Determination of 4-demethoxy-3'-deamino-3'-aziridinyl-4'-methylsulphonyldaunorubicin+ ++ and its 13-hydroxy metabolite by direct injection of human plasma into a column-switching liquid chromatography system with mass spectrometric detection.

A selective, sensitive and fully automated column-switching LC system using direct injection of human plasma followed by mass spectrometry (MS) detection was developed and validated to determine the concentrations of 4-demethoxy-3'-deamino-3'-aziridinyl-4'-methylsulphonyldaunorubicin++ + (PNU-159548) and its 13-hydroxy metabolite (PNU-169884). A 50-microl human plasma sample was directly introduced into a C4-alkyl-diol silica clean-up column separating analytes from proteins and polar endogenous compounds using water and methanol as the mobile phase. The fraction containing PNU-159548 and its metabolite was back-flushed and transferred to the analytical column. The compounds were separated using a Zorbax SB C8 column (150x4.6 mm, 5 microm) under gradient conditions with the mobile phase containing acetonitrile and 2 mM ammonium formate, pH 3.5. MS detection was by atmospheric pressure ionisation with multiple reaction monitoring in positive ion mode. Linearity was demonstrated over the calibration range of 0.051-10.291 ng/ml for PNU-159548 and 0.104-10.434 ng/ml for PNU-169884. The assay was validated with respect to accuracy, precision and analyte stability. On the basis of the validation data, the developed analytical method was found to be suitable for use in Phase I clinical studies.

A case-control study on lymphocytic subsets in elderly bearing a gastroenteric cancer.

The aim of this work is to evaluate the differences in lymphocytic sub-classes between elderly patients with gastroenteric cancer and elderly patients with a non neoplastic disease. A group of 88 patients over 60, consecutively admitted to the III Division General Surgery for gastro-enteric cancer has been collected for the study, the control group consisted of 74 patients also over 60, consecutively admitted over the same period for benign abdominal diseases. In all patients the following data were measured: body mass index (BMI), white blood cells (WBC), total lymphocytes, total T lymphocytes (CD3+), helper T lymphocytes (CD4+), suppressor T lymphocytes (CD8+), CD4+/CD8+ ratio, B lymphocytes, CD5+ B lymphocytes, activated T lymphocytes (CD3+ HLA-DR+), CD4+ "naive" lymphocytes (CD4+ CD45 RA+), CD4+ "memory" lymphocytes (CD4+ CD45 RO+), NK lymphocytes (CD16+ 56+), red blood cells (RBC), total serum cholesterol, albumin, total serum proteins. The main lymphocytic subsets were on an average lower in the cancerous elderly group with respect to the non cancerous. As the tumour progressively increases in size (T), total lymphocytes significantly decrease, while CD4+ progressively decreases with nodal involvement (N). In the cancerous elderly, we found a lower immune response. The immune system appears to be less efficient also in association with tumor growth, especially when T and N get worse. The response of effector cells to the tumour seems not specific.

One year follow-up results in the surgical treatment of gastroesophageal reflux disease.

BACKGROUND: Gastroesophageal reflux disease (GERD) is a common intestinal disorder. Although fundoplication immediately achieves good results, some problems arise about duration. METHODS: From 1990 to 1992, thirty-seven patients underwent operation for GERD, the indications for surgery being: persistence of reflux symptoms after at least 6 months of medical therapy, esophagitis, manometric evidence of LES incompetence, augmented esophageal exposure to gastric juice documented by 24 hours pH monitoring. Nissen-Rossetti was the technique used; intraoperative calibration was 29.8 mmHg. RESULTS: Twenty-five patients were studied 12 months after the operation. They were submitted to clinical examination, gastroscopy, manometry, 24 hours pH monitoring. Clinically 2 patients were unable to belch. All of them showed LESP and intra-abdominal HPZ length decreased (32.3% and 13.5% respectively). The factors influencing LESP 12 months after surgery are age and intraoperative calibration. Pressure decrease is related to age and calibration. An older patient will show a smaller decrement, to a higher intraoperative pressure corresponds a higher pressure decrease with time. CONCLUSIONS: For these reasons we do not recommend hypercalibration especially in the elderly.

