PubMed Health⌕ Search

Biomedical subjects

Kathryn Graham

Publications and source records attributed to Kathryn Graham.

28 records · Page 2Linked to original sources

5'-(3')-nucleotidase mRNA levels in blast cells are a prognostic factor in acute myeloid leukemia patients treated with cytarabine.

We analyzed cytosolic 5'-(3')-nucleotidase (dNT-1) mRNA expression by quantitative polymerase chain reaction at diagnosis in leukemic blasts from 114 patients with acute myeloid leukemia (AML) treated with ara-C. Our results show that low dNT-1 mRNA expression in leukemic blasts at diagnosis is correlated with a worse clinical outcome and suggest that this enzyme may have a role in sensitivity to ara-C in AML patients.

Acute Disease↗

Nitric oxide and cyclic GMP increase the expression of matrix metalloproteinase-9 in vascular smooth muscle.

Interactions and possible cross talk between inducible nitricoxide synthase (iNOS), cyclooxygenase-2 (COX-2) and matrix metalloproteinase-9 (MMP-9), were studied in rat aortic vascular smooth muscle cells stimulated with bacterial lipopolysaccharide (LPS), interferon-gamma (IFN-gamma), and phorbol 12-myristate13-acetate (PMA). The expression and activity of iNOS, COX-2, and MMP-9 were characterized at the transcriptional, protein, and enzyme activity levels. The NOS inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME) was used to investigate the effects of NO on COX-2 and MMP-9 at the transcriptional level. The measurements of mRNAs for these enzymes using real-time polymerase chain reaction (PCR) showed that COX-2 mRNA was up-regulated 2.3-fold, whereas MMP-9 mRNA up-regulation was 11.7-fold in the presence of LPS, IFN-gamma, and PMA. Real-time PCR results indicated that L-NAME exerted an inhibitory effect on COX-2 and MMP-9 mRNA synthesis. Both superoxide dismutase (SOD) and the SOD mimetic Mn(III)tetrakis(1-methyl-4-pyridyl)porphyrin pentachloride (MnTMPyP) did not modify significantly the up-regulation of these enzymes, indicating that neither superoxide nor peroxynitrite are involved in this mechanism. Furthermore, NO-mediated up-regulation of MMP-9 was cGMP-dependent since 1H-[1,2,4] oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), an inhibitor of soluble guanylate cyclase, blocked, in a concentration-dependent manner, the increased expression of MMP-9, an effect reversed by 8-bromo-cGMP, a soluble analog of cGMP. Our findings suggest that NO and cGMP are necessary to up-regulate the expression of MMP-9.

Animals↗

Aggression involving alcohol: relationship to drinking patterns and social context.

AIMS: The present study examines the relationships between: (1) alcohol involvement/perceived intoxication level of participants and aggression severity; (2) respondent drinking patterns and involvement in alcohol-related aggression; and (3) social context and alcohol-related aggression. DESIGN: Random digit dialing (RDD) with computer assisted telephone interviewing (CATI) was used to obtain a random sample of Ontario adults aged 18-60 (response rate of 67%). PARTICIPANTS: Respondents who reported that they had been involved personally in physical aggression in the past 12 months were the focus of the present study. MEASUREMENTS: Questions were asked regarding the most recent incident of physical aggression, including whether the respondent and opponent drank alcohol prior to aggression, perceived intoxication levels at the time, number of participants, relationship to opponent, social context of aggression, time of day and day of week. Three items were used to assess aggression severity: injury to respondent, use of threats by respondent or opponent and police involvement. FINDINGS: (1) Injury to respondent and threats by respondent were not associated with alcohol involvement per se, but were significantly related to perceived level of alcohol intoxication; (2) drinking pattern of respondent was significantly associated with alcohol-related aggression but unrelated to aggression that did not involve alcohol; and (3) a number of contextual factors (e.g. gender, number of participants, time of day) were found to be associated with alcohol involvement in aggression. CONCLUSIONS: The results suggest that both drinking pattern and contextual factors are important in distinguishing between alcohol-related aggression and non-alcohol-related aggression. As well, alcohol intoxication may be an important predictor of aggression severity.

Adolescent↗

The relationship of average volume of alcohol consumption and patterns of drinking to burden of disease: an overview.

