The molecular genetics of endocrine tumours

The molecular genetics of endocrine tumours is an area of great interest, due to the heterogeneity of endocrine tumour types, the association of hormone over-production in some cases, and the wide variation in tumour behaviour. Genes implicated fall into functional categories such as oncogenes, in which mutations tend to cause activation, and tumour suppressor genes, in which mutations lead to loss of function. Oncogenes include the receptor tyrosine kinases such as RET, signal transduction proteins and other molecules such as cell cycle regulators and nuclear proteins. Tumour suppressor genes include cell cycle regulators such as p53 and other molecules such as the MEN 1 gene. Loss of heterozygosity studies help in the initial localisation of the latter. Endocrine tumours, as with other tumours, develop as a result of a combination of genetic events, and in the paediatric age group they often occur in the setting of familial cancer syndromes. In this review we analyse the main genetic lesions which have been described in endocrine tumours. There has been an explosion of knowledge in the last 5 years including the identification of the causative genes for MEN 2 and most recently for MEN 1. Characterisation of such genes also aids in the study of somatic mutations in sporadic versions of the same tumour types as occur in the familial syndromes. Identification of a genetic predisposition to a certain tumour has management implications that are still to be clarified in most cases, although in the case of MEN 2 the guidelines for prophylactic thyroidectomy are generally well accepted.     

Effects of the antimigraine compound zolmitriptan (''Zomig'') on psychomotor performance alone and in combination with diazepam in healthy volunteers

Posterior lenticonus is a protrusion of the posterior capsule and cortex into the vitreous. The etiology is widely debated because of the rare nature of the condition. Lenticonus can present with concurrent ocular conditions, which can disrupt normal visual development. Currently, the only treatment option for posterior lenticonus is lensectomy, which may still have a reduced chance of visual success secondary to the associated disease. Although strabismus and amblyopia are commonly associated, keratoconus has not previously been reported with unilateral posterior lenticonus. Considering treatment of the associated condition may allow the patient to delay or forego surgical intervention.     

Hepatocellular carcinoma in primary biliary cirrhosis and its impact on outcomes

In this study we have determined the incidence of hepatocellular carcinoma (HCC) development in primary biliary cirrhosis (PBC) and its effects on patient survival. Six hundred and sixty seven patients with liver histology compatible with or diagnostic of PBC were seen over a 20-year period. Two hundred and seventy three patients who had stage III or IV disease on their last biopsy and who had been followed up for at least 1 year following that biopsy (total follow-up with advanced disease 2,010 patient years) were identified (243 female, 30 male). Patients who developed HCC were identified and their confounding risk factors were excluded. Mayo risk scores were calculated for each clinic attendance and expected survival for each time point was compared with subsequent actual survival. Sixteen cases of HCC were seen in the patients with stage III or IV disease on last biopsy, providing an overall incidence of 5.9% in this group. Fourteen of these patients had died of HCC related causes, and 2 patients were alive at the census point. The incidence of HCC was significantly higher in males with stage III/IV disease than in females (20% vs. 4.1%, P < .005). Nine of one hundred and eight (8.3%) total female deaths in this group was attributable to HCC compared with 5 of 11 (45.5%, P < .05) male deaths. HCC was not seen in any of the 394 patients with stage I and II PBC followed-up over the same time period. Throughout the disease course of all PBC patients with HCC, the Mayo prognostic model over-predicted survival. Whereas it is a relatively rare complication of cirrhotic PBC in women, HCC is a relatively common cause of death in male PBC patients with cirrhosis. HCC typically develops several years after the onset of cirrhosis, and is poorly predicted by prognostic models. In view of these findings, consideration should be given to careful screening for HCC in male PBC patients with cirrhosis. The risk of HCC development may be an additional reason to consider earlier transplantation in these patients.     

Hydrogen-bonded trimers of DNA bases and their interaction with metal cations: ab initio quantum-chemical and empirical potential study

Neutral (G.GC, A.AT, G.AT, T.AT, and C(imino).GC) and protonated (CH+.GC and AH+.GC) hydrogen-bonded trimers of nucleic acid bases were characterized by ab initio methods with the inclusion of electron correlation. In addition, the influence of metal cations on the third-strand binding in Purine-Purine-Pyrimidine (Pu.PuPy) reverse-Hoogsteen triplets has been studied. The ab initio calculations were compared with those from recently introduced force fields (AMBER4.1, CHARMM23, and CFF95). The three-body term in neutral trimers is mostly negligible, and the use of empirical potentials is justified. The only exception is the neutral G.GC Hoogsteen trimer with a three-body term of -4 kcal/mol. Protonated trimers are stabilized by molecular ion-molecular dipole attraction and the interaction within the complex is nonadditive, with the three-body term on the order of -3 kcal/mol. There is a significant induction interaction between the third-strand protonated base and guanine. The calculations indicate an enhancement of the third-strand binding in the G.GC reverse-Hoogsteen trimer due to-metal cation coordination to the N7/O6 position of the third-strand guanine. Interactions between metal cations and complexes of DNA bases are in general highly non-additive; the three-body term is above-10 kcal/mol in a complex of a divalent cation (Ca2+) with the GG reverse-Hoogsteen pair. The pairwise additive empirical potentials qualitatively underestimate the binding energy between cation and base.     

