Biomedical subjects

D W Russell

Publications and source records attributed to D W Russell.

At least 19 recordsLinked to original sources

PubMed2006

Aerobic exercise, but not flexibility/resistance exercise, reduces serum IL-18, CRP, and IL-6 independent of beta-blockers, BMI, and psychosocial factors in older adults.

Increased serum levels of inflammatory mediators have been associated with numerous disease states including atherosclerosis, Type II diabetes, hypertension, depression, and overall mortality. We hypothesized that a long-term exercise intervention among older adults would reduce serum inflammatory cytokines, and this reduction would be mediated, in part, by improvements in psychosocial factors and/or by beta-adrenergic receptor mechanisms. Adults age 64 were randomly assigned to either an aerobic exercise treatment (CARDIO) or a flexibility/strength exercise treatment (FLEX) 3 days/week, 45 min/day for 10 months. A subgroup of subjects treated with non-selective beta(1)beta(2) adrenergic antagonists were included to evaluate the potential role of beta-adrenergic receptor adaptations as mediators of an exercise-induced change in inflammation. The inflammatory mediators [C-reactive protein (CRP), IL-6, tumor necrosis factor (TNF)-alpha, and IL-18] and the psychosocial factors (depression, perceived stress, optimism, sense of coherence, and social support) were measured pre- and post-intervention. The CARDIO treatment resulted in significant reductions in serum CRP, IL-6, and IL-18 compared to the FLEX treatment (significant treatment x time interaction, p<.05), whereas TNFalpha declined in both groups (main effect of time, p=.001). However, several psychosocial factors (depression, optimism, and sense of coherence) improved in both groups suggesting that the reduction of CRP, IL-6, and IL-18 in the CARDIO group was not mediated by improvements in psychosocial scores. With respect to the potential role of beta-adrenergic receptors, both CARDIO subjects treated with beta-adrenergic antagonists and those who were not treated with those medications demonstrated similar reductions in serum CRP, IL-6, IL-18, and TNFalpha. In summary, we have observed that an aerobic exercise intervention can significantly reduce serum inflammatory mediators, but beta-adrenergic receptors and psychosocial factors do not appear to be involved.

Adaptation, Physiological↗

PubMed2005

The exercise-induced enhancement of influenza immunity is mediated in part by improvements in psychosocial factors in older adults.

The primary goal of this study was to determine whether exercise-associated improvements of the immune response to influenza vaccination were mediated by improvements in psychosocial factors in older adults. At baseline, prior to the exercise intervention, older adult participants were immunized with influenza vaccine. Blood samples collected pre-immunization, 1, 4, and 12 weeks post-immunization were analyzed for anti-influenza antibody, whereas influenza-specific cytokine (IFNgamma) was evaluated at 1 week post-immunization. Depression and sense of coherence were measured pre-immunization. Four weeks post-immunization, participants were randomly assigned to either an aerobic exercise group (n=14) or a control group (n=14). After a 10-month exercise intervention, the immunization, blood collections, and psychosocial measures were repeated. At the post-intervention evaluation, exercise participants had improved scores on depression and sense of coherence. Also post-intervention, exercise participants had a greater increase in antibody and IFNgamma production. After controlling for the effect of both psychosocial measures, the exercise treatment remained significant with respect to antibody titer suggesting that the increases in antibody were not mediated by improvement in the psychosocial factors. In contrast, the enhancement of IFNgamma appeared to be mediated at least in part by the psychosocial factors. After controlling for psychosocial factors, exercise treatment was no longer significantly related to the change in IFNgamma. Taken together, our findings may suggest that the mechanism(s) of exercise-induced improvement in immunocompetence involve both physiological and psychological pathways.

Affect↗

PubMed2001

On the turnover of brain cholesterol in patients with Alzheimer's disease. Abnormal induction of the cholesterol-catabolic enzyme CYP46 in glial cells.

