Causes of death and clinical diagnostic errors in extreme aged hospitalized people: a retrospective clinical-necropsy survey.

BACKGROUND: There are little data on causes of death in extreme aged. We compared, using autopsy findings, main cause of death, overall disease status, and accuracy rate of clinical diagnoses in extreme aged and persons dying at younger ages. METHODS: We reviewed the complete clinical and autopsy records of 114 consecutive inpatients (97 women, 17 men, age range 97-106, mean 99, median 98) who died in Trieste, Italy, and represented 99% of all extreme-aged person deaths in the hospital and 70% in the area. The control group included 151 patients (66 women, 85 men, age range 65-74, mean 70, median 70) who died during the same period in that hospital. RESULTS: Vascular and respiratory diseases together caused 84% of deaths in extreme aged. The main causes of death were pneumonia (n = 40, 35%), pulmonary embolism (n = 16, 14%), stroke (n = 12, 11%), and myocardial infarction (n = 8, 7%). Cancer was responsible for 6% (7/114) of deaths in extreme aged and 42% (64/151) in the control group. In 5% of extreme aged, autopsy findings did not explain death. The premortem diagnostic accuracy rate for clinical diagnoses was good in 44% of extreme aged, sufficient in 18%, poor in 28%, and not evaluable in 10%, and was significantly different from controls. Pneumonia, pulmonary embolism, and myocardial infarction were markedly underestimated by clinicians in both groups. CONCLUSIONS: Extreme aged die mainly of cardiovascular and respiratory diseases and, in most cases, of acute events. Senescence is a rare cause of death. Death from cancer is substantially lower than in persons dying at younger ages. In contrast to no autopsy studies, most extreme aged in our study were found to have specific diseases that explained their deaths.

Polymorphism of the apolipoprotein E gene and early carotid atherosclerosis defined by ultrasonography in asymptomatic adults.

Clinical and autoptical studies have suggested a predisposing role of the allele E4 of apolipoprotein E (apoE) in the development of atherosclerosis and cardiovascular disease. To investigate the possible contribution of apoE allele polymorphism to the carotid intima-media thickness (IMT) as assessed by ultrasound, we studied 260 asymptomatic nondiabetic subjects (121 men, 139 women; mean +/- SD age, 53 +/- 7 years), randomly selected from the population register of the inhabitants of Trieste, Italy. B-mode ultrasound was used to quantify the maximum IMT at 12 sites on the near and far wall of the common, bifurcation, and internal carotid arteries. ApoE genotypes were determined from amplified apoE sequences by restriction isotyping. The frequencies of E2, E3, and E4 alleles were 0.073, 0.827, and 0.100, respectively. As expected, subjects with E4 allele had the highest levels of total serum cholesterol and LDL cholesterol, subjects with E2 allele had the lowest levels, and those with E3 genotype had intermediate levels. The echographic measurements of carotid IMT showed increasing values from E2 to E4 carriers. After adjustment for total and LDL cholesterol serum levels, triglycerides, ratio of LDL to HDL cholesterol, age, sex, and body mass index, ANCOVA showed that the common carotid IMT was significantly greater (P = .029) in subjects with E4 allele compared with E3 carriers. Our data confirm the influence of apoE4 on cholesterol levels and clearly show that apoE genotype affects carotid atherosclerosis in its early stages in middle-aged asymptomatic subjects.

Activation of coagulation by a LDL-apheresis device.

LDL-apheresis often induces an almost constant and progressive increase of the differential pressure of plasma flowing through the dextran sulphate cellulose column, reducing the efficacy of the treatment. On two occasions we were able to identify a fibrin plug by immunofluorescence. Our aim was to verify the modification of some coagulation indicators in patients undergoing LDL-apheresis and whether an activation of coagulation occurs in the LDL-apheresis device. Blood samples were obtained from six patients with familial hypercholesterolaemia who were undergoing LDL-apheresis. During the same session further blood/ plasma samples were taken from the LDL-apheresis device at different sites and at different volumes of filtered blood. In patients after LDL-apheresis the following modifications were found: a 25% decrease of fibrinogen and a slight increase in F1 + 2 plasma levels. No relevant changes in thrombin-antithrombin complexes and fibrinopeptide A plasma levels were noted. In the LDL-apheresis device the main results were: (a) fibrinogen was trapped in the dextran sulphate cellulose column in the early phases; (b) activation of coagulation was recognisable in the plasma separator during the procedure and progressively increased with duration of LDL-apheresis; (c) thrombin-antithrombin complexes, formed in the plasma separator, were retained by the dextran sulphate cellulose column. In conclusion, LDL-apheresis activates coagulation in the device. Shortening cycle time or using nafamostat mesilate as an anticoagulant, could be interesting alternatives for improving the procedure.

