Environmental influences on hemostasis and thrombosis. Diet and smoking. High levels of factor VII coagulant activity (VIIc) and fibrinogen concentration are independently associated with an increased risk of acute coronary heart disease in middle-aged men. Studies have, therefore, been undertaken to determine the responsiveness of these hemostatic factors to changes in diet and smoking habit. Plasma VIIc increases acutely with an increase in total fat intake, but fibrinogen is unaffected. In the general community, men who have a high total fat intake for their body size tend to have a high VIIc level. Changes in the dietary ratio of saturated to polyunsaturated fat of up to 14 days' duration have no effect on factor VIIc or fibrinogen (there are conflicting reports on the influence of dietary very-long-chain polyunsaturated fatty acids on fibrinogen concentration). Cigarette smokers have a higher fibrinogen concentration than do nonsmokers, but their levels slowly revert toward those of nonsmokers when the habit is relinquished.


Triggering and hourly variation of onset of arterial thrombosis. Information obtained during the past decade suggests that the onset of myocardial infarction and sudden cardiac death is frequently triggered by daily activities. The importance of physical or mental stress in triggering coronary thrombosis is supported by finding that (1) the frequencies of the onset of myocardial infarction, sudden cardiac death, and stroke show marked circadian variations, with similar increases in the period from 6 AM to noon; (2) the frequency of transient myocardial ischemia shows a similar increase in the morning, and episodes are often preceded by mental or physical triggers; (3) a ruptured atherosclerotic plaque, often nonobstructive by itself, lies at the base of most coronary thrombi; (4) a number of physiologic processes that could lead to plaque rupture, a hypercoagulable state, or coronary vasoconstriction, are accentuated in the morning; and (5) aspirin and beta-adrenergic blocking agents that affect certain of these processes have been shown to prevent disease onset. The hypothesis presented is that occlusive coronary thrombosis occurs when (1) an atherosclerotic plaque becomes vulnerable to rupture; (2) mental or physical stress causes the plaque to rupture; and (3) increases in coagulability or vasoconstriction, triggered by daily activities, contribute to complete occlusion of the coronary artery lumen. Recognition of the circadian variation--and the possibility of frequent triggering--of the onset of acute disease suggests the need for pharmacologic protection of patients during the vulnerable periods and provides clues to the mechanism of disease onset, the investigation of which may lead to improved methods of prevention.


Lipoprotein(a). Link between structure and pathology. It is now established that high plasma levels of lipoprotein(a) are associated with an increased risk of atherosclerotic cardiovascular disease. However, the mechanisms underlying this increased risk have not been elucidated. Lipoprotein(a) represents a class of lipoprotein particles having a cholesteryl ester-rich low-density lipoprotein (LDL)-like structure with a protein moiety represented by apolipoprotein B100 covalently linked to apolipoprotein(a), the specific marker of lipoprotein(a). Lipoprotein(a) particles with a triglyceride-rich core have also been described. Apolipoprotein(a) is a glycoprotein containing about 30% carbohydrates by weight, with a polypeptide chain highly polymorphic in size (300-700 kDa) and structurally similar to plasminogen. There appears to be a relation between apolipoprotein(a) size and lipoprotein(a) species. From a number of studies, it is becoming apparent that lipoprotein(a) can transverse the endothelium and accumulate in the arterial initima either extra- or intracellularly. Immunochemical evidence has also indicated that apolipoprotein(a) in the artery wall is colocalized with fibrin(ogen), suggesting that this complexation may have an atherogenic potential by promoting the transformation of resident macrophages into foam cells. This might also occur by the chemical modification of lipoprotein(a) by the action of either oxygen-free radicals, malondialdehyde, or interactions with matrix components. These findings invite the speculation that much of the apolipoprotein B detected in atherosclerotic lesions is contributed by lipoprotein(a). The role that lipoprotein(a) size and density heterogeneity and apolipoprotein(a) polymorphism might play in the intima accumulation of apolipoprotein B is not established.


Assembly of plasmin-generating proteins on the surface of human endothelial cells. Traditionally, plasmin generation has been conceptualized as a process oriented on the surface of a fibrin-containing thrombus. Recent work, however, indicated that plasminogen and its activators, tissue plasminogen activator (t-PA) and urokinase, can assemble on the surface of cultured human umbilical vein endothelial cells (HUVECs). On binding to HUVECs, plasminogen is activated by t-PA approximately 12-fold more efficiently than fluid-phase plasminogen, and is converted to a plasmin-modified form, possibly unique to cell surfaces. In addition, t-PA interacts with HUVECs at two sites. The major binding site preserves its activity and represents a true (relative molecular weight 40,000) membrane-associated exoreceptor. The low-density lipoprotein (LDL)-like lipoprotein, lipoprotein(a), is highly associated with atherosclerosis, bears striking sequence homology to plasminogen, and competes with plasminogen for cell surface binding. In summary, functional assembly of plasminogen and t-PA may represent an important thromboregulatory system.


On the role of coagulation and fibrinolysis in atherosclerosis. Atherosclerosis is probably caused by multiple interacting factors such as disturbed lipid metabolism; endothelial cell damage, leading to platelet aggregation and monocyte invasion with the release of mitogenic factors; and disorders of fibrin balance, leading to persisting fibrin deposits. Deficient fibrinolysis may (1) predispose to fibrin deposition and contribute to the pathogenesis of atherosclerosis and (2) contribute to occlusive thrombus formation on fissured plaque, provoking atherothrombosis. Prospective epidemiologic studies have so far not provided definitive evidence that deficient fibrinolysis constitutes a significant risk factor for the development of atherosclerosis. Two recent findings, however, strongly suggest a contribution: (1) Increased lipoprotein(a) levels that reduce tissue-type plasminogen activator (t-PA)-mediated clot lysis are a clear risk factor for atherosclerosis; and (2) increased plasminogen activator inhibitor-1 (PAI-1) levels in patients with disturbed glucose tolerance predispose to an accelerated development of atherosclerotic disease. However, deficient fibrinolysis constitutes a risk factor for the development of thrombotic complications (acute myocardial infarction) in patients with coronary artery disease. The potential role of deficient fibrinolysis in the pathogenesis of atherosclerosis and of atherothrombosis suggests that drugs normalizing deficient endogenous fibrinolysis by either reducing PAI-1 synthesis or by stimulating endogenous t-PA synthesis may be of clinical value. Although regulation of the gene expression of PAI-1 and t-PA is presently under active investigation, no potent specific and safe agents to downregulate PAI-1 or to upregulate t-PA have as yet been identified. Retinoic acid appears to be a specific inducer of t-PA synthesis in human endothelial cells in culture and may constitute a model for the development of drugs that stimulate endogenous t-PA synthesis.


Estrogen-associated thromboembolism.

Estrogen-associated thromboembolism. Most of the linkage of atherosclerosis and thrombosis with estrogens is epidemiologic in origin. Although the effects of estrogens on the mechanisms of hemostasis are wide ranging, many are benign; only a few may account for thrombus formation. Platelet function tests have provided extensive but contradictory data, and interpretation is limited because it is uncertain whether a rise in one or more of these parameters is a primary or secondary effect. The most consistent effects of estrogens on coagulation proteins are elevations of fibrinogen; factors II, VII, IX, X, and XII; protein C; and plasminogen. Although these elevations have been attributed to the estrogenic component in oral contraceptives, the progestogen concentration may also influence these increases. Among other coagulation proteins studied, the following are unaffected by oral contraceptive use: factors V, VIII, and XI; prekallikrein; and high-molecular-weight kininogen. In contrast, protein S values are decreased. The plasma concentration of plasmin inhibitor is unchanged, whereas both proteinase inhibitor and macroglobulin are significantly increased by oral contraceptive use. Cl esterase inhibitor is decreased in women taking oral contraceptives and correlates with the increase in Hageman factor. Antithrombin III is one plasma inhibitor for which a decrease in quantity and activity have been associated with a thrombotic tendency in humans. Although data on estrogen-associated changes in the quantity of antithrombin III have been conflicting, the ability of plasma to inhibit factor Xa is significantly reduced in a dose-dependent manner among pre- and postmenopausal estrogen users.(ABSTRACT TRUNCATED AT 250 WORDS)


Hemostatic factors according to menopausal status and use of hormone replacement therapy. The rise in cardiovascular disease (CVD) risk after menopause may be reduced by hormone replacement therapy (HRT) although the mechanism is unclear. Because little is known about the potential role of hemostatic factors, fibrinogen level and other coagulation parameters were measured in a study on the change in CVD risk factors through the climacteric (the Healthy Women Study). Of 239 subjects measured to date, 32 taking aspirin or other medications thought to alter coagulation were excluded from analyses. Results (adjusted for age and obesity) showed that women taking HRT had lower plasma concentrations of fibrinogen and higher levels of plasminogen and factor VIIc than did postmenopausal subjects not taking HRT. Pre- as compared with postmenopausal women had lower plasma levels of fibrinogen, factor VIIc, and antithrombin III. Adjusting for cigarette smoking did not change the findings. Thus, among women aged 49 to 55, selected hemostatic measures varied (within normal ranges) by menopausal status and were altered by HRT. These findings generally support a hypothesis of hemostatic change contributing to the increase of CVD after menopause. The fact that subjects taking HRT showed no increase in fibrinogen relative to premenopausal women is consistent with an observed decreased risk of CVD among women taking HRT, while the implication of an elevation in factor VIIc among these women is uncertain.


