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Biomedical subjects

K Graham

Publications and source records attributed to K Graham.

At least 37 records · Page 2Linked to original sources
PubMed2000

M11L: a novel mitochondria-localized protein of myxoma virus that blocks apoptosis of infected leukocytes.

M11L, a novel 166-amino acid membrane-associated protein expressed by the poxvirus, myxoma virus, was previously found to modulate apoptosis after infection of rabbit leukocytes. Furthermore, infection of rabbits with an M11L knockout virus unexpectedly produced lesions with a profound proinflammatory phenotype. We show here that M11L is antiapoptotic when expressed independently of other viral proteins, and is directed specifically to mitochondria by a short COOH-terminal region that is necessary and sufficient for targeting. This targeting region consists of a hydrophobic domain flanked by basic amino acid residues, adjacent to a positively charged tail. M11L blocks staurosporine-induced apoptosis by preventing mitochondria from undergoing a permeability transition, and the mitochondrial localization of this protein is essential for this function. We show that M11L is specifically required to inhibit the apoptotic response of monocytes/macrophages during virus infection, as cells of this lineage undergo apoptosis when infected with the M11L knockout virus. As monocyte apoptosis is uniquely proinflammatory, we propose that this observation reconciles the paradoxical proapoptotic and proinflammatory phenotypes of the M11L knockout virus. We suggest that apoptosis of tissue macrophages represents an important antiviral defense, and that the inhibition of apoptosis by viral proteins can be directed in a cell-specific fashion.

Amino Acid Sequence↗
PubMed2000

Post-translational modification of the myxoma-virus anti-inflammatory serpin SERP-1 by a virally encoded sialyltransferase.

SERP-1 is a secreted serpin (serine-proteinase inhibitor) encoded by myxoma virus, a poxvirus pathogen of rabbits. SERP-1 is required for myxoma-virus virulence, and the purified protein has been shown to possess independent anti-inflammatory activity in animal models of restenosis and antigen-induced arthritis. As an inhibitor of serine proteinases, SERP-1 acts against tissue-type plasminogen activator, urokinase-type plasminogen activator, plasmin, thrombin and Factor Xa. In the present study, examination of SERP-1 glycosylation-site mutants showed that the N-linked glycosylation of Asn(172) was essential for SERP-1 secretion, whereas mutation of Asn(99) decreased secretion efficiency, indicating that N-linked glycosylation plays an essential role in the processing and trafficking of SERP-1. Furthermore, comparison of SERP-1 from wild-type myxoma virus and a virus containing a targeted disruption of the MST3N sialyltransferase locus demonstrated that SERP-1 is specifically modified by this myxoma-virus-encoded sialyltransferase, and is thus the first reported viral protein shown to by modified by a virally encoded glycosyltransferase. Sialylation of SERP-1 by the MST3N gene product creates a uniquely charged species of secreted SERP-1 that is distinct from SERP-1 produced from other eukaryotic expression systems, though this has no apparent effect upon the kinetics of in vitro proteinase inhibition. Rather, the role of viral sialylation of SERP-1 likely relates to masking antigenicity or targeting SERP-1 to specific sites of action in vivo.

Amino Acid Sequence↗
PubMed2000

Gender differences in alcohol consumption and adverse drinking consequences: cross-cultural patterns.

AIMS: To examine the consistency and/or variability of gender differences in drinking behavior cross-culturally. DESIGN, SETTING, PARTICIPANTS: Women's and men's responses in 16 general population surveys from 10 countries, analyzed by members of the International Research Group on Gender and Alcohol. MEASUREMENTS: Comparable measures of drinking, versus abstention, typical drinking frequencies and quantities, heavy episodic drinking, intoxication, morning drinking, and alcohol-related family and occupational problems. FINDINGS: Women and men differed little in the probability of currently drinking versus abstaining, but men consistently exceeded women in typical drinking frequencies and quantities and in rates of heavy drinking episodes and adverse drinking consequences, while women were consistently more likely than men to be life-time abstainers. In older age groups, both men and women drank smaller quantities of alcohol and were more likely to stop drinking altogether, but drinking frequencies did not change consistently with age. CONCLUSIONS: A theoretical synthesis proposes that gender roles may amplify biological differences in reactions to alcohol, and that gender differences in drinking behavior may be modified by macrosocial factors that modify gender role contrasts.

Adult↗
PubMed2000

Evaluating theories of alcohol-related aggression using observations of young adults in bars.

