Biomedical subjects
Publications and source records attributed to T Harris.
The recent availability of whole-genome sequences and large numbers of protein-coding regions from high-throughput cDNA analysis has fundamentally changed experimental biology. These efforts have provided huge databases of protein sequences, many of which are of unknown function. Deciphering the functions of these myriad proteins presents a major intellectual challenge.
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Commercial efforts in structural genomics focus on providing to pharmaceutical customers information that relates to the suitability of specific proteins as drug targets and the informed selection and refinement of lead compounds generated by high-throughput screening and rational approaches. These efforts follow a variety of business models and are impacted by activities in the public domain, recent technological advances, and the changing intellectual property landscape.
The relationship between persistent ERK (extracellular signal-regulated kinase) activity, cyclin D1 protein and mRNA levels and cell cycle progression in human cultured airway smooth muscle was examined in response to stimulation by ET-1 (endothelin-1), thrombin and bFGF (basic fibroblast growth factor). Thrombin (0.3 and 3 u ml(-1)) and bFGF (0.3 and 3 nM) increased ERK activity for more than 2 h and increased cell number, whereas ET-1 (100 nM) transiently stimulated ERK activity and was non-mitogenic. The MEK1 (mitogen-activated ERK kinase) inhibitor, PD 98059 (30 microM), inhibited both ERK phosphorylation and activity, and either prevented (thrombin 0.3 and 3 u ml(-1), bFGF 300 pM) or attenuated (bFGF 3 nM) DNA synthesis. Thrombin and bFGF increased both cyclin D1 mRNA and protein levels. PD 98059 decreased cyclin D1 protein levels stimulated by the lower but not higher thrombin concentrations. Moreover, increases in cyclin D1 mRNA levels were unaffected by PD 98059 pretreatment, irrespective of the mitogen or its concentration, suggesting that inhibition of cyclin D1 protein levels occurred by a post-transcriptional mechanism. These findings indicate that the control of cyclin D1 protein levels may occur independently of the MEK1/ERK signalling pathways. The inhibition of S phase entry by PD 98059 at higher thrombin concentrations appears to result from effects on pathways downstream or parallel to those regulating cyclin D1 protein levels. These findings suggest heterogeneity in the signalling of DNA synthesis in human cultured airway smooth muscle.
BACKGROUND: Muscle weakness, low body weight, and chronic diseases are often observed in the same people; however, the association of muscle strength with mortality, independent of disease status and body weight, has not been elucidated. The aim was to assess hand grip strength as a predictor of all-cause mortality within different levels of body mass index (BMI) in initially disease-free men. METHODS: Mortality was followed prospectively over 30 years. Maximal hand grip strength tests and BMI assessments were done at baseline in 1965 to 1970. The participants were 6040 healthy men aged 45 to 68 years at baseline living on Oahu, Hawaii. RESULTS: The death rates per 1000 person years were 24.6 in those with BMI <20, 18.5 in the middle BMI category, and 18.0 in those with BMI > or = 25. For grip strength tertiles, the mortality rates were 24.8 in the lowest, 18.5 in the middle, and 14.0 in the highest third. In Cox regression models, within each tertile of grip strength, BMI showed only minimal effect on mortality. In contrast, in each category of BMI there was a gradient of decreasing mortality risk with increasing grip strength. Among those with BMI <20, the adjusted relative risks (RRs) of mortality over 30 years were 1.36 (95% confidence interval 1.14-1.63) for those in the lowest third of strength at baseline, 1.27 (1.02-1.58) in the middle, and 0.92 (0.66-1.29) in the highest third. Correspondingly, for those with BMI 20-24.99, the RRs of death were 1.25 (1.08-1.45), 1.14 (1.00-1.32), and 1.0 (reference) in the lowest, middle, and highest third of grip strength, respectively. In those with BMI > or =25, the RRs were 1.39 (1.16-1.65) in the lowest, 1.27 (1.08-1.49) in the middle, and 1.14 (0.98-1.32) in the highest third of grip strength. Models were adjusted for age, education, occupation, smoking, physical activity, and body height. CONCLUSIONS: In healthy middle-aged men, long-term mortality risk was associated with grip strength at baseline, independent of BMI. The possible interpretation of the finding is that early life influences on muscle strength may have long-term implications for mortality. Additionally, higher strength itself may provide greater physiologic and functional reserve that protects against mortality.
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BACKGROUND: TSEN (MNS33) is a low-incidence antigen in the MNS blood group system encoded by hybrid glycophorin genes. TSEN is expressed by a unique amino acid sequence that results from the junction of GPA(58) to GPB(27), if the GPB carries S antigen. Until this study, only one example of anti-TSEN had been found. Antibody screening red blood cells (RBCs) positive for both S and s (ref. No. C873) reacted with four patient sera. Initially, the RBCs had been typed as S+s+, but later were typed as S-s+ in another laboratory. Two other RBC samples, one from a volunteer blood donor (D.L.), the other from a patient whose serum contained anti-En(a)FR (J.S.), also gave anomalous results when tested with anti-S. We suspected the presence of TSEN-positive hybrids on all three RBC samples. MATERIALS AND METHODS: Reactive sera (O.B., E.C., S.K., R.F.) were tested against RBCs with normal MNS phenotypes and with TSEN-positive RBCs. The RBCs of D.L., J.S. and C873 were tested with anti-S whose reactivity with S+s+ TSEN+ RBCs had been established previously, and with the original example of anti-TSEN. Immunoblotting was performed on the C873, D.L. and J.S. RBC membranes using a monoclonal antibody to an epitope common to both glycophorin A and glycophorin B. RESULTS: The sera from O.B., E.C., S.K. and R.F. were strongly reactive on the indirect antiglobulin test with TSEN+ RBCs. The RBCs of C873, D.L. and J.S. were typed as TSEN+. Immunoblotting pattern of D.L. and C873 were consistent with TSEN heterozygotes, while that of J.S. was consistent with a TSEN homozygote. CONCLUSIONS: Based on the estimated number of screening events with C873 RBCs, the incidence of anti-TSEN is approximately 1 in 20,000 sera. The antibody is found in patients with and without documented exposure to allogeneic RBCs. All known examples of anti-TSEN are IgG, but their clinical significance is not known.