Evidence is accumulating for a link between cerebral cholesterol metabolism and Alzheimer's disease (AD). Here we focus on a possible relationship between AD and a newly discovered mechanism for cholesterol efflux from the brain, involving conversion of brain cholesterol into 24S-hydroxycholesterol by the neuronal oxidative enzyme CYP46. There was a marked difference in the distribution of CYP46 in brains of control and AD patients. The neuronal cells were less stained in AD brains than in controls while marked positive staining was found in glial cells in AD but not in controls. The dynamic changes in the mechanisms for cholesterol efflux from the brain are of interest in relation to the link between brain cholesterol and amyloid beta-protein in AD.

Aged↗

PubMed2001

The hypocholesterolemic agent LY295427 reverses suppression of sterol regulatory element-binding protein processing mediated by oxysterols.

The sterol LY295427 reduces plasma cholesterol levels in animals by increasing the expression of hepatic low density lipoprotein (LDL) receptors. Here we trace the hypocholesterolemic activity of LY295427 to an ability to reverse oxysterol-mediated suppression of sterol regulatory element-binding protein (SREBP) processing. Micromolar concentrations of LY295427 induced the metabolism of LDL in oxysterol-treated cultured cells and inhibited the stimulation of cholesteryl ester synthesis mediated by oxysterols. cDNA microarray and RNA blotting experiments revealed that LY295427 increased levels of the LDL receptor mRNA and those of other SREBP target genes. The compound stimulated the accumulation of SREBPs in the nuclei of cells grown in the presence of oxysterols within 4-6 h of addition to the medium. Induction required components of the normal SREBP-processing pathway, including the SREBP cleavage-activating protein and the Site 1 protease. LY295427 overcame the suppression of SREBP processing mediated by several oxysterols but not by LDL-derived cholesterol. We conclude that LY295427 achieves a therapeutically desirable end point by an unique mechanism of action.

Animals↗

PubMed2001

Gene transfer into murine hematopoietic stem cells with helper-free foamy virus vectors.

Gene transfer into hematopoietic stem cells (HSCs) is an ideal treatment strategy for many genetic and hematologic diseases. However, progress has been limited by the low HSC transduction rates obtained with retroviral vectors based on murine leukemia viruses. This study examined the potential of vectors derived from the nonpathogenic human foamy virus (HFV) to transduce human CD34(+) cells and murine HSCs. More than 80% of human hematopoietic progenitors present in CD34(+) cell preparations derived from cord blood were transduced by a single overnight exposure to HFV vector stocks. Mice that received transduced bone marrow cells expressed the vector-encoded transgene long term in all major hematopoietic cell lineages and in over 50% of cells in some animals. Secondary bone marrow transplants and integration site analysis confirmed that gene transfer occurred at the stem cell level. Transgene silencing was not observed. Thus vectors based on foamy viruses represent a promising approach for HSC gene therapy. (Blood. 2001;98:604-609)

Animals↗

PubMed2001

Introduction of single base substitutions at homologous chromosomal sequences by adeno-associated virus vectors.

Adeno-associated virus (AAV) vectors can modify homologous chromosomal sequences at high rates. This gene targeting transduction pathway is distinct from the integrating and episomal pathways used in gene addition approaches. In previous studies, AAV vectors were used to introduce small insertion and deletion mutations at homologous chromosomal loci. Here we show that AAV-mediated gene targeting can also be used to introduce all possible types of single base substitution mutations at the endogenous single-copy hypoxanthine phosphoribosyl transferase locus. Southern blot and sequence analysis showed that the point mutations were introduced with high fidelity. We also show that AAV vectors can repair chromosomal alkaline phosphatase genes containing point mutations. Our results suggest that AAV vectors can be used to introduce single base substitutions at high frequencies in normal human cells, including the correction of point mutations responsible for genetic diseases.

Alkaline Phosphatase↗

PubMed2001

Comparisons of marriage and family therapists, psychologists, psychiatrists, and social workers on job-related measures and reactions to managed care in Iowa.