AIMS: The objective of the present study is to evaluate 36 explanations of alcohol-related aggression that have been proposed in the research literature in terms of their relevance to naturally-occurring incidents of aggression involving alcohol. DESIGN: The study involved content analysis of descriptions of 105 incidents of aggression. SETTING AND PARTICIPANTS: Bars frequented by young adults. MEASUREMENTS: Step-by-step descriptions of incidents of aggression reported by researcher-observers based on 93 nights of observation in bars between midnight and 3 a.m. FINDINGS: Some explanations relating to the effects of alcohol (e.g. focused on the present, reduced anxiety about sanctions or danger, heightened emotionality) and the environment (e.g. generally permissive environment, expectation by patrons that aggression will be tolerated) were found to be relevant to most incidents, while other explanations (e.g. crowding, release of pent-up anger) were directly relevant to only a few or no incidents. Incidents involving male-to-male aggression were more likely than incidents involving both males and females to be attributable to expectations, acceptance of aggression, power concerns, male honor and "macho" values. Principal components analysis identified five groupings of explanations: risk-taking effects of alcohol, cognitive impairment from alcohol, hyperemotional effects of alcohol, "macho" subculture, and permissive environment. CONCLUSIONS: The findings are consistent with a model of alcohol-related aggression that involves multiple contributing factors including alcohol effects and situational contexts. The greater relevance of certain explanations and the natural groupings of explanations point to directions for future research.

Adolescent↗
PubMed2000

Alcohol-related aggression in the general population.

OBJECTIVE: This study estimates the relationships between drinking in the event and drinking patterns and different levels of aggression severity. METHOD: A telephone survey of 1,001 adults (542 women) age 18 and over was conducted (response rate of 67%) using computer assisted telephone interviewing (CATI). Respondents were asked whether they had been personally involved in a serious argument, an incident involving threat, or physical aggression in the past year and whether anyone had been drinking alcohol in the most recent incident. Respondents also reported their typical alcohol consumption patterns. RESULTS: The proportion of respondents reporting involvement in serious arguments, threats or physical aggression was 19.8%, 11.8% and 12.0%, respectively. Someone in the incident had been drinking in 38.1% of serious arguments, 56.5% of threats and 67.9% of incidents of physical aggression. When gender, age, education, marital status and employment status were controlled for, high quantity drinking (as measured by the largest number of drinks consumed on one drinking occasion in the past year), overall estimated annual volume of alcohol consumed, and frequency of consuming five drinks per occasion were significantly greater for physical aggression, compared with arguments and no aggression. However, drinker status (abstainer/drinker) and frequency of drinking were not significantly associated with involvement in aggression. In a logistic regression analysis controlling for demographic variables, a composite measure of alcohol consumption was highly significant for physical aggression versus no aggression and for physical versus verbal aggression. Physical aggression was also associated with being younger, separated/ divorced and a student. CONCLUSIONS: The results suggest that alcohol intoxication, rather than mere alcohol consumption, is associated with aggression. Moreover, alcohol intoxication is more strongly associated with physical aggression than with verbal aggression.

Adolescent↗
PubMed2000

Results of a pilot program for training bar staff in preventing aggression.

One hundred and twenty-one staff from eight bars in Ontario, Canada participated in a three-hour training program that used a peer learning model to teach problem-solving skills regarding the prevention and management of aggressive behavior in bars. Participants showed significant positive changes in knowledge and attitudes regarding effective approaches to preventing aggression. The majority of participants reported that the training made them think about ways they handed problem situations and that they would change the way they handle problems in the future. Participants rated most aspects of the training as very useful, especially the group discussion. The program illustrates the potential for increasing skills and knowledge of bar staff in preventing aggression and associated injury.

Adult↗
PubMed2000

Introduction: community action research and the prevention of alcohol problems at the local level.

Many community action projects from around the world exist to reduce alcohol problems at the local level. The role of research within this international movement is discussed within this introduction for the entire special issue on community action research in alcohol problem prevention. Previous community prevention programs have utilized a variety of prevention strategies: (a) an educational approach which focuses on changing behavior through changes in knowledge, attitudes, and information; and (b) an environmental approach which focuses on changing behavior through changes in the social and economic systems within a community. Many projects have used both approaches. This special issue provides a current overview of many types of community action projects from different countries and summarizes what has been learned to date from these experiences.

Alcoholism↗
PubMed2000

Community action research: who does what to whom and why? Lessons learned from local prevention efforts (international experiences).