AIMS: As part of a larger study to estimate the global burden of disease attributable to alcohol: to quantify the relationships between average volume of alcohol consumption, patterns of drinking and disease and injury outcomes, and to combine exposure and risk estimates to determine regional and global alcohol-attributable fractions (AAFs) for major disease and injury categories. DESIGN, METHODS, SETTING: Systematic literature reviews were used to select diseases related to alcohol consumption. Meta-analyses of the relationship between alcohol consumption and disease and multi-level analyses of aggregate data to fill alcohol-disease relationships not currently covered by individual-level data were used to determine the risk relationships between alcohol and disease. AAFs were estimated as a function of prevalence of exposure and relative risk, or from combining the aggregate multi-level analyses with prevalence data. FINDINGS: Average volume of alcohol consumption was found to increase risk for the following major chronic diseases: mouth and oropharyngeal cancer; oesophageal cancer; liver cancer; breast cancer; unipolar major depression; epilepsy; alcohol use disorders; hypertensive disease; hemorrhagic stroke; and cirrhosis of the liver. Coronary heart disease (CHD), unintentional and intentional injuries were found to depend on patterns of drinking in addition to average volume of alcohol consumption. Most effects of alcohol on disease were detrimental, but for certain patterns of drinking, a beneficial influence on CHD, stroke and diabetes mellitus was observed. CONCLUSIONS: Alcohol is related to many major disease outcomes, mainly in a detrimental fashion. While average volume of consumption was related to all disease and injury categories under consideration, pattern of drinking was found to be an additional influencing factor for CHD and injury. The influence of patterns of drinking may be underestimated because pattern measures have not been included in many epidemiologic studies. Generalizability of the results is limited by methodological problems of the underlying studies used in the present analyses. Future studies need to address these methodological issues in order to obtain more accurate risk estimates.

Acute Disease↗

Deoxycytidine kinase and cN-II nucleotidase expression in blast cells predict survival in acute myeloid leukaemia patients treated with cytarabine.

The cytotoxic activity of cytarabine (ara-C) in leukaemic blasts depends on activating enzymes such as deoxycytidine kinase (dCK) and inactivating enzymes such as the 5'-nucleotidases. We have analysed dCK and 'high-Km' 5'-nucleotidase (cN-II) mRNA expression by the quantitative real-time polymerase chain reaction at diagnosis in leukaemic blasts from 115 acute myeloid leukaemia (AML) patients treated with ara-C. The prognostic value of these parameters as well as that of the cN-II/dCK ratio was determined. In univariate analyses: (1) low levels of dCK, high levels of cN-II and a high cN-II/dCK ratio predicted shorter disease-free survival (DFS); (2) low levels of dCK and cN-II/dCK ratio also predicted shorter overall survival (OS). In a multivariate analysis taking into account other clinical and laboratory variables: (1) high cN-II expression, a high cN-II/dCK ratio, age >/= 60 years and an unfavourable karyotype were independent prognostic factors for DFS; and (2) a high cN-II/dCK ratio, age >/= 60 years and an unfavourable karyotype predicted shorter OS. Age, karyotype and cN-II/dCK ratio were used to define a prognostic score that permitted the identification of high- and low-risk groups. Our results suggest that dCK and cN-II mRNA expression in leukaemic blasts at diagnosis is correlated with clinical outcome and may play a functional role in the resistance to ara-C in patients with AML.

5'-Nucleotidase↗

Alcohol as a risk factor for global burden of disease.

AIM: To make quantitative estimates of the burden of disease attributable to alcohol in the year 2000 on a global basis. DESIGN: Secondary data analysis. MEASUREMENTS: Two dimensions of alcohol exposure were included: average volume of alcohol consumption and patterns of drinking. There were also two main outcome measures: mortality, i.e. the number of deaths, and disability-adjusted life years (DALYs), i.e. the number of years of life lost to premature mortality or to disability. All estimates were prepared separately by sex, age group and WHO region. FINDINGS: Alcohol causes a considerable disease burden: 3.2% of the global deaths and 4.0% of the global DALYs in the year 2000 could be attributed to this exposure. There were marked differences by sex and region for both outcomes. In addition, there were differences by disease category and type of outcome; in particular, unintentional injuries contributed most to alcohol-attributable mortality burden while neuropsychiatric diseases contributed most to alcohol-attributable disease burden. DISCUSSION/CONCLUSIONS: The underlying assumptions are discussed and reasons are given as to why the estimates should still be considered conservative despite the considerable burden attributable to alcohol globally.