[Associations between arterial hypertension and other cardiovascular risk factors in subjects over 65 years of age]. / Associazione tra ipertensione arteriosa ed altri fattori di rischio cardiovascolare in soggetti ultrasessantacinquenni.

The goal of this study was to evaluate whether in subjects aged 65 or over hypertensive patients have a greater prevalence of risk factors than normotensives. 1369 subjects, aged 65 or over, have been retrospectively investigated. The following risk factors were considered: cigarette smoking, left ventricular hypertrophy, diabetes mellitus and atrial fibrillation (analyzed as dichotomous variables), B.M.I., blood concentration of total, -LDL-HDL cholesterol, triglycerides and total/HDL cholesterol ratio (analyzed as continuous variables). The mean number of risk factors was calculated in hypertensive and normotensive subjects; the association between hypertension and risk factors was evaluated using univariate and multiple logistic regression analysis. 451 subjects (32.9%) were found to be hypertensives. The average number of risk factors was significantly greater in hypertensive than in normotensive subjects (1.85 +/- 1.27 vs 1.39 +/- 1.15, p < 0.001), and, in both groups, in men than in women. Left ventricular hypertrophy (p < 0.001), total cholesterol (p < 0.001), diabetes mellitus (p < 0.001) and atrial fibrillation (p < 0.01) were found to be independently associated with the presence of hypertension. We concluded that among the elderly there is a greater prevalence of risk factors in hypertensive than in normotensive subjects and that some risk factors--left ventricular hypertrophy, atrial fibrillation, diabetes mellitus, and blood levels of atherogenic lipids--are independently associated with the presence of hypertension.

Carotid plaque, aging, and risk factors. A study of 457 subjects.

BACKGROUND AND PURPOSE: The aim of this study was to assess the prevalence of extracranial carotid artery atherosclerosis and its relation to principal cardiovascular risk factors at different ages in a sample of the general population. METHODS: B-mode ultrasonography was used to investigate the carotid district in 457 subjects (231 men and 226 women; mean age, 55.4 +/- 18.7 years; range, 18 to 97 years) in the metropolitan area. The ultrasonographic findings were then related to risk factors. RESULTS: Carotid plaques were found in 178 subjects (38.9%). The prevalence of atherosclerosis, number of plaques, and severity of stenosis were observed to increase with age. Age (P < .0001), cigarette smoking (P < .0001), male sex (P < .001), total cholesterol (P < .05), and, inversely, the ratio of high-density lipoprotein cholesterol to total cholesterol (P < .05) were found to be independently associated with carotid atherosclerosis. Stratified analysis by sex and age showed effect modifications by age on cigarette smoking, total cholesterol, and the ratio of high-density lipoprotein cholesterol to total cholesterol. After multivariate analysis including interaction terms, cigarette smoking and cholesterol levels were not longer found to be associated with carotid atherosclerosis in elderly subjects. Age (P < .01), total cholesterol (P < .05), and diabetes (P < .05) were positively related to the severity of vascular narrowing. CONCLUSIONS: There is a high prevalence of asymptomatic carotid atherosclerosis in the general population, particularly among the very old. The association between risk factors and carotid atherosclerosis is less pronounced in the elderly than in younger subjects.

Risk factors for atherosclerosis and aging.