Assessing the outcomes of coronary artery bypass graft surgery: how many risk factors are enough? Steering Committee of the Cardiac Care Network of Ontario

OBJECTIVES: We sought to determine whether more comprehensive risk-adjustment models have a significant impact on hospital risk-adjusted mortality rates after coronary artery bypass graft surgery (CABG) in Ontario, Canada. BACKGROUND: The Working Group Panel on the Collaborative CABG Database Project has categorized 44 clinical variables into 7 core, 13 level 1 and 24 level 2 variables, to reflect their relative importance in determining short-term mortality after CABG. METHODS: Using clinical data for all 5,517 patients undergoing isolated CABG in Ontario in 1993, we developed 12 increasingly comprehensive risk-adjustment models using logistic regression analysis of 6 of the Panel's core variables and 6 of the Panel's level 1 variables. We studied how the risk-adjusted mortality rates of the nine cardiac surgery hospitals in Ontario changed as more variables were included in these models. RESULTS: Incorporating six of the core variables in a risk-adjustment model led to a model with an area under the receiver operating characteristic (ROC) curve of 0.77. The ROC curve area slightly improved to 0.79 with the inclusion of six additional level 1 variables (p = 0.063). Hospital risk-adjusted mortality rates and relative rankings stabilized after adjusting for six core variables. Adding an additional six level 1 variables to a risk-adjustment model had minimal impact on overall results. CONCLUSIONS: A small number of core variables appear to be sufficient for fairly comparing risk-adjusted mortality rates after CABG across hospitals in Ontario. For efficient interprovider comparisons, risk-adjustment models for CABG could be simplified so that only essential variables are included in these models.     

Adrenal gland incidentaloma in the oncologic patient: is its histologic study obligatory?

We evaluated the performance of an automatic polymerase chain reaction (PCR) detection system for identification of Mycobacterium tuberculosis in respiratory specimens. Six hundred and two respiratory specimens, including 557 sputa and 45 bronchial washing samples, were analyzed using the COBAS AMPLICOR Mycobacterium tuberculosis (MTB) test. The results were compared with those obtained from acid-fast microscopy, conventional culture, and clinical history. In cases of discrepancy between the results of the COBAS AMPLICOR MTB test and culture, the medical history of the patient was reviewed, the COBAS AMPLICOR MTB test was repeated, and the gene encoding M. tuberculosis superoxide dismutase was screened using PCR (SOD-PCR). Fourteen samples were excluded because the internal control test result was negative. Of 57 specimens that were culture positive for Mycobacterium species, 40 appeared to have growth of M. tuberculosis and 21 were smear positive for acid-fast bacteria. The sensitivity, specificity, and positive and negative predictive values for the COBAS AMPLICOR MTB test evaluated at our laboratory were 85.0% (34/40), 99.3% (544/548), 89.5% (34/38), and 98.9% (544/550), respectively. Three specimens that were culture positive for M. tuberculosis but negative by COBAS AMPLICOR MTB test were positive when rechecked by both COBAS AMPLICOR MTB test and SOD-PCR. Among the four specimens with positive reactions on both COBAS AMPLICOR MTB test and SOD-PCR that were culture negative, two were from patients who had been receiving antituberculosis treatment, one was from a patient who had been treated for tuberculosis for 1 year, and the other was from a patient who died of sepsis with adult respiratory distress syndrome. In more than 70% of smear-negative and culture-positive specimens and 86.4% of smear-positive specimens, M. tuberculosis was identified by the COBAS AMPLICOR MTB test within 10 hours after receipt of the specimens. Our data show that the COBAS AMPLICOR MTB test provides rapid and accurate detection of M. tuberculosis in respiratory specimens.     