BACKGROUND: An excess of both depression and undesirable life events in first-degree relatives of probands with depression as compared with controls has been reported. This association may have reflected a familial factor in common. AIMS: To examine the familiality of life events and depression and whether there may be a common familial factor influencing vulnerability to depression and the experiencing of life events. METHOD: In a sib-pair design, 108 probands with depression and their siblings were compared with 105 healthy controls and their siblings for psychopathology and life events. RESULTS: The lifetime relative risk of depressive disorder in the siblings of depressed subjects as compared with siblings of controls was 9.74, although these groups did not differ in the life events measures. Several categories of events showed significant sibling correlations, but this was due to the same event affecting both members of the pair. CONCLUSIONS: Although depressive disorder was strongly familial, the familial effects on life events were largely explained by shared experiences. There was no evidence for a common factor influencing both depression and life events.
OBJECTIVE: To assess the relationship between impaired glucose tolerance and both vascular dementia and AD. BACKGROUND: Diabetes and abnormalities of glucose metabolism have been associated with stroke and poor cognitive function. In addition, glycoproteins and glycosylation have been postulated to be associated with the development of neuritic plaques characteristic of AD. METHODS: A historical prospective cohort study of Japanese-American men (n = 3,774), who were examined at ages 45 to 68 (1965 through 1968) and again at ages 71 to 93 (1991 through 1993). Measurements were obtained by clinical and home examinations: assessment of glucose intolerance (nonfasting 1 hour after glucose load) from 1965 through 1968 and history of diabetes diagnosed by a physician at examinations given from 1965 through 1968 and from 1976 through 1978. At the 1991 through 1993 examinations, the Cognitive Assessment Screening Instrument (CASI)-an instrument designed for use in cross-cultural settings combining features of the Folstein Mini-Mental State Examination, the Modified Mini-Mental State Examination, and the Hasegawa Dementia Screening Scale-was used. Diagnosis and classification of AD and vascular dementia were made by a consensus panel using neuropsychologic assessment data, a neurologist's evaluation, and information from a family informant. Diagnostic and Statistical Manual of Mental Disorders, 3rd ed., revised criteria were used to establish dementia, and subclassification by cause was based on other published criteria. RESULTS: No association between AD and diabetes, present either 25 or 15 years previously, was found after adjustment for age and education in a multiple regression model. A significant association was found between impaired glucose tolerance at baseline and vascular dementia (p < 0.01). CONCLUSIONS: These findings confirm expected relationships between impaired glucose tolerance and stroke-related dementia but do not support an association of disordered glucose metabolism with AD.
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OBJECTIVE: To assess the efficacy and safety of an external urethral barrier for the management of mild to moderate stress urinary incontinence in adult women. METHODS: Four hundred eleven women with the symptom of stress urinary incontinence in 12 United States centers participated. Additional inclusion and exclusion criteria were applied before protocol device use, and ultimately 390 subjects began device use. Outcome measures for efficacy and safety were assessed. Efficacy was evaluated by the number of leakage episodes using a voiding diary, subjective urinary leakage severity, incontinence impact scores, and pad testing. Safety was evaluated by symptom assessment, urinalysis, urine culture, measurement of postvoid residual urine volume, vulvar cytology, vaginal culture, and (n = 81) cystometric testing. RESULTS: Efficacy was indicated by statistically significant reductions in the number of leakage episodes, subjective leakage severity scores, incontinence impact scores, and pad-test loss during device use. The data also indicated that the device was safe, as evidenced by the lack of statistically significant changes in the percentage of subjects with urinary tract infections during device use or in postvoid residual urine volume and cystometric indices. Symptoms of vulvar irritation or lower urinary tract discomfort occurred in a small percentage of subjects but were generally transient, and only three women discontinued using the device. CONCLUSION: The external urethral barrier appears to be a safe nonsurgical alternative to absorbent products for the management of mild to moderate stress urinary incontinence in adult women.
OBJECTIVES: To evaluate the validity, reliability and feasibility of the TOSCE, a new means of formative assessment for medical students, from the perspectives of examiners, simulated patients and students. DESIGN: Teams of five students rotate through five clinical stations, performing one of four tasks in turn, whilst the fifth member of the team 'rests'. SETTING: St George's Hospital Medical School, London. SUBJECTS: Third-year medical students, their examiners and simulated patients. RESULTS: All participants felt the TOSCE session had high validity although some students were unfamiliar with some subjects. Stations were double-marked and agreement rates and Cohen's Kappa ranged from 67 to 94% and 0.04-0.88, respectively. Analysis of the causes of disagreement led to improved marking schedules and enhanced reliability. CONCLUSIONS: The feasibility of the exercise as a formative assessment was demonstrated by the confidence of the staff participating both as examiners and simulated patients and from the majority of students who welcomed the learning experience.
OBJECTIVES: The prