The effect of stimulus type and background noise on hearing abilities of the round goby Neogobius melanostomus.

The auditory abilities of the round goby Neogobius melanostomus were quantified using auditory evoked potential recordings, using tone bursts and conspecific call stimuli. Fish were tested over a range of sizes to assess effects of growth on hearing ability. Tests were also run with and without background noise to assess the potential effects of masking in a natural setting. Neogobius melanostomus detected tone bursts from 100 to 600 Hz with no clear best frequency in the pressure domain but were most sensitive to 100 Hz tone stimuli when examined in terms of particle acceleration. Responses to a portion of the N. melanostomus call occurred at a significantly lower threshold than responses to pure tone stimulation. There was no effect of size on N. melanostomus hearing ability, perhaps due to growth of the otolith keeping pace with growth of the auditory epithelium. Neogobius melanostomus were masked by both ambient noise and white noise, but not until sound pressure levels were relatively high, having a 5-10 dB threshold shift at noise levels of 150 dB re 1 µPa and higher but not at lower noise levels.

The suprabasal expression of alpha 6 beta 4 integrin is associated with a high risk for malignant progression in mouse skin carcinogenesis.

Enhanced expression of the alpha 6 beta 4 integrin complex has been linked to malignant progression in mouse skin carcinogenesis. To determine if alpha 6 beta 4 expression can predict risk for malignant conversion among populations of benign skin tumors, we analyzed the distribution of alpha 6 beta 4 and other markers of progression in papillomas at high and low risk for malignant progression. After initiation with 7,12-dimethylbenz[a]anthracene, mice were promoted with 12-O-tetradecanoylphorbol-13-acetate to induce predominantly low risk tumors or promoted with mezerein to produce predominantly high risk tumors. When tumors first appeared at 8 weeks after promotion, high risk papillomas demonstrated basal and suprabasal alpha 6 beta 4 expression, loss of keratin 1, and aberrant expression of keratin 13. In these tumors alpha 6 beta 4 expression coincided with an expansion of the proliferating compartment as indicated by suprabasal bromodeoxyuridine labeling. In contrast, alpha 6 beta 4 immunostaining was confined to basal cells in low risk tumors, keratin 1 was abundant, and keratin 13 was absent in the majority of this group, while proliferating cells were largely in the basal compartment. By 33 weeks, alpha 6 beta 4 suprabasal expression continued to distinguish groups at higher risk for malignant conversion, but keratin 13 was expressed in all groups. At this time, high risk tumors displayed focal expression of keratin 8 and gamma-glutamyltranspeptidase, markers also found in chemically induced carcinomas. Keratin 8 and gamma-glutamyltranspeptidase were expressed only in alpha 6 beta 4 positive cells. These results indicate that expression of alpha 6 beta 4 integrin in suprabasal strata serves as an early predictive marker to identify benign squamous tumors at high risk for malignant progression.

Dietary lipid predictors of coronary heart disease in men. The Framingham Study.

The relationship between dietary lipids and the 16-year incidence of coronary heart disease (CHD) morbidity and mortality was examined in two male cohorts, aged 45 to 55 years (n = 420) and 56 to 65 years (n = 393) from the Framingham Study. Dietary lipids were assessed through a single 24-hour recall at the initiation of follow-up in 1966 to 1969. In the younger cohort, there were significant positive associations between the incidence of CHD and the proportion of dietary energy intake from total fat and monounsaturated fatty acids. The proportion of energy intake from saturated fatty acids had a marginally significant positive association with CHD. The associations remained even after adjustment for cardiovascular disease risk factors, including serum cholesterol level, suggesting that their effects are at least partially independent of other established risk factors. In contrast to the younger cohort, none of the dietary lipids were associated with CHD in the older cohort. Dietary intervention for the prevention of CHD in younger men is supported by these findings.

Profile for estimating risk of heart failure.

