Familial aggregation of nonhematological malignancies in relatives of patients with hematological neoplasms.

Familial aggregation of nonhematological malignant disorders (NHMD) was compared in 189 families of patients with hematological neoplasms (HN) with a control group of 36 families of patients with benign hematological disorders and a second group of 33 families of patients with diabetes mellitus. A self-administered questionnaire was used requesting from each family a full list of first- and second-degree relatives, their vital status, current age or age at death, and a list of their chronic diseases, including all malignant disorders. There was no evidence of a significantly increased tendency for developing NHMD among relatives of patients with HN as compared to controls (adjusted odds ratio of 0.88; 95% confidence interval 0.61-1.27). Moreover, in the HN group, no significant difference in the frequency of NHMD was found between the families with and without familial aggregation of HN. Based on the present analysis and our previous observations on familial aggregation of HN, we conclude that the increased aggregation of malignant disorders among relatives of patients with HN is unique to the hematopoietic system and might result from a genetic predisposition to HN in these families.

Increased cardiovascular disease mortality rates in traumatic lower limb amputees.

We evaluated the 24-year mortality rates of male traumatic lower limb amputees (n = 201) of the Israeli army, wounded between 1948 and 1974 compared with a cohort sample representing the general population (n = 1,832). Mortality rates were significantly higher (21.9% vs 12.1%, p <0.001) in amputees than in controls. Cardiovascular disease (CVD) mortality was the main cause for this difference. The prevalence of selected risk factors for CVD was determined in 101 surviving amputees (aged 50 to 65 years) and a sample of the controls (n = 96) matched by age and ethnic origin. Amputees had higher plasma insulin levels (during fasting and in response to oral glucose loading) and increased blood coagulation activity. No differences were found in rates of current symptoms of ischemic heart disease or of cerebrovascular disease, obesity, hypertension, altered plasma lipoprotein profile, impaired physical activity, smoking, or nutritional habits. Traumatic lower limb amputees had increased mortality rates due to CVD. Surviving amputees had hyperinsulinemia, increased coagulability, and increased sympathetic and parasympathetic responses (described previously). These established CVD risk factors may explain the excess mortality due to CVD in traumatic amputees.

Methodology of a two-step quantified nutritional questionnaire and its effect on results.

The effects of methodology on the results of epidemiologic studies that involve collection of nutritional data, especially those involving long-term-onset illnesses such as cancer, have not yet been carefully evaluated. We present methodological features of a quantitative dietary history and physical activity questionnaire and discuss their contribution to the final results. The results of our analysis are as follows: 1) Forty-seven percent of the population consumed > 100 food items yearly. 2) The mean number of calories contributed by items eaten less than once a week exceeded 200 kcal/day in 50% of interviewees. 3) Seventy-six percent of the patients had undergone dietary changes during the course of adult life. Of the 379 individuals who reported no changes when asked general questions, 61.8% reported changes when asked specifically about each food item in the questionnaire. 4) Physical activity was significantly correlated with mean daily energy intake (r = 0.208, p < 0.001). We conclude that certain methodological features of questionnaires, such as extensive listing of food items, precise documentation of food quantity, inquiries about former eating habits, and inclusion of questions about physical activity, increase accuracy in evaluations of dietary habits. Our analysis provides practical information for future planning of nutritional questionnaires.

Interrelationships among measures of autonomic activity and cardiovascular risk factors during orthostasis and the oral glucose tolerance test.