Update on fibrinogen as a cardiovascular risk factor. Mounting data support a causal connection between high-normal fibrinogen levels and atherosclerotic cardiovascular disease. There is clearly a thrombogenic component to atherosclerosis and the onset of clinical manifestations. This offers the possibility to better identify high-risk candidates and also to protect them by reducing blood fibrinogen concentration or blocking its action. The relationship of antecedent fibrinogen to the subsequent development of cardiovascular disease is examined, based on 18 years of surveillance of a cohort of 1274 men and women aged 47 to 79 years who participated in the Framingham Study. The association with the development of peripheral arterial disease and cardiac failure is now examined in addition to previously studied relationships to coronary heart disease and stroke. In men and women, there is a significant age-adjusted relationship of fibrinogen level to coronary heart disease and to cardiovascular disease in general. In women, a significant relationship to cardiac failure and peripheral arterial disease, but not to stroke, was also found. These data on women are unique as they are not available elsewhere. Age-adjusted cardiovascular, all-cause, and coronary heart disease mortality were all related to fibrinogen in both sexes. In men, fibrinogen impact was the greatest for stroke and the least for peripheral arterial disease. For women, the impact on coronary heart disease was greatest. The absolute risk for an elevated fibrinogen level was greatest for coronary heart disease in both sexes. Average fibrinogen values are higher in women and in persons with other risk factors, including hypertension, cigarette smoking, diabetes, obesity, and elevated hematocrit. However, there is an independent contribution of fibrinogen to cardiovascular disease in general and coronary disease in particular, on adjustment for coexistent risk factors. Fibrinogen enhances the risk of cardiovascular disease in hypertensives, diabetics, and cigarette smokers. About half the cardiovascular risk of cigarette smoking appears due to the higher fibrinogen values. Now, five prospective studies document the excess incidence of cardiovascular events in persons with elevated fibrinogen levels within the "normal range." Each standard deviation increase in fibrinogen is associated with a 30% increment of coronary heart disease in men and a 40% increase in women. Fibrinogen should be added to the list of major cardiovascular risk factors. Trials of intervention to lower fibrinogen in high-risk coronary candidates are needed.


The Atherosclerosis Risk in Communities (ARIC) Study. Introduction and objectives of the hemostasis component. The Atherosclerosis Risk in Communities (ARIC) Study is an observational epidemiologic study conducted in four communities. ARIC has two major components: One records the occurrence of myocardial infarction resulting in hospitalization and coronary heart disease death in adults aged 35 to 74 living in the communities; the other is a prospective study of representative cohorts aged 45 to 64. Measurement of hemostatic factors is part of the cohort study, whose major objectives include investigating etiologic factors associated with atherosclerosis and its clinical outcomes. Arterial intimal-medial wall thickness, an index of early atherosclerosis, is measured precisely from ultrasound images of carotid and popliteal arteries. Participants (n = 15,801) completed their first examination, which included measurements of factors associated with coagulation (fibrinogen, factor VII, factor VIII, and von Willebrand factor) and coagulation inhibition (protein C and antithrombin III). Measures of coagulation activation, platelet activation, and fibrinolytic activity will be performed on stored plasma from selected case patients and control subjects.


Association of coagulation factors and inhibitors with carotid artery atherosclerosis. Early results of the Atherosclerosis Risk in Communities (ARIC) Study. Several population studies have shown that plasma levels of fibrinogen and factor VII are significantly associated with ischemic cardiovascular events. However, there is little information regarding the association of hemostatic factors with early atherosclerosis. To evaluate this, we compared the plasma concentrations of several coagulation proteins (fibrinogen, factor VII, factor VIII, von Willebrand factor, protein C, and antithrombin III) between 385 case patients, defined by high-resolution B-mode ultrasonography as having carotid arterial wall thickening, and 385 age-, race-, and sex-matched control subjects. These case patients and control subjects were selected from participants in a prospective population investigation, the Atherosclerosis Risk in Communities (ARIC) Study, who were examined between May 1987 and May 1989. Plasma fibrinogen, factor VII, protein C, and antithrombin III levels were significantly higher in case patients than in control subjects (P < 0.05). Factor VIII and von Willebrand factor were not different. These findings were supported by quartile distribution and univariate analysis. However, only fibrinogen remained significantly associated with carotid atherosclerosis on multivariate analysis taking other atherosclerosis risk factors into consideration. A one standard deviation increase in fibrinogen (67 mg/dL) was associated with a 1.6-fold increase in the odds of carotid atherosclerosis univariately (P < 0.001) and with a 1.3-fold increase in the odds multivariately (P = 0.010). Further analysis revealed that the association of fibrinogen with carotid atherosclerosis was somewhat stronger in cigarette smokers than in nonsmokers. This early case-control analysis of the ARIC Study demonstrates a significant association between plasma fibrinogen concentration and early atherosclerosis in the carotid arteries. In the context of published findings from population studies, our results indicate that plasma fibrinogen concentrations may be a useful marker for identifying individuals at high risk of developing arterial thrombotic disorders.


Relations between hemostasis variables and cardiovascular risk factors in middle-aged adults. Atherosclerosis Risk in Communities (ARIC) Study Investigators. The relations between hemostatic variables and cardiovascular risk factors were examined in a biracial population sample of middle-aged adults. Fibrinogen, factor VII, factor VIII, von Willebrand factor, protein C, and antithrombin III levels varied considerably by age, sex, and race. Hemostatic variables also were associated with several life-style and biochemical risk factors. For the most part, higher levels of the risk factors were associated with higher levels of the hemostatic variables. The findings point to potential confounders that warrant consideration in cardiovascular disease studies, and/or mechanisms by which cardiovascular risk is conferred. They also suggest that modification of the cardiovascular risk factors may have the potential to alter the risk of thrombosis.


Platelet aggregation and coronary heart disease risk factor variation in Australian populations with different coronary heart disease mortality. In a cross-sectional analytic study, we examined the differences in coronary heart disease (CHD) risk factors, including coagulation factors and platelet aggregation, among males from southern European countries and those of Anglo-Celtic descent who had widely different CHD standardized mortality ratios. The participants included 169 men aged 40 to 49 years, 27% of whom were born in southern European countries. The subjects had no history of heart disease and no other clinical conditions, or were not taking medications known to affect hemostasis. Data obtained included their medical history and CHD-related risk behaviors, blood pressure, height, weight, abdominal and pelvic circumference, and coagulation, fibrinolysis, platelet activity, lipids, and lipoproteins profiles. There were significant differences between the two groups in the prevalence of a positive family history, mean apolipoprotein A1 levels, and platelet aggregation responses to ADP. Other established risk factors, including coagulation factor levels, were not significantly different.


The distribution of coagulation factors VII and VIII and fibrinogen in adults over 65 years. Results from the Cardiovascular Health Study. The Cardiovascular Health Study (CHS) was designed to examine cardiovascular disease and its risk factors in older adults. We report here the distributions of the coagulation factors fibrinogen, factor VII, and factor VIII in a population-based cohort of men and women 65 years or older. In other studies of middle-aged individuals, these factors were shown to be associated with cardiovascular risk. In the CHS cohort, all three factors were elevated, compared to levels reported in middle-aged individuals, and fibrinogen and factor VIII values were higher in each successive age group; factor VII values, in contrast, declined slightly with age in the CHS cohort. Compared to white subjects, blacks had higher values for fibrinogen and factor VIII and lower values for factor VII. While women had markedly higher values for factor VII and factor VIII than men at all ages in the CHS, mean fibrinogen values were not different between men and women.


The relationship between hemostatic tests and cardiovascular risk factors in patients with angina pectoris. European Concerted Action on Thrombosis and Disabilities (ECAT) Angina Pectoris Group. Baseline data are presented of the ECAT Angina Pectoris Study. Both plasminogen activator inhibitor and fibrinogen were positively associated with a number of cardiovascular risk factors such as smoking, body mass index, and also with the presence of coronary stenosis. Results indicate a role of the hemostatic system in the progress of coronary arteriosclerosis.


The influence of dietary change on hemostatic risk variables. In the 1970s in the Diet-Antismoking Trial, of the Oslo Study, colleagues and I found that the majority of high-risk men with elevated serum cholesterol and elevated triglyceride concentrations had impaired fibrinolytic capacity. Later on, both our group and others found a similar negative correlation between serum triglyceride levels and fibrinolytic capacity. Furthermore, in a prospective study of dietary intervention in individuals with both elevated cholesterol and triglyceride levels, we found that dietary lowering of serum triglyceride levels was significantly and positively correlated with an improvement in fibrinolytic capacity. In another study, we made the same observation for the coagulation factor VII-phospholipid complex: the more the triglycerides were reduced by diet, the greater was the change in factor VII complex. This correlation was highly significant and independent of changes in serum cholesterol. Platelet function is also influenced by dietary habits, but except for the effects of a fish oil-enriched diet, few data are available about the dietary effects on platelet function. It seems, however, that in individuals with elevated lipid levels and elevated blood pressure, increased platelet reactivity is a highly prevalent finding. Many of the hemostatic risk variables are associated with the so-called "metabolic risk syndrome" characterized by an increase in serum insulin level, together with increased relative body weight, mild hypertension, hyperlipidemia, and physical inactivity. This syndrome can often be influenced favorably by life-style changes. A controlled study with interventions in diet and activity level has just been started by our group.


Antiplatelet and anticoagulant drugs in coronary vascular disease. The stimulation of platelets, activation of the coagulation cascade, release of platelet-derived vasoconstrictors, and endothelial dysfunction all contribute to the thrombotic vascular occlusion that results in myocardial infarction. Despite the importance of platelets in the initiation of this process, they are activated by multiple endogenous mediators. Thus, one might anticipate that redundancy in the system would confound the efficacy of antiplatelet drugs that were mediator-specific. The success of aspirin in clinical trials is likely to reflect the role of thromboxane A2 (TxA2) as an amplification signal for other platelet agonists. Activated platelets provide a substrate for assembly of the prothrombinase complex and both heparin and warfarin also reduce the mortality due to thrombotic vascular disease. The relative efficacy of these compounds versus aspirin and the safety of their combination, particularly in the setting of therapeutic thrombolysis, are under investigation. Novel antiplatelet agents, particularly those directed against the glycoprotein 11b/111a complex, are more potent than aspirin in animal models. Similarly, direct thrombin inhibitors seem superior to heparin. Whether such compounds can be administered safely in effective doses to humans is under study. It is hoped that the success of aspirin does not impede the clinical evaluation of theoretically more attractive antithrombotic drugs.


