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Biomedical subjects

K Hirst

Publications and source records attributed to K Hirst.

At least 19 recordsLinked to original sources

Presence of diabetes risk factors in a large U.S. eighth-grade cohort.

OBJECTIVE: The study was conducted in 12 middle schools to determine the prevalence of diabetes, pre-diabetes, and diabetes risk factors in eighth-grade students who were predominantly minority and evaluate the feasibility of collecting physical and laboratory data in schools. RESEARCH DESIGN AND METHODS: Anthropometric measurements and fasting and 2-h post-glucose load blood draws were obtained from approximately 1,740 eighth-grade students. RESULTS: Mean recruitment rate was 50% per school, 49% had BMI > or = 85th percentile, 40.5% had fasting glucose > or = 100 mg/dl, 0.4% had fasting glucose > or = 126 mg/dl, and 2.0% had 2-h glucose > or = 140 mg/dl and 0.1% > or = 200 mg/dl. Mean fasting insulin value was 30.1 microU/ml, 36.2% had fasting insulin > or = 30 microU/ml, and 2-h mean insulin was 102.1 microU/ml. Fasting and 2-h glucose and insulin values increased across BMI percentiles, and fasting glucose was highest in Hispanic and Native American students. CONCLUSIONS: There was a high prevalence of risk factors for diabetes, including impaired fasting glucose (> or =100 mg/dl), hyperinsulinism suggestive of insulin resistance (fasting insulin > or = 30 microU/ml), and BMI > or = 85th percentile. These data suggest that middle schools are appropriate targets for population-based efforts to decrease overweight and diabetes risk.

Adolescent↗

Genome-wide search for sarcoidosis susceptibility genes in African Americans.

Sarcoidosis, a systemic granulomatous disease of unknown etiology, likely results from an environmental insult in a genetically susceptible host. In the US, African Americans are more commonly affected with sarcoidosis and suffer greater morbidity than Caucasians. We searched for sarcoidosis susceptibility loci by conducting a genome-wide, sib pair multipoint linkage analysis in 229 African-American families ascertained through two or more sibs with a history of sarcoidosis. Using the Haseman-Elston regression technique, linkage peaks with P-values less than 0.05 were identified on chromosomes 1p22, 2p25, 5p15-13, 5q11, 5q35, 9q34, 11p15 and 20q13 with the most prominent peak at D5S2500 on chromosome 5q11 (P=0.0005). We found agreement for linkage with the previously reported genome scan of a German population at chromosomes 1p and 9q. Based on the multiple suggestive regions for linkage found in our study population, it is likely that more than one gene influences sarcoidosis susceptibility in African Americans. Fine mapping of the linked regions, particularly on chromosome 5q, should help to refine linkage signals and guide further sarcoidosis candidate gene investigation.

Black or African American↗

VEGF gene transfer for diabetic neuropathy.