Overstimulation of sympathetic nervous system activity is related to atherosclerotic cardiovascular disease risk, but the role of parasympathetic activity in this association is not clear. This study evaluated sympathetic and parasympathetic function by spectral analysis of heart rate variability and plasma levels of norepinephrine (NE) epinephrine (EPI), dihydroxyphenylglycol (DHPG), dihydroxyphenylalanine (DOPA) and dihydroxyphenylacetic acid (DOPAC). It also examined the interrelationships among these parameters and established atherosclerotic cardiovascular disease risk factors in 53 men (mean age 59.5 years). During supine rest, low-frequency power correlated positively with high-frequency power (r = 0.58, p < 0.001), plasma NE correlated with plasma DHPG (r = 0.41, p < 0.001) and plasma DOPA with DOPAC (r = 0.47, p < 0.001) but neither low- nor high-frequency power was correlated with plasma levels of any catechol. Among risk factors, plasma NE correlated with fasting insulin and mean arterial blood pressure, and urine NE correlated with body mass index. Both low- and high-frequency power correlated positively with insulin levels. Orthostasis decreased high-frequency power and increased low-frequency power and plasma NE levels. During the oral glucose tolerance test, both high- and low-frequency power increased, plasma NE levels were unchanged, and plasma EPI levels decreased [88.5 +/- 18 (SEM) versus 52.5 +/- 12 pM, p = 0.001]. The results suggest that orthostasis decreases and the oral glucose tolerance test increases parasympathetic outflows, whereas both stimuli increase sympathetic outflows. Among all atherosclerotic cardiovascular disease risk factors, hyperinsulinaemia showed the strongest association with autonomic nervous system activity, especially parasympathetic activity. Estimates of sympathetic responses obtained from power spectral analysis of heart rate variability agree poorly with those from plasma levels of catechols, possibly because of a parasympathetic contribution to low-frequency power and independence of sympathoneural outflows to the arm and heart.

Insulin resistance and autonomic function in traumatic lower limb amputees.

This study examined plasma insulin response to oral glucose load and autonomic nervous system activity in male lower limb amputees (n = 52) aged 50-65 years, compared to matched controls (n = 53). The groups had similar body mass index, blood pressure and plasma lipid levels. The amputees had higher mean fasting plasma insulin levels (18.4 +/- 9.7 (SD) versus 13.7 +/- 5.1 mU/l, p = 0.005) and during an oral glucose tolerance test (OGTT) (1 h levels 88.1 +/- 45.3 versus 62.1 +/- 42.7, p = 0.016) with similar plasma glucose levels, indicating insulin resistance. At baseline with the subjects supine, there were no group differences in low- or high-frequency power of heart rate variability or in plasma levels of norepinephrine (NE) or epinephrine (EPI). In response to orthostasis, the groups had similarly increased plasma NE levels. During the OGTT, amputees had significantly larger increments in low-frequency power than did controls (2.2 +/- 1.3 versus 1.6 +/- 0.9 (beats/min)2 respectively, p < 0.01) and plasma NE levels increased significantly in amputees (1595 +/- 849 versus 1941 +/- 986 pM, p = 0.0008) but not in controls. At 1 h after glucose administration, plasma EPI levels were decreased significantly from baseline in both groups; at both 1 and 2 h after glucose administration, plasma EPI levels were higher in the amputees than controls. Amputees appear to have a combination of enhanced sympathoneural responsiveness and attenuated suppression of adrenomedullary secretion during glucose challenge. As catecholamines antagonize insulin effects, one possible explanation for insulin resistance in amputees is hyperglycaemia-induced sympathoneural activation and a failure of hyperglycaemia to decrease adrenomedullary secretion.

Acute myocardial infarction in the young--the role of smoking. The Investigators of the International Tissue Plasminogen Activator/Streptokinase Mortality Trial.

Patients who received thrombolytic therapy for acute myocardial infarction in a large international trial were divided into two groups on the basis of age; those < or = 40 years (n = 269) and those > 40 years (n = 7787). The younger group included more men (89.9% vs 75.9%, P = 0.009) and fewer patients had a history of coronary artery disease, hypertension, and diabetes mellitus. A family history of cardiovascular disease was significantly more prevalent among the young patients (53.4% vs 41.9%, P = 0.0002). Significantly more younger patients than older patients were smokers at the time of infarction (76.2% vs 42.9%, P < 0.0001) and the average number of cigarettes smoked per day was also significantly higher in young patients (27.8 +/- 14.3 vs 19.9 +/- 12.9, P < 0.01). Younger patients had a better outcome, with lower rates of cardiogenic shock (1.1% vs 7.0%, P = 0.0002), stroke (0.0% vs 1.9%, P = 0.02) and haemorrhage (1.9% vs 5.9%, P = 0.006), as well as a better Killip class at discharge (Killip > 1 in 4.5% vs 8.0%, P < 0.001), and lower hospital and 6-month mortality (0.7% and 3.1% vs 8.3% and 12%, P < 0.001, respectively). The better outcome of younger patients with acute myocardial infarction is related to their better baseline characteristics. Young patients with acute myocardial infarction have a strong family history of cardiovascular disease and a high prevalence of smoking. Smoking is the most important modifiable risk factor in these patients.

Outcome of thrombolytic therapy in relation to hospital size and invasive cardiac services. The Investigators of the International Tissue Plasminogen Activator/Streptokinase Mortality Trial.

OBJECTIVE: The outcome of patients with acute myocardial infarction who received thrombolytic therapy was assessed in relation to the size and comprehensiveness of cardiovascular services in the admitting hospitals. METHODS: Two characteristics were obtained for each of the 438 hospitals: number of beds and in-house availability of cardiovascular services (coronary catheterization laboratory and coronary angioplasty or bypass surgery). Hospitals were grouped into four categories on the basis of size (< or = 300 vs > 300 beds) and availability of cardiovascular services. Baseline and outcome variables were compared by chi 2 analysis and logistic regression. Patients were followed up for 6 months. RESULTS: Baseline variables were comparable among hospital categories except for significant differences in the distribution of antecedent angina and time to treatment. Significantly more coronary angioplasties and bypass surgeries were performed in patients first treated in hospitals with coronary revascularization services (4.1% and 4.2% vs 1.0% and 1.9%, P < .0001). Rates of strokes (1.9% vs 1.3% and 1.6%, P = .54), hospital mortality (11.9% vs 8.5%, (P = .11), and 6-month mortality (17.0% vs 11.8% and 12.3%, P = .03) were highest among patients treated in small hospitals that had coronary revascularization facilities. The rate of invasive procedures was higher in the smaller hospitals (odds ratio [OR], 1.44; 95% confidence limits [CL], 1.11 and 1.87; P = .006) and in hospitals with coronary revascularization services (OR, 4.05; 95% CL, 3.14 and 5.22; P < .0001); hemorrhage was more frequent in centers with coronary revascularization facilities (OR, 1.39; 95% CL, 1.13 and 1.71; P = .002). Rates of hospital mortality and 6-month mortality were similar. CONCLUSIONS: Patients with acute myocardial infarction treated with thrombolytic therapy have the same mortality in small centers without in-house coronary revascularization services as in larger centers with such services.

Persistent abnormalities in red cell parameters following treatment of lymphoma.

Patients who have recovered from malignant lymphoma are at an increased risk of secondary acute leukemia (AL), and overt AL is frequently preceded by a myelodysplastic syndrome. Although the statistical risk is significant, only a minority of the patients will be so affected. We have reviewed peripheral blood counts of patients with Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) treated in the Departments of Hematology at the Edith Wolfson and Chaim Sheba Medical Centers, Israel. Included were only those who went into a complete remission and remained lymphoma free for extended periods. There were 85 patients with HD and 36 with NHL. In both groups peripheral blood counts at diagnosis were within the normal range. A prolonged follow-up (> 4 y), during which no further treatment was given, revealed a sustained increment over time of MCV (delta MCV) both in HD and NHL. A persistent monocytosis in HD patients was also evident. delta MCV was larger in HD. The difference at the end of the follow-up period was as follows: 10.1 fl + 11.8 in HD vs 5.0 fl + 6.2 in NHL, (P < 0.001). In addition, a significant loss of the normal correlation between the MCV and levels of hemoglobin was seen at the last follow-up. The change in MCV was present in all treatment groups, its magnitude increasing from radiotherapy to chemotherapy to combined radio chemotherapy. This trend is in analogy to the risk of secondary AL which is lower in NHL vs HD. Furthermore, it is lowest post radiotherapy and highest when both treatment modalities are used.(ABSTRACT TRUNCATED AT 250 WORDS)

Familial aggregation of haematological neoplasms: a controlled study.