In order to investigate the association between atherosclerosis and risk factors in aged subjects, Doppler ultrasound scans were used to identify the presence and severity of carotid and femoral atherosclerosis in a sample of 457 community living subjects (mean age 55.4 +/- 18.7 years) of the metropolitan area; the ultrasonographic findings were then related to primary cardiovascular risk factors. Carotid and femoral plaques were found respectively in 178 (38.5%) and in 180 (39.4%) subjects. Prevalence of atherosclerosis, number of plaques and percentage of stenosis have been observed to increase with age. All the main cardiovascular risk factors (age, male sex, hypertension, cigarette smoking, diabetes and hypercholesterolemia) resulted significantly associated with both carotid and femoral atherosclerosis in the total series and, more strongly, in subjects aged under 65. On the contrary, most of these associations disappeared in subjects aged 65 or more. Multiple logistic regression analysis confirmed that in this age group only age and male sex were independently associated with carotid and femoral atherosclerosis; of the other risk factors cigarette smoking alone was an independent risk factor for femoral atherosclerosis. We conclude that in the elderly, in spite of the age-related increase in carotid and femoral atherosclerosis, the association between risk factors and atherosclerotic disease is less relevant than at younger ages.

[Ischemic stroke and transient ischemic attacks: a case-control study of the risk factors in elderly hospitalized patients]. / Stroke ischemico e attacchi ischemici transitori: studio caso-controllo sui fattori di rischio in pazienti anziani ospedalizzati.

We have evaluated in a case-control study the association of the main risk factors with cerebrovascular ischemic accidents in elderly patients. Two hundred and twenty patients aged 65 year or more (average age 77.3 +/- 7.3 yr, 93 males and 127 females) admitted to our Division for stroke (122) or transient ischemic attacks (TIA) (98) were enrolled: 220 hospitalized patients, age and sex-matched, without actual or previous cardiovascular clinical manifestations were the control group. Advanced senile decay, hepatic or renale failure and malignancies were considered exclusion criteria for both groups. The following risk factors have been considered: family history, obesity, cigarette smoking, diabetes, hypercholesterolemia, hypertriglyceridemia, atrial fibrillation, left ventricular hypertrophy, and related continuous variables. After logistic multiple regression analysis, atrial fibrillation, hypertension and blood cholesterol concentration above 240 mg/dl were significantly and independently associated with stroke, while only hypertension and hypercholesterolemia were associated with TIA. The unexpected finding of a significant association between hypercholesterolemia and cerebrovascular ischemia seems attributable to the choice of hospitalized patients as control group. These results indicate that hypertension and atrial fibrillation are independently associated with ischemic stroke even in advanced age.

Risk factors for atherosclerosis: ultrasound evaluation of carotid and femoral arteries in patients examined by coronary angiography.

The carotid and femoral arteries of 209 subjects (161 men and 48 women), consecutively tested by coronary angiography during the first four months of 1990, were examined using a B-Mode Echo-doppler. The angiographic examination was performed for suspected ischemic disease or to complement hemodynamic tests for valvular cardiopathy. The relationship between the main risk factors and the degree of atherosclerotic vascular involvement in the coronary, carotid and femoral districts was examined using standardised partial correlation coefficients. Cigarette smoke (expressed as number of cigarettes per day or as duration of exposure to smoke), total blood cholesterol concentration and age were positively correlated with the degree of atherosclerotic involvement in all three vascular regions; triglyceridemia values were correlated only in the coronary region. These relations were observed both in patients below and above 65 years of age; in the elderly group no correlation was found between blood cholesterol concentration and coronary involvement and between triglycerides levels and atherosclerotic disease in the three districts. Our results suggest that some risk factors (high blood cholesterol concentration and history of smoking) correlate with severity of atherosclerotic involvement even in advanced age.

[Lipid parameters and cardiovascular risks in elderly patients hospitalized for ischemic cardiopathy. A case-control study]. / Parametri lipidici e rischio cardiovascolare in pazienti anziani ospedalizzati per cardiopatia ischemica. Uno studio caso-controllo.