This study compares marriage and family therapists (MFTs) to psychologists, psychiatrists, and social workers on job-related measures, such as job autonomy, job satisfaction, burnout, and intention to stay in their present position, as well as on reactions to a managed care initiative in the state of Iowa. Findings indicate that MFTs scored significantly lower than other practitioners on job autonomy and intention to stay in their present position, but there were no differences in job satisfaction or burnout. Marital and family therapists also reported less dissatisfaction with the managed care initiative than psychiatrists, although virtually all practitioners were dissatisfied with the managed-care program. These findings indicate some dissatisfaction within the MFT profession and may be relevant to practitioners seeking to change or expand their practice, as well as to the needs of MFTs in their training programs.

Adult↗

PubMed2001

Unexpected virilization in male mice lacking steroid 5 alpha-reductase enzymes.

Mice lacking steroid 5 alpha-reductase 1 and 2 were produced by gene targeting and breeding. Male mice without 5 alpha-reductase 2 or without both enzymes had fully formed internal and external genitalia and were fertile, but had smaller prostates and seminal vesicles than controls. T accumulated to high levels in the reproductive tissues of the mutant mice. DHT administration increased seminal vesicle and coagulating gland weights in mice deficient in 5 alpha-reductase 2 and increased the weights of the prostate, seminal vesicle, and coagulating gland in animals deficient in both enzymes. An inhibitor of both 5 alpha-reductases (GI 208335X) decreased prostate and coagulating gland weights of control mice, but had no effect in those lacking 5 alpha-reductase 1 and 2. Castration reduced the sizes of these tissues in animals of all genotypes. Androgen-dependent gene expression was decreased in the seminal vesicles of mice lacking one or more 5 alpha-reductases and was restored by administration of T or DHT. Female mice missing both enzymes exhibited parturition and fecundity defects similar to those of animals without 5 alpha-reductase 1. We conclude that T is the only androgen required for differentiation of the male urogenital tract in mice and that the synthesis of DHT serves largely as a signal amplification mechanism.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗

PubMed2001

Alternate pathways of bile acid synthesis in the cholesterol 7alpha-hydroxylase knockout mouse are not upregulated by either cholesterol or cholestyramine feeding.

Bile acids are synthesized via the classic pathway initiated by cholesterol 7alpha-hydroxylase (CYP7A1), and via alternate pathways, one of which is initiated by sterol 27-hydroxylase (CYP27). These studies used mice lacking cholesterol 7alpha-hydroxylase (Cyp7a1(-/-)) to establish whether the loss of the classic pathway affected cholesterol homeostasis differently in males and females, and to determine if the rate of bile acid synthesis via alternate pathways was responsive to changes in the enterohepatic flux of cholesterol and bile acids. In both the Cyp7a1(-/-) males and females, the basal rate of bile acid synthesis was only half of that in matching Cyp7a1(+/+) animals. Although bile acid pool size contracted markedly in all the Cyp7a1(-/-) mice, the female Cyp7a1(-/-) mice maintained a larger, more cholic acid-rich pool than their male counterparts. Intestinal cholesterol absorption in the Cyp7a1(-/-) males fell from 46% to 3%, and in the matching females from 58% to 17%. Bile acid synthesis in Cyp7a1(+/+) males and females was increased 2-fold by cholesterol feeding, and 4-fold by cholestyramine treatment, but was not changed in matching Cyp7a1(-/-) mice by either of these manipulations. In the Cyp7a1(-/-) mice fed cholesterol, hepatic cholesterol concentrations increased only marginally in the males, but rose almost 3-fold in the females. CYP7A1 activity and mRNA levels were greater in females than in males, and were increased by cholesterol feeding in both sexes. CYP27 activity and mRNA levels did not vary as a function of CYP7A1 genotype, gender, or dietary cholesterol intake. We conclude that in the mouse the rate of bile acid synthesis via alternative pathways is unresponsive to changes in the enterohepatic flux of cholesterol and bile acid, and that factors governing gender-related differences in bile acid synthesis, pool size, and pool composition play an important role in determining the impact of CYP7A1 deficiency on cholesterol homeostasis in this species.