Among diabetics, peripheral neuropathy is common and ultimately accounts for significant morbidity. The ultimate consequence of such sensory defects involving the lower extremities may be foot ulceration initiated by trauma that is inapparent to the patient. Such ulcerations often lead to lower extremity amputation, a complication that is 15 times higher in diabetic versus non-diabetic patients. Preliminary clinical studies have demonstrated improvement in signs and symptoms of sensory neuropathy in patients with lower extremity vascular occlusive disease following intramuscular injection of naked DNA encoding vascular endothelial growth factor (VEGF). To determine if such a strategy could be applied to diabetic patients, including those without evidence of large vessel occlusive disease, we investigated the hypothesis that experimental diabetic neuropathy results from destruction of the vasa nervorum and can be reversed by administration of an angiogenic growth factor. In two different animal models of diabetics, nerve blood flow and the number of vasa nervorum were found to be markedly attenuated resulting in severe peripheral neuropathy. In contrast, following VEGF gene transfer, vascularity and blood flow in nerves of treated animals were similar to those of non-diabetic controls; constitutive overexpression of VEGF resulted in restoration of large and small fiber peripheral nerve function. These findings implicate microvascular disruption as the basis for diabetic neuropathy and suggest that angiogenic growth factors may constitute a novel treatment strategy for this pernicious disorder. Accordingly, we now seek to address the following two objectives: 1. Objective #1: is to evaluate the safety and impact of phVEGF165 gene transfer on sensory neuropathy in patients with diabetes and associated macrovascular disease involving the lower extremities. 2. Objective #2: is to evaluate the safety and impact of phVEGF165 gene transfer on sensory neuropathy in patients with diabetes without macrovascular disease involving the lower extremities. The protocol outlined in this Investigational New Drug Application has been designed as a Phase I/II, single-site, dose escalating, double-blind, placebo controlled study to evaluate the safety and impact of phVEGF165 gene transfer on sensory neuropathy in patients with diabetes with or without macrovascular disease involving the lower extremities. Diabetic males or females > 21 years old with sensory neuropathy with or without macrovascular disease will be eligible. A total of 192 patients will be recruited into two arms of the study (each arm consisting of 96 patients) over a period of 4 years (the fifth year will be limited to follow-up examinations). The 96 patients in each of the two arms of the study will comprise 3 cohorts, each consisting of 32 patients. Within each of these cohorts, patients will be randomized to receive phVEGF165 or placebo based upon a 3:1 randomization ratio. Thus, at the completion of the study, 24 patients will have each received a given dose (1, 2, or 4 mg phVEGF165) and 24 patients will have received placebo. Doses will be employed in a serial dose-escalating fashion. The entire volume of the study drug will be divided and delivered in 8 intramuscular injections administered into the foot, calf muscle, or distal thigh muscle of the affected extremity. Following the initial set of injections, repeat treatment with an identical dose will be provided 2 and 4 weeks after initial treatment.

Adult↗

The use of hepatitis C viral RNA levels in liver tissue to distinguish rejection from recurrent hepatitis C.

Persistence of hepatitis C virus (HCV) after orthotopic liver transplantation is almost universal in HCV-infected patients. Histological examination of liver biopsy specimens can be variable in distinguishing between recurrent hepatitis C and acute cellular rejection. The purpose of this study is to determine whether hepatic HCV RNA levels can be used to distinguish rejection from recurrent HCV by determining whether hepatic HCV RNA levels correlate with histological characteristics and clinical course. Seventy-two biopsy specimens were evaluated from 36 liver transplant recipients with HCV and elevated liver-related enzyme levels. Based on histological findings and clinical response to therapy, patients were defined as belonging to 1 of 5 groups: (1) definite rejection, (2) probable rejection, (3) indeterminate findings, (4) probable HCV, and (5) definite HCV. Hepatic HCV RNA was quantified using the Amplicor Monitor assay (Roche Diagnostic Systems Inc, Branchburg, NJ). There was a difference across groups in HCV RNA levels (P =.046). The median HCV RNA level was 10,695 copies/mg of tissue DNA in the definite-HCV group compared with 1,024 copies/mg of tissue DNA in the definite-rejection group. Using pairwise comparisons, significant differences were found between definite HCV and definite rejection, probable HCV and definite rejection, probable HCV and probable rejection, and probable HCV and indeterminate. Our findings support the following conclusions. (1) In liver transplant recipients, hepatic HCV RNA levels are statistically greater in patients with recurrent HCV than rejection, although there is considerable overlap between groups. (2) Patients with low HCV RNA levels were unlikely to have recurrent HCV. (3) Patients with minimal and indeterminate findings on biopsy (group 3) had low HCV RNA levels.

Adult↗

The Next Step Trial: impact of a worksite colorectal cancer screening promotion program.

BACKGROUND: The Next Step Trial was a randomized trial of worksite colorectal cancer screening promotion and nutrition interventions for automobile industry employees at increased risk of colorectal cancer. Interventions were tested at 28 worksites with 5,042 employees. This report describes results of the screening promotion intervention. METHODS: Worksites randomized to the control group received a standard program including rectal examination, fecal occult blood testing, and flexible sigmoidoscopy. Intervention worksites received an enhanced program (i.e., standard program plus an educational booklet/telephone call). Compliance (i.e., completion of all recommended screening examinations) and coverage (i.e., completion of at least one screening examination), the primary and secondary outcomes, were measured over 2 years. RESULTS: In the 2 years prior to baseline, 61% of employees had been screened. After random assignment, baseline differences in several employee characteristics and worksite screening procedures were detected, including more past history of screening in control worksites. After adjusting for differences, we found modest, but higher, compliance and coverage in intervention compared with control worksites (odds ratio [95% confidence limits] = 1.46 [1.1-2.0] and 1.33 [1.1, 1.6], respectively). CONCLUSIONS: Adding a personally tailored behavioral intervention to a standard colorectal cancer screening program can promote continued employee participation in screening as measured by compliance. Further research is needed to assess intervention effects in other populations.