Advances in molecular biology techniques suggest that many haematological neoplasms originate from a transformation process at the level of the haemopoietic pluripotential stem cell. While familial aggregation has been reported for many haematological neoplasms, most studies were uncontrolled and examined the presence of the same haematological neoplasm as the index case. We assessed the familial aggregation of all haematological neoplasms in 4061 family members of 189 patients with various haematological neoplasms and two control groups: 955 relatives of 36 patients with non-malignant haematological disorders and 508 relatives of 33 patients with type II diabetes mellitus. Data collection included self-administered questionnaires. The odds ratio for haematological neoplasms among relatives of the index cases adjusted for age, sex, ethnicity, number of relatives in the family, and degree of familial linkage in the study group versus the two control groups was 3.62 (95% confidence interval, 1.44-9.07; P < 0.01). The vast majority of the haematological neoplasms among family members did not belong to the same histopathological category as the index cases. The data support the hypothesis of a genetic predisposition to haematological neoplasms. The fact that the aggregation is not disease specific is consistent with a defect in the pluripotent haemopoietic stem cell.

Fasting plasma glucose in screening for NIDDM in the U.S. and Israel.

OBJECTIVE--To demonstrate the inadequacy of fasting plasma glucose for screening for NIDDM, even among groups at high risk for diabetes. RESEARCH DESIGN AND METHODS--Representative samples of adults 40-69 years of age in the U.S. (n = 2,035) and Israel (n = 2,316) were selected. Fasting plasma glucose (FPG) was measured and a 2-h oral glucose tolerance test (OGTT) was administered. Subjects with undiagnosed NIDDM were identified using internationally accepted diagnostic criteria (FPG > or = 7.8 mM or 2-h plasma glucose > or = 11.1 mM). RESULTS--Only 31-38% of subjects with undiagnosed NIDDM had fasting hyperglycemia (> or = 7.8 mM), and 36% in the U.S. and 19% in Israel had normoglycemia (< 6.1 mM). Postchallenge glucose, diagnostic of diabetes, was associated with all fasting values, including values < 5.0 mM. Based on sensitivity, specificity, and positive predictive value, no FPG level provided a satisfactory cutoff point to use in screening for undiagnosed NIDDM. Sensitivity at each FPG cutoff point varied little among groups classified by age, sex, race, blood pressure status, or body mass index (BMI) levels > 23, but sensitivity was lower among those with BMI levels < 23. CONCLUSIONS--In the clinical setting, FPG is commonly used in screening for NIDDM. However, fasting values < or = 7.8 mM are highly insensitive for detecting NIDDM. Lower FPG cutoff points tha achieve acceptable sensitivity are accompanied by inadequately low specificity, require a high percentage of patients to be retested, and result in a low yield of diabetes among those screened. Clinicians and researchers who seek detection of undiagnosed NIDDM should use the OGTT, because FPG lacks adequate sensitivity and specificity for this purpose.

"King sized" hearts in infants: comparison of cardiac to body mass in ventricular septal defect in various age-groups.

Heart and body weight were reviewed in reports of 223 human cadavers. Of these, 146 were of control (normal) hearts and 77 of hearts with ventricular septal defects. In each case the heart weight as a percentage of body weight was calculated (defined as pathological heart-body ratio). It was observed that under the age of 4 years, monstrous cardiomegalies may reach 3.2% of the total body weight. These "king sized" hearts were not found above the age of 4.

