Determinants of all causes of death in samples of Italian middle-aged men followed up for 25 years.

A total of 1712 men aged 40 to 59 years in two rural cohorts of northern and central Italy have been followed up for 25 years after an entry examination in 1960. Forty one individual characteristics have been considered as possible predictors of death in the next 25 years. After exclusion of 55 men with life threatening diseases (cardiovascular and cancer) and of 161 men because of missing measurements, 1495 men have been analysed for relation between entry factors and subsequent death (n = 670). Twelve factors eventually emerged as powerful predictors of future death: in hierarchical order, age, blood pressure, forced expiratory volume, cigarette smoking, xanthelasma, mother life-status, arm circumference, father life-status, shoulder-pelvis ratio, vital capacity, arcus senilis, and serum cholesterol. Discrimination as provided by logistic modelling placed 19.6% of all cases in the upper decile of the estimated risk, 36.8% in the upper quintile, 2.5% in the lowest decile, and 7.1% in the lowest quintile. Out of those located in the lowest decile of risk, 11.4% died within 25 years while the corresponding percentage in the upper decile was 87.3%. Use of the Cox model yielded slightly better coefficients than logistic function.     

Inter-cohort differences in coronary heart disease mortality in the 25-year follow-up of the seven countries study

Sixteen cohorts of men aged 40–59 years at entry were examined with the measurement of some risk factors and then followed-up for mortality and causes of death for 25 years. These cohorts were located in the USA (1 cohort), Finland (2), the Netherlands (1), Italy (3), the former Yugoslavia (5), Greece (2), and Japan (2), and included a total of 12,763 subjects.Large differences in age-adjusted coronary heart disease (CHD) death rates were found, with extremes of 45 per 1000 in 25 years in Tanushimaru, Japan, to 288 per 1000 in 25 years in East Finland. In general, higher rates were found in the US and Northern European cohorts as compared to the Southern European and Japanese cohorts. However, during the last 10 years of follow-up large increases of CHD death rates were found in some Yugoslavian areas. Out of 5 measured entry characteristics treated as age-adjusted levels (serum cholesterol, systolic blood pressure, cigarette smoking, body mass index and physical activity at work), only serum cholesterol was significant in explaining cohort differences in CHD death rates.Over 50% of the variance in CHD death rates in 25 years was accounted for by the difference in mean serum cholesterol. This association tended to decline with increasing length of follow-up, but this was due to the great changes in mean serum cholesterol in the two Jugoslavian cohorts of Velika Krsna and Zrenjanin. When these two cohorts were excluded the association increased with time.Changes in mean serum cholesterol between year 0 and 10 helped in explaining differences in CHD death rates from year 10 onward.It can be concluded that this study suggests that mean serum cholesterol is the major risk factor in explaining cross-cultural differences in CHD.     

A high frequency of the A30, B18, DR3, DRw52, DQw2 extended haplotype in Sardinian celiac disease patients: Further evidence that disease susceptibility is conferred by DQ A1*0501, B1*0201

This study characterizes by serological and molecular methods the HLA class I and class II alleles in a group of celiac disease children, their parents and a control group of Sardinian descent. We found the DR3-DQw2 haplotype in all patients which was, in almost all cases (84%), associated with the HLA-A30, B18, DR3, DRw52, DQw2 extended haplotype named "Sardinian haplotype" because of its frequency (12-15%) in this Caucasian population. This is the first time that this DQw2-linked haplotype has been reported with such a high frequency in CD. However, no different distribution of "Sardinian haplotype" was found comparing CD patients with 91 haplotyped DQw2-positive controls. This finding indicates that the DQw2 antigen in Sardinians is almost always associated with the A30, B18, DR3, DRw52, DQw2 extended haplotype. The DQA1 and DQB1 second exon sequence analysis of the B18,DR3 and B8,DR3 haplotypes showed the DQA1*0501 and DQB1*0201 alleles which shared the already published sequences. DPB1 subtyping showed the DPB1*0301 allele more frequently (p less than 0.005) in CD patients but this difference was no longer significant when patients and controls, both heterozygous for the DR3-DQw2 haplotype, were compared. We suggest that the divergent HLA extended haplotypes and DP allele associated with CD, described in different Caucasian populations, can be explained by the particular DQw2 linkage disequilibrium in each population.     