Carotid atherosclerosis: echographic patterns versus histological findings.

The study was carried out on 25 whole carotid arteries explanted from a corpse and perfused at constant pressure to reproduce the conditions of an in vivo examination as much as possible. Out of 5 samples with intimal thickening detected by echo, fibrosis of the tunica media was observed by the pathologist in 4 and microcalcification in 1. In 4 vessels with soft plaques at echo scanning, a wide necrotic area (2 cases), slack connective tissue (1 case) and cystic lesions (1 case) were observed. Hard lesions with (5 cases) or without (2 cases) a cone of shadow at echo evaluation corresponded to fibrous (2 cases) or fibrocalcific (3 cases) plaques. The histological study of the two echo-diagnosed thrombi showed an intermediate echographic pattern and the main feature of the non-occluding thrombus was the absence of a lumen-lesion interface. Mixed plaques were diagnosed at echo in 9 arteries and the correspondent histological aspect was a typical atheromatous lesion in all cases. Thus, the comparison of the ultrasound image with the histological findings proved the reliability of echography in the detection of atheromatous lesions with an excellent agreement between the results at the 2 examinations. Since the type of carotid lesions has an impact upon clinical events these results might support the use of vascular ultrasound images in clinical applications.

Fibrinogen, D-dimer and thrombin-antithrombin complexes in a random population sample: relationships with other cardiovascular risk factors.

Fibrinogen is an independent risk factor for cardiovascular disease and both D-Dimer and Thrombin-Antithrombin complexes may be suitable as laboratory markers of deep venous thrombosis and are becoming more widespread in clinical practice. The aim of our study was to evaluate their normal range and to examine their correlation with various cardiovascular risk factors. Fibrinogen, D-Dimer and Thrombin-Antithrombin complexes were assessed in 516 normal subjects randomly selected from the National Health Service register of Trieste (Italy). In our community the mean value of fibrinogen was 283 +/- 71 mg/dl. Fibrinogen increases with age in males and was significantly higher in male smokers. In non-smokers, females had significantly higher fibrinogen values than males. The mean value of D-Dimer was 306 +/- 130 ng/ml. In females it is significantly higher. The fibrinogen and D-Dimer correlation coefficient was 0.20 (p < 0.001). The mean level of Thrombin-Antithrombin complexes was 6.25 +/- 6.8 ng/ml with a distribution markedly skewed towards the left; males had lower concentration than females (p = 0.047). Multiple regression analysis for fibrinogen as a dependent variable showed that D-Dimer, LDL-cholesterol, Body-Mass Index and Thrombin-Antithrombin complexes were poor predictors for fibrinogen plasma levels (R2 = 0.23) and that fibrinogen, ApoA1 and age can explain only about 10% of the observed variability in D-Dimer.

Early carotid atherosclerosis in asymptomatic adults with primary moderate hypercholesterolemia: a case-control study.

It has been shown that severe hypercholesterolemia is associated with carotid atherosclerosis but it is unclear whether this is true for moderate hypercholesterolemia. The aim of the study was to determine the prevalence of ultrasound detectable extent and severity of carotid intima-media thicknesses in 143 asymptomatic (79 males, 64 females, age range 45-64 years) primary moderate hypercholesterolemic patients (serum LDL cholesterol range 160-190 mg/dl). This group was compared with 143 asymptomatic normolipidemic subjects (serum LDL cholesterol < or = 130 mg/dl and serum triglycerides < 200 mg/dl) matched for age, sex and other cardiovascular risk factors. The maximum intima-media thickness (IMT) was measured using B-mode ultrasonography at 12 sites on the near and the far wall of the common, bifurcation and internal carotid arteries. The mean-maximum IMT at the 12 sites was compared in cases and controls. Moreover, the prevalence of intima-media thickening (i.e. at least one of the 12 sites with an IMT equal to or greater than 1.0 mm but less than 1.3) and plaques (i.e. at least one of the 12 sites with an IMT equal to or greater than 1.3 mm) was considered in the two groups. The mean-maximum intima-media thickness was 0.97 +/- 0.12 mm in hypercholesterolemic patients and 0.93 +/- 0.05 mm in controls (P < 0.0001). Intima-media thickening and plaques were detected in 76% of hypercholesterolemics vs. 57% of controls (P < 0.0002). Gender did not influence these differences.(ABSTRACT TRUNCATED AT 250 WORDS)

Lipoprotein(a) serum concentration in familial combined hyperlipidemia.

