High mobility group proteins 1 and 2 recognize chromium-damaged DNA

Chromium (Cr) is a human carcinogen and a potent DNA damaging agent. Incubation of DNA with CrCl3 resulted in dose-dependent binding of Cr to DNA and, at concentrations >20 microM, altered the electrophoretic mobility of a 100 bp oligonucleotide. We also demonstrate that high mobility group (HMG) proteins 1 and 2 bind Cr-damaged DNA (Cr-DNA). Protein binding was lesion density-dependent, with maximal binding to DNA treated with 100 microM CrCl3. HMG2 binds to Cr-DNA with a calculated Kd of approximately 10(-9) M. These proteins also bound DNA obtained from chromate-treated cells. These results suggest that the covalent attachment of Cr to DNA induces alterations in DNA structure which are recognized by HMG1 and HMG2. Therefore, these proteins may function as Cr-damaged DNA recognition proteins in vivo and as a consequence of binding, may play a role in directing the cellular response to Cr-DNA adduct formation.      

A study of colo-rectal carcinoma in the Asian and European populations in the city of Leicester from 1981 to 1991

For many years clinical reports have suggested that colo-rectal cancer is uncommon in the Asian population resident in England and a report in 1990 confirmed this in Asians living in Bradford. This study aims to establish the incidence of colo-rectal cancer in the Asian population resident in the city of Leicester during the 11 y period 1 January 1981-31 December 1991. The relative frequency of colo-rectal carcinoma in Asians compared to Europeans over the period studied was 0.16 (Asian/European, 95% confidence interval (CI) 0.04-0.75). This difference was statistically significant and further analysis showed that there was a real trend with an increased relative frequency amongst the younger age groups. Although there was a significantly lower incidence of colo-rectal carcinoma in the Asian population in Leicester city over the period studied it is unknown whether this is due to environmental or genetic factors. During the next decade it is likely to become clearer as to whether this difference will persist or whether there will be an increase in the incidence of colo-rectal carcinoma in Asians in Leicestershire.     

Sputum tumour necrosis factor-alpha and leukotriene concentrations in cystic fibrosis

It is postulated that a vigorous host inflammatory response in the cystic fibrosis lung contributes to lung injury. Tumour necrosis factor-alpha (TNF-alpha) may play a part in that process and in the generation of leukotrienes. Therefore, the relationships between sputum TNF-alpha, leukotriene concentration, and lung function abnormalities in 16 children with cystic fibrosis were investigated. Each subject provided sputum samples and performed spirometry. TNF-alpha was measured by enzyme linked immunosorbent assay; individual leukotrienes were separated using high performance liquid chromatography and quantified by radioimmunoassay. The geometric mean concentration of TNF-alpha was 129.7 pg/ml and 95% confidence interval 48.2 to 348.3. Mean (SEM) leukotriene B4 (LTB4) was 97.8 (22.9) pmol/g and total cysteinyl leukotrienes were 60.9 (14.8) pmol/g. Mean (SD) forced expiratory volume in one second (FEV1) of the group was 53 (15)% of predicted and forced vital capacity (FVC) was 65 (14)% of predicted. There was a significant positive correlation between TNF-alpha and both LTB4 and the total cysteinyl leukotriene sputum content. An inverse relationship existed between TNF-alpha and FEV1 and FVC. Moreover, a negative correlation was observed between sputum LTB4 and FEV1 and FVC. These results suggest that TNF-alpha and the leukotrienes may participate in the airways inflammation and airflow obstruction observed in cystic fibrosis subjects and support the hypothesis that TNF-alpha upregulates the 5-lipoxygenase pathway in vivo.     

Interleukin-1 alpha, soluble interleukin-2 receptor, and IgG concentrations in cystic fibrosis treated with prednisolone

The cytokines interleukin-1 and interleukin-2 participate in the inflammatory response, and may contribute to hypergammaglobulinaemia G and the development of lung injury in cystic fibrosis. Anti-inflammatory treatment with corticosteroids may attenuate this response. The effect of a 12 week course of oral prednisolone on spirometry and serum concentrations of interleukin-1 alpha (IL-1 alpha), soluble interleukin-2 receptor (sIL-2R), and IgG was investigated in 24 children with cystic fibrosis. Prednisolone was administered, in a double blind and placebo controlled manner, at an initial dose of 2 mg/kg daily for 14 days and tapered to 1 mg/kg on alternate days for 10 weeks. The treated group (n = 12) experienced an increase in forced expiratory volume in one second and forced vital capacity at 14 days, however, these changes were smaller at 12 weeks. In the treated group, change in pulmonary function was associated with decreased serum IgG and cytokine concentrations. Prednisolone suppresses serum concentrations of these cytokines, which may participate in the inflammatory response, the excessive synthesis of IgG, and airflow obstruction observed in cystic fibrosis patients.     