After correcting for worse baseline characteristics, women treated with thrombolytic therapy for acute myocardial infarction have the same mortality and morbidity as men except for a higher incidence of hemorrhagic stroke. The Investigators of the International Tissue Plasminogen Activator/Streptokinase Mortality Study.

BACKGROUND: In the prethrombolytic era, women with myocardial infarction were reported to have a worse outcome than men. This analysis evaluates the association of sex with morbidity and mortality after thrombolytic therapy. METHODS AND RESULTS: Data were analyzed from 8261 of the 8387 randomized patients with acute myocardial infarction who received thrombolytic therapy in the International Tissue Plasminogen Activator/Streptokinase Mortality Study (baseline data were missing for 126 patients) and were followed for 6 months. Women made up 23% (n = 1944) of the study population. Baseline characteristics were worse in women: they were 6 years older, were more likely to have a history of previous infarction (P < .01), antecedent angina (P < .01), hypertension (P < .0001), or diabetes (P < .0001); were in a higher Killip class on admission (P < .0002); and received thrombolytic therapy 18 minutes later than men (P < .0001). Fewer women were smokers (P < .0001). Women had a higher hospital (12.1% versus 7.2%, P < .0001) and 6-month mortality (16.6% versus 10.4%, P < .0001) and were more likely to develop cardiogenic shock (9.1% versus 6.3%, P < .0001), bleeding (7.2% versus 5.3%, P < .01), and hemorrhagic (1% versus 0.3%, P < .001) or total stroke (2.2% versus 1.1%, P < .0001) during hospitalization. Reinfarction rates and requirement for angioplasty or surgery did not differ. After correction for worse baseline characteristics, women had similar morbidity and mortality apart from a significantly higher incidence of hemorrhagic stroke, which remained significant even after accounting for weight and treatment allocation (odds ratio, 2.90; P < .01). CONCLUSIONS: After thrombolytic therapy for acute myocardial infarction, women have similar morbidity and mortality to men but suffer from a higher incidence of hemorrhagic stroke.

Significance of diabetes mellitus in patients with acute myocardial infarction receiving thrombolytic therapy. Investigators of the International Tissue Plasminogen Activator/Streptokinase Mortality Trial.

OBJECTIVES: The purpose of this study was to evaluate the risks and benefits associated with thrombolytic therapy in patients with diabetes presenting with acute myocardial infarction. BACKGROUND: Diabetes mellitus is associated with adverse risk factors and a hypercoagulable state that may adversely affect the outcome of thrombolytic therapy. METHODS: Data were analyzed from 8,055 of the 8,239 patients with acute myocardial infarction who received thrombolytic therapy in the International Tissue Plasminogen Activator/Streptokinase Mortality trial (diabetes history was missing for 184 patients). RESULTS: There were 883 patients with and 8,272 patients without diabetes. Among the diabetic patients, 160 were receiving insulin therapy. Baseline risk factors were significantly worse in diabetic patients, who were older and had a higher rate of previous infarction and antecedent angina and a higher Killip grade at admission. Bleeding and hemorrhagic and ischemic stroke rates were similar among diabetic and nondiabetic patients. Hospital and 6-month mortality rates were highest among diabetic patients receiving insulin therapy (16.9% and 23.1%, respectively), followed by diabetic patients not receiving insulin therapy (11.8% and 17.8%), and lowest in nondiabetic patients (7.5% and 10.7%, p < 0.0001). Whereas diabetes of 5 years' duration was associated with a mortality rate similar to that of nondiabetic patients, a > 5-year duration was associated with a relative mortality risk of 1.38 (95% confidence interval [CI] 0.88 to 2.15) and a > 10-year duration with a relative mortality risk of 1.99 (95% CI 1.40 to 2.81). The independent relative risk for incremental mortality from discharge to 6 months was 1.74 (95% CI 1.21 to 2.50). Mortality rate among diabetic patients was lowest in patients who received both streptokinase and heparin (9.8% vs. 16.1% in patients who received streptokinase but no heparin, p < 0.05). CONCLUSIONS: The relative mortality of diabetic versus nondiabetic patients was similar to that observed in previous studies of patients with myocardial infarction not receiving thrombolytic therapy, indicating that mortality in diabetic patients receiving thrombolytic therapy is reduced to the same extent as in nondiabetic patients. In addition, risk of bleeding and stroke was not increased, indicating that diabetic patients can safely receive thrombolytic therapy for the same indications as nondiabetic patients.