Alcohol Drinking↗

Drinking and its burden in a global perspective: policy considerations and options.

AIMS: To identify the policy implications of the magnitude and characteristics of alcohol consumption and problems, viewed globally, and to summarize conclusions on the effectiveness of the strategies available to policymakers concerned with reducing rates of alcohol problems. DESIGN/METHODS/SETTING: This summative article draws on the findings of the articles preceding it and of reviews of the literature. FINDINGS AND CONCLUSIONS: Overall volume of consumption is the major factor in the prevalence of harms from drinking. Since consumption and associated problems tend to increase with economic development, policymakers in developing economies should be especially aware of the need to develop policies to minimize overall increases in alcohol consumption. Unrecorded consumption is also an important consideration for policy in many parts of the world, and poses difficulties for alcohol control policies. Drinking pattern is also an important contributing factor toward alcohol-related harm. Although some drinking patterns have been shown to produce beneficial health effects, because the net effect of alcohol on coronary disease is negative in most parts of the world, policies that promote abstinence or lower drinking overall may be the safest options. Moreover, sporadic intoxication is common in many parts of the world, and policies are unlikely to change this drinking pattern at least in the short to medium term. At the same time, because injuries comprise a large proportion of the burden of alcohol, it is appropriate to enhance these policies with targeted harm reduction strategies such as drinking and driving countermeasures and interventions focused on reducing alcohol-related violence in specific high-risk settings. Alcohol consumption is a major factor for the global burden of disease and should be considered a public health priority globally, regionally, and nationally for the vast majority of countries in the world. The need for alcohol policy is even stronger when it is taken into consideration that the burden of alcohol estimated in the WHO Global Burden of Disease project includes primarily health problems related to drinking. From the limited evidence available, however, social problems related to drinking seem to impose at least as much burden. Moreover, the burden for both social and health harms fall not only on the drinker, but also on others. There is a broad literature on policy interventions to reduce alcohol problems. Effective strategies include controls over distribution and sale, taxation, drinking-driving countermeasures, brief interventions by health workers or counselors, and selected harm reduction measures. There is a need to develop the growing literature on comparative evaluations of cost-effectiveness of such strategies. In addition, international agreements are needed to support the effectiveness of national strategies.

Alcohol Drinking↗

Emotional effect of physical aggression among adults in the general population in a Canadian province.

The emotional effect of personal involvement in physical aggression was examined in a random sample of 1,753 adults from Ontario, Canada, using Computer Assisted Telephone Interviewing (response rate of 67%). Respondents reported a range of emotional responses from feeling good or justified to feeling angry, upset, terrified, disgusted, hurt, and embarrassed. Open-ended responses regarding emotional response were rated by the authors for 149 incidents of aggression, which yielded five categories: (1) positive impact 4%, (2) no feeling or no effect 31%, (3) mildly negative 20%, (4) moderately negative 28%, and (5) severely negative 17% (Kappa statistic of interrater agreement=.77). The substantial proportion of incidents involving positive or no emotional response suggests that a greater understanding of aggression among individuals can be gained by the development and application of a quantitative measure of emotional response that reflects the full range of emotions (positive and negative), using dimensions identified in this study such as feeling upset, fear, and anger.

Adolescent↗

Clinically validated benchmarking of normalisation techniques for two-colour oligonucleotide spotted microarray slides.

Acquisition of microarray data is prone to systematic errors. A correction, called normalisation, must be applied to the data before further analysis is performed. With many normalisation techniques published and in use, the best way of executing this correction remains an open question. In this study, a variety of single-slide normalisation techniques, and different parameter settings for these techniques, were compared over many replicated microarray experiments. Different normalisation techniques were assessed through the distribution of the standard deviation of replicates from one biological sample across different slides. It is shown that local normalisation outperformed global normalisation, and intensity-based 'LOWESS' outperformed trimmed mean and median normalisation techniques. Overall, the top performing normalisation technique was a print-tip-based LOWESS with zero robust iterations. Lastly, we validated this evaluation methodology by examining the ability to predict oestrogen receptor-positive and -negative breast cancer samples with data that had been normalised using different techniques.

Algorithms↗