Stress, attachment and skin diseases: a case-control study

Objectives In this case-control study we tested the hypothesis of an association between some psychosomatic skin diseases, attachment style and stress. Patients and methods A total of 177 cases and 194 controls seen between November 1992 and November 1993 at the Istituto Dermopatico dell'lmmacolata (IDD) in Rome, were enrolled into the study. Cases were outpatients with first diagnosis of hyperidrosis, chronic urticaria, generalized pruritus or alopecia areata. Controls were outpatients seen in the same period of time with first diagnosis of pigmenled nevi, keratosis or mycosis. The presence and weight of life stress events were assessed by u standard precoded questionnaire based on the Schedule of Recent Experiences (SRE) and on the Life Experiences Survey (LES). The attachment style was assessed by a modified version of the Shaver and Hazan questionnaire about feelings in a love relationship. We calculated 3 scores for each individual and classified study subjects in 2 groups: 1) "free" (= secure attachment); 2) "not free" (not secure attachment: anxious-ambivalent or avoidant). Questionnaires were self-administered in the presence of a trained psychologist. Adjusted odds ratios (OR) were calculated using a multiple logistic function. Results No association was found between the different stress scores and the skin diseases considered. The crude odds ratio for life stress events in the previous year was 1.4 (95% CI 0.8–2.7). After multiple adjustment for age, sex, marital status and education, the estimated OR was 1.6 (95% CI 0.8–3.0). One significant association emerged between the adult attachment style defined as “not free” and psychosomatic skin diseases: the adjusted OR was 4.0 (95% CI 1.4–12).     

Contrast medium in power Doppler ultrasound for assessment of synovial vascularity: comparison with arthroscopy

OBJECTIVE: To evaluate the reliability of contrast-unenhanced power Doppler (CUPD) and contrast-enhanced power Doppler (CEPD) ultrasound (US) assessment of synovial vascularity of knee joint synovitis by prospective comparison with the "gold standard," arthroscopy. METHODS: A total of 18 knees of 17 patients with refractory rheumatoid and psoriatic knee joint synovitis were examined by US. Recognition of PD synovial vessel flow and its spatial arrangement in relation to the pannus/cartilage interface (P/CI) or fluid/synovium interface (F/SI) were studied by CUPD- and CEPD-US after a single intravenous bolus of galactosel palmitic acid (Levovist). Arthroscopy video recordings were reanalyzed by computer image analysis to assess synovial vascular marking. CUPD and CEPD flow signal scores were compared with each other and with corresponding vascular marking scores. Using villous vascular marking as reference, CUPD and CEPD sensitivity and specificity were measured. Interobserver variability was evaluated. RESULTS: Compared with the unenhanced PD method, contrast administration increased the PD flow signal score in 13/18 knees (72.2%), allowing increased detection of F/SI PD flow signal configuration (p < 0.018) and of the coexistence of P/CI and F/SI PD imaging (p < 0.0078). With arthroscopy as reference, contrast-enhanced PD was found to be more useful than the unenhanced method, showing more reproducible PD signal scores (p = 0.05 vs p = nonsignificant), as well as higher sensitivity (80% vs 30%), but lower specificity (62% vs 87%), in the recognition of increased vascularity of synovial villi. Interobserver agreement was 100%. CONCLUSION: The prospective comparison with arthroscopy showed the reliability of the CEPD method in synovial vessel recognition and its potential clinical usefulness in assessment of knee joint synovitis.     