Thrombolytic therapy for myocardial ischemia and infarction. Thrombolysis during the early hours of a myocardial infarction significantly improves patient survival in a hospital. Beyond 6 hours, up to 24 hours, thrombolysis may still contribute to a reduction in mortality. However, further confirmation is desirable before such therapy late in the course of an evolving infarct can be routinely recommended. Although clot-specific agents such as recombinant tissue-type plasminogen activator (rt-PA) produce a higher initial patency rate, reocclusion rates are higher in the absence of the profound systemic fibrinolysis produced by agents such as streptokinase. This may explain the GISSI-2 results where 15-day survival was no different between the streptokinase- and rt-PA-treated subjects. Although the manner of heparin administration may have clouded these results, current research is directed toward looking at combinations of thrombolytic agents that would combine drugs efficient in producing early patency with those that produce a more pronounced fibrinolytic state. More effective adjunctive therapy is also under intense investigation, particularly specific antithrombin agents that would produce more effective anticoagulation following thrombolysis, and more effective antiplatelet agents that would help prevent reocclusion.


Long-term anticoagulant treatment after acute myocardial infarction. The Warfarin Re-Infarction Study. High levels of fibrinogen and clotting factor VII are associated with an increased risk for subsequent death and cardiovascular disease in apparently healthy individuals. Furthermore, pathoanatomic studies and coronary angiography have confirmed a relationship between coronary thrombus formation and acute Q-wave infarction. Effective antithrombotic agents may prevent or limit thrombus formation and events related to thrombosis. The Warfarin Re-Infarction Study (WARIS) studied the effect of warfarin in survivors of acute myocardial infarction. Patients aged 75 years or less were randomized in a double-blind, placebo-controlled study to test whether long-term treatment with warfarin reduces the risk of death, reinfarction, and thromboembolic morbidity. A total of 1918 patients were screened for participation; 1214 were recruited. The mean follow-up was 37 months. Analyzed on an intention-to-treat basis, 123 (20%) in the placebo group died, versus 94 (15%) in the warfarin group, a risk reduction of 24% (P = 0.026). Considering patients on treatment or within 28 days after discontinuing the test medication, 92 in the placebo group died, as compared with 60 of the warfarin-treated patients, a risk reduction of 35% (P = 0.005). Relapsing myocardial infarction (fatal and nonfatal) was reduced by 43% (P = 0.0001). The incidence of cerebrovascular attacks was lower in the warfarin group (16 patients) than the placebo group (41 patients), a highly significant reduction of 61% (P = 0.0003). Serious bleeding occurred in 11 patients taking warfarin, an incidence of 0.6% per year. In conclusion, long-term anticoagulant therapy may be recommended after acute myocardial infarction.


Young maternal age and parity. Influences on pregnancy outcome. The influence of very young maternal age and parity on pregnancy outcome was examined in a cohort of nearly 900 adolescents and mature women from Camden, New Jersey. Young primigravid primiparas (aged 12 to 15 years) were compared with mature primigravid primiparas (18 to 29 years). Young multiparas (19 years or younger, with a first pregnancy at the age of 12 to 15 years) were compared with mature, multiparas (19 to 29 years old, with a first pregnancy at 18 years or older). After controlling for confounding factors, young primiparas were found to have a modest increase in preterm delivery, which was not statistically significant. However, low gynecologic age contributed disproportionately to the risk of preterm delivery in this group, with risk decreasing with each year from menarche (Cox's proportional hazard, 0.80; 95% confidence interval [CI], 0.68 to 0.94). Among multiparas, there were several statistical interactions associated with increased risk of small-for-gestational-age infants, including interactions between young age and low pre-pregnancy body mass (adjusted odds ratio [AOR], 5.74; 95% CI, 2.18 to 15.08), young age and a prior low-birth-weight infant (AOR, 10.58; 95% CI, 3.89 to 28.77), and young age and a prior preterm delivery (AOR, 5.52; 95% CI, 2.04 to 14.98). Thus, while chronologic age per se may not be a good predictor of pregnancy outcome, adolescents remain a high-risk group because of factors that are more common among them (e.g., biologic immaturity, inadequate prenatal care, poverty, minority status, low prepregnancy weight) and because factors associated with an early adolescent pregnancy, such as low gynecologic age, may continue to influence the outcome of subsequent pregnancies.


An epidemiologic case-control study of breast cancer and exposure to hair dyes. An epidemiologic case-control study of 1617 patients with a primary breast cancer and 1617 control subjects was conducted to test the hypothesis that use of hair dyes is related to breast cancer. No overall association was observed between breast cancer risk and "ever use" of hair dyes (odds ratio, 1.04; 95% confidence interval, 0.90 to 1.21), age when hair dye use started and age when it stopped, duration of hair dye use (years), types of hair dyes used, and estimated lifetime number of individual applications. The current data set also failed to show an increased risk for breast cancer in women who had been diagnosed with benign breast disease and were exposed to hair dyes.


Alcohol, beer, and lung cancer in postmenopausal women. The Iowa Women's Health Study. There are data to suggest a relationship between alcohol consumption, particularly beer, and lung cancer. This hypothesis was tested on data from a cohort of 41,837 Iowa women aged 55 to 69 years. Women were recruited by mail and provided information on alcohol and tobacco use, physical activity, and education. Compared to a randomly selected group of women without lung cancer (n = 1900), those with lung cancer (n = 109) consumed more alcohol (measured on the Willett food frequency questionnaire) (10.2 versus 3.6 g/d; P = 0.001). The difference was accounted for largely by differences in beer consumption (3.5 versus 0.6 glass/wk; P = 0.003). Liquor consumption by patients was about double that by control subjects (1.7 versus 0.8 glass/wk; P = 0.063). Wine consumption was low and did not differ between those with and those without lung cancer. The relationship between beer consumption and lung cancer risk appeared U-shaped. After adjusting for the other variables (including six categories of pack-years of smoking), beer consumption remained a significant predictor of lung cancer risk. Those drinking 1 or more beers per week had an odds ratio of 2.0 (95% confidence interval, 1.02 to 3.80) compared with those consuming less than 1 glass per week. There was no evidence of interaction with smoking. The association of beer with lung cancer does not appear to be explained solely by confounding with cigarette smoking, although that remains by far the single strongest predictor of risk.


Height and weight at various ages and risk of breast cancer. A study of 1529 breast cancer patients and 1901 control subjects enabled evaluation of risk in relation to lifetime changes in body size. Tallness, regardless of when achieved, was associated with an increased risk of breast cancer diagnosed at both young (< 50 years) and older ages, with adult height of 68 in or more increasing risk by nearly 50 to 80% compared with statures of less than 62 in. The association of risk with weight was less clear. Subjects who described themselves as heavier than average at ages 8 to 9 or 16 years were at reduced risk, particularly for older-onset breast cancer. Higher body mass indices based on reported weights during early adulthood were also associated with reduced risk. Measures of body mass beyond the age of 20, however, were less strongly related to risk. These inconsistent patterns appeared to be explained by an effect on risk of weight gain later in life, which was related to reduced risks for young-onset breast cancer and increased risks for later disease. The effect of weight change for early-onset breast cancer was not restricted to in situ cancers and could therefore not be attributed to detection bias. The direct relationship of body mass change with older onset disease was restricted to invasive cancers, consistent with observations of poor breast cancer prognosis among obese women. Further attention on the relationship of anthropometric variables to risk of breast cancer should focus on the timing of weight gain as well as the distribution of body fat.


Components of adult height and height loss. Secular trend and effects of aging in women in the DOM project. Between 1984 and 1987, adult height, sitting height, arm span, and iliac crest height were measured in 13,386 women of the DOM project. Combined effects of secular trends between cohorts born in 1911 to 1945 and aging between ages 40 to 74 years showed a decrease in stature of 4.9 +/- 0.3 cm (mean +/- standard error of mean) and in sitting height of 3.9 +/- 0.2 cm. Height and sitting height diminished but no effect of aging on arm span was found in 380 women measured again after 5 years. When arm span and iliac crest height did not change with age, they reflected a secular trend (1.6 +/- 0.3 cm and 0.5 +/- 0.3 cm). This implies an age-related decline in stature of -3 cm in 35 years.


The association between water fluoridation and hip fracture among white women and men aged 65 years and older. A national ecologic study. For the past 45 years, there has been a great deal of debate regarding the health issues surrounding the fluoridation of public water supplies. In order to assess the association between fluoridation and hip fracture, we identified 129 counties across the United States considered to be exposed to public water fluoridation and 194 counties without exposure. Data from the Health Care Financing Administration and the Department of Veterans Affairs were used to calculate the incidence of hip fracture among white persons, aged 65 years or older, in fluoridated and nonfluoridated counties. There was a small statistically significant positive association between fracture rates and fluoridation. The relative risk (95% confidence interval) of fracture in fluoridated counties compared to nonfluoridated counties was 1.08 (1.06 to 1.10) for women and 1.17 (1.13 to 1.22) for men. As comparisons were made at the grouped level, it may be inappropriate at this time to draw inferences at the individual level. The relationship observed at the county level needs to be duplicated at the individual level with more precise measures of fluoride exposure.


Caffeine intake and asthma symptoms.

Caffeine intake and asthma symptoms. Methylxanthines in the form of coffee and tea may be dietary factors that function as pharmacologic bronchodilators. To examine this hypothesis, we analyzed data from the Second National Health and Nutrition Examination Survey (NHANES II). NHANES II was conducted on a sample representative of the civilian noninstitutionalized US population, which included white and black adults aged 30 years or older. We examined the relationship of usual coffee and tea consumption from a medical history questionnaire to the presence of asthma and wheezing symptoms. Subjects who drank coffee on a regular basis had a 29% reduction in the odds of having current asthma symptoms (odds ratio, 0.71; 95% confidence interval, 0.55 to 0.93) when compared with non-coffee drinkers. The effect exhibited a significant dose-response relationship, with the number of cups of coffee consumed per day being inversely related to asthma prevalence. This relationship was independent of age, gender, and cigarette smoking. Tea consumption was not significantly related to asthma prevalence in this cohort.


