Thrombocytopenia following liver transplantation is associated with platelet consumption and thrombin generation

PSA-based screening substantially increases the prostate cancer detection rate and the percentage of organ-confined tumors. It appears that there is some benefit from screening for prostate cancer because of the increased amount of potentially curable disease discovered and the fact that 96% of the pathologically staged tumors detected have histologic features associated with aggressive cancer. Additional evidence that nearly all tumors detected on the basis of initial PSA screening are apt to be clinically significant may be derived from the information that PSA-based screening decreases the incidence of incidental A1 grade III and A2 tumors but does not increase the detection of clinically insignificant A1 grade I and II tumors. At this time, PSA represents the most effective and valuable tool to detect early prostate cancer; therefore, PSA should be used to improve early diagnosis of prostate cancer. Some advances have been made with the introduction of age-specific reference ranges and the ability to measure free to total PSA ratios. The data presented support the clinical usefulness of age-specific reference ranges for serum PSA. Calculation of the free to total PSA ratio is valuable in deciding which screening volunteers require further evaluation, increases the specificity of PSA screening, and as demonstrated may be useful in deciding which patients with isolated PIN should undergo repeat biopsies. Based on these facts, PSA truly can be described as the most important and useful marker for adenocarcinoma of the prostate. Based on these encouraging results and the obligingness of the social insurances, we will be able to continue PSA screening for early detection of prostate cancer for all concerned Tyrolean men in the future.     

Human Mycobacterium bovis infection in the south-west of Ireland 1983-1992: a comparison with M. tuberculosis

Epidemiological and bacteriological aspects of human Mycobacterium bovis disease were investigated in south-west Ireland (counties Cork & Kerry, population 536,000) over the years 1983-92 inclusive and compared to M. tuberculosis. Results showed a small, stable incidence of culture positive M. bovis human disease, mean annual incidence 0.56 per 100,000 population compared to a higher but declining incidence of culture positive M. tuberculosis (15.3 per 100,000 in 1983, 9.0 per 100,000 in 1992). Male patients were the majority, 63.4 per cent of M. bovis; 62.4% of M. tuberculosis (p = 0.03). Fifty three per cent of M. bovis cases (n = 30) were pulmonary, compared to 85% of M. tuberculosis (n = 626; p = 0.0001). M. bovis patients were older (p = 0.02), mean age 58.4 years (SD 18.9) compared to 48.5 (SD 22.2). The mycobacterial smear positive rate was similar in both groups taken as a whole. No rural-urban difference in incidence was found in either disease, suggesting in the case of M. bovis initial infection in childhood via contaminated milk in the pre-pasteurisation era.     

Exogenous and endogenous catecholamines inhibit the production of macrophage inflammatory protein (MIP) 1 alpha via a beta adrenoceptor mediated mechanism

Noradrenaline (NA) and adrenaline (Ad) are modulators of cytokine production. Here we investigated the role of these neurotransmitters in the regulation of macrophage inflammatory protein (MIP)-1alpha expression. Pretreatment of RAW 264.7 macrophages with NA or Ad decreased, in a concentration-dependent manner (1 nM-100 microM), MIP-1alpha release induced by bacterial lipopolysaccharide (LPS 10 ng ml(-1) LPS). The effect of NA was reversed by the selective beta-adrenoceptor antagonist propranolol (10 microM), but not by the alpha-adrenoceptor antagonist phentolamine (10 microM). In the concentration range of 10 nM-10 microM, isoproterenol, a beta-adrenoceptor agonist, but not phenylephrine (a selective alpha1-adrenoceptor agonist) or UK-14304 (a selective alpha2-adrenoceptor agonist) mimicked the inhibitory effects of catecholamines on MIP-1alpha production. Increases in intracellular cyclic adenosine monophosphate, elicited either by the selective type IV phosphodiesterase inhibitor rolipram (0.1 - 10 microM), or by prostaglandin E2, (10 nM-10 microM) decreased MIP-1alpha release, suggesting that increased cyclic AMP may contribute to the suppression of MIP-1alpha release by beta-adrenoceptor stimulation. Northern blot analysis demonstrated that NA (100 nM-10 microM), Ad, isoproterenol, as well as rolipram (100 nM-10 microM) decreased LPS-induced MIP-1alpha mRNA accumulation. NA and Ad (1-100 microM) also decreased MIP-1alpha production in thioglycollate-elicited murine peritoneal macrophages. Pretreatment of mice with either isoproterenol (10 mg kg(-1), i.p.) or rolipram (25 mg kg(-1), i.p.) decreased LPS-induced plasma levels of MIP-1alpha, while propranolol (10 mg kg(-1), i.p.) augmented the production of this chemokine, confirming the role of a beta-adrenoceptor mediated endogenous catecholamine action in the regulation of MIP-1alpha production in vivo. Thus, based on our data we conclude that catecholamines are important endogenous regulators of MIP-1alpha expression in inflammation.     