Low titer, competitive insulin autoantibodies are spontaneously produced in autoimmune diseases of the thyroid.

The occurrence of multiple endocrine autoimmunity with organ-specific autoantibodies is well known. In this study we evaluated the presence of competitive insulin autoantibodies (IAA) in immune and non-immune diseases of the thyroid, utilizing a sensitive and specific radiobinding assay. We studied 37 patients with Graves' disease, 44 patients with Hashimoto's thyroiditis, 11 patients with non-immune thyroid diseases and 30 normal controls. In 5/37 (13.5%), 7/44 (15.9%) patients with Graves' and Hashimoto's diseases, respectively, but in none of those with non-immune thyroid disease or of the controls, IAA levels exceeded our upper limit of normal range (50 nunits/ml) (P < 0.01). Positive IAA levels ranged between 50 and 123 nunits/ml with fluctuation of these levels over time. Islet cell antibodies were not detected in any of the patients and the controls in the study. No association was found between propylthiouracile treatment and level of IAA. In none of 10 IAA-positive patients was the early phase insulin secretion of the intravenous glucose tolerance test below 46 mu units/ml, and in 2 subjects repeated tests after 3 years showed conserved insulin secretion. In conclusion, our findings show that 15% of patients with autoimmune thyroid diseases, produce specific IAA which do not seem to reflect aggressive beta cell destruction.

Comparative case fatality analysis of the International Tissue Plasminogen Activator/Streptokinase Mortality Trial: variation by country beyond predictive profile. The Investigators of the International Tissue Plasminogen Activator/Streptokinase Mortality Trial.

OBJECTIVES: This study was designed to examine the variation in mortality rates among countries participating in the International Tissue Plasminogen Activator/Streptokinase Mortality Trial. BACKGROUND: Despite uniform inclusion and exclusion criteria and protocol in this trial, 30-day mortality rates (irrespective of treatment allocation) ranged from 4.2% to 14.8% among the participating countries. METHODS: With use of the risk factors identified by a multi-variate logistic model, the total study group was classified into deciles on the basis of each patient's risk profile and individual probability of dying within 30 days. Expected mortality rates were then calculated and compared with actual mortality for each decile of the total study group, as well as for patients from each country. RESULTS: Independent risk factors for mortality were older age (odds ratio 1.97 for each 10-year increment), systolic hypotension (blood pressure < 95 mm Hg) at entry (odds ratio 3.7), Killip class > 1 at entry (odds ratio 3.5), history of antecedent angina (odds ratio 1.23 to 1.49), history of diabetes mellitus (odds ratio 1.64), previous infarction (odds ratio 1.23) and history of never smoking (odds ratio 1.37). The overall mortality rate among the 1,612 patients in risk deciles 9 and 10 was 26%; for the 1,606 patients in deciles 1 and 2 it was 1.2%, with a sensitivity of 58.6% and a specificity of 83.7%. The logistic model closely predicted and explained the different mortality rates for most countries (the differences between expected and actual mortality were nonsignificant). However, in the total study group, the difference between the expected and actual mortality was significant (p < 0.001). This difference was mainly ascribed to the two countries with the highest and lowest mortality rates. When the patients from these two countries were excluded from the analysis, the overall difference became nonsignificant. CONCLUSIONS: These findings suggest that the recognized risk factors associated with increased case fatality in acute myocardial infarction account only in part for mortality differences across or within populations.