Comparability of risk factors for coronary heart disease among blacks and whites in the NHANES-I Epidemiologic Follow-up Study. The incidence of new coronary events and the predictive strength of the major coronary risk factors were evaluated in a biracial sample drawn from the general U.S. population. In this cohort of 12,599 persons, free of reported coronary heart disease (CHD) at baseline, both hospitalizations and deaths coded to this cause were recorded prospectively. Based on CHD as the underlying cause of death, black men and women experienced higher age-adjusted mortality than their white counterparts (BM = 6.15, WM = 5.59, BW = 3.72 and WW = 2.58 [cumulative deaths, percent]), while having lower hospitalization rates than did whites. In a univariate logistic regression model, with all incident events as the endpoint, the predictive strength of the coronary risk factors was remarkably similar for the four sex-race groups. Notable exceptions included smoking, where the data from this study are problematic, and body mass index, where a relationship was noted only among white women. In a multivariate model, the beta coefficients were similar for age, systolic blood pressure, cholesterol, and income; the statistical significance varied among the groups. Within the power of this study to examine between-race differences, the predictive strength of the standard risk factors are very similar. None of the within-sex, between-race differences in the multivariate relationships were significant, although sizable percentage differences were noted. Blacks appeared to receive less hospital care for CHD, despite higher rates of fetal events.


Cardiovascular disease risk factors and glucose tolerance. The Wadena City Health Study. Cardiovascular risk factors were examined in 453 subjects participating in the Wadena City Health Study, a population-based study to assess the relationship between diabetes and glucose intolerance with age. Each subject was classified as either having non-insulin-dependent diabetes mellitus (NIDDM), impaired glucose tolerance (IGT), or normoglycemia, using WHO criteria. Age- and body-mass-adjusted levels of systolic and diastolic blood pressure were lowest for those with normoglycemia, intermediate for those with IGT, and highest for those with NIDDM. Age- and body-mass-adjusted levels of high-density lipoprotein cholesterol were lowest for those with NIDDM, intermediate for those with IGT, and highest for those with normoglycemia, while triglyceride levels were highest for those with NIDDM, intermediate for those with IGT, and lowest for those with normoglycemia in women but not in men. Low-density lipoprotein cholesterol levels were lowest for those with NIDDM, intermediate for those with IGT, and highest for those with normoglycemia. With the exception of men with IGT, no differences by glycemic strata were observed for plasma total cholesterol. The prevalence of smoking showed no consistent pattern by glycemic status. These findings suggest that individuals with IGT have an atherogenic risk factor pattern that may put them at greater risk for coronary heart disease than those with normoglycemia. Intervention strategies such as diet, exercise, and/or drug therapy should be tested to evaluate whether these are effective in preventing conversion to overt diabetes and normalizing cardiovascular disease risk factors.


Long-term weight fluctuation and non-insulin-dependent diabetes mellitus in white women. The association of long-term weight fluctuation with non-insulin-dependent diabetes mellitus (NIDDM) was investigated for a population of 8232 white female members of the Taking Off Pounds Sensibly (TOPS) weight-awareness program, between the ages of 40 and 50 years. An index of weight fluctuation was developed using current weight, weight at the time maximum height was reached, and recalled maximum and minimum weights for the third and fourth decades for each member of the study population. A logistic regression of diabetes prevalence as a function of weight fluctuation, waist-hip ratio, relative weight, and family history index showed standardized odds ratios of 1.10, 1.22, 1.19, and 1.06, respectively. The results suggest that the magnitude of long-term weight fluctuation is associated with the development of NIDDM.


A prospective study of postmenopausal estrogen therapy and subsequent incidence of non-insulin-dependent diabetes mellitus. The potential influence of postmenopausal estrogen therapy on the subsequent development of non-insulin-dependent diabetes mellitus (NIDDM) is relatively unexplored, despite postulated effects of these hormones on glucose tolerance. We examined the association between postmenopausal hormone use and the subsequent incidence of NIDDM in a prospective cohort of 21,028 postmenopausal US women aged 30 to 55 years and free of diagnosed diabetes, cardiovascular disease, and cancer in 1976. During 12 years of follow-up (422,991 person-years), we confirmed 1249 cases of NIDDM. Current users of postmenopausal hormones had a relative risk of NIDDM of 0.80 (95% confidence interval, 0.67 to 0.96) as compared with never users, after adjustment for age and body mass index (BMI). Past users of these hormones had an age- and BMI-adjusted relative risk of 1.07 (0.93 to 1.23). These results were not materially altered by multivariate adjustment for age, BMI, family history of diabetes, and coronary risk factors. Comparable results were obtained when the analysis was restricted to symptomatic NIDDM as the outcome. We observed no appreciable modification of these associations by family history of diabetes or category of BMI. Duration of current or past use of postmenopausal hormones and dose of conjugated estrogen were not significantly related to incidence of NIDDM. Type of hormone (estrogen alone, progesterone alone, or combination) also did not appear to influence NIDDM risk. These prospective data indicate that postmenopausal hormone therapy is unlikely to be associated with a material increase in the incidence of NIDDM among women.


Lower endogenous androgens predict central adiposity in men. Central adiposity, sometimes described as male pattern fat distribution, is adversely related to cardiovascular risk and mortality independent of other measures of obesity. In a cohort of 511 men aged 30 to 79 years in 1972 to 1974, levels of androstenedione, testosterone, and sex hormone-binding globulin measured at baseline were inversely related to subsequent central adiposity, estimated 12 years later using the waist-hip circumference ratio. The observed differences in waist-hip ratio between top and bottom tertiles of these hormones and sex hormone-binding globulin were similar to mean waist-hip ratio differences between men with stroke or ischemic heart disease and those without in another prospective study. These findings, consistent with studies suggesting that testosterone seems to mobilize the abdominal depot on males, suggest that "male pattern" fat distribution may be a misleading description for central adiposity, at least, in men. Degree of maleness as indicated by total androgen levels is, in fact, negatively associated with central adiposity. However, the role of sex hormone-binding globulin in regulating androgenic activity warrants further investigation.


Disease determinants of sporadic salmonellosis in four northern California counties. A case-control study of older children and adults. A population-based, case-control study of sporadic salmonellosis was conducted in 1988 and 1989 in four northern California counties. The study included 120 patients and 265 control subjects. Conditional logistic regression analysis (adjusted for age) revealed that patients were more likely to consume undercooked chicken prior to the onset of disease (odds ratio [OR], 23.57; 95% confidence interval [CI], 2.89 to 192.30). Elevated associations were also found with recent travel to foreign countries (OR, 9.69; 95% CI, 3.18 to 29.56), diabetes (OR, 6.29; 95% CI, 1.56 to 25.34), hormonal replacement therapy (principally conjugated estrogen) in older women (OR, 4.20; 95% CI, 1.82 to 9.71), and antibiotic therapy prior to illness (OR, 1.96; 95% CI, 0.86 to 4.37). The problems of studying self-selected cases that may lead to alternative explanations for these findings are also discussed.


Plasma 25-hydroxyvitamin D3 and its relation to physical activity and other heart disease risk factors in the general population. The relation between plasma levels of 25-hydroxyvitamin D3, the main metabolite of sun-induced vitamin D, and major coronary heart disease risk factors was examined in 295 men, aged 35 to 64 years, who were randomly sampled from the general population. Men who did regular vigorous leisure-time activity had a mean plasma 25-hydroxyvitamin D3 level that was 4.8 nmol/L (95% confidence limits: 0.1, 9.5) higher than that in inactive men, with the increase greatest in the winter months. Plasma 25-hydroxyvitamin D3 was positively associated with weekly hours of sun exposure (r = 0.27, P < 0.01), and showed a weak inverse association with age (r = -0.12, P < 0.05) and diastolic blood pressure (r = -0.15, P < 0.05), although this latter finding was no longer significant when allowance was made for the effects of age and season on vitamin D levels. In contrast, plasma 25-hydroxyvitamin D3 had no relation with either serum total or high-density-lipoprotein cholesterol levels, body mass index, or cigarette smoking. We hypothesize that vigorous leisure-time activity may protect against coronary heart disease, in part, by increasing body levels of vitamin D.


Reliability of recalled physical activity, cigarette smoking, and alcohol consumption. Reliability of recalled measures of physical activity and alcohol and tobacco use was examined in a cohort of 873 men and women in three California communities. In personal interviews in 1972, participants provided baseline data on these three habits. In repeat interviews in 1983, they recalled their habits in 1972 and reported their current habits. On average, recalled physical activity levels significantly exceeded those originally reported (1899 kcal/d versus 1345 kcal/d, P < 0.001) and were similar to current reported levels (1822 kcal/d). Similarly, recalled alcohol and cigarette consumption was higher than the original reports (alcohol: 126 versus 119 g/wk; cigarettes: 8.5 versus 6.2/d). By contrast, current reported alcohol (103 g/wk) and cigarette consumption (4.6/d) were lower than at baseline. Analysis of variance was used to partition the variation in recalled and original habits into components due to interpersonal variation in true measures, errors in recall, and residual reporting error. Interpersonal variation accounted for only 20% of the total variation in physical activity, but for 48 to 60% of total variation in cigarette smoking and alcohol consumption. These results suggest that inconsistencies among studies of chronic disease and physical activity may arise from either large random measurement errors in individual assessments or from homogeneity of activity levels among the populations studied.


Validity of self-reported pregravid weight. Self-reported pregravid weight is a commonly used baseline indicator of nutritional status in prenatal weight gain studies. This study assesses the validity of self-reported pregravid weight in 1591 gravidas who entered into prenatal care within the first trimester of pregnancy from 1986 to 1988 at the University of Maryland Medical Systems. A significant difference of 4.3 lb (t = 25.56, P < 0.001) was found between self-reported pregravid weight and estimated pregravid weight. Limits of agreement (interval within which 95% of the differences between the self-reported and measured weights) were constructed by population characteristics. Multiple linear regression models with estimated pregravid weight as the dependent variable were estimated by self-reported pregravid weight, body weight, height, age, race, education, insurance status, and marital status groups. A model with self-reported pregravid weight as the sole independent variable was found to explain 88% of the variance in estimated pregravid weight. Results of this study suggest that the validity of self-report pregravid weight varies with sociodemographic and anthropometric factors. Adjustment by a simple regression equation can minimize error in self-reported pregravid weight.