Animals↗

PubMed2001

Genetic analysis of intestinal cholesterol absorption in inbred mice.

A genetic mapping strategy was employed to identify chromosomal regions harboring genes that influence the absorption of intestinal cholesterol in the mouse. Analysis of seven inbred strains of male mice (129P3, AKR, BALB/c, C3H/He, C57BL/6, DBA/2, and SJL, all from Jackson Laboratories) revealed substantial differences in their abilities to absorb a bolus of cholesterol delivered by gavage. Crosses between high (AKR, 129) and low (DBA/2, SJL) absorbing strains revealed evidence for the presence of dominant genes that increase and decrease cholesterol absorption. Backcrosses between F1 offspring and parental strains (DBA/2xAKD2F1 and 129xSJL129F1) followed by linkage analyses revealed four quantitative trait loci that influenced cholesterol absorption. Analyses of recombinant inbred strains identified an additional three loci affecting this phenotype. These seven quantitative trait loci, which map to different chromosomes and are termed Cholesterol absorption 1-7 (Chab1-7) loci, together influence the absorption of intestinal cholesterol in mice and are likely to be involved in different steps of this complex pathway.

Animals↗

PubMed2001

Genetic analysis of cholesterol accumulation in inbred mice.

Genetic linkage analysis in the laboratory mouse identified chromosomal regions containing genes that contribute to cholesterol accumulation in the liver and plasma. Comparisons between five inbred strains of mice obtained from the Jackson Laboratory (DBA/2, AKR, C57BL/6, SJL, and 129P3) revealed a direct correlation between intestinal cholesterol absorption and susceptibility to diet-induced hypercholesterolemia. This correlation was lost in the F1 generation arising from crosses between high- and low-absorbing strains. Linkage analyses in AKxD recombinant inbred strains and 129xSJL129F1 N2 backcross mice identified four quantitative trait loci (QTL) that influenced Liver cholesterol accumulation (Lcho1-4) and one locus that affected Plasma cholesterol accumulation (Pcho1). These loci map to five chromosomes and, with one exception, are different from the seven QTL identified previously that influence intestinal cholesterol absorption. We conclude that a large number of genes affects the amount of cholesterol absorbed in the small intestine and its accumulation in the liver and plasma of inbred mice.

Animals↗

PubMed2000

Oxysterol biosynthetic enzymes.

Oxysterols, herein defined as derivatives of cholesterol with a hydroxyl group on the side chain, play several roles in lipid metabolism. Members of this class regulate the expression of genes that participate in both sterol and fat metabolism, serve as substrates for the synthesis of bile acids, and are intermediates in the transfer of sterols from the periphery to the liver. Three abundant naturally occurring oxysterols are 24-hydroxycholesterol, 25-hydroxycholesterol, and 27-hydroxycholesterol. The cholesterol hydroxylase enzymes that synthesize each of these have been isolated over the last several years and their study has produced insight into the biology of oxysterols. This article focuses on the properties of these enzymes.

Animals↗

PubMed2000

Disruption of the sterol 27-hydroxylase gene in mice results in hepatomegaly and hypertriglyceridemia. Reversal by cholic acid feeding.