Automobiles↗

Nutrition intervention for high-risk auto workers: results of the Next Step Trial.

BACKGROUND: The Next Step Trial tested interventions encouraging prevention and early detection practices in automotive-industry employees at increased colorectal cancer risk. This article describes results of the nutrition intervention promoting low-fat, high-fiber eating patterns. METHODS: Twenty-eight worksites (5,042 employees at baseline) were randomized to a 2-year nutrition intervention including classes, mailed self-help materials, and personalized dietary feedback. Control worksites received no intervention. Nutrition outcomes were assessed by mailed food frequency questionnaires (FFQs) Primary nutrition outcomes included percentage energy from fat and fiber density (g/1,000 kcal) at 1 year postrandomization. Secondary outcomes included servings of fruits/vegetables and dietary measures at 2 years postrandomization. Analyses were adjusted for within worksite correlations and baseline covariates. Fifty-eight percent of employees returned FFQs. RESULTS: At 1 year, there were modest but statistically significant intervention effects for fat (-0.9 %en), fiber (+0.5 g/1,000 kcal), and fruits/vegetables (+0.2 servings/day) (all P < 0.007). At 2 years, due to significant positive changes in control worksites, intervention effects were smaller, significant for fiber only. Intervention effects were larger in younger (<50 years), active employees and class attendees. CONCLUSION: The nutrition intervention produced significant but modest effects on dietary fat and fiber and fruits/vegetables in these high-risk employees. Age and dose effects suggest younger employees may be more responsive to this intervention.

Adult↗

Psychosocial correlates of healthful diets among male auto workers.

A better understanding of factors associated with healthful eating practices can improve the design and evaluation of dietary intervention programs. Up to now, little information has been available about these factors in high-risk but healthy populations. This article presents findings of a study of psychosocial factors, including stage of change, and their relationship to patterns of consumption of dietary fat, fiber, and fruits and vegetables in a population of males at increased risk of colorectal cancer. Data are from the baseline survey for the Next Step Trial, a randomized, controlled trial of worksite nutrition and colorectal cancer screening promotion interventions. The respondents (n = 2764) were actively employed or retired auto workers at increased colorectal cancer risk. The psychosocial constructs measured were predisposing factors (benefits, motivation, knowledge; eight items; Cronbach alpha = 0.50), enabling factors (barriers, norms, social support; six items; Cronbach alpha = 0.55), and stages of change for adopting diets lower in fat and higher in fiber/fruits and vegetables. The measures of diet, assessed with a food frequency questionnaire, were intakes of fat, fiber, and servings of fruits and vegetables. There were strong and statistically significant positive associations between both predisposing and enabling scale scores and stages of change for fat and fiber. The percentage of respondents in maintenance stage ranged from 4-80% for fat and 11-81% for fiber, across low to high predisposing scale scores; for enabling scale scores, ranges were 11-71% for fat and 22-81% for fiber. Stage of change was associated with fat, fiber, and fruit and vegetable intake in a stepwise manner, with the greatest change observed between action and maintenance. Correlations with dietary outcomes were significantly greater for predisposing factors (r = -0.30 for fat and 0.36 for fiber) than for enabling factors (r = -0.23 for fat and 0.28 for fiber). Multiple regression models, which included the predisposing and enabling factor scales, stage of change, and covariates related to diet, explained a total of between 16 and 27% of the variance in diet. Predisposing and enabling factors are significantly associated with of stage of change and current diet in this high-risk sample of male auto workers. Stage of change is the strongest correlate examined and seems to serve as a mediating factor for dietary change. Results from the Next Step Trial will provide additional data on whether and how health promotion interventions influence these factors, and whether such changes are associated with dietary change.

Aged↗

Bone mineral density and biochemical markers of bone turnover in healthy elderly men and women.

BACKGROUND: Osteoporosis risk in middle-aged women is twofold greater than that in men, and the difference increases with age. Gender differences in bone mineral density, estimated rates of bone loss, and usefulness of markers of bone metabolism for predicting bone density have not been well described in healthy elders aged 65 and above. The purpose of this cross-sectional analysis was to describe associations of bone mineral density at the hip, spine, and whole body with age, serum osteocalcin, and urinary N-telopeptide crosslinks of Type I collagen in healthy elderly men and women. METHODS: A total of 1,087 healthy adults (273 men and 814 women) aged 65 to 87 years were enrolled in a collaborative study at 3 sites: Tufts University (Boston, MA), University of Connecticut Health Center (Farmington, CT), and Creighton University (Omaha, NE). Bone mineral density (BMD) at three regions of the hip, the lumbar spine, and whole body was determined by dual-energy x-ray absorptiometry. Serum osteocalcin was measured by immunoassay, and measurement of N-telopeptide crosslinks (Ntx) in urine was made using an enzyme-linked radioimmunoassay (ELISA). RESULTS: Among women, the age-related decline in BMD at all non-spine skeletal sites was significantly different from zero, with the largest decline seen at the femoral neck (-.0038 g/cm2/y, p < .001) and the smallest at the trochanter of the hip (-.0023 g/cm2/y, p = .03). Among men, the changes at all non-spine sites were not significant. In both sexes, spine BMD tended to increase with age (men, +.0045 g/cm2/y, women, +.0003 g/cm2/y). Serum osteocalcin and urinary Ntx were inversely related to BMD at all skeletal sites, but the weakest associations were observed at the spine. Individuals whose values of both osteocalcin and Ntx were in the lowest quartiles of the respective sex-specific distributions had mean femoral neck BMD that were 11% higher than individuals with marker values in the highest quartiles. CONCLUSIONS: These findings suggest that age-related decreases in BMD may vary by gender and skeletal site. Determinations of osteocalcin and N-telopeptide crosslinks at a single point in time may potentially be used as indicators of current bone status, particularly at non-spine skeletal sites.

Aged↗

A generalized Michaelis-Menten response surface.

We describe an application of recently developed generalized Michaelis-Menten response surface and non-linear mixed model methodologies to model glucose utilization in foetal sheep. More specifically, we model the response surface of glucose utilization rate in the foetal sheep as a function of glucose and insulin concentrations using a three-dimensional analogue of the Michaelis-Menten pharmacokinetic model. To account for multiple measurements per sheep, we apply the non-linear mixed effects model proposed by Lindstrom and Bates using the EM algorithm computational scheme presented by Hirst et al.

Animals↗

The transcription factor, the Cdk, its cyclin and their regulator: directing the transcriptional response to a nutritional signal.

The Pho80-Pho85 cyclin-cdk complex prevents transcription of PHO5 by inhibiting the ability of the basic-helix-loop-helix transcription factor Pho4 to activate transcription in response to high phosphate conditions. In low phosphate the Pho80-Pho85 complex is inactivated and Pho4 is then able to activate the acid phosphatase gene PHO5. We show here that Pho4 and the homeobox protein Pho2 interact in vivo and act cooperatively to activate the PHO5 UAS, with interaction being regulated by the phosphate switch. In addition, we also demonstrate that an additional factor, Pho81, interacts in high phosphate with both the Pho80 cyclin and with Pho4. In low phosphate, Pho80 and Pho81 dissociate from Pho4, but retain the ability to interact with each other. The evidence presented here supports the idea that Pho81 acts as a phosphate-sensitive trigger that regulates the ability of the Pho80-Pho85 cyclin-cdk complex to bind Pho4, while DNA binding by Pho4 is dependent on the phosphate-sensitive interaction with Pho2.

Acid Phosphatase↗

The activation domain of a basic helix-loop-helix protein is masked by repressor interaction with domains distinct from that required for transcription regulation.

While there are many examples of protein-protein interactions modulating the DNA-binding activity of transcription factors, little is known of the molecular mechanisms underlying the regulation of the transcription activation function. Using a two-hybrid system we show here that transcription repression of the basic domain/helix-loop-helix factor PHO4 is mediated by complex formation with the PHO80 repressor. In contrast to other systems, such as inhibition of GAL4 by GAL80 or of p53 by MDM2, where repression is mediated by direct interaction at regions overlapping the transcription activation domain, interaction with PHO80 involves two regions of PHO4 distinct from those involved in transcription activation or DNA-binding and dimerization. The possibility that repression of PHO4 by PHO80 may represent a general mechanism of transcription control, including regulation of the cell-type-specific transcription activation domain of c-Jun, is discussed.