The lipoprotein(a) (Lp(a) concentrations in serum were measured by an ELISA technique in 53 subjects affected by familial combined hyperlipidemia (FCHL) and in 347 healthy individuals. Lp(a) geometric means did not differ significantly between the two groups despite the different distributions. In hyperlipidemic subjects, the distribution was markedly shifted to the right (median 17 mg/dl) while in controls it was highly skewed to the left (median = 11 mg/dl). In FCHL, Lp(a) serum levels did not differ between patients with or without coronary heart disease (CHD). It was concluded that, differently from familial hypercholesterolemia (FH), in FCHL Lp(a) may not be elevated in comparison with an adequate control population.

Efficacy of ciprofibrate in primary type II and IV hyperlipidemia: the Italian multicenter study.

The 127 diet-resistant primary hyperlipidemic patients received 100 mg of ciprofibrate daily for 12 weeks. In the 63 patients with type IIa hyperlipidemia and 41 patients with type IIb hyperlipidemia, serum levels of total cholesterol, very-low-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, very-low-density lipoprotein triglycerides, and apolipoprotein (apo) B decreased significantly and levels of high-density lipoprotein cholesterol and apo A-I increased significantly. Similar changes occurred in the 23 type IV patients, except that high-density lipoprotein cholesterol levels increased significantly and apo B levels did not change. No clinically significant side effects or drug-related abnormal laboratory test results were noted. It is concluded that ciprofibrate is a safe and potent hypolipidemic agent.

[Effects of low-dose cholestyramine in long-term therapy of hypercholesterolemia]. / Effetti della colestiramina a basse dosi nella terapia a lungo termine dell'ipercolesterolemia.

Sixty-nine patients (mean age 49 +/- 13 years), affected by primary hypercholesterolemia (65 type IIa and 4 type IIb), were treated for 2 years with 12 gr/day cholestyramine subdivided in two doses. Total serum cholesterol decreased from 353 (sd 66) mg/dl to 291 (sd 62) mg/dl (p less than 0.001) at the third month active treatment remaining thereafter constant. Overall, LDL-cholesterol reduced by 30% in cases with a familial form of the metabolic disorder, by 27% and 30% in those with polygenic or indefinite hypercholesterolemia, respectively. HDL-cholesterol remained unchanged during the study whereas serum triglycerides tended toward an increase. The frequency of reported side effects ranged between 11% and 23% of cases. Mostly they were constipation and abdominal discomfort which, however, did not cause a definitive discontinuation of the resin. The favourable side effect profile and the efficacy confirmed that low-dose cholestyramine represents the first choice drug for hypercholesterolemia.

Ketanserin in mild to moderate hypertension in the elderly: a double-blind study versus methyldopa.

In a double-blind study of 30 elderly patients with mild to moderate essential hypertension, the antihypertensive effects of ketanserin and methyldopa were compared. The patients were randomly assigned to receive 20 mg of ketanserin or 250 mg of methyldopa twice daily for two weeks; the dose was then doubled for the rest of the three-month period. Two of the ketanserin group dropped out of treatment, one because of psychic depression, the other because of epigastric pain. After three months of therapy with ketanserin, systolic blood pressure decreased in a dose-dependent manner from 190 +/- 20 to 175 +/- 20 mmHg (P less than 0.05) and diastolic blood pressure from 106 +/- 8 to 91 +/- 9 mmHg (P less than 0.001). Blood pressure was reduced to 160/90 mmHg or less in eight of the 13 ketanserin patients and in five of the 15 methyldopa patients. In both groups heart rate and body weight remained constant. No orthostatic hypotension or hypertensive rebound after ketanserin withdrawal was recorded. It is concluded that 40 mg of ketanserin twice daily can control hypertension in the elderly.

A hyperalphalipoproteinaemic family with normal cholesteryl ester transfer/exchange activity.