CONTEXT: We devised a risk appraisal function to assess the hazard of heart failure in persons who are predisposed by coronary disease, hypertension, or valvular heart disease. OBJECTIVE: To provide general practitioners and internists with a cost-effective method to select people at high risk who are likely to have impaired left ventricular systolic function and may therefore require further evaluation and aggressive preventive measures. METHODS: The routinely measured risk factors used in constructing the heart failure profile include age, electrocardiographic left ventricular hypertrophy, cardiomegaly on chest x-ray film, heart rate, systolic blood pressure, vital capacity, diabetes mellitus, evidence of myocardial infarction, and valvular disease or hypertension. Based on 486 heart failure cases during 38 years of follow-up, 4-year probabilities of failure were computed using the pooled logistic regression model for each sex; a simple point score system was employed. A multivariate profile was also produced without the vital capacity or chest x-ray film because these may not be readily available in some clinical settings. RESULTS: Using the risk factors that make up the multivariate risk formulation-derived from ordinary office procedures-the probability of developing heart failure can be estimated and compared with the average risk for persons of the same age and sex. Using this risk profile, 60% of events in men and 73% in women occurred in subjects in the top quintile of multivariate risk. CONCLUSIONS: Using this multivariate risk formulation, it is possible to identify high-risk candidates for heart failure who are likely to have a substantial yield of positive findings when tested for objective evidence of presymptomatic left ventricular dysfunction. The risk profile may also identify candidates who are at high risk for heart failure because of multiple, marginal risk factor abnormalities that might otherwise be overlooked.

Fas ligand/Fas-mediated apoptosis in human coronary artery smooth muscle cells: therapeutic implications of fratricidal mode of action.

OBJECTIVE: This study aimed to determine the mode of action of Fas ligand (FasL)/Fas at mediating apoptosis so as to evaluate the potential of FasL in gene therapy for restenosis. METHODS: Passaged human coronary artery smooth muscle (HCASM) cells were infected with recombinant adenoviral vectors expressing murine FasL. Various parameters of FasL expression and apoptosis were measured using FACS, immunofluorescence, calorimetric, and cytotoxicity assays. RESULTS: Most HCASM cells under normal growth conditions expressed Fas and were shown to be susceptible to membrane bound but not soluble FasL. However, some FasL expressing cells survived for up to 7 days. These surviving cells were observed to be spatially distributed and were not in direct physical contact with each other. Upon examination, it was determined that although the majority of the surviving cells expressed FasL, only 30% expressed both Fas and FasL. These cells were capable of inducing apoptosis of target cells and some were also susceptible to FasL expressing cells, provided that the effector and target cells were in close physical contact. FasL/Fas-mediated apoptosis was inhibited by p35, a baculovirus gene that inhibits caspases. Additionally, in contrast to HCASM cells, neither membrane-bound nor soluble FasL induced apoptosis in coronary artery endothelial cells. CONCLUSIONS: FasL expressing HCASM cells do not undergo FasL/Fas mediated "suicide" but kill neighboring cells bearing Fas in a "fratricidal" manner. A small population of HCASM cells expresses no surface Fas. These results imply that HCASM cells transduced in vivo with FasL may serve as "scavengers" and exert a bystander effect on surrounding cells that may be enhanced by co-expression of p35. As FasL-mediated apoptosis occurs in coronary arterial smooth muscle but not endothelial cells, FasL may also offer an advantage over other genes for use in restenosis since the latter may indiscriminately delay re-endothelialization at the sites of gene.

Enhancement of Fas ligand-induced inhibition of neointimal formation in rabbit femoral and iliac arteries by coexpression of p35.

Adenovirus-mediated gene transfer of Fas ligand (FasL) inhibits neointimal formation in balloon-injured rat carotid arteries. Vascular smooth muscle (VSM) cells coexpressing murine FasL and p35, a baculovirus gene that inhibits caspase activity, are not susceptible to FasL-mediated apoptosis in vitro but are capable of inducing apoptosis of VSM cells that do not express p35. We reasoned that coexpression of p35 in FasL-transduced VSM cells in vivo would promote their survival, enhance FasL-induced apoptosis of adjacent VSM cells, and thereby facilitate a greater inhibition of neointimal formation. In balloon-injured rabbit femoral arteries, either Ad2/FasL/p35 or Ad2/FasL was infused into the injured site and withdrawn 20 min later. Both vectors induced a dose-dependent reduction (p < 0.05) of the neointima-to-media ratio when assessed 14 days later. However, Ad2/FasL/p35 exhibited a significantly greater inhibition of neointimal formation than Ad2/FasL. In a more clinically relevant model of restenosis, rabbit iliac arteries were injured with an angioplasty catheter under fluoroscopic guidance. Adenoviral vectors were delivered locally to the injured site over a period of 2 min, using a porous infusion balloon catheter. Twenty-eight days after gene transfer angiographic and histologic assessments indicated a significant (p < 0.05) inhibition of iliac artery lumen stenosis and neointimal formation by Ad2/FasL/p35 (5 x 10(11) particles per artery). The extent of inhibition was comparable to that achieved with Ad2/TK, an adenoviral vector encoding thymidine kinase (5 x 10(11) particles per artery) and coadministration of ganciclovir for 7 days. These data suggest that coexpression of p35 in FasL-transduced VSM cells is more potent at inhibiting neointimal formation and as such represents an improved gene therapy approach for restenosis.