Relation between chemosensitivity and the ventilatory response to exercise in chronic heart failure

OBJECTIVES: This study sought to establish the chemosensitivity of patients with chronic heart failure. BACKGROUND: The ventilatory response to exercise is often increased in patients with chronic heart failure, as characterized by the steeper regression slope relating minute ventilation to carbon dioxide output. We hypothesized that the sensitivity of chemoreceptors may be reset and may in part mediate the exercise hyperpnea seen in this condition. METHODS: Hypoxic and peripheral hypercapnic chemosensitivity were studied in 38 patients with chronic heart failure (35 men, 3 women; mean [+/-SE] age 60.2 +/- 1.3 years; radionuclide left ventricular ejection fraction 25.7 +/- 2.3%) and 15 healthy control subjects (11 men, 4 women; mean age 54.9 +/- 3.0 years) using transient inhalations of pure nitrogen and single breaths of 13% carbon dioxide, respectively. The change in chemosensitivity during mild exercise (25 W) was assessed in the first 15 patients and all control subjects. Central hypercapnic chemosensitivity was also characterized in 25 patients and 10 control subjects by the rebreathing of 7% carbon dioxide in 93% oxygen. Cardiopulmonary exercise testing was performed in all subjects. RESULTS: Maximal oxygen consumption was 16.6 +/- 0.9 versus 29.7 +/- 2.2 mol/kg per min (p < 0.0001), and the ventilation-carbon dioxide output regression slope was 37.2 +/- 1.5 versus 26.5 +/- 1.4 (p < 0.0001) in patients and control subjects, respectively. Hypoxic and central hypercapnic chemosensitivity were enhanced in patients (0.707 +/- 0.076 vs. 0.293 +/- 0.056 liters/min per % arterial oxygen saturation [SaO2], p = 0.0001 and 3.15 +/- 0.41 vs. 2.02 +/- 0.25 liters/min per mm Hg, p = 0.025, respectively) and correlated significantly with the ventilatory response to exercise. Hypoxic chemosensitivity was augmented during exercise in patients and in control subjects but remained higher in the former (1.530 +/- 0.27 vs. 0.685 +/- 0.12 liters/min per %SaO2, p = 0.01). The peripheral hypercapnic chemosensitivity of patients at rest and during exercise was similar to that in control subjects, consistent with its lesser contribution to overall carbon dioxide chemosensitivity. CONCLUSIONS: Enhanced hypoxic and central hypercapnic chemosensitivity may play a role in mediating the increased ventilatory response to exercise in chronic heart failure.     

Socioeconomic disparities in preventive care persist despite universal coverage. Breast and cervical cancer screening in Ontario and the United States

OBJECTIVE: To compare the association of income and education with breast and cervical cancer screening in Ontario, Canada, and the United States. DESIGN: Survey using data from the Ontario Health Survey and the US National Health Interview Survey. PARTICIPANTS: A multistage random sample of women aged 18 years and older living in households in Ontario (N = 23,521) and the United States (N = 23,932) in 1990. MAIN OUTCOME MEASURE: Persons were considered screened if they reported a Papanicolaou test within the previous 2 years, a clinical breast examination within the previous year, or a mammogram within the previous year. RESULTS: Papanicolaou test and clinical breast examination rates were similar between countries, but mammography rates were two to three times higher in the United States across all age groups. Compared with women with less than a high school degree, college graduates were more likely to receive screening (odds ratio [OR], 1.5; 95% confidence interval [CI], 1.2 to 1.7) and there was no difference between countries. Across all procedures, women with higher incomes were more likely to receive screening. For Papanicolaou test and clinical breast examination, there was no difference between countries. Compared with the lowest income, the OR was 1.7 (95% CI, 1.3 to 2.1) in Ontario and 1.9 (95% CI, 1.6 to 2.2) in the United States for Papanicolaou test and 2.1 (95% CI, 1.6 to 2.8) in Ontario and 2.1 (95% CI, 1.8 to 2.6) in the United States for the clinical breast examination for women with income greater than $45,600 (US dollars). For mammography screening, the association of income with use was greater in the United States: the OR was 1.8 (95% CI, 1.3 to 2.6) in Ontario and 2.7 (95% CI, 2.3 to 3.2) in the United States for women with income greater than $45,600 (US dollars). CONCLUSIONS: Despite the long-time presence of universal insurance coverage in Ontario the disparities in the use of cancer screening procedures by the poor were similar to the United States. Universal coverage is not sufficient to overcome the large disparities in screenings across socioeconomic status demonstrated in both countries.     

Applying the realized probability of dying to cancer survival

Age comparisons of survival in cancer cohorts generally utilize relative survival rates, which are based on indicators of the probability of survival for a given number of years after diagnosis. Cancer relative survival rates for the same number of years tend to decline as age at diagnosis increases. However, the same number of years of survival reflects higher relative longevity at older ages than at younger ages. The realized probability of dying (RPD) is a survival measure that expresses individual survival time after diagnosis relative to the survival distribution of an age-, race-, and sex-specific reference population, in effect weighing individual survival time more heavily as age at diagnosis increases. The purpose of this study was to apply the RPD as a survival measure in cancer epidemiology. Two cohorts of cancer patients, white males with prostate cancer and white females with breast cancer, aged 55 years and over at diagnosis, were followed for 15 years. Although older subjects survived less time after diagnosis than younger subjects, they achieved more favorable RPD values. We present survival analysis methods for analyzing the RPD in this population, an approach not previously used with this measure. The implications for use of the RPD in cancer epidemiology are discussed.     

Flauoprotein structure and mechanism 2. Monoamine oxidases: old friends hold many surprises

The two forms of monoamine oxidase (MAO), A and B, continue to be of major interest to biochemists, pharmacologists, neurologists, and gerontologists. Despite intensive study for more than half a century, unexpected and unique properties of these enzymes continue to come to light. Recent studies have centered on their kinetic mechanism, their unique predilection for substrates related to the neurotoxic tertiary amine MPTP, and their putative role in aging and in the etiology of neurodegenerative diseases. New and potent inhibitors of MAO A and MAO B continue to be developed because of their potential use in clinical medicine. Some are effective in the picomolar range but MAO B from different mammalian species shows remarkable differences in sensitivity to these agents.