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Biomedical subjects

D A Dawson

Publications and source records attributed to D A Dawson.

At least 19 recordsLinked to original sources
PubMed2001

A comparative assessment of the efficacy and side-effect liability of neuroprotective compounds in experimental stroke.

There are many examples of compounds showing neuroprotective efficacy in animal models of stroke but not in clinical trials. It is possible that some or all of these compounds possess poor therapeutic ratios, which results in the administration of sub-efficacious doses in order to avoid the emergence of side-effects. In order to explore this possibility, this study compared the therapeutic ratios of a number of neuroprotective agents that have undergone clinical trials. Neuroprotective efficacy was established using the mouse permanent (24 h) middle cerebral artery occlusion model. Side-effect liability was determined by assessment of motor coordination using the rotarod test. The therapeutic ratio was calculated as the ratio between the minimum effective dose (MED) for significant impairment in rotarod performance and the MED for significant neuroprotection. Compounds were administered i.p. 30 min prior to rotarod testing or onset of ischemia. Drugs such as Ifenprodil, Cerestat and Selfotel, that have failed in clinical trials, were found to have very low therapeutic ratios of < or = 1, whereas compounds with more tolerable clinical side-effect profiles were found to have higher therapeutic ratios (2, 10 and 10 for Sipatrigine, Remacemide and sPBN, respectively). It is concluded that the lack of efficacy of a number of neuroprotectants in clinical trials may well be a consequence of their poor therapeutic ratios.

Animals↗
PubMed2001

Alcohol and mortality from external causes.

OBJECTIVE: The aim of this study was to examine the relationship between alcohol consumption, considering both volume of intake and drinking pattern, and the risk of death from external causes. METHOD: A prospective study of mortality from external causes was conducted using data from the 1988 National Health Interview Survey linked with the National Death Index for 1988 through 1995. During the 7.5-year follow-up interval, there were 155 deaths from external causes among the 42,910 adults 18 years of age and over included in the sample. Proportional hazards models were used to adjust for censoring due to competing causes of death and for the effects of potentially confounding background variables including age, gender, marital status, education, smoking and poor health at baseline. RESULTS: Relative to lifetime abstainers and infrequent drinkers, the risk of death from external causes increased directly with volume of intake, exhibiting a logarithmic-shaped risk curve. There was no evidence of reduced risk among light or moderate drinkers. When usual quantity and frequency were examined, the only drinkers at significantly increased risk were those who drank less than once a month but usually drank 5+ drinks (or, to a lesser extent, 3+ drinks) and those who drank at least twice a week and usually drank 2+ drinks. Former drinkers also were at increased risk. Age strongly affected the drinking pattern parameters. CONCLUSIONS: Quantity and frequency of drinking are proxies for in-the-event risks associated with alcohol intake and their cumulative effect on mortality risk. The results are discussed with particular attention to the role of factors that may affect the association between usual quantity of drinks consumed and the in-the-event risk of mortality from external causes.

Adolescent↗
PubMed2001

Screening for high- and moderate-risk drinking during pregnancy: a comparison of several TWEAK-based screeners.

PURPOSE: This study investigated the use of the TWEAK and nine alternative screeners for predicting high-risk and moderate-risk drinking during pregnancy. METHOD: The analysis was based on self-reports from 404 lifetime drinkers who presented for an initial visit at nine prenatal clinics in Washington, DC. Data were collected anonymously by having women directly enter their responses onto an audio, computer-assisted interview that was programmed onto a laptop computer. Pregnancy risk drinking status was based on both average daily volume of intake and frequency of drinking 3+ drinks in a day. Each of the alternative screeners was constructed by adding one additional risk indicator to the TWEAK, and three different scoring options were explored. RESULTS: Using thresholds of 2 points for high-risk drinking and 1 point for moderate-risk drinking, the TWEAK demonstrated a sensitivity and specificity of 70.6% and 73.2% for high-risk drinking and a sensitivity and specificity of 65.6% and 63.7% for any (high- or moderate-) risk drinking during pregnancy. None of the alternative screeners resulted in significant improvement, but the addition of current smoking status showed enough promise to warrant further testing in larger samples. CONCLUSIONS: Despite some loss in sensitivity and specificity, the TWEAK, in its original or a modified form, can be extended to measures of high-risk drinking that incorporate infrequent heavy intake and can be used to test for moderate- as well as high-risk drinking. Because identification of moderate-risk drinkers substantially increases the pool of women targeted for intervention, cost implications must be considered in designing appropriate interventions.