Amino Acid Sequence↗

Gender differences in lipid alterations following combined pancreas-kidney transplantation.

We have previously demonstrated that the lipid profile improves following successful combined pancreas-kidney transplantation (PKT). In this study, we examined whether changes in the lipid profile were different in men than in women following PKT. Fasting total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL), and the TC to HDL ratio (TC/HDL) were evaluated in 47 patients (27 men and 20 women) with normal graft function following PKT. Lipids were evaluated at regular intervals 3.5 months to 2.2 years post-PKT (a total of 317 observations). After PKT, TC/HDL decreased (P < .05), TC was unchanged, and HDL increased (P < .05) in both men and women. Although TG decreased in both men and women, it reached statistical significance in men only (P < .05). There were no significant differences in any lipid parameters between men and women before PKT, but after PKT, TC, TG, and HDL were higher in women (240 +/- 11, 183 +/- 17, and 64 +/- 19 mg/dL, respectively) than in men (207 +/- 6, 143 +/- 11, and 53 +/- 2 mg/dL, P < .05 for each). When post-PKT values were analyzed for trends over time, both TC and TG decreased (P < .05 for both) without any significant difference in trends between men and women. When six individuals who had received lovastatin at any time during their postoperative course were removed from analysis, the gender differences in TG post-PKT and the decrease in TG over time were no longer statistically significant (P > .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗

Frozen section evaluation of donor livers before transplantation.

Frozen section examination was performed on 385 donor livers before transplantation. Exclusion criteria were applied to the donor livers examined to exclude potentially dysfunctional livers. The exclusion criteria included the following: severe macrovesicular steatosis, ischemic necrosis, prominent chronic portal inflammation, prominent periductular fibrosis, granulomatous inflammation, bridging fibrosis, and malignancy. Twenty-seven of the 385 donor livers examined were excluded before transplantation. The following histologic features were present in the excluded livers: severe steatosis (22), ischemic necrosis (2), portal inflammation (1), and periductular fibrosis (2). Steatosis was present in 51 of the 385 (13.25%) organs examined, including 22 of the donor organs excluded before transplantation. Twenty-nine livers with mild to moderate steatosis were implanted into size and blood type-matched recipients. Indicators of allograft function (prothrombin time and bilirubin) and damage (aspartate aminotransferase and alanine aminotransferase) were measured daily for the first 10 days after transplant. There was no statistically significant difference between the group of nonfat livers and donor livers containing mild steatosis. Statistically significant higher posttransplant serum alanine aminotransferase and prothrombin time levels were present in the patients with livers implanted with mild versus moderate steatosis. The 1-year survival rate for patients receiving fatty versus nonfatty donor livers was not statistically different (Kaplan-Meier, P = 0.592). No significant differences were found in the clinical and laboratory characteristics of donors whose organs were implanted compared with the clinical and laboratory characteristics of donors whose organs were excluded. The primary nonfunction rate after applying the exclusion criteria was 1.4%, which is a significant decrease compared with our primary nonfunction rate of 8.5% before using frozen section examination. Frozen section examination is useful in excluding donor organs which may become dysfunctional after transplantation.

Adenosine↗

Authentic temperature-regulation of a heat shock gene inserted into yeast on a high copy number vector. Influences of overexpression of HSP90 protein on high temperature growth and thermotolerance.