Reports of two independent studies suggest that familial hyperalphalipoproteinaemia (FHALP) may be caused by a deficiency of cholesteryl ester transfer/exchange activity (CETP). We also have studied CETP in the plasma of an Italian FHALP kindred. The study group was divided into blood relatives with greater than 1.70 mM high-density-lipoprotein cholesterol (HDL-C) (group I, n = 9), with less than 1.70 mM-HDL-C (group II, n = 12) and in spouses (group III, n = 6). Two different assays were performed to measure CETP activity. In method A the interfering endogenous lipoproteins in the plasma samples were removed by poly(ethylene glycol) precipitation or by ultracentrifugation at a relative density (d) of 1.180. The CETP-activity of these samples was measured in a system consisting of fixed amounts of HDL and cholesteryl [1-14C]oleate-labelled low-density lipoproteins (LDL). In method B, trace amounts of HDL (radiolabelled with cholesteryl [1-14C]oleate) were incubated with plasma for 3 h at 37 degrees C and the distribution of the label among lipoproteins was measured (CET activity). The results can be summarized as follows. The mean CETP activities measured by method A were 187, 213 and 243 nmol/h per ml in groups I, II and III respectively. The proband with the highest HDL-C (4.98 mM) had a CETP activity of 231 nmol/h per ml. The corresponding CET activities measured by method B and expressed as percentage transfer/h were 4.3, 8.0 and 11.2 in groups I-III. The proband with HDL-C = 4.98 mM had a value of only 1.7%/h. There was a strong negative correlation between percentage CE transfer and HDL-C concentration. Calculating these data in terms of CE exchange (nmol/h per ml), groups I, II and III exhibited mean activities of 86, 124 and 110 nmol/h per ml respectively; for the proband this value was 80 nmol/h per ml. Only a slight correlation was found between these values and the HDL-C value. Thus by both methods, (A), measuring the CETP activity per se and (B), measuring the activity in whole plasma (reflecting the activity of the protein and the concentration and composition of lipoproteins), no major differences could be found between the three groups. In our family, therefore, no connection between FHALP and CETP deficiency could be found. It is concluded that, for hyper- and dys-lipoproteinaemic samples, a careful selection of the assay procedure as well as the mode of calculating results is essential. Since this may not hold the previous studies, the supposed connection between FHALP and CETP deficiency is challenged.

HLA antigens in familial hyper-alphalipoproteinemia.

Tissue typing for HLA-A, B and C antigens was performed in 28 subjects belonging to a family in which an inherited increase of high density lipoprotein cholesterol (HDL-C) is present. Nine subjects had definite hyper-alphalipoproteinemia (HDL-C greater than 80 mg/dl) and 3 "borderline" values (HDL-C greater than 70 mg/dl). There is not any linkage between the presence of HDL-C elevation and the HLA haplotypes.

Cholesterol-lowering and HDL-raising properties of lecithinated soy proteins in type II hyperlipidemic patients.

Plasma lipoprotein changes were evaluated in 65 type II patients undergoing sequential 4-week dietary treatments with: (I) standard low-lipid diet; (II) low-lipid diet with total replacement of animal proteins with textured soy proteins containing 6% of lecithin (L-TVP); (III) standard low-lipid diet; (IV) low-lipid diet with a 50% substitution of animal proteins with L-TVP. Total cholesterolemia was significantly reduced in both periods of L-TVP administration: -18.6% during phase II (total replacement) and -13.2% during phase IV (partial replacement). High-density lipoprotein (HDL) cholesterol levels tended to increase during L-TVP administration. However, only patients in the mid- and low tertiles for HDL cholesterolemia showed a significant increase of HDL levels during L-TVP. This 'normalizing' activity of L-TVP on plasma lipoproteins, even when administered as a partial dietary substituent, may be of clinical interest for subgroups of patients at high vascular risk.

[Platelet aggregation in hyperlipoproteinemias]. / L'aggregabilità piastrinica nelle iperlipoproteinemie.

The Authors studied platelet aggregation in 42 hyperlipoproteinemic patients (10 with type IIA familiar, 7 with type IIA, 7 with type IIB, 18 with type IV and V). None of them suffered from clinically detectable vascular complications. The control group included 42 normolipoproteinemic subjects, closely matched for age and sex. Platelet aggregation, according Born's method, was statistically increased in hyperlipoproteinemia type IIA, but only when induced by epinephrine as aggregating agent. No statistical significance was demonstrated when hyperlipoproteinemic smokers and no smokers were compared. A positive family history of myocardial infarction and/or diabetes mellitus could be demonstrate affect on platelet aggregation.

[Clinical and statistical study of 843 hospitalized diabetics]. / Indagine clinico-statistica su 843 diabetici ospedalizzati.

A retrospective cross study of 843 hospitalized diabetics is reported. The heterogeneity of the sample was obviated to some extent by subdividing it into age, duration and diabetes mellitus treatment groups. The major part of the sample consisted of elderly patients presenting the characteristic correlations between hyperglycaemia, overweight and triglyceridaemia common to insulin-resistant diabetes. Impairment of the cardiovascular system and particularly the coronary circulation, was particularly serious. Stress is laid on the need to standardize study of the diabetic in the interests of a correct, epidemiological and clinical approach to the disease.