Short-term intraindividual variability in hemostasis factors. The ARIC Study. Atherosclerosis Risk in Communities Intraindividual Variability Study. Recent epidemiologic studies found that there is a strong association of hemostatic factors with ischemic heart disease. The Atherosclerosis Risk in Communities (ARIC) Intraindividual Variability (IIV) Study was conducted to estimate the various components of variation in hemostasis factors measured in the ARIC Study and to estimate the measures of repeatability of these factors. A total of 39 subjects (16 men, 23 women) were studied. Each had blood collected three times, with a 1- to 2-week interval between each visit. The contributions of between-person variability, within-person (biologic) variability, and processing and assay variability were estimated. Then the reliability coefficient R was estimated as the proportion of total variance accounted for by between-person variance. The reliability coefficient can be interpreted as the correlation between measures made at repeat visits. Among the various analytes, the reliability coefficients were quite high for activated partial thromboplastin time and plasma factor VIII (R = 0.92, 0.86, respectively). Low repeatability was obtained for antithrombin III activity and protein C (R = 0.42, 0.56, respectively). The lack of repeatability for these variables derives mostly from the processing (field center and laboratory) variation. Other analytes--fibrinogen, plasma factor VII, and von Willebrand factor--were intermediate in repeatability. In comparing the analyte-specific high-level to low-level groups, no substantial difference of within-person plus method coefficient of variation between the two groups was found for any analyte except for factor VIII, whereas the corresponding variance components for most analytes were higher for the higher analyte level. Reliability coefficients from this ARIC IIV study are generally higher than those found in other studies, and this is related to the relative variations in populations studied and to the time between measurements.


Interpretation of linear regression models that include transformations or interaction terms. In linear regression analyses, we must often transform the dependent variable to meet the statistical assumptions of normality, variance stability, or linearity. Transformations, however, can complicate the interpretation of results because they change the scale on which the dependent variable is measured. In this setting, the inclusion of product terms or the transformation of some independent (or predictor) variables may further complicate interpretation. In this article, we present some interpretations of linear models that include transformations or product terms. We illustrate these interpretations using regression analyses designed to study determinants of serum testosterone levels. These examples show how one can present results using simple measures, such as medians, and interpret regression parameters.


The effect on response rates of offering a small incentive with a mailed questionnaire. To determine whether response rates to a mailed questionnaire sent to population control subjects could be increased through offer of a small incentive, half of the control subjects (n = 477) in a case-control study of renal cell carcinoma were randomly selected to receive a contact letter offering a lottery ticket if a completed questionnaire was returned; the remaining subjects (n = 477) received the same letter but with no mention of a lottery ticket. Overall response rates did not differ between the two groups (72.6% versus 74.4%), although a higher percentage of those offered a lottery ticket responded without follow-up (24.4% versus 18.5%). Binomial regression modeling of the effect of the lottery ticket offer, sex, age, and percent of urban dwellers on response indicated a significant effect only for percent of urban dwellers, the rate of response increasing with a decreasing percentage of urban dwellers. The effect of sex was of borderline significance (P = 0.05), with females having the higher rate of response.


Human immunodeficiency virus/acquired immunodeficiency syndrome in pregnant women. A pregnant woman experiences selective immunosuppression as a physiologic response to the presence of a genetically heterologous fetus. Case reports early in the acquired immunodeficiency syndrome (AIDS) epidemic suggested that adverse human immunodeficiency virus (HIV)-related clinical outcomes might be causally associated with pregnancy. A review of relevant published data indicates that: (1) Adverse clinical outcomes of pregnancy are common among HIV-infected pregnant women, but no studies to date have fully disentangled the many confounding factors. (2) HIV-related complications are common in pregnancy only among immunosuppressed (< 300 CD4+ cells/mm3) women. (3) The distinct effect of pregnancy on the expression of HIV infection cannot be evaluated in the absence of appropriately controlled observations. (4) Cofactors for perinatal transmission are poorly understood. (5) Research into the motives for reproductive decisions and behaviors is of critical importance for improving our health education and outreach efforts for high-risk women. (6) Adequate clinical treatment and prophylactic health care services must be made easily accessible and available to women at high risk of HIV disease. (7) Treatment with available antiviral and anti-Pneumocystis drugs is advisable for HIV-infected pregnant women with fewer than 300 to 350 CD4+ cells/mm3, though data to definitively guide therapeutic decision making are not available. (8) Large multicenter studies are needed to recruit patients and to retain them in sufficient numbers, allowing for better evaluation of the many variables determining clinical outcomes for HIV-infected mothers and their infants. The natural history of HIV in pregnant women must be studied to facilitate clinical decision making, and to design and implement interventions, including prevention (behavior change, vaccines) and treatment (chemotherapy, immunotherapy).


When, where, and how do immunizations fail? There are two main reasons for failure of immunizations: (1) failure of the vaccine delivery system to provide potent vaccines properly to persons in need; and (2) failure of the immune response, whether due to inadequacies of the vaccine or factors inherent in the host. The first category is by far the most important worldwide. The major factor contributing to failure of the delivery system is failure to vaccinate; in the developing world this is commonly a result of inadequacy of the vaccine supply. Other important factors include barriers to immunizations, improper use of vaccines, vaccine ineffectiveness at the time of use, and factors relating to client attitudes and knowledge. Failure of the immune response may be either primary or secondary (loss of protection after initial effectiveness). The shortcomings of existing vaccines must not deter us from taking maximal advantage of their benefits.


Infection and immune response in the elderly. A number of immunologic functions have been shown to decline in an age-related fashion, particularly cell-mediated immunity and antibody response to an immunogen. Underlying degenerative diseases and medications further contribute to the immunologic abnormalities noted in the elderly. The elderly in hospitals and nursing homes are a particularly vulnerable subset, with a high incidence of institutionally acquired infection. Aspects of disease prevention in the elderly are discussed.


Maintenance of functioning in the elderly. Dramatic declines in age-specific mortality have led to large increases in the number of older people in the United States and other industrialized populations. While increased survival time is to be desired, it is important to consider the functional ability of those who survive to older ages, and whether preventive activities can lead to higher levels of functioning. Using data from the Alameda County Study, results indicating that incident chronic diseases are associated with poorer levels of physical functioning are presented. Many of the behavioral, social, and demographic risk factors that are associated with risk of chronic disease and mortality in this cohort are also associated with poorer physical functioning. Thus, interventions that reduce or delay the development of chronic diseases in the elderly may also result in higher levels of physical functioning. These same risk factors also modify the impact of chronic disease on functioning. Therefore, interventions that reduce risk factors for chronic disease may increase levels of functioning in those who survive with or without disease.


Conceptual problems in identifying risk factors for functional decline in the elderly: a commentary. Assessment of risk factors for chronic disease and disability among the elderly is a complex issue. Findings may be affected by the age at which the putative risk factor was measured, interval between the time of measurement of risk and outcome, possibility of changing patterns of exposure throughout the life span, and selective survival. We illustrate the complexity of risk assessment with findings from the Iowa 65+ Rural Health Study on the relationship between body mass and changing physical function. In baseline cross-sectional analyses, both high and low body mass were associated with poorer function. In 6-year longitudinal analyses limited to persons who were functionally intact at baseline, high body mass was associated with poorer lower-extremity function but relatively preserved upper-extremity function. High body mass was also associated with elevated rates of transient impairments. Extremes of teenage body habitus were associated with impaired physical function in old age. Function was poorest among those with a lifetime history of high body mass, and changes in body mass were complexly associated with subsequent function. Thus conceptual and analytic models of chronic illness and disability need to consider multiple, changing exposures over the lifetime, as well as the impact of illness, disability, and their treatment on subsequent risk factor exposure.


Health effects of military service. Lessons learned from the Vietnam experience. This article examines the methodologic difficulties encountered in studies of the long-term effects of the Vietnam War on the psychological and physical health of veterans. Alternate study designs and exposure and outcome measurements are examined in relation to psychological (post-traumatic stress disorder and alcohol use or abuse) and physical (mortality and birth defects in children) health outcomes. All major epidemiologic studies of post-traumatic stress disorder and alcohol use or abuse utilize cross-sectional research designs. Mortality and birth defect studies use cohort, case-control, or proportionate mortality strategies. Exposure is measured using either definitive dichotomous indicators of service in Southeast Asia or more complex indicators of the Vietnam experience (i.e., combat, herbicide exposure, atrocities, abusive violence) that are of suspect validity. In studies of psychological health, outcomes are based exclusively on self-reported symptoms, while investigations of mortality and birth defects use death certificates and hospital records. Epidemiologic research on the effects of the Vietnam conflict has been hampered by problems in research design and the inherent difficulties of measuring wartime exposures and long-term health outcomes.


The Sebutape technique for monitoring androgen dependent disorders. Sebaceous gland function is androgen dependent in man and animals. Many studies have suggested a relationship between the rate of sebum excretion and the severity of androgen-dependent disorders. We present a review of a recently developed non-invasive method to accurately measure sebum excretion. The Sebutape technique provides information that may be used in monitoring androgen-dependent disorders and in screening the efficacy of antiandrogens.


Comparative study of community versus hospital-acquired Staphylococcus aureus bacteraemia. We prospectively investigated 274 consecutive Staphylococcus aureus septicaemias in adult patients between January 1983 and December 1989 to evaluate outcome in hospital acquired and community acquired episodes. Epidemiologic, clinical, laboratory and therapeutic parameters were analyzed with univariate and multivariate statistical tests. Ninety episodes of Staphylococcus aureus bacteraemia were acquired in the community and 184 in hospital. Diabetes mellitus and renal failure were accompanied by a clear increase in bacteraemia related death in the community-acquired category. Correct antibiotic therapy showed a better response in the community-acquired group. Bacteraemia related death was 22.6% for episodes acquired in the hospital and 18.8% for those originating in the community.


Hepatitis C virus and Hashimoto's thyroiditis. We report two cases of Hashimoto's thyroiditis associated with chronic active hepatitis C virus (HCV). Our data suggest that HCV infection might be involved in this autoimmune disease.