Exercise training reduces myocardial lipid peroxidation following short-term ischemia-reperfusion

PURPOSE: The purpose of these experiments was to test the hypothesis that endurance exercise training will reduce myocardial lipid peroxidation following short-term ischemia and reperfusion (I-R). METHODS: Female Sprague-Dawley rats (4 months old) were randomly assigned to either a sedentary control group (N = 13) or to an exercise training group (N = 13). The exercise trained animals ran 4 d.wk-1 (90 min.d-1) at approximately 75% V02max. Following a 10-wk training program, animals were anesthetized, mechanically ventilated, and the chest was opened by thoracotomy. Coronary occlusion was achieved by a ligature around the left coronary artery; occlusion was maintained for 5 min followed by a 10-min period of reperfusion. RESULTS: Although training did not alter (P > 0.05) myocardial activities of antioxidant enzymes (superoxide dismutase and glutathione peroxidase), training was associated with significant increase (P > 0.05) in heat shock protein (HSP72) in the left ventricle. Compared with controls, trained animals exhibited significantly lower levels (P < 0.05) of myocardial lipid peroxidation following I-R. CONCLUSION: These data support the hypothesis that exercise training provides protection against myocardial lipid peroxidation induced by short-term I-R in vivo.     

Visualization of C7-T1 on portable lateral cervical spine radiographs using a lead-lined acrylic filter

OBJECTIVE: To determine whether lead-lined acrylic cervical filters can improve the quality of portable lateral cervical spine (c-spine) radiographs for trauma patients. METHODS: Twenty trauma patients who required portable c-spine x-rays had these taken with a lead filter attached to the collimator of the portable x-ray machine to improve penetration and visualization of lower cervical structures without overpenetrating upper cervical structures. The radiographs of these patients were compared with the first portable c-spine radiographs without filters for 20 controls matched for gender and injury severity. The comparison of radiographs was done by an experienced emergency physician and a neuroradiologist blinded to whether the filter was used. RESULTS: The two groups were similar for demographic and clinical characteristics. There was a significant improvement in the ability to visualize the C7-T1 level for the filter group compared with the control group (65% vs 30%, p < 0.05). Agreement between the physicians was excellent (kappa = 0.79, 95% CI = 0.60-0.99). CONCLUSIONS: Lead-lined acrylic filters improve the ability to visualize the lower c-spine in trauma patients.     

Non-anticoagulant heparin increases endothelial nitric oxide synthase activity: role of inhibitory guanine nucleotide proteins

Heparin, which is widely used clinically, has recently been shown to have specific properties affecting the vascular endothelium. We hypothesized that heparin stimulates endothelial nitric oxide synthase (eNOS) activity by a mechanism independent of its anticoagulant properties and dependent on an inhibitory guanine nucleotide regulatory protein (Gi). We determined the effect of both heparin and N-acetyl heparin (Non-Hep), a heparin derivative without anticoagulant properties, on eNOS activity in cultured bovine aortic endothelial cells and on endothelium-dependent relaxation in isolated vascular rings. The eNOS activity was determined by measuring both citrulline and nitric oxide (NO) metabolite formation. Heparin and Non-Hep dose-dependently increased basal eNOS activity (ED50 1.0 microgram/ml or 0.15 U/ml), an effect that was significantly inhibited by pertussis toxin (100 ng/ml), a Gi-protein inhibitor. Agonist-stimulated (acetylcholine, 10 microM) eNOS activity was potentiated following pre-treatment with both heparin and Non-Hep and reversed by pertussis toxin. Heparin and Non-Hep induced a dose-dependent relaxation in preconstricted thoracic aortic rings, an effect that was significantly inhibited by pertussis toxin, endothelial inactivation (following treatment with sodium deoxycholate) and NG-nitro-L-arginine-methyl ester (L-NAME). We conclude that heparin and non-anticoagulant heparin induce endothelium-dependent relaxation following activation of eNOS by a mechanism involving a Gi-protein. Administration of heparin derivatives without anticoagulant properties may have therapeutic implications for the preservation of eNOS in conditions characterized by endothelial dysfunction.     

Measuring the effect of a hygiene behaviour intervention by indicators of behaviour and diarrhoeal disease

A social marketing approach used both qualitative and quantitative methods to develop a hygiene behaviour intervention in rural north-east Thailand. Behaviours were preselected from a previous study and the intervention was designed to promote hand washing, especially before feeding a baby, cooking, eating, and after defaecation or cleaning a baby's bottom, and dish washing immediately after eating. A bacteriological indicator (enumerating faecal streptococci using a finger impression technique) was developed to measure changes in hand washing behaviour and observation (spot checks) of dirty dishes to indicate dish washing practice. There was a significant improvement in both behaviours and a significant reduction in diarrhoeal disease as a result of the intervention. Furthermore, both indicators were retrospectively found to be positively related to diarrhoeal disease incidence. However, receiving and being able to recall the intervention messages was not necessarily sufficient to ensure behaviour change, as some adults found it difficult to change old habits. Villages showing the greatest improvement tended to have a stronger sense of community than others and to have more people actively involved in the intervention.