CD533 significantly enhanced radiosensitivity of tumor cells under conditions of intrinsic and Ad-mediated EGFRvIII expression. CONCLUSIONS: We conclude that EGFRvIII confers significant radioresistance to tumor cells through enhanced cytoprotective responses, and we have demonstrated that dominant-negative EGFR-CD533 effectively inhibits EGFRvIII function. These data affirm the broad potential of EGFR-CD533 to radiosensitize human malignant glioma cells.     

Donor bone marrow-derived chimeric cells present in renal transplant recipients infused with donor marrow. I. Potent regulators of recipient antidonor immune responses

BACKGROUND: Even though a number of transplant centers have adopted donor-specific bone marrow cell (DBMC) infusions to enhance donor cell chimerism, to date there has been no direct evidence linking chimerism with tolerance induction in human organ transplant recipients. METHODS: Cells of donor phenotype were isolated 1 year postoperatively from the peripheral blood lymphocytes and iliac crest bone marrow of 11 living-related-donor (LRD) renal transplant recipients, who had received perioperative donor bone marrow cell infusions. These recipient-derived donor (RdD) cells were characterized phenotypically by flow cytometric analysis and functionally as modulators in mixed lymphocyte reaction (MLR) and cell-mediated lympholysis (CML) assays. RESULTS: The yield of RdD cells ranged from 0.1 to O.9% of the starting material with the majority being TcRalphabeta, CD3 positive T cells, a substantial percentage of which coexpressed CD28. At 1 year posttransplant almost 50% of the LRD-kidney/DBMC recipients tested so far exhibited donor-specific unresponsiveness in MLR (7/17) and CML (6/13) reactions and this trend was further enhanced at 23 years. In the recipients with residual positive antidonor immune responses, the RdD cells inhibited recipient antidonor MLR and CML responses significantly more strongly than freshly isolated and similarly treated iliac crest bone marrow cells from the donor. RdD cells also inhibited the MLR of the recipient to third party allogeneic stimulator cells; however, this nonspecific effect was significantly weaker than specific inhibition. We also established long-term bone marrow cultures stimulated every 2 weeks with irradiated alogeneic feeder cells, that had similar functional properties thus possibly providing us with an in vitro correlate the RdD cells. CONCLUSIONS: These results clearly support the notion that the infused donor cells play a positive role in the induction and/or maintenance of transplant tolerance.     

Angiogenesis during tumor progression in the oral cavity is related to reduced apoptosis and high tumor cell proliferation

Angiogenesis, the growth of new blood vessels, is believed to aid tumor progression and metastasis. Tumor progression is also influenced by the extent of proliferation and apoptosis. This study, therefore, analyzed in lesions of the oral cavity, the significance of angiogenesis in relation to apoptosis, expression of apoptosis regulatory p53, bax and bcl-2 proteins as well as tissue proliferation defined by cyclin D1 expression. Results from this study suggest that angiogenesis increases as histological abnormality increases in the oral mucosa. The expression of apoptosis regulatory proteins also appears to be altered in a histologically dependent manner. The correlation seen between CD34 expression, cyclin D1 and TUNEL reactive cells suggests that increased angiogenesis, decreased apoptosis and deregulated proliferation occur simultaneously during tumor progression in the oral mucosa. Presence of a mutant p53, increased bcl-2 expression and altered bax expression are also involved in this complex process.     

Chondrosarcoma of the nasal septum

Chondrosarcoma of the head and neck region are relatively uncommon, arising rarely in the naval septum. The reported cases of nasal septal chondrosarcomas are extensive lesions with involvement of paranasal sinuses, orbit or skull base at the lime of diagnosis. Those limited to the nasal cavity is extremely rare and to date there has been one case report in English language literature. We present a case of chondrosarcoma of the nasal septum with involvement of the nasal cavity alone and no evidence of bony erosion. Initial multiple biopsies showed mature chondromatous areas with no atypia. The patient had wide excision of the tumour. The final biopsy of the excised specimen revealed foci of well-differentiated chondrosarcoma. Wide surgical excision with adequate margins should be considered as the treatment of choice in lesion of nasal septum even if initial biopsies are negative for malignancy. Hence this case report.