The pleiotropic effects of interleukin 7 and their pathologic and therapeutic implications. Interleukin-7 (IL-7) is a cytokine initially described as a growth factor for B cell progenitors. IL-7 also induces T cell proliferation and has pleiotropic effects. IL-7 enhances T-lymphocyte cytotoxicity, stimulates anti-tumoural properties of monocytes/macrophages, and induces tumour rejection in mice. It could thus be of interest in immunotherapy and may play a role in the generation of lymphoid neoplasia because leukaemic cells of B and T lineage express functional IL-7 receptors. Finally, IL-7 is, as IL-2, a cytokine of pivotal importance in the immune system, and so could be involved in abnormal immune response such as autoimmunity.


Left ventricular diastolic filling in type I diabetes mellitus: a pulsed Doppler echocardiographic study. Doppler echocardiography was used to assess left ventricular diastolic performance in young patients with type I diabetes mellitus and no clinical signs of heart disease. The pattern of transmitral diastolic flow velocity was determined in 82 patients (56 men, 26 women; age 17.7 +/- 7.6) with type I diabetes mellitus and no heart disease. Maximal early diastolic flow velocity (E peak), maximal late diastolic velocity (A peak), the ratio of maximal flow velocity in late diastole to that in early diastole (A/E ratio) and the ratio of the time velocity integral of the diastole (1/3 FF) were measured in all 82 patients and repeated during exercise in 63 of them. Twenty healthy volunteers served as controls. Mean values of the Doppler indexes were not significantly different between the patients and the 20 controls, but diabetic patients with microvascular complications showed patterns of left ventricular diastolic flow velocity which suggested altered diastolic performance, namely lower E peak velocity, higher A peak velocity, raised A/E ratio and reduced 1/3 FF. Among the 63 examined during exercise, different diastolic flow patterns in response to effort made it possible to identify 15 patients with a high rate of autonomic dysfunction, indicating probable impairment of diastolic function and a need for close follow-up. Diastolic abnormalities may occur in young diabetic patients without evidence of heart disease and suggest Doppler evaluation is a sensitive method for identifying patients at potential risk of developing clinical heart disease.


Post transfusion hepatitis: comparison between homologous and autologous blood transfusion. To assess whether the use of autologous blood transfusion may affect the incidence of post-transfusion hepatitis in transfused patients who undergo cardiac surgery. One thousand one hundred and twelve polytransfused patients having undergone cardiac surgery were studied from October 1982 through September 1990. Patients were transfused with homologous blood from selected volunteer donors; autologous blood collection or blood saving were introduced in September 1986. Routine laboratory tests were carried out upon hospitalization and monthly for a six-month period. Patients with hepatitis were followed for at least 24 months and liver biopsy was performed in those with chronic hepatitis. Ninety-four (9.8%) of the 959 polytransfused patients developed non-A, non-B post-transfusion hepatitis; anti-hepatitis C virus antibodies were present in 52 out of the 72 patients tested. The mean incubation period for post-transfusion hepatitis was 70 days; hospitalization was required in 47.9% of the patients. The mean number of transfused units was 12.9 in patients who developed post-transfusion hepatitis and 6.96 in the those who did not. Hepatitis was chronic in 42% of the 94 patients; in the others alanine aminotransferase levels normalized in a mean period of 10.3 months. None of the 237 patients who received autologous blood had hepatitis. In our study the role of surgical teams in preventing post-transfusion hepatitis was shown to be essential. The high percentage of chronicity and symptom-free hepatitis observed is a further reason to reduce homologous blood transfusions and instore careful follow-up of polytransfused patients.


Maximal electrical stimulation in neurogenic detrusor hyperactivity: experiences in multiple sclerosis. We report our experiences with maximal tolerable electrical stimulation in neurogenic bladder dysfunction due to multiple sclerosis. 27 female patients were treated with an intravaginal electrode carrier and an external pulse generator. The devices were individually adjustable with respect to electrode positioning and stimulation parameters. The frequency was 20 Hz. The threshold for sensation of the electrical stimulus was determined by slowly increasing the current and care was taken to stimulate with maximal tolerable stimuli. Urodynamic evaluation was done before and after cessation of treatment. During stimulation, 85% of the patients were free of symptoms. Three months after cessation of treatment only 18% remained free of symptoms, but the symptoms were not as pronounced as before treatment. Electrical stimulation using intravaginal electrodes represents a practical technical choice to treat motor urge incontinence in multiple sclerosis patients, although chronic stimulation is needed to retain improvement.


Cushing's syndrome and pregnancy: aetiologies and prognosis in twenty-two patients. The association of an active Cushing's syndrome and pregnancy is a rare event which raises specific diagnostic difficulties and bears poor maternal and foetal prognoses. We report our series of 22 patients. Age range was 19-34 (mean +/- SEM = 27.3 +/- 1.5) the onset of hypercorticism occurred before the pregnancy (n = 2), during the pregnancy (n = 15) or in the early post-partum (n = 5). The diagnosis was made during the pregnancy of 4 patients and in the post-partum of 18. Cushing's syndrome was revealed by the local manifestations of an adrenocortical tumour in 3 patients and by the clinical features of hypercorticism in 19 patients: mainly morphological changes (n = 19), high blood pressure (n = 12), and/or accelerated hair growth (n = 7). Aetiological distribution was noteworthy by the unusual predominance of primary adrenocortical tumours (n = 16) especially adrenocortical carcinomas (n = 8). Cushing's disease was present in only 4 patients and in 2 an ectopic ACTH secretion was observed. This association implied a high rate of complications for the mother: high blood pressure (n = 12), diabetes (n = 3), preeclampsy (n = 3) and pulmonary embolism (n = 1) and for the infant: prematurity (n = 16), hypotrophy (n = 4), adrenal insufficiency (n = 1), virilization (n = 1), stillbirth (n = 1). During their pregnancy 18 patients had a symptomatic treatment while only 4 patients (3 with adrenocortical carcinoma and one with an ACTH-secreting phaeochromocytoma) had a unilateral adrenalectomy. This condition is difficult to recognize: the diagnosis of Cushing's syndrome may be obscured by normal hormonal modifications of the pregnant state; it also forbears particular severity because of maternal and foetal complications, the unusual prevalence of malignant tumours and the particular difficulty in curing or merely controlling the hypercorticism.


Modeling 3-D slow phase velocity estimation during off-vertical-axis rotation (OVAR). Off-vertical-axis rotation (OVAR) in darkness generates continuous compensatory eye velocity. No model has yet been presented that defines the signal processing necessary to estimate head velocity in three dimensions for arbitrary rotations during OVAR. The present study develops a model capable of estimating all 3 components of head velocity in space accurately. It shows that processing of two patterns of otolith activation, one delayed with respect to the other, for each plane of eye movement is not sufficient. (A pattern in this context is an array of signals emanating from the otoliths. Each component of the array is a signal corresponding to a class of otolith hair cells with a given polarization vector as described by Tou and Gonzalez in 1974.) The key result is that estimation of head velocity in space can be achieved by processing three temporally displaced patterns, each representing a sampling of gravity as the head rotates. A vector cross product of differences between pairs of the sampled gravity vectors implements the estimation. An interesting property of this model is that the component of velocity about the axis of rotation reduces to that derived previously using the pattern estimator model described by Raphan and Schnabolk in 1988 and Fanelli et al in 1990. This study suggests that the central nervous system (CNS) maintains a current as well as 2 delayed representations of gravity at every head orientation during rotation. It also suggests that computing vector cross products and implementing delays may be fundamental operations in the CNS for generating orientation information associated with motion.


Influence of visual, vestibular, cervical, and somatosensory tilt information on ocular rotation and perception of the horizontal. By combining a tilting chair and a tilting room we investigated the subjective horizontal (SH) and ocular counterrotation (OCR) as a function of body tilt, trunk tilt, and tilt of a visual frame. Significant influences of (isolated or combined) vestibular and visual information were found, but no influence of neck proprioception. A second and similar experiment, however, now conducted with subjects devoid of labyrinthine function, suggested a contribution of the neck as well as of somatosensory origin. This made a reinterpretation of our data for normal subjects possible.


Fitting adaptation models to velocity step responses: simulation of normal and abnormal responses. A method is described to obtain suitable parameter values for an adaptation model that can be used to simulate velocity step (VS) responses. The input parameters are the dominant time constant fitted to the first part of the VS response and the time of reversal in nystagmus direction. This method allows a particular solution for the model previously defined by others with a vestibulo-ocular reflex (VOR) time constant, a time constant of adaptation, and a fixed (unitary) gain of the adaptation element. However, because it might be arbitrary to assume a unitary gain, we also studied a more general model with a variable gain element. It appeared that patients showing short responses had a short VOR time constant and less adaptation than normal. Patients exhibiting prolonged responses appeared to have an excessively long VOR time constant and more adaptation than normal, presumably to compensate for the long time constant.


Relation between perception of vertical axis rotation and vestibulo-ocular reflex symmetry. Subjects seated in a vertical axis rotation chair controlled their rotational velocity by adjusting a potentiometer. Their goal was to null out pseudorandom rotational perturbations in order to remain perceptually stationary. Most subjects showed a slow linear drift of velocity (a constant acceleration) to one side when they were deprived of an earth-fixed visual reference. The amplitude and direction of this drift can be considered a measure of a static bias in a subject's perception of rotation. The presence of a perceptual bias is consistent with a small, constant imbalance of vestibular function that could be of either central or peripheral origin. Deviations from perfect vestibulo-ocular reflex (VOR) symmetry are also assumed to be related to imbalances in either peripheral or central vestibular function. We looked for correlations between perceptual bias and various measures of vestibular reflex symmetry that might suggest a common source for both reflexive and perceptual imbalances. No correlations were found. Measurement errors could not account for these results since repeated tests in the same subjects of both perceptual bias and VOR symmetry were well correlated.