Adult↗
PubMed2000

Comparative evaluation of the combined osteolathyritic effects of two nitrile combinations on xenopus embryos.

Two nitrile combinations, beta-aminopropionitrile (beta APN) with aminoacetonitrile (AAN) and betaAPN with beta APN (as a sham combination), were evaluated using the frog embryo mixture toxicity assay to determine their combined osteolathyritic effects and to compare the results with theoretical effects for two combined effects models. In separate tests each nitrile was tested with copper sulfate to determine the importance of copper in osteolathyrogen-induced disruption of connective tissue cross-linking. Frog embryos (Xenopus laevis) were exposed for 96 h, with daily solution removal and replacement. Preserved tadpoles were evaluated for osteolathyritic lesions. For the nitrile:nitrile combinations, the chi(2) goodness-of-fit test was used to compare the resulting mixture-response curves to theoretical curves for dose-addition and independence. For beta APN with AAN, the combined osteolathyritic effect for five of the seven mixture curves generated was greater than expected for each of the combined effects models. For beta APN with beta APN, the combined effect for all seven mixture curves was consistent with dose-addition, the combined effect expected for chemicals inducing toxicity by the same mechanism. For the nitrile:copper combinations, the EC(50) for beta APN-induced osteolathyrism was increased two- to threefold (i.e. made less toxic) by co-administration with copper sulfate, while the EC(50) for AAN-induced osteolathyrism was unchanged. The results are consistent with the idea that beta APN and AAN induce osteolathyrism, at least in part, by different mechanisms.

Aminoacetonitrile↗
PubMed2000

Drinking as a risk factor for sustained smoking.

Data from a nationally representative sample of US adults (n=42862) were used to explore the associations between drinking and smoking, on a lifetime and past-year basis, and between drinking and smoking cessation for a subsample of past-year smokers (n=12586). Smoking cessation was defined as current nonsmoking (as of the time of interview) that had lasted at least 3 months. The proportions of both lifetime and past-year smokers increased with volume of alcohol intake and frequency of heavy drinking and were greater for individuals with DSM-IV alcohol abuse or dependence than for individuals without these disorders. For example, the proportion of past-year smokers rose from 22.5% of lifetime abstainers to 53.0% of heavy drinkers, from 23.8% of those who never drank 5+ drinks on any drinking day to 61.8% of those who drank 5+ drinks weekly or more often and from 27.6% of individuals without past-year DSM-IV alcohol abuse or dependence to 55.5% of those with either of these disorders. The proportion of past-year smokers who had stopped smoking decreased from 7.8% of former drinkers to 4.6% of heavy drinkers, from 7.3% of those who never drank 5+ drinks to 3.4% of those who did so weekly or more often and from 6.7% among individuals without past-year abuse or dependence compared to 4.4% among those with either disorder. In a multivariate analysis that adjusted for background variables and smoking history, average daily ethanol intake was not significantly associated with the odds of smoking cessation, but drinking 5+ drinks at least once a month reduced the odds of cessation by 42%. Having an alcohol use disorder increased the odds of smoking cessation below the age of 30 (an effect that disappeared after adjusting for the interaction between age group and having children in the home), but had an increasingly negative effect on smoking cessation at older ages.

Adult↗
PubMed2000

Towards agreement on ways to measure and report drinking patterns and alcohol-related problems in adult general population surveys: the Skarpö conference overview.