In order to evaluate whether and to what extent elevated blood lipid concentrations and clinical expressions of coronary heart disease (CHD) are associated in the elderly, we studied the risk of CHD (myocardial infarction and angina pectoris) in a population of elderly hospitalized patients (210 subjects, 126 men and 84 women, average age 76 +/- 6 years) exposed to risk factors. 210 patients, free from current and previous cardiovascular diseases, age and sex matched, were recruited as the control group. Advanced senile decline, severe hepatic or renal failure and malignancies were considered exclusion criteria for both groups. The following dichotomic variables (familial history of CHD, cigarette smoking, clinical history of arterial hypertension or diabetes mellitus, hypercholesterolemia, hypertriglyceridemia) and continuous variables (total, LDL and HDL cholesterol, triglycerides, total/HDL cholesterol ratio, body mass index (BMI), years of exposure to risk factors) were considered. Using a stepwise multiple logistic regression forward method, the following variables resulted significantly associated with the risk of CHD: total/HDL cholesterol ratio (OR 1,89), BMI (OR 1,04), period of hypertension (OR 1,04) and cigarette smoke exposure (OR 1,007). We conclude that in the elderly the total/HDL cholesterol ratio can be a more predictive and reliable index of coronary risk than blood total cholesterol concentration.

[Prevalence and risk factors of carotid and femoral atherosclerosis in a sample of the city of Turin]. / Prevalenza e fattori di rischio dell'aterosclerosi carotidea e femorale in un campione della città di Torino.

Presence and severity of carotid and femoral atherosclerosis, in relation to the principal cardiovascular risk factors, have been non invasively evaluated using echodoppler in a sample of 457 subjects (average age 55.4 +/- 18.7 years) of the metropolitan area of Turin. Data of prevalence have been standardized for age and gender in order to obtain an estimate of prevalence representative of the city. In both districts, prevalence of lesions, echo structural characteristics of the plaques and related degree of stenosis have been considered. Results indicate a high prevalence of carotid and femoral atherosclerosis (38.5% and 39.4% respectively), and, particularly, of concomitant involvement of both districts (30%). Prevalence of the lesions and degree of stenosis rise with advancing age; nevertheless stenosis > 75% were not found among the oldest patients. Bifurcations were the most frequent site of lesion and the "hard" echo structure was the most commonly represented, especially in subjects over 45 years. After multiple logistic regression model both carotid and femoral atherosclerosis were strongly and independently associated with age, male sex, smoke of cigarette and plasma cholesterol concentration.

A four year clinical and echographic follow-up of asymptomatic carotid plaque.

Eighty-five patients with asymptomatic carotid plaque--a diagnosis revealed by B-mode high-resolution echotomography--were followed up for four years; the echoplaque changes were compared with the clinical history. Eight patients died (2 from stroke, 4 from myocardial infarction, and 2 from lung tumor) and were excluded from the follow-up. Three patients underwent carotid thromboendarterectomy (TEA) (1 bilateral), and these 4 carotids were not considered in the total series. At the first echo Doppler evaluation of 150 carotids, plaques were observed in 112; 38 vessels were free of lesions. Of the 150 carotids, 8 revealed a new plaques. In regard to the echogenic pattern, 95 of the 112 plaques (84.8%) remained unchanged, 16 (14.3%) progressed, and regression of a small homogeneous plaque was observed in 1 patient (0.9%). An increase of the degree of vascular stenosis, was observed in 23 of the 150 carotids (15.3%). Cerebral ischemic symptoms occurred in 5 patients. In 1 patient who suffered from stroke, a new, soft, dyshomogeneous plaque in the carotid of the side of the lesion was observed. In 3 patients (2 with strokes, 1 with transient ischemic attack) the occlusion of a previous severe stenosis was observed. The fifth patient had a stroke on the side of an unchanged, ulcerated hemodynamic lesion. A valid criterion for identifying a risky plaque should be the joint evaluation of the echostructural characteristics and the degree of stenosis.

Stimulation of phagocytic activity of neutrophilic granulocytes by sera of patients with solid tumors.

The effect of serum of patients with solid tumors on the phagocytic activity of normal neutrophilic granulocytes was investigated. The largest groups of tumors studied were carcinoma of colon/rectum, sarcomas and melanomas. Sera from all three groups of patients were found to have highly significant (p < 0.001) stimulatory effects on granulocyte phagocytic activity. These findings contrast with previously reported depression of granulocyte phagocytic activity associated with various forms of leukemia and lymphomas.