This paper describes lessons learned about community action research, drawing upon papers written and presented at a recent international conference on community action research and the prevention of alcohol and other drug problems. Projects reflected both action and evaluation research traditions and focused on a variety of issues from moderation of drinking to alcohol-related violence, and on range of target populations from youth to specific ethnic groups. The interventions described ranged from policy-based prevention to education and training and to secondary prevention and treatment. Lessons identified in the papers are discussed within three broad areas: the community targeted for change; the implementation of community projects; and community action research projects generally. The common lessons emerging from these diverse projects provide useful lessons on which to base future progress in community action research.

Alcoholism↗
PubMed1999

Role of the myxoma virus soluble CC-chemokine inhibitor glycoprotein, M-T1, during myxoma virus pathogenesis.

Myxoma virus is a poxvirus that causes a virulent systemic disease called myxomatosis in European rabbits. Like many poxviruses, myxoma virus encodes a variety of secreted proteins that subvert the antiviral activities of host cytokines. It was recently demonstrated that the myxoma virus M-T1 glycoprotein is a member of a large poxvirus family of secreted proteins that bind CC-chemokines and inhibit their chemoattractant activities in vitro. To determine the biological role of M-T1 in contributing to myxoma virus virulence, we constructed a recombinant M-T1-deletion mutant virus that was defective in M-T1 expression. Here, we demonstrate that M-T1 is expressed continuously during the course of myxoma virus infection as a highly stable 43-kDa glycoprotein and is dispensable for virus replication in vitro. Deletion of M-T1 had no significant effects on disease progression or in the overall mortality rate of infected European rabbits but heightened the localized cellular inflammation in primary tissue sites during the initial 2 to 3 days of infection. In the absence of M-T1 expression, deep dermal tissues surrounding the primary site of virus inoculation showed a dramatic increase in infiltrating leukocytes, particularly monocytes/macrophages, but these phagocytes remained relatively ineffective at clearing virus infection, likely due to the concerted properties of other secreted myxoma virus proteins. We conclude that M-T1 inhibits the chemotactic signals required for the influx of monocytes/macrophages during the acute-phase response of myxoma virus infection in vivo, as predicted by its ability to bind and inhibit CC-chemokines in vitro.

Animals↗
PubMed1999

Efficacy and safety of lovastatin in adolescent males with heterozygous familial hypercholesterolemia: a randomized controlled trial.

CONTEXT: Heterozygous familial hypercholesterolemia (HeFH) is a common disorder associated with early coronary artery disease, especially in men. The age at which drug therapy should be started is still controversial, as is the use of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). OBJECTIVE: To assess the lipid-lowering efficacy, biochemical safety, and effect on growth and sexual development of lovastatin in adolescent boys with HeFH. DESIGN: One-year, double-blind, placebo-controlled, balanced, 2-period, 2-arm randomized trial. In the first period (24 weeks), lovastatin was increased at 8 and 16 weeks and the dosage remained stable during the second period (24 weeks). The study was conducted between 1990 and 1994. SETTING: Fourteen pediatric outpatient clinics in the United States and Finland. PATIENTS: Boys aged 10 to 17 years with HeFH. Of 132 randomized subjects (67 intervention, 65 placebo), 122 (63 intervention, 59 placebo) and 110 (61 intervention, 49 placebo) completed the first and second periods, respectively. INTERVENTION: Lovastatin, starting at 10 mg/d, with a forced titration at 8 and 16 weeks to 20 and 40 mg/d, respectively, or placebo. MAIN OUTCOME MEASURES: The primary efficacy outcome measure was low-density lipoprotein cholesterol (LDL-C). Primary safety measures were growth and sexual development. RESULTS: Compared with placebo, LDL-C levels of patients receiving lovastatin decreased significantly (P<.001) by 17%, 24%, and 27% receiving dosages of 10, 20, and 40 mg/d, respectively, and remained 25 % lower than baseline at 48 weeks. Growth and sexual maturation assessed by Tanner staging and testicular volume were not significantly different between the lovastatin and placebo groups at 24 weeks (P = .85) and 48 weeks (P = .33); neither were serum hormone levels or biochemical parameters of nutrition. However, the study was underpowered to detect significant differences in safety parameters. Serum vitamin E levels were reduced with lovastatin treatment consistent with reductions in LDL-C, the major carrier of vitamin E in the circulation. CONCLUSIONS: This study in adolescent boys with HeFH confirmed the LDL-C-reducing effectiveness of lovastatin. Comprehensive clinical and biochemical data on growth, hormonal, and nutritional status indicated no significant differences between lovastatin and placebo over 48 weeks, although further study is required.