A thematic conference of the Kettil Bruun Society (KBS) for Social and Epidemiological Research on Alcohol was held in Skarpö, near Stockholm, on April 3-7, 2000. The goals of the meeting were to develop consensus sets of questionnaire items for measuring alcohol consumption and social harm, to delineate statistical and practical concerns related to the aggregation of consumption and harm data and to identify summary measures to be used for descriptive purposes and in analyses of the association between alcohol intake and alcohol-related outcomes. The results of the conference discussions are summarized below, with emphasis on both areas where the conference yielded recommendations for measures and methods of aggregation for analysis, and on areas where consensus could not be obtained and/or where additional research is needed.

Alcohol Drinking↗
PubMed2000

Alternative measures and models of hazardous consumption.

Hazardous alcohol consumption has been conceptualized (1) as all alcohol consumed on days when some threshold, usually approximately 60 g, is exceeded, and (2) as only that portion of intake that exceeds this threshold. The first measure is hypothesized to be a better predictor of acute alcohol-related outcomes, because of its greater capacity to discriminate between individuals who frequently exceed the hazardous threshold by a small amount and those who infrequently exceed the threshold by a large amount. To test this hypothesis, the two approaches were used to construct alternative estimates of a number of measures of hazardous consumption. Individually and in combination, these measures were compared in a series of multiplicative models predicting four alcohol-related outcomes: impaired driving, fighting, interpersonal problems and injuries. There was no consistent evidence for one approach being superior to the other as a predictor of these outcomes. In fact, the use of appropriate linear transformations of the consumption variables had a far greater effect on improving the proportion of variance explained. The most highly predictive models were those based on frequency of hazardous consumption, mean volume of hazardous intake consumed per hazardous drinking day, volume of nonhazardous intake and their interactions. Differences among models were small, and models using combinations of simple, easy-to-obtain measures performed nearly on a par with those utilizing far more complex measures.

Adolescent↗
PubMed2000

Analysis of the combined osteolathyritic effects of beta-aminopropionitrile and diethyldithiocarbamate on xenopus development.

In order to examine the mechanistic basis between combined effects and mechanisms of action, two osteolathyrogens, beta-aminopropionitrile (betaAPN) and diethyldithiocarbamate (DTC), were tested together on Xenopus embryos. In a separate test, DTC was also tested with copper sulfate to determine the importance of copper in DTC-induced osteolathyrism. Frog embryos (Xenopus laevis) were exposed for 96 h, with daily solution removal and replacement. Preserved tadpoles were evaluated for osteolathyritic lesions. For the betaAPN:DTC test, a 1.2-factor matrix design was used, producing two single chemical and seven mixture-response curves. The chi(2) goodness-of-fit test was used to compare the experimental mixture-response curves with theoretical effects for two combined effects models, dose-addition and independence. All seven mixture curves were consistent with expected results for dose-addition, but the correlations were generally not high. For the DTC:copper test, the three mixture-response curves generated showed that added copper increased the DTC-alone EC(50), but there was no corresponding right shift at the top of the response curves, as observed previously with betaAPN and copper. In the betaAPN:DTC and DTC:copper tests, DTC alone showed a biphasic concentration-osteolathyrism curve, and the slope of the response curve for DTC alone in each test was statistically different than the slope for the betaAPN alone response curve. Taken together, the results suggest the potential for a second osteolathyritic effect of DTC that affected the combined toxicity enough to produce a dose-addition correlation without the chemicals necessarily having the same mechanism.

Aminopropionitrile↗
PubMed2000

Drinking patterns among individuals with and without DSM-IV alcohol use disorders.