Visual-vestibular interaction during head-free pursuit of pseudorandom target motion in man. Recordings of head and eye movement were made during pursuit of mixed-frequency, pseudorandom target motion to study the mechanism of vestibulo-ocular reflex (VOR) suppression during head-free pursuit. When high velocity stimuli were used, slow-phase gaze velocity gains decreased significantly with increases in both absolute target velocity and the velocity ratio between the frequency components. These changes occurred independently of changes in the head displacement gain, which remained relatively constant at the lower frequency and were directly attributable to impaired suppression of the VOR. Similar effects were seen when visual feedback was degraded by tachistoscopic illumination of the target. The results indicate that visual feedback, rather than an efference copy of the head velocity signal, is essential for suppression of slow-phase vestibular eye movement during head-free pursuit. When head-free and head-fixed pursuit were compared, striking similarities were seen for both slow phase gaze velocity gain and phase, indicating that gaze control during smooth pursuit is largely independent of the degree of associated head movement. This suggests that the VOR is not switched off during head-free pursuit. An estimate of the underlying VOR gain was obtained by recording the vestibular response produced by active head movements in darkness. The rather higher estimates of VOR gain obtained using an imaginary earth-fixed target paradigm were found to predict head-free gains more closely than the gains obtained during imaginary pursuit of a moving target, suggesting that such measures may be more representative of the underlying VOR gain.


Context-specific adaptation of the gain of the vestibulo-ocular reflex in humans. Previous experiments show that altered visual feedback can change VOR gain. Such changes also presumably occur when eyeglasses are donned and doffed, or when bifocals are worn. In these cases, a nonvisual cue accompanies the required gain adjustment (frames on/off for eyeglasses, looking up/down for bifocals). We set out to show that a subject can establish two VOR gains, and to determine if one of the associated nonvisual cues alone is sufficient to subsequently determine which gain to employ. Each of three subjects sat in a rotating chair inside an OKN drum during 2 hours of sinusoidal rotation at 0.2 Hz, 30 degrees/s peak. For 10 minutes the chair and drum counterrotated , driving VOR gain toward 1.7, while subjects looked up 20 degrees. Chair and drum were then coupled for 10 minutes, driving gain toward zero, during which subjects looked down 20 degrees. This sequence was repeated for 2 hours. Immediately thereafter, VOR gains were measured while subjects looked alternately up and down, using 20 degrees to 40 degrees step rotations. A fixation target, presented before and after each step, provided accurate gain determination by measuring the size of the re-fixation saccade. Results show a consistent reduced VOR gain looking downward (average 6%) and increased gain looking upward (average 6%) and increased gain looking upward (average 8%). We conclude that humans can adjust their VOR gain dependent on a situational context; we speculate that this context can take many forms.


Patterns of low-frequency rotational responses in bilateral caloric weakness patients. Analysis of low-frequency (0.01 to 0.16 Hz), sinusoidal rotary chair responses of 24 patients with bilateral caloric weakness revealed a wide range of vestibulo-ocular reflex (VOR) impairment. The rotational stimuli presented allowed characterization of the degree of VOR impairment from severe to no impairment even in patients with absent responses to ice water caloric irrigation. Five patterns of responses were described, which helps to explain the lack of correlation often seen between caloric and rotary chair test results, especially when rotational testing does not extend down to at least 0.02 Hz. Bilateral caloric weakness was confirmed in 79% and 71% of patients by test frequencies of 0.01 and 0.02 Hz. Rotational stimuli of 0.04, 0.08, and 0.16 Hz gave notably poorer performance with 54%, 50%, and 29% confirmation.


Senescence of human visual-vestibular interactions. 1. Vestibulo-ocular reflex and adaptive plasticity with aging. The human horizontal vestibulo-ocular reflex (VOR) was studied as a function of aging (18 to 89 years) over a broad range of frequencies (0.025 to 4 Hz) and peak velocities (50 degrees to 300 degrees/s) of angular head movement. Eye movements were recorded using the search-coil technique. High stimulus frequencies and amplitudes were employed in order to challenge the VOR sufficiently to enhance potential age-related deficits in its pathways and functions. Further, the possibility that adaptive plastic mechanisms, which normally restore failing VOR function, might themselves deteriorate with aging was tested. Subjects were studied before and after an 8-h period while wearing 2 x binocular magnifying lenses. Demonstrable differences were observed in the human VOR as a function of natural aging. These differences were most pronounced in phase measures (increasing lead with aging), both at low frequency and low head velocity, and at modest frequency but high head velocity. Gain decrements were also observed with aging, but the changes were more subtle. The modifications in the VOR may be interpreted as an age-dependent deterioration in VOR performance. The course of age-related changes in response characteristics, particularly phase lead at the highest stimulus amplitude, are similar to age-related anatomical deterioration reported in peripheral vestibular structures. These changes resemble those in young patients with vestibular lesions, and are consistent with the notion that aging entails a progressive bilateral peripheral vestibular loss. Adaptive plastic mechanisms, which normally maintain VOR performance when altered responses result in visual-vestibular mismatch during head rotation, also deteriorate with aging. Again, the phenomenon resembles that in younger but vestibulopathic individuals. The effect is most profound at high frequencies and head velocities commensurate with natural behavior.


Vestibular and cardiac reactions to open-sea exposure. Nineteen healthy male volunteers were exposed to a 72-hour open-sea stay in a lifeboat in order to study whether randomized protracted stimulation of different parts of the vestibular system would cause a decrease of vestibular activity as assessed by unilateral calorization of the horizontal vestibular canal. The influence on the autonomic nervous system was investigated by calculating the heart rate by the R-R intervals at ECG at rest and at maximum speed of the nystagmus slow phase. Calorization and ECG investigations were performed immediately before and after the open-sea exposure. Seven healthy males who were not exposed to the open sea served as controls. They were investigated in the same manner as the test subjects, that is twice, 3 days apart. All test subjects experienced seasickness. After the sea stay, the caloric nystagmus response had decreased significantly more than in the controls. In 7 subjects with the most pronounced vestibular habituation, the resting heart rate decreased significantly after the sea exposure. Caloric stimulation of the labyrinths did not cause any specific change of the heart rate. It is concluded that prolonged open-sea exposure causes vestibular habituation to unilateral labyrinthine stimulation. Furthermore, there are some indications that the mechanism that is responsible for vestibular habituation to some extent influences the function of the autonomic nervous system, resulting in a decreased pulse rate.


Contribution of a posturographic six-test set to the evaluation of patients with peripheral vestibular disorders. A posturographic six-test set was developed in order to investigate the contribution of each sensory input in the balance performance of patients with peripheral vestibular disturbances. In test 1 (t1) the three sensory inputs are contributing to balance. In (t2), the contribution of vision is excluded by closing the eyes; in (t3) the neck proprioceptor is influenced by extreme retroflexion of the head, and in (t4) the input of the foot-ankle proprioceptor is altered by standing on foam rubber. The first two conditions are combined with the third one in (t5-t6). This test procedure compares the results obtained when the input of one (or two) sensors is impeded or altered with the results when the same sensors are uninfluenced. This comparison allows us to evaluate the individual contribution of the sensory inputs involved in the process of balance, especially in the compensation process in patients with benign paroxysmal positioning vertigo (BPPV) and with Ménière's disease. This comparative evaluation shows several "formulae." So can formulae with positive tests for head in retroflexion condition be more frequently met in the BPPV-group, whereas influence of visual exclusion is more frequently seen in the Ménière group.


An adjustment to eye movement measurements that compensates for the eccentric position of the eye relative to the center of the head. We describe a procedure for modifying horizontal eye movement measurements in a way that effectively removes signal contributions due to the eccentric location of the eyes relative to the center of rotation of the head. This procedure helps standardize measured signals so that data collected under different experimental conditions and from different subjects may be compared directly. We also present techniques for accurately determining specific parameters of head geometry that are required by the procedure. This method may be used for modifying eye movement responses to visual target motion, head motion, or both, and does not assume continual fixation of the visual target. Also, this method may be employed when either curved (iso-distance) or flat display screens are used for presenting the visual stimuli.


A fast, portable desaccading program.

A fast, portable desaccading program. This short communication reports a program for detecting and removing saccades, quick phases and blink signals from eye movement records to allow determination of slow phase eye velocity (SPV) during vestibular stimulation. The program is written in C and is simple, fast, and independent of computer type.


Stimulus velocity dependence of human vertical optokinetic nystagmus and afternystagmus. Stimulus velocity dependence of human VOKN and VOKAN was investigated using 20 degrees, 40 degrees, 60 degrees, and 80 degrees/s optokinetic stimulation. In our experimental conditions, 40 degrees/s was found to be the most appropriate stimulus velocity for inducing reliable VOKN and VOKAN based on the analysis of SPV, gain, and the area under the VOKAN decay curve. There was a clear trend toward up/down asymmetry of VOKN gain, with higher upward OKN SPV than downward at 40 degrees/s. VOKAN with both short and long time constant components was induced in 5 of 11 subjects, but only when the stimulus was upgoing. Stimulation at 20 degrees/s in either direction produced a decay with only a short time constant. VOKN-SPV and the area under VOKAN decay curve at 40 degrees/s showed no significant difference from the corresponding values at 60 degrees/s or 80 degrees/s, indicating that following and the velocity storage mechanism had saturated at 40 degrees/s. However, the gain at 60 degrees/s and 80 degrees/s became low and eye movement regularity was poor. Stimulation at 20 degrees/s may activate mainly the vertical pursuit mechanism, as it did not produce up/down asymmetry. It is proposed that, as in the horizontal case, two kinds of mechanisms are involved in vertical stripe-following eye movements, which represent smooth pursuit and optokinetic systems respectively.


Electrically evoked motile responses of mammalian type I vestibular hair cells. Vestibular hair cells, type I and II, with membrane potentials around -64 mV were prepared from guinea pig ampullar cristae and maculae. In type I cells, current injection, application of voltage steps during membrane patch-clamping, or extracellular alternating current (ac) fields evoked fast length changes of 50 nm to 500 nm of the cell "neck." Mechanical responses were determined by computerized video techniques with contrast-enhanced digital image subtraction (DIS) and interpeak pixel counts (IPPC) or by double photodiode measurements. These techniques allowed spatial resolutions of 300 nm, 120 nm, and 50 nm, respectively. In contrast to measurements of high-frequency movements of auditory outer hair cells (OHCs), the mechanical responses of type I VHCs were restricted to low frequencies below 85 Hz. In addition to recently reported slow motility of VHCs, the present results suggest that fast mechanical VHC responses could significantly influence macular and cupular mechanics. Isometric and isotonic variants are discussed. The observed frequency maxima gap between VHCs and OHCs is suggested to contribute to a clear separation of the auditory and the vestibular sensory modality.


Predictive mechanisms of head-eye coordination and vestibulo-ocular reflex suppression in humans. Head and eye movements of human subjects have been recorded during head-free pursuit in the horizontal plane of a target executing sinusoidal motion at a frequency of 0.26 to 0.78 Hz and a peak velocity of +/- 96 degrees/s. The target was not presented continuously but was exposed for brief durations of 120 to 320 ms as it passed through the centre of the visual field at peak velocity. This technique allowed the timing of each response to be assessed in relation to the onset of target appearance. During the first 3 to 4 target presentations, there was a progressive buildup of both head velocity and the smooth component of gaze velocity, while, simultaneously, the responses became more phase-advanced with respect to target onset. In the steady state, similar temporal response trajectories were observed for head and gaze velocity, which were initiated approximately 500 ms prior to target onset, rose to a peak that increased with the duration of target exposure, and then decayed with a time constant of 0.5 to 1 s. Whenever the target failed to appear as expected, the gaze and head velocity trajectories continued to be made, indicating that predictive suppression of the vestibulo-ocular reflex (VOR) was taking place in darkness. In a further experiment, subjects attempted to suppress the VOR during whole body oscillation at 0.2 or 0.4 Hz on a turntable by fixating a head-fixed target that appeared for 10 to 160 ms at the time of peak head velocity. Again, VOR suppression was initiated prior to target appearance in the same manner as for natural head movements, and when the target suddenly disappeared but rotation continued, predictive VOR suppression was observed in darkness. The similarity of these predictive effects to those obtained previously for head-fixed pursuit provides further support for the hypothesis that both pursuit and visual suppression of the VOR are controlled primarily by identical visual feedback mechanisms.


An analysis of ocular counterrolling in response to body positions in three-dimensional space. Four normal subjects underwent ocular counterrolling testing in a tiltable chair. Measurements were taken in 62 different body positions in steps of 30 degrees varied rolls and pitches. In each body position the eyes were recorded on video and their roll angle was determined automatically by computer analysis. The ocular counterrolling profile showed a periodic characteristic with maximal amplitude at roll tilts of 60 degrees. In this study we can clearly show that the eyes' rolling response is not systematically affected when lateral body tilts are combined with any tilts in the pitch direction. This undoubtedly implies that the ocular counterrolling was mainly stimulated by the subject's roll angle. As an empirical contribution, this study provides new data specially to be used in modelling and simulating the function of otolith organs.


The high-frequency oscillopsia test.

The high-frequency oscillopsia test. There is a need to develop bedside tests of the vestibulo-ocular reflex (VOR) that could be used in the clinical situation to screen patients who may be candidates for further evaluation. In 1984 Barber described the oscillopsia test, which compared visual acuity with and without head movement. Barber indicated that head movement should occur at greater than 1 Hz. This study was performed to evaluate the oscillopsia test at higher frequencies (2 to 7 Hertz) in the hope of improving its performance. The sensitivity and specificity of this test were evaluated using three examiners (the authors) and were referenced to clinical electronystagmographic results in 115 patients and 17 control subjects. The oscillopsia test evaluated in this study was highly specific, but not highly sensitive. It did not detect vestibular loss or subjective dizziness in more than 50% of cases. The high frequency oscillopsia test does not appear to be an effective screening test for VOR abnormalities or vestibular loss.


Mechanics of the cupula: effects of its thickness. Mechanical aspects of the ampullar diaphragm, that is the crista ampullaris and the cupula, related to its thickness, are studied by a numerical method. Numerical methods are able to go beyond the limits of analytical approaches and are the only methods able to take into account this thickness. A finite elements method is applied to the median plane slice of the ampullar diaphragm. One assumes that the cupula sticks firmly without slipping, to the ampullar wall and to the crista ampullaris. The computation takes into account the pressures on the liquid interfaces and the deformations of the ampulla. So the volume swept over by the cupula during quasi-static deformations can be evaluated and the global elasticity coefficient of the human cupula can be calculated. The related value of the long time constant of the semicircular canal is close to the value obtained when measuring, in vivo, the activity on the vestibular nerve in animals. The thick cupula model clearly shows two different spatial distributions of strain on the hairs of the sensory cells, leading to a discrimination between the vestibular inflating pressure and the transcupular pressure difference. This result matches recent neurophysiological data and brings a new insight in the mechanics of the vestibular angular accelerometer and its regulation.


Characteristics of nystagmus evoked by electrical stimulation of the uvular/nodular lobules of the cerebellum in monkey. Electrical stimulation in the monkey vestibulocerebellum has previously been shown to produce ocular nystagmus, but large stimulating current values were used. Using long duration (< or = 10-second) stimulus pulse trains and low current values (< 50 microA), we studied the nystagmus evoked by microstimulation in the uvular/nodular regions of the cerebellum. In doing this, we found quantitative differences in the nystagmus evoked from these two regions. Stimulation of the nodulus typically produced a vigorous nystagmus with a contralateral slow phase and a prolonged afternystagmus in the same direction. In contrast, stimulation of the uvula typically produced a regular ipsilateral nystagmus pattern with a very short, if any, afternystagmus in the same direction. In addition, at some stimulation sites in the uvula we observed an adaptation in the slow phase eye velocity during the time that the stimulation remained on. This effect could result in a secondary nystagmus, with a slow phase velocity direction opposite to that first evoked by the stimulation, followed by a prolonged afternystagmus in the direction of the secondary nystagmus at stimulus offset. The nystagmus evoked by these cerebellar stimulations differs from both natural nystagmus produced by large field visual motion and from the nystagmus produced by electrical stimulation of the nucleus of the optic tract. The nystagmus produced by uvular and nodular stimulation shows a shorter latency and a more rapid slow phase eye velocity buildup. The uvula stimulations also showed a much shorter afternystagmus. Also, the same nystagmus was evoked whether the animal was in a lighted or dark surround. These characteristics and recent single-unit recording studies in the uvula seem to suggest that the uvula acts not as a direct input to the velocity storage mechanism, but instead perhaps as part of an internal regulator for balance between the bilateral vestibular nuclei which are normally part of the nystagmus response. On the other hand, the nodulus, with its prolonged afternystagmus in the same direction as the evoked nystagmus, may be involved as a part of the velocity storage mechanism.


The influence of age on susceptibility to motion sickness in monkeys. A longitudinal study on the effects of age on the susceptibility to motion sickness in the squirrel monkey was carried out over a 10-year period (1982 to 1991). The typical life span of squirrel monkeys is 15 years. Ten mature male squirrel monkeys of the Bolivian subspecies were found to be susceptible to motion sickness induced by a combination of vertical oscillation at 0.5 Hz and rotation in the horizontal plane at 25 rotations per minute (RPM) in a visually unrestricted environment. Signs of motion sickness were quantified according to a rating scale based on Graybiel's diagnostic criteria. Latency to vomiting/retching and severity of sickness obtained from year 1 (baseline), 3, 5, 7 and 10 were subjected to repeated-measures design analysis. There were no significant differences in the susceptibility level (as measured by latency to vomiting/retching and cumulative sickness scores) in the monkeys throughout the 10-year period. The habituation to 7 consecutive daily exposures remained the same throughout the same period. We conclude that, in the squirrel monkeys from maturity to near the end of their life span, there is no change in susceptibility to motion sickness with aging.


The dynamics of spatial orientation during complex and changing linear and angular acceleration. The dynamics of spatial orientation perception were examined in a series of experiments in which a total of 43 subjects were passively exposed to various combinations of linear and angular acceleration during centrifuge runs. Perceptual effects during deceleration were much stronger than effects during acceleration. The dynamics of spatial orientation perception differed substantially from changes in the vestibulo-ocular reflex (VOR). VOR was fairly well predicted by a current model, but our experiments revealed perceived change in attitude (roll, pitch, yaw tilt position in space) and perceived angular velocity in space that was not reflected by parallel changes in the plane or magnitude of the VOR. This series of experiments establishes several facts concerning spatial orientation perception beyond the predictive domain of any current model. New concepts are needed and several are suggested to deal with changing reactions to complex combinations of linear and angular accelerations.


The effects of dynamic visual stimulation on perception and motor control. A set of research findings is described that deals with three principal laboratory measures of visual orientation (vection and postural and manual control). Two studies are highlighted, one of which compared the latencies of vection and visually induced postural change and the other of which investigated manual tracking under visually disorienting conditions. The first study showed that although vection and postural change are somewhat related to each other (for example, both were greater in response to roll and pitch as opposed to linear visual motion), the onset of vection is delayed by several seconds relative to the initiation of visually induced postural shifts. The second study showed that manual biases induced by visual roll motion are not overcome using a thumb-and-forefinger (pyramidal) motor strategy, and may not be equivalent to the "giant hand" illusion that is believed to reflect the predominance of the vestibulospinal (extrapyramidal) motor pathways during extreme spatial disorientation. These and other findings indicate that various visual orientation effects may involve at least partially independent mechanisms.


The spatial disorientation problem in the United States Air Force. Spatial disorientation (SD) in flight wastes hundreds of millions of dollars worth of defense capability annually and continues to kill air-crew. SD results primarily from inadequacies of human visual and vestibular sensory systems in the flying environment; but other factors, such as task saturation and distraction, precipitate it. The United States Air Force is conducting a three-pronged research and development effort to solve the SD problem. We are attempting 1) to elucidate further the mechanisms of visual and vestibular orientation and disorientation, 2) to develop ground-based and inflight training methods for demonstrating to pilots the potential for SD and the means of coping with it, and 3) to conceive and evaluate new ways to display flight control and performance information so that pilots can maintain accurate spatial orientation.