Adolescent↗
PubMed1999

Long-term blood cholesterol-lowering effects of a dietary fiber supplement.

BACKGROUND: The study evaluated the blood cholesterol-lowering effects of a dietary supplement of water-soluble fibers (guar gum, pectin) and mostly non-water-soluble fibers (soy fiber, pea fiber, corn bran) in subjects with mild to moderate hypercholesterolemia (LDL cholesterol, 3.37-4.92 mmol/L). METHODS: After stabilization for 9 weeks on a National Cholesterol Education Program Step 1 Diet, subjects were randomly assigned to receive 20 g/d of the fiber supplement (n = 87) or matching placebo (n = 82) for 15 weeks and then receive the fiber supplement for 36 weeks. The efficacy analyses included the 125 subjects (58 fiber; 67 placebo) who were treatment and diet compliant. One hundred two (52 fiber; 50 placebo) completed the 15-week comparative phase. Of these subjects 85 (45 fiber; 40 placebo) elected to continue in the 36-week noncomparative extension phase. RESULTS: The mean decreases during the 15-week period for LDL cholesterol (LDL-C), total cholesterol (TC), and LDL-C/HDL-C ratio were greater (P < 0.001) in the fiber group. The mean changes from pre-treatment values in LDL-C, TC, and LDL-C/HDL-C ratio for subjects in the fiber group were -0.51 mmol/L (-12.1%), -0.53 mmol/L (-8.5%), and -0.30 (-9.4%), respectively. The corresponding changes in the placebo group were -0.05 mmol/L (-1.3%), -0.05 mmol/L (-0.8%), and 0.05 (1.5%), respectively. The fiber supplement had no significant effects (P > 0.05) on HDL cholesterol (HDL-C), triglyceride, iron, ferritin, or vitamin A or E levels. Similar effects were seen over the subsequent 36-week noncomparative part of the study. CONCLUSIONS: The fiber supplement provided significant and sustained reductions in LDL-C without reducing HDL-C or increasing triglycerides over the 51-week treatment period.

Adolescent↗
PubMed1999

The effect of botulinum toxin A on gastrocnemius length: magnitude and duration of response.

Thirty-nine ambulant children (22 with hemiplegia, 17 with diplegia) with spastic cerebral palsy receiving isolated gastrocnemius muscle injection with botulinum toxin A were studied prospectively. The children had a mean age of 6 years (range 3 to 13 years). Measurement of gastrocnemius muscle length was used to estimate the dynamic component of each child's spasticity and to quantify the response. There was a strong correlation between the dynamic component of spasticity before injection and the corresponding magnitude of the response after injection. Children undergoing repeated injections showed similar correlations. A strong correlation was found between the duration of response and the dynamic component. Children with hemiplegia showed twice the duration for a given dynamic component compared with those with diplegia when injected with the same total dose per unit body weight. Long-term lengthening did not occur for the cohort, although some patients showed a response at a 12-month follow-up. By delaying shortening, the injections may have a role in delaying the need for surgery. Injections were well tolerated with few side effects.

Adolescent↗
PubMed1999

High- or low- technology measurements of energy expenditure in clinical gait analysis?

The repeatability of energy-expenditure measurements were studied in five children and four adults without disabilities using the Cosmed K4 (high technology). The ability to detect change in measurements was compared between this instrument and the Physiological Cost Index (PCI; low technology). The results of repeatability (95% range) for oxygen cost were 13.1% in children and 13% in adults. In contrast, the SD of PCI was 6 to 72% of the mean in adults and wider in children (91%; 95% range). The validity of PCI as an outcome measure was questioned. In addition, 177 children with motor disability were prospectively studied using the Cosmed K4. Previous experience with the Cosmed K2 (intermediate technology) helped to develop a practical and repeatable protocol for testing children with disability using the Cosmed K4. The protocol commenced with 5 minutes of rest to achieve baseline values of heart rate and oxygen consumption, followed by 10 minutes of continuous walking at a self-selected speed on a 10-metre level oval walking track. The test concluded with 5 minutes of rest to monitor the return to baseline values. Ninety-one percent of the children with disability quickly reached a steady-state of oxygen consumption and carbon-dioxide production. The carbon-dioxide sensor in the Cosmed K4 has enabled a new group of severely involved children with cerebral palsy (9%) to be defined. These children have been termed 'physiologically marginal ambulators'.