OBJECTIVE: The purpose of this study was to compare alcohol consumption patterns among individuals with and without alcohol use disorders, using a representative sample of the general population that would not exaggerate differences as a result of selection biases associated with treatment for alcohol problems. METHOD: Based on data from 18,352 past-year drinkers selected from a nationally representative sample of U.S. households, 11 measures of past-year alcohol consumption were compared for three diagnostic groups: (1) individuals who did not meet the criteria for either alcohol abuse or dependence, i.e., those without a DSM-IV alcohol use disorder (AUD); (2) those classified with abuse only; and (3) those classified with alcohol dependence, with or without abuse. RESULTS: For all measures reflecting frequency and quantity of drinking, frequency of heavy drinking and intoxication, and frequency of atypical temporal drinking patterns, the values for abusers lay midway between those for individuals without an AUD and those with dependence. Individuals with alcohol use disorders drank a greater proportion of their ethanol intake in the form of beer and a lower proportion in the form of wine than did those without an AUD. Of all the consumption measures considered, frequency of intoxication showed the strongest association with the probability of having an AUD, followed by frequency of drinking 5 + drinks, prevalence of morning drinking and total volume of intake. The ratios of consumption measures for individuals with disorders relative to those without an AUD showed relatively little significant variation across demographic subgroups of the population. CONCLUSIONS: The findings supported the distinction between the disorders of alcohol abuse and dependence, and implicated loss of control as an important element of this distinction. They also indicated that even among individuals with alcohol use disorders, demographic differentials reflecting cultural, physiological and normative forces were maintained and should be considered in approaches to treatment.

Adolescent↗
PubMed2000

The link between family history and early onset alcoholism: earlier initiation of drinking or more rapid development of dependence?

OBJECTIVE: This study examines the association between early onset alcoholism and family history to determine whether family history of alcoholism is predictive of earlier initiation of drinking, more rapid onset of dependence once drinking has begun, or both. METHOD: Using cross-sectional, retrospective data from a large, nationally representative sample of U.S. adults, discrete time proportional hazards models were used to assess the effects of family history saturation (% of alcoholic first- and second-degree relatives) on: ( 1) the risk of initiating drinking among all adults (N = 42,862; 58.4% female) and (2) the risk of progressing from initiation of drinking to onset of dependence among lifetime drinkers (n = 27,616; 50.7% male). Models were estimated for different time periods, to see if the effect of family history saturation varied over time in a manner suggestive of a stronger association with early onset dependence. RESULTS: The positive effect of family history saturation on the risk of initiating drinking was strongest prior to age 15 and declined steadily with increasing age. It was slightly weaker for men than women. After controlling for early initiation of drinking, the direct positive effect of family history saturation on the risk of progressing to dependence increased over time and was slightly reduced among individuals who started drinking before age 18. The indirect effect of family history on the risk of developing dependence, via its effect on early drinking as a risk factor for dependence, was strongest in the interval from 3 to 9 years after initiation of drinking. CONCLUSIONS: The association between family history and early onset alcoholism appears to be driven most clearly by family history predicting earlier initiation of drinking. The weak effect of family history on the development of dependence within the first 3 years after initiation of drinking may reflect the preponderance of developmentally limited dependence during this time period. The data are consistent with the links established between novelty seeking, impulsivity and early onset alcoholism. While supporting the possibility of genetic effects via dopaminergic and serotonergic function, these findings also suggest that environmental factors may play an important part in helping to explain the association between family history and early onset alcoholism.

Adolescent↗
PubMed2000

Alcohol consumption, alcohol dependence, and all-cause mortality.