Dietary models for root caries.

A stepwise multiple logistic regression was computed to assess which of the nutritional variables differentiate the healthy and diseased group of participants in the Forsyth Specialized Caries Center (n = 275). Variables considered as candidates for the model included the consumption per week of sugars, starch, cheese, fruits and fruit juices, noncariogenic foods, and dairy products. Two variables--sugars and cheese--were statistically significant by the stepwise procedure. Increased intake of sugar was associated with being in the root caries group, whereas high intake of cheese was negatively associated with root caries. Thus, cheese seems to have a protective effect after sugar intake is controlled for. Odds ratios were computed to quantify the influence of the variables. An increase of two exposures of sugar per day corresponded with an odds ratio of 1.26. The odds ratio continues to increase with sugar intake so that an increase to five exposures per day gives an odds ratio of 1.79. This model is consistent with past in vitro studies suggesting that cheese protects against caries formation when sugar intake is controlled for and that increasing frequency of sugar intake increases the odds of root caries.

The 'preclinical phase' of probable Alzheimer's disease. A 13-year prospective study of the Framingham cohort.

OBJECTIVE: To evaluate the interval between the onset of detectable cognitive impairment and clinical diagnosis in individuals with probable Alzheimer's disease (AD), and to identify the pattern of the earliest changes in cognition in probable AD. DESIGN: Longitudinal follow-up of a community-based cohort sample. In 1976 through 1978, a screening neuropsychological examination was administered to Framingham Study participants. These subjects were then followed up prospectively for development of probable AD for up to 13 years. SETTING: This study was conducted at a community-based center for epidemiologic research. PARTICIPANTS: The surveillance sample consisted of 1045 participants in the Framingham Study aged 65 to 88 years who were free of dementia at the time of the neuropsychological screening examination. MAIN OUTCOME MEASURES: Scores on a group of neuropsychological tests were entered into a series of age- and education-adjusted multiple regression procedures, with the presence or absence of probable AD as the outcome variable. RESULTS: Considered individually, most of the screening neuropsychological measures were significantly related to later AD diagnosis. When stepwise regression procedures were employed, only measures of verbal memory and immediate auditory attention span remained significantly related to AD diagnosis. Of note, subjects later diagnosed with probable AD performed at higher levels than normal subjects on the Digit Span test at initial screening. Regression results were essentially unchanged even when the AD sample was restricted to those individuals for whom the screening examination preceded the clinical onset of dementia by 7 years or more. CONCLUSIONS: These findings support previous contentions that a "preclinical phase" of detectable cognitive deficits can precede the clinical diagnosis of probable AD by many years, and they also support the hypothesis that problems with secondary verbal memory are among the first signs of AD.

Incidence of dementia and probable Alzheimer's disease in a general population: the Framingham Study.

OBJECTIVE: To determine the incidence of dementia and Alzheimer's disease (AD) in a general population sample. BACKGROUND: Utilizing subjects in the Framingham Study cohort determined to be free of dementia in 1976 to 1978, or on biennial examination 17 in 1982, all new cases of dementia arising in this cohort over a maximum of 10 years of follow-up were ascertained. METHODS: On biennial examination 14/15, a screening neuropsychologic examination was administered to 2,117 subjects, and cases of probable prevalent dementia were identified. Beginning on examination 17 and on all successive biennial examinations, a Mini-Mental State Examination was administered. Subjects previously free of dementia and falling below age-education levels were evaluated by a neurologist and neuropsychologist to determine if dementia was present and to ascertain the dementia type using standard criteria. RESULTS: Five-year incidence of dementia increased with age, doubling in successive 5-year age groups. Dementia incidence rose from 7.0 per 1,000 at ages 65 to 69 to 118.0 per 1,000 at ages 85 to 89 for men and women combined. Incidence of probable AD also doubled with successive quinquennia from 3.5 at ages 65 to 69 to 72.8 per 1,000 at ages 85 to 89 years. Incidence of dementia and of probable AD did not level off with age and was not different in men and women. CONCLUSIONS: In a general population sample, we determined incidence of dementia and of probable AD and will use these incident cases for study of precursors and natural history in this elderly cohort, which has been under close surveillance for over 40 years.