Heat shock protein HSP90 is relatively abundant in eukaryotic cells even in the absence of heat shock. Its precise function is still unclear, although it is apparently required in higher levels for growth at high temperatures. In this study Saccharomyces cerevisiae transformants were constructed with 50-150 copies of the homologous heat-inducible gene for HSP90 (HSP82) present on a high copy number episomal vector. These transformants were then used to demonstrate: (i) that this heat shock gene displays essentially normal regulation when present in yeast at high copy numbers; (ii) that yeast is an expression host suitable for the high level synthesis of HSP90; and (iii) that increasing normal cellular levels of HSP90 affects a number of physiological properties. The HSP82 gene is normally single-copy in the haploid yeast genome, yet even at 50 to 150 copies per cell it displayed almost normal basal and heat shock-induced levels of expression. Proper regulation of the heat shock element sequence controlling HSP82 is therefore not lost at high gene copy levels. In unstressed cultures in exponential growth at 25 degrees C the low basal expression of the multiple HSP82 gene copies caused a 3 to 7-fold HSP90 overproduction, but HSP90 levels increased 10-fold to 30-40% of total cell protein following temperature upshift to 39 degrees C for 75 min. Heat induction of the chromosomal genes for other heat shock proteins in the same cells was not suppressed relative to cells which were isogenic but for the possession of just a single HSP82 gene, this constituting further evidence that yeast can authentically regulate a large number of heat shock genes. HSP90 overproduction was not protective against heat killing, causing strain-dependent reductions in growth at 37.5 degrees C and in thermotolerance.

Autoradiography↗

Starvation for His-tRNAHis in yeast causes translational arrest without a high level of misincorporation of glutamine at histidine codons.

The hts1.1 temperature-sensitive histidinyl-tRNA synthetase mutation enables Saccharomyces cerevisiae to be starved for His-tRNAHis by upshift to the non-permissive temperature of 38 degrees C. If yeast behaves similarly to bacterial and mammalian cells, this lack of His-tRNAHis should greatly enhance misreading at histidine codons (CAU/CAC) by Gln-tRNAGln, resulting in substitution of the neutral amino acid glutamine in place of histidine, a basic amino acid. Such misreading causes the isoelectric point (pI) of proteins to shift to lower values, and is readily detectable as "stuttering" on two-dimensional (2D) protein gels. By gel analysis of pulse-labelled proteins of hts1.1 yeast cells that were overexpressing phosphoglycerate kinase (PGK), our study sought to detect this specific translational error in PGK protein. It was not detected by this relatively sensitive technique, indicating that missense errors due to glutamine insertion at histidine codons do not occur in yeast at the readily-detectable level found in bacterial and mammalian cells.

Codon↗

Lipid status after combined pancreas-kidney transplantation and kidney transplantation alone in type I diabetes mellitus.

This study was designed to compare changes in lipid status following organ transplantation between type I diabetes mellitus (DM-I) patients receiving combined pancreas-kidney transplantation (PKT) with those receiving kidney transplantation alone (KTA). A retrospective chart review was used to identify pre- and posttransplantation fasting total cholesterol (TC) and triglycerides (TG) in three groups: DM-I patients receiving KTA (DM:KTA; n = 14), DM-I patients receiving PKT (DM:PKT; n = 20), and kidney transplant recipients without DM (NDM; n = 16). The groups were matched for age, gender, weight, duration of dialysis, smoking history, and duration of diabetes mellitus. Linear regression was used to analyze differences in lipid trends over time (up to 24 months posttransplantation) and the effects of prednisone dose, cyclosporine dose, and serum creatinine. Preoperative TC was significantly lower in the DM:KTA group (P < 0.05) compared with DM:PKT or NDM. There were no significant differences in preoperative TG between the three groups. TC and TG decreased over time only in DM:PKT (P = 0.0112, P = 0.0278, respectively). TC increased and TG was unchanged over time in DM:KTA (P = 0.0003, P = 0.1103, respectively). Neither TC nor TG changed over time in NDM. Trends of TC and TG for DM:PKT were significantly different from DM:KTA (P < 0.01 for both). Trend of TC for NDM was also significantly different from DM:PKT (P = 0.0061). Prednisone dose was significantly related to TC in DM:KTA and NDM (P < 0.01) while cyclosporine dose was significantly related to TC for DM:KTA only (P = 0.0013) in the presence of time. None of the variables tested (prednisone dose, cyclosporine dose, and serum creatinine) significantly affected TG in the presence of time. In summary, TC and TG decreased over time only in DM:PKT. In contrast, TC increased while TG was unchanged in DM:KTA over the same interval (0-24 months). If these trends continue, the beneficial change in lipids in the DM:PKT group may translate into a net improvement in atherosclerosis-mediated events for diabetic patients with chronic renal failure who receive PKT compared with those who do not.

Adult↗