Sterol 27-hydroxylase (CYP27) participates in the conversion of cholesterol to bile acids. We examined lipid metabolism in mice lacking the Cyp27 gene. On normal rodent chow, Cyp27(-/-) mice have 40% larger livers, 45% larger adrenals, 2-fold higher hepatic and plasma triacylglycerol concentrations, a 70% higher rate of hepatic fatty acid synthesis, and a 70% increase in the ratio of oleic to stearic acid in the liver versus Cyp27(+/+) controls. In Cyp27(-/-) mice, cholesterol 7alpha-hydroxylase activity is increased 5-fold, but bile acid synthesis and pool size are 47 and 27%, respectively, of those in Cyp27(+/+) mice. Intestinal cholesterol absorption decreases from 54 to 4% in knockout mice, while fecal neutral sterol excretion increases 2.5-fold. A compensatory 2.5-fold increase in whole body cholesterol synthesis occurs in Cyp27(-/-) mice, principally in liver, adrenal, small intestine, lung, and spleen. The mRNA for the cholesterogenic transcription factor sterol regulatory element-binding protein-2 (SREBP-2) and mRNAs for SREBP-2-regulated cholesterol biosynthetic genes are elevated in livers of mutant mice. In addition, the mRNAs encoding the lipogenic transcription factor SREBP-1 and SREBP-1-regulated monounsaturated fatty acid biosynthetic enzymes are also increased. Hepatic synthesis of fatty acids and accumulation of triacylglycerols increases in Cyp27(-/-) mice and is associated with hypertriglyceridemia. Cholic acid feeding reverses hepatomegaly and hypertriglyceridemia but not adrenomegaly in Cyp27(-/-) mice. These studies confirm the importance of CYP27 in bile acid synthesis and they reveal an unexpected function of the enzyme in triacylglycerol metabolism.

Adrenal Glands↗

PubMed2000

Expression cloning of an oxysterol 7alpha-hydroxylase selective for 24-hydroxycholesterol.

The synthesis of 7alpha-hydroxylated bile acids from oxysterols requires an oxysterol 7alpha-hydroxylase encoded by the Cyp7b1 locus. As expected, mice deficient in this enzyme have elevated plasma and tissue levels of 25- and 27-hydroxycholesterol; however, levels of another major oxysterol, 24-hydroxycholesterol, are not increased in these mice, suggesting the presence of another oxysterol 7alpha-hydroxylase. Here, we describe the cloning and characterization of murine and human cDNAs and genes that encode a second oxysterol 7alpha-hydroxylase. The genes contain 12 exons and are located on chromosome 6 in the human (CYP39A1 locus) and in a syntenic position on chromosome 17 in the mouse (Cyp39a1 locus). CYP39A1 is a microsomal cytochrome P450 enzyme that has preference for 24-hydroxycholesterol and is expressed in the liver. The levels of hepatic CYP39A1 mRNA do not change in response to dietary cholesterol, bile acids, or a bile acid-binding resin, unlike those encoding other sterol 7alpha-hydroxylases. Hepatic CYP39A1 expression is sexually dimorphic (female > male), which is opposite that of CYP7B1 (male > female). We conclude that oxysterol 7alpha-hydroxylases with different substrate specificities exist in mice and humans and that sexually dimorphic expression patterns of these enzymes in the mouse may underlie differences in bile acid metabolism between the sexes.

Amino Acid Sequence↗

PubMed2000

Disruption of the oxysterol 7alpha-hydroxylase gene in mice.

Mice without oxysterol 7alpha-hydroxylase, an enzyme of the alternate bile acid synthesis pathway with a sexually dimorphic expression pattern, were constructed by the introduction of a null mutation at the Cyp7b1 locus. Animals heterozygous (Cyp7b1(+/-)) and homozygous (Cyp7b1(-/-)) for this mutation were grossly indistinguishable from wild-type mice. Plasma and tissue levels of 25- and 27-hydroxycholesterol, two oxysterol substrates of this enzyme with potent regulatory actions in cultured cells, were markedly elevated in Cyp7b1(-/-) knockout animals. Parameters of bile acid metabolism as well as plasma cholesterol and triglyceride levels in male and female Cyp7b1(-/-) mice were normal. The cholesterol contents of major tissues were not altered. In vivo sterol biosynthetic rates were unaffected in multiple tissues with the exception of the male kidney, which showed a approximately 40% decrease in de novo synthesis versus controls. We conclude that the major physiological role of the CYP7B1 oxysterol 7alpha-hydroxylase is to metabolize 25- and 27-hydroxycholesterol and that loss of this enzyme in the liver is compensated for by increases in the synthesis of bile acids by other pathways. A failure to catabolize oxysterols in the male kidney may lead to a decrease in de novo sterol synthesis.

Animals↗

PubMed2000

Direct and moderating effects of community context on the psychological well-being of African American women.

The effects of community characteristics on well-being were examined among 709 African American women. Direct and moderating effects of neighborhood characteristics on distress were tested. Aggregate-level ratings of neighborhood cohesion and disorder were significantly related to distress, although the relation between cohesion and distress became nonsignificant when individual risk factors were statistically controlled. Aggregate-level neighborhood variables interacted significantly with individual risk and resource variables in the prediction of distress, consistent with trait-situation interaction theories (D. Magnusson & N. S. Endler, 1977). Community cohesion intensified the benefits of a positive life outlook. Community disorder intensified both the benefits of personal resources and the detrimental effects of personal risk factors. Results showed evidence of resilience among African American women.

Adaptation, Psychological↗

PubMed2000

Blood cholesterol screening influence of fasting state on cholesterol results and management decisions.

OBJECTIVE: To compare fasting and nonfasting total and high-density lipoprotein (HDL) cholesterol values in adults and to determine how closely classification into risk groups for coronary heart disease based on nonfasting blood tests compares with classification based on fasting studies. DESIGN: Cross-sectional study. SETTING: A community hospital general internal medicine clinic. PATIENTS: One hundred eighty-one patients at least 20 years of age receiving medical care at a community hospital general internal medicine clinic. INTERVENTIONS: Total and HDL cholesterol levels were measured twice in each patient within 7 days, once while not fasting and once after a minimum 12-hour fast. MEASUREMENTS AND MAIN RESULTS: Fasting and nonfasting total and HDL cholesterol values were compared, patients were classified into desirable, borderline-high, and high cholesterol groups on the basis of fasting and nonfasting blood studies. There were small, statistically significant but clinically insignificant differences in fasting and nonfasting results for total cholesterol. Nonfasting HDL cholesterol levels were similar to fasting HDL levels. The agreement in classification of patients into desirable and high-cholesterol groups between fasting and non-fasting blood testing was 86.7% and 89.5%, respectively. In the borderline-high group, for whom levels of HDL cholesterol are important in determining subsequent management, there was 95% agreement between fasting and nonfasting HDL cholesterol results. Only a small fraction of the patients were classified into lower-risk groups by the nonfasting assessment, creating the potential for less-rigorous monitoring and treatment of their cholesterol status than if fasting results were utilized. These findings were confirmed in this study also for the subgroups of men aged 35 years and older and women aged 45 years and older. CONCLUSIONS: Screening nonfasting adults for total and HDL cholesterol is appropriate for making decisions about primary prevention of coronary heart disease.

Adult↗

PubMed2000

Self-esteem, self-serving cognitions, and health risk behavior.

The current article reviews prospective and experimental research on the relation between self-esteem and perceptions of vulnerability. These studies demonstrate that individuals with high self-esteem who engage in risk behavior often utilize a variety of self-serving cognitive strategies that protect them from fully acknowledging their vulnerability to the potential negative consequences of their behavior; e.g., they minimize their estimates of personal risk and overestimate the prevalence of the risk behavior among their peers. The article also provides data on an additional self-serving cognitive strategy employed by adolescents with high self-esteem--alteration of perceptions of others' reactions to their own risk behavior. Finally, the article reviews the emerging literature on the relation between these cognitive strategies and maladaptive health behavior, and proposes that whether these strategies are maladaptive depends on the nature of the threat and the availability of opportunities to engage in compensatory self-enhancement.

Adolescent↗