Precursors of extracranial carotid atherosclerosis in the Framingham Study.

To investigate cardiovascular risk factors and carotid atherosclerosis, we related previously measured risk factors to carotid atherosclerosis as determined by duplex ultrasonography in the Framingham Study cohort. Risk factors measured prospectively on 1,116 cohort members, ages 66 to 93, were related to the severity of carotid atherosclerosis measured by carotid ultrasonography performed during biennial examination no. 20 (1988 to 1990). The degree of carotid atherosclerosis was expressed as a percent carotid stenosis and, for statistical analysis, subjects were divided into four groups according to percent carotid stenosis. The prevalence of significant carotid stenosis in the general population was low--7% in women and 9% in men. A multivariate logistic regression model showed that age, cigarette smoking, systolic blood pressure, and cholesterol were independently related to carotid atherosclerosis. Alcohol consumption was also significant in men, but not in women. In addition, our results indicate that both current and former smoking in both sexes was related to the degree of carotid atherosclerosis.

Long-term influence of fibrinogen on initial and recurrent cardiovascular events in men and women.

Examination of the long-term relation of a single fibrinogen determination to initial and recurrent atherosclerotic cardiovascular events over 20 years of follow-up revealed a powerful and comparably independent impact on initial events in both sexes but an influence on recurrent events only in men.

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 health risks of smoking. The Framingham Study: 34 years of follow-up.

This study summarizes the effects of both the rate and the cumulative dose of cigarette smoking on the health of the original Framingham cohort, 5209 individuals aged 30 to 62 years at entry. After 34 years of follow-up, it was observed that cigarette smoking was the prime determinant of chronic cough, and reduced both forced vital capacity and the 1-second forced expiratory volume. A significant relationship was observed between cigarette smoking and the incidence of cancer of the lung, stroke and transient ischemic attacks, intermittent claudication, and total cardiovascular disease, and most especially the average annual death rate. Cigarette smoking was significantly related to coronary heart disease in men 45 to 64 years old, although not related in women or older men. The data confirm and extend the evidence of the detrimental influence of cigarette smoking on health.

Dietary predictors of serum cholesterol in men: the Framingham cohort population.

This study examines the cross-sectional relationships between diet and serum cholesterol in a sample of 413 Framingham cohort males, ages 37-70. Regression analyses controlling for age, calories, and coronary heart disease risk factors showed that the direct predictors of serum cholesterol included: fat (g) (p less than 0.05), cholesterol (mg/1000 calories) (p less than 0.05), protein (g and calorie density) (p less than 0.05 and p less than 0.001, respectively), Metropolitan relative weight (p less than 0.05), and systolic blood pressure (p less than 0.001). Fat (calorie density) and cholesterol (mg) were marginally significant direct positive predictors (0.05 less than or equal to p less than or equal to 0.10). Inverse correlates of serum cholesterol were total carbohydrate (g and calorie density) and simple carbohydrate (calorie density) (p less than 0.001). A marginally inverse correlate of serum cholesterol was complex carbohydrate (calorie density) (0.05 less than or equal to p less than or equal to 0.10). These cross-sectional results show that dietary variables predict serum cholesterol levels in men independent of other coronary heart disease risk factors.

Trends in CHD and risk factors at age 55-64 in the Framingham Study.

In a preliminary analysis to assess secular changes in cardiac morbidity, mortality, and risk factors in the Framingham Heart Study, there is a suggestion of decline in coronary heart disease (CHD) mortality in women but not in men. For subjects age 55 to 64 in 1953, 1963 and 1973, the ten-year CHD mortality rates per 1000 were 93, 84 and 99 for men; and 34, 39, and 24 for women, respectively. In contrast, CHD prevalence rates have increased significantly for men (102, 134 and 159 per 1000) and marginally for women (55, 65 and 69 per 1000). Incidence of CHD increased slightly in men (187, 210 and 208 per 1000 over the three decades) and decreased in women (131, 132, 110). Some coronary risk factors improved, while others changed unfavourably.