Serum total and free thyroxine and thyrotropin in normal and pregnant women, neonates, and women receiving progestogens

Total serum thyroxine levels are significantly increased throughout pregnancy, returning to normal by 6 weeks post partum. Conversely, percentage-free serum thyroxine is decreased throughout pregnancy (normal at 6 weeks post partum). Thus, the absolute concentration of free thyroxine, the most important component from the physiologic standpoint, remains normal during pregnancy. Thyroid-stimulating hormone (TSH) increases significantly during the first and second trimesters of pregnancy but returns to normal levels at term. In cord serum of neonates, absolute free thyroxine level is greater than that in pregnant women at term; TSH values are greater than those in women at term and in euthyroid nonpregnant women. The use of progestogens for four or more menstrual cycles results in total, percentage-free, and absolute free thyroxine levels comparable to those found in women during pregnancy. The serum levels of TSH are normal.     

Peripheral α2-adrenoceptor-mediated sympathoinhibitory effects of mivazerol

Summary— Mivazerol is a new compound that could potentially reduce perioperative cardiovascular morbidity and mortality in patients with or at risk of coronary disease and submitted to surgery. This action of mivazerol depends on a well documented centrally mediated reduction in sympathetic nerve activity, but a direct peripheral decrease in sympathetic neurotransmitter release induced by activation of prejunctional α₂-adrenoceptors located on sympathetic nerve endings could also contribute. To investigate this issue, the effects of mivazerol on the pressor, systemic and regional hemodynamic (pulsed Doppler technique) as well as on the cardiac responses to electrical stimulation of the spinal cord (SCS) were measured in pithed rats in the absence and in the presence of mivazerol. Mivazerol exerted strong sympathoinhibitory effects: SCS-induced increases in blood pressure, total peripheral resistance and heart rate were dose-dependently reduced by mivazerol, but among the regional vascular beds investigated, only the hindlimb vasoconstrictor responses were significantly drug-affected. All these sympathoinhibitory effects of mivazerol were abolished by prior yohimbine administration. Simultaneously, mivazerol did not induce any postjunctional adrenoceptor blockade as it did not affect noradrenaline cardiac and hemodynamic effects. On the contrary, through postjunctional α₂-adrenoceptor stimulation, mivazerol, in this pithed preparation, dose-dependently increased blood pressure, total peripheral and hindlimb vascular resistances, but heart rate was not affected. We conclude that, in the pithed rat, mivazerol exerts strong peripheral sympathoinhibitory effects. The mechanism involved is prejunctional α₂-adrenoceptor activation as i) mivazerol does not display any postsynaptic α-adrenoceptor blocking effect — it even behaves as a postsynaptic α₂-adrenoceptor agonist — and ii) yohimbine abolishes mivazerol's sympathoinhibitory effects. Thus, direct peripheral together with central mechanisms contribute to mivazerol's sympathoinhibitory effects and ultimately to its cardioprotective action.     

HCMR interviews physician administrator leaders. Interview by Michael J. Enright

This interview departs from HCMR's usual format, interviewing several leaders in health care administration for their ideas on current economic pressures, the impact of competition and joint ventures, attitudes toward equity and capital formation, and competition between the interest of clinical medicine and the cost of care. The physician administrators interviewed hold senior administrative positions: Charles Edwards, President and Chief Executive Officer of Scripps Clinic and Research Foundation; Robert A. Henry, President and Chief Executive Officer of Swedish-American Corporation; William S. Kiser, Chairman of the Board of Governors at Cleveland Clinic Foundation; W. Eugene Mayberry, Chairman of the Board of Governors at Mayo Clinic; and Ronald P. Kaufman, Vice-President for Medical Affairs of George Washington University Hospital. All are members of the Board of Regents or Fellows of the American College of Physician Executives.