Adult↗
PubMed1999

Clients speak: participatory evaluation of a nonconfrontational addictions treatment program for older adults.

OBJECTIVES: To describe the important aspects of the Lifestyle Enrichment for Senior Adults (LESA) program from the clients' perspective and why these aspects were important to them. METHODS: The study used a participatory approach. Researchers collaborated with counselors and clients to develop an evaluation that (a) respected the experiences and knowledge of people in the program and (b) provided an accurate assessment of the important aspects of the program from the clients' perspective. One-to-one interviews were conducted with 52 clients. RESULTS: Clients' relationships with counselors, the positive emotions experienced during individual and group counseling, and the program's flexibility were of key importance. Allowing clients to choose their level of involvement and the general acceptance of drinkers also contributed to perceived benefits of the program. DISCUSSION: The benefits of client-centered addictions therapy warrant closer examination. Senior adults' motivation for behavior change may be highly sensitive to the relational aspects of the treatment approach.

Age Factors↗
PubMed1999

Alcohol use and psychosocial well-being among older adults.

OBJECTIVE: The objective of this study was to examine the relationships of three dimensions of alcohol consumption (frequency of drinking, usual total weekly consumption and quantity per occasion) with social and leisure status, stress and psychological well-being among people ages 65 and older. METHOD: Nurse interviewers completed in-house surveys with 826 older persons (65% women) in one community (67% response rate of the census sample). RESULTS: Overall, relationships tended to be modest or nil. Those relationships between negative functioning and heavier alcohol use that did emerge tended to be associated with higher quantity drinking (i.e., drinks per drinking day) and to some extent volume, but not with frequency of drinking. Of the psychosocial variables, poorer psychological well-being, especially depression, was most highly correlated with heavier drinking. These results were the same controlling for sex, age, education, health and use of depressant medications. CONCLUSIONS: Higher quantity and volume of alcohol use among older people show a modest positive association with poorer psychological well-being, independent of other potentially confounding variables such as sex, age, health or use of depressant medications. Frequency of drinking, however, was not related to psychosocial status.

Aged↗
PubMed1999

The relationship between psychosocial well-being and alcohol and drug use following substance misuse treatment.

The relationship between psychosocial status and alcohol and drug use at 12-month follow-up was evaluated for clients of two addictions treatment programs (90 treated for alcohol; 51 for drugs or drugs and alcohol). Psychosocial status at follow-up was mostly unrelated to alcohol use among clients who were not using drugs prior to treatment. Among drug users, returning to both alcohol and drug use was strongly associated with poorer psychosocial status, with partial correlational analyses indicating that (a) drug use was the main factor associated with poorer status and (b) poorer status was likely a consequence rather than a precursor of drug use. The implications of these findings are discussed.

Adult↗
PubMed1998

Long-term effects of low-density lipoprotein apheresis using an automated dextran sulfate cellulose adsorption system. Liposorber Study Group.

The short-term effectiveness of low-density lipoprotein (LDL) apheresis using a dextran sulfate cellulose adsorption column technique was previously examined in a 9-center, 22-week controlled trial in 64 patients with familial hypercholesterolemia (FH) who did not adequately respond to diet and drug therapy. Forty-nine patients (40 treatment, 9 controls) subsequently received LDL apheresis procedures as part of an optional follow-up phase. This study reports on the long-term safety, lipid lowering, and clinical efficacy of LDL apheresis for the 5-year period that includes both the initial controlled study and follow-up phase. During this time, patients received a total of 3,902 treatments of which 3,314 treatments were given during the follow-up phase. Adverse events were infrequent, occurring in 142 procedures (3.6%). Immediate reduction in LDL cholesterol was 76% both in homozygotes and in heterozygotes. Patients with homozygous FH had a progressive decrease in pretreatment LDL cholesterol level along with an increase in high-density lipoprotein (HDL) cholesterol level. There was no appreciable change in pretreatment lipoprotein level over time in heterozygotes. The rate of cardiovascular events during therapy with LDL apheresis and lipid-lowering drugs was 3.5 events per 1,000 patient-months of treatment compared with 6.3 events per 1,000 patient-months for the 5 years before LDL apheresis therapy. These findings support the long-term safety and clinical efficacy of LDL apheresis in patients with heterozygous and homozygous FH who are inadequately controlled with drug therapy.

Adolescent↗