Adjusting capitation using chronic disease risk factors: a preliminary study.

Researchers have sought ways to modify Medicare's capitation formula, the adjusted average per capita cost (AAPCC), by including measures of individual health status. The present study assesses the value of risk factors for disease as predictors of hospitalization for Framingham Heart Study participants (1,210 males and 1,496 females) 60-65 years of age. Regression models including several common physiologic measures and prior hospitalizations yielded adjusted R2s of 9.69 percent for males and 3.61 percent for females. The contributions of the risk factors and prior hospitalization were about equal and independent. These results confirm the potential utility of disease risk factors for adjusting the AAPCC.

Differential effects of experience on house officers' admission diagnoses for patients with possible myocardial infarction.

The effect of the level of training on house staff's abilities to accurately diagnose acute ischemic heart disease (AIHD) and admit patients presenting in an emergency room was assessed. A validated mathematical instrument, which calculates patients' probabilities of AIHD, was used to retrospectively stratify admitted patients. Sensitivity rates of house staff were similar for patients with high probabilities (greater than or equal to 40%) of AIHD (ns). When probabilities of AIHD were low (less than 40%), junior residents correctly admitted a significantly higher proportion of patients with confirmed AIHD than did interns (86% versus 63%, respectively; p less than 0.06). Specificity was unaffected by the level of house staff training for patients with probabilities of AIHD less than 40% (ns). In the high probability group of patients, the interns' specificity rate (54%) was significantly better than the 20% for junior residents (p less than 0.03); however, when clinical severity was controlled for, no differences by level of training were found.

Management of risk factors.

The development of atherosclerotic disease and stroke has been related to a number of host and environmental factors delineated in recent years. The relative impact of each of these risk factors is becoming clearer, and controlled clinical trials have demonstrated the efficacy of risk factor modification in stroke prevention. This article reviews the incidence of stroke, various risk factors including hypertension, diabetes, obesity, and race, and stroke prevention through risk factor management.

Concept of bridging the gap from youth to adulthood.

Clinical atherosclerotic cardiovascular disease reaches substantial incidence beginning at age 45 years in men and age 55 years in women but has its onset in childhood. Lesions progress in relation to exposure to identified risk factors and, once initiated, tend to be self-perpetuating. Because predisposing factors are often initiated in childhood, interventions beginning early in life are optimal for prevention of adult disease. Even genetically predisposed people usually require an unfavorable lifestyle for the atherogenic trait to be expressed. No combination of risk factors entirely accounts for the increase in clinical atherosclerotic events with advancing age. This may be a reflection of longer exposure to risk factors or impaired ability to cope with them in advanced age. The declining risk factor risk ratios with advancing age may be a consequence of the selective early removal of those most susceptible from the population at risk. Risk of major cardiovascular events increases about 2.5-fold with each 10 years of age, even in people without major risk factors who are considered at low risk for atherosclerotic cardiovascular events. However, at any age vulnerability to cardiovascular events is strongly influenced by the burden of risk factors. Decreased risk ratios with advanced age are offset by a greater absolute risk. The female advantage over men erodes with age, with the menopause and with acquisition of an unfavorable lipid profile and glucose intolerance.

Implementation of a practical digital imaging system for routine gross photography in an autopsy environment.

BACKGROUND: The autopsy environment places stringent requirements on a digital imaging system. These requirements must be addressed if the system is to be functional, easy to use, and reliable. DESIGN: After clearly defining the requirements for such a system, we implemented routine digital imaging in a busy academic autopsy suite. RESULTS: The new technology was immediately accepted by both the resident staff and the technical staff. Although a 35-mm camera was always available for traditional photography, it was rarely used. An interesting side effect of implementing digital imaging was a nearly twofold increase in the number of images taken per autopsy case. The requirements, features, and utility of a digital imaging system are discussed. CONCLUSION: Digital imaging in an autopsy environment can be both practical and cost-effective. It provides many advantages over traditional 35-mm photography and can be the first step toward numerous additional improved services.