Prognosis of lean and fat hypertensives

A population sample of 1,645 men aged 40-59 at entry examination has been followed up for 25 years. When hypertensives (160 and/or 95 mm Hg or more; n = 432) were divided into fat and lean on the basis of body mass index (cut off at 24.9), the latter group showed a nonsignificant higher risk of dying during the subsequent 25 years (relative risk = 1.15). Univariate and multivariate analyses suggest that among lean people there is an excess of smokers partly explaining the excess risk of lean hypertensives. Both univariate and multivariate analyses also proved that the relationship of fatness-leanness indicators to total mortality is U-shaped and applies to hypertensives as well as to nonhypertensives, and to the whole population. Evidence has been given that changing the definition of fatness-leanness (cutoff of body mass index of 27.9) the relative risk of lean versus fat hypertensives may reverse (0.93). This suggests that a large part of the problem is artificial and should not be tackled without considering the parabolic relationships of indicators of obesity to mortality.     

Fission yeast orb6, a ser/thr protein kinase related to mammalian rho kinase and myotonic dystrophy kinase, is required for maintenance of cell polarity and coordinates cell morphogenesis with the cell cycle

The molecular mechanisms that coordinate cell morphogenesis with the cell cycle remain largely unknown. We have investigated this process in fission yeast where changes in polarized cell growth are coupled with cell cycle progression. The orb6 gene is required during interphase to maintain cell polarity and encodes a serine/threonine protein kinase, belonging to the myotonic dystrophy kinase/cot1/warts family. A decrease in Orb6 protein levels leads to loss of polarized cell shape and to mitotic advance, whereas an increase in Orb6 levels maintains polarized growth and delays mitosis by affecting the p34^cdc2 mitotic kinase. Thus the Orb6 protein kinase coordinates maintenance of cell polarity during interphase with the onset of mitosis. orb6 interacts genetically with orb2, which encodes the Pak1/Shk1 protein kinase, a component of the Ras1 and Cdc42-dependent signaling pathway. Our results suggest that Orb6 may act downstream of Pak1/Shk1, forming part of a pathway coordinating cell morphogenesis with progression through the cell cycle.     

A common mutation of the insulin receptor substrate-1 gene is a risk factor for coronary artery disease

Insulin resistance is associated with increased risk of atherosclerosis. Insulin receptor substrate-1 (IRS-1) plays a key role in tissue insulin sensitivity. A common mutation (G972R) of the IRS-1 gene has been shown to impair IRS-1 function, and it has been associated with reduced insulin sensitivity and lipid abnormalities. This led us to investigate the role of the G972R mutation in predisposing individuals to coronary artery disease (CAD). The DNA of 318 subjects with angiographically documented coronary atherosclerosis (>50% stenosis) and 208 population control subjects was analyzed for the presence of the G972R mutation. This mutation was detected by nested polymerase chain reaction and BstNI restriction enzyme digestion. The frequency of the G972R mutation was significantly higher among patients with CAD than controls (18. 9% versus 6.8%, respectively; P<0.001). After controlling for other coronary risk factors, the relative risk of CAD associated with the G972R mutation was 2.93 (95% CI 1.30 to 6.60; P<0.02) in the entire cohort. This risk was found to be even higher in the subgroups of obese subjects (odds ratio [OR] 6.97, 95% CI 2.24 to 21.4; P<0.001) and subjects with clinical features of insulin resistance syndrome (OR 27.3, 95% CI 7.19 to 104.0; P<0.001). The IRS-1 gene variant was associated with a higher frequency of diabetes mellitus (14.9% among carriers versus 6.5% among noncarriers; P<0.01) and with a 60% increase of plasma total triglycerides (P<0.001). Also, plasma concentrations of total cholesterol and the ratio of total cholesterol to HDL cholesterol were significantly (P<0.001) higher among carriers than noncarriers, although to lesser a extent. These effects were independent of CAD status. The G972R mutation in the IRS-1 gene was found to be a significant independent predictor of CAD. Moreover, this mutation greatly increased the risk of CAD in obese subjects and in patients with the cluster of abnormalities of insulin resistance syndrome. Besides the increased frequency of diabetes, carriers showed a more atherogenic lipid profile, suggesting a potential role of the IRS-1 gene in the pathogenesis of lipid abnormalities associated with CAD.