BACKGROUND: This study examined the effects of alcohol consumption and DSM-IV alcohol dependence on the risk of mortality. METHODS: Data from the 1988 National Health Interview Survey Alcohol Supplement were matched to the National Death Index for the years 1988 to 1995 (baseline n = 37,682 U.S. adults age > or =25 linked to 3,586 deaths). All mortality analyses were based on proportional hazards models that adjusted for age, sex, race/ethnicity, marital status, education, income, labor force status, body mass index, smoking status, and poor health indicators at baseline. RESULTS: When dependence was not considered and all past-year abstainers were used as the reference group, both light and moderate drinkers exhibited a reduced risk of mortality, with hazards ratios of 0.76 (0.68-0.84) and 0.84 (0.74-0.96). Heavy drinkers had about the same risk of dying as did past-year abstainers, and very heavy drinkers had an increased risk that was not significant (OR = 1.17, CI = 0.93-1.47). When lifetime abstainers were used as the reference category, the protective effect of moderate drinking fell short of significance, and there were nearly significant increased risks among former drinkers and very heavy drinkers. When dependence was considered, light and moderate drinkers without dependence had a reduced mortality risk regardless of reference group, and there was no significant effect among heavy or very heavy drinkers without dependence. Among dependent drinkers, there was no protective effect of light or moderate drinking, and very heavy drinkers had a significantly increased risk (OR = 1.56 relative to past-year abstainers and 1.65 relative to lifetime abstainers). CONCLUSIONS: Because alcohol dependence nullifies the protective effect of light and moderate drinking, it is important to understand its role as an independent risk factor for mortality. Differences between dependent and nondependent drinkers who drank comparable amounts suggest that this risk may result from longer and heavier drinking histories before baseline, more severe health problems at baseline, more heavy episodic drinking, and, possibly, differences in beverage preference.

Adult↗
PubMed2000

US low-risk drinking guidelines: an examination of four alternatives.

BACKGROUND: This study compared four sets of US low-risk drinking guidelines (two interpretations of the US Dietary Guidelines and two variations of the NIAAA physicians' guidelines) in terms of adherence and how well they predicted five different alcohol-related outcomes. METHODS: Using data from a nationally representative sample of 17,542 US adults 21 years of age and over who drank 12 or more drinks in the past year, this study assessed the sensitivity, specificity, overall accuracy, positive and negative predictive values, and odds ratios of the various drinking guidelines (specifically, of having exceeded them with different degrees of frequency) as predictors of alcohol dependence, impaired driving, liver disease, peptic ulcer, and hypertension. RESULTS: The proportions of past-year regular drinkers exceeding the four sets of guidelines varied from 20.9%, whose average intake exceeded the weekly limits, to between 21.0% and 42.7% who exceeded the daily guidelines at least once a week, and to between 69.2% and 94.2% who ever exceeded the daily limits in the year preceding the interview. Sensitivity and odds ratios were highest for the ever exceeding the Dietary Guidelines daily limits, intermediate for ever exceeding the two variations based on the NIAAA physicians' guidelines, and lowest for exceeding the Dietary Guidelines interpreted as weekly limits. The opposite pattern was observed for specificity and overall predictive accuracy. When frequently exceeding the daily limits was considered, their sensitivity declined but their specificity and positive predictive value increased. CONCLUSIONS: If sensitivity and specificity are deemed equally important, the NIAAA physicians' guidelines incorporating both daily and weekly limits seem to do the best job of balancing these dimensions in the prediction of a variety of alcohol-related outcomes.

Adolescent↗
PubMed1999

Alternative definitions of high risk for impaired driving: the overlap of high volume, frequent heavy drinking and alcohol dependence.

This paper examines the distributions of past-year volume of ethanol intake, frequency of drinking 5+ drinks and alcohol dependence in a representative sample of 18,352 U.S. current drinkers aged 18 years or over. Within categories defined by these three partially overlapping domains, it presents rates of self-perceived impaired driving, i.e. driving after having had too much to drink, in the year preceding interview. High volume drinkers, those with an average daily ethanol intake of 1 ounce or more, composed 19.7% of current drinkers and accounted for 66.5% of all reported ethanol consumption, 72.6% of all heavy drinking days, 49.2% of all alcohol dependence and 62.8% of all impaired driving incidents. Frequent heavy drinkers, those who drank 5+ drinks at least once a week, composed 12.3% of current drinkers and accounted for 42.9% of all reported ethanol consumption, 81.9% of all heavy drinking days, 40% of all alcohol dependence and 57% of all impaired driving incidents. Drinkers with DSM-IV alcohol dependence composed 9.9% of current drinkers and accounted for 28.9% of all reported ethanol consumption, 37% of all heavy drinking days and 56.9% of all impaired driving incidents. The overlap of these three high risk groups, each of which had a probability of at least one impaired driving incident per year, was far from complete. Of individuals who met any of these criteria for high risk drinking (i.e. high volume, frequent heavy drinking or dependence), more than half met only one criterion and only one in seven met all three. The group that did meet all three criteria had such a high rate of impaired driving incidents, an average of 5.14/year, that it accounted for 36.4% of all such incidents despite making up only 3.8% of all current drinkers. The results are discussed in terms of their implications for targeting prevention and intervention efforts, e.g. whether targeting one problematic aspect of drinking behavior will reach drinkers with other types of problem behaviors as well.

Accidents, Traffic↗
PubMed1999

Evaluation of serologic and viral detection methods for diagnosing feline herpesvirus-1 infection in cats with acute respiratory tract or chronic ocular disease.

OBJECTIVE: To determine the value of virus isolation (VI), immunofluorescent antibody (IFA) assay, serum neutralization (SN), and ELISA for the diagnosis of clinical feline herpesvirus-1 (FHV-1) infection in cats. ANIMALS: 46 clinically normal cats, 17 cats with signs of acute respiratory tract disease, and 38 cats with signs of chronic ocular disease. PROCEDURE: Conjunctival swabs for VI, conjunctival scrapings for IFA testing, and venous blood samples for SN or ELISA testing were obtained from all cats. RESULTS: FHV-1 was detected in 10.9 and 28.3% of clinically normal cats and in 18.2 and 33.3% of cats with FHV-1-associated disease by VI and the IFA assay, respectively. There were no significant differences in the viral detection rate between cats with acute respiratory tract disease and cats with chronic ocular disease or between diseased cats and clinically normal cats; however, FHV-1 was never detected by both methods in clinically normal cats. Overall FHV-1 seroprevalence was 97% when tested by ELISA and 66% when tested by SN. Seroprevalence did not vary significantly among the 3 groups for either serologic test. Magnitude of SN and ELISA titers varied greatly but independently of presence or absence of clinical signs of FHV-1-associated disease. Sensitivity, specificity, and positive and negative predictive values were assessed for VI and the IFA assay--jointly and individually--and for each SN and ELISA titer magnitude. Values never all exceeded 50%. CLINICAL IMPLICATIONS: Because FHV-1 can be detected commonly in clinically normal cats by the IFA assay or VI, neither test appears to aid in the clinical diagnosis of FHV-1 infection. Seroprevalence does not appear to vary between affected and clinically normal cats. SN, ELISA, VI, and the IFA assay appear to be of limited value in the diagnosis of FHV-1-associated disease in cats. Concurrent assessment of the IFA assay and VI results may permit exclusion of FHV-1 as an etiologic agent if results of both tests are negative.

Acute Disease↗
PubMed1999

Development of a simple multiplex polymerase chain reaction for the simultaneous detection of factor V Leiden and prothrombin 20210A mutations.

BACKGROUND: The demand for thrombophilia testing at the molecular level is increasing, and consequently, the work load of the routine molecular laboratory is also increasing. Efforts to lighten the work load, economize on time, and strive for reduced costs while still maintaining quality assurance are thus necessary. METHODS AND RESULTS: A multiplex polymerase chain reaction (PCR) for the detection of factor V Leiden and prothrombin 20210A mutations was designed that enables the use of the same inexpensive restriction enzyme, controls for the digestion, and produces easily interpretable results. CONCLUSION: The use of this new multiplex PCR and digestion analysis enabled us to simultaneously perform a routine screen for factor V Leiden and prothrombin 20210A mutations.

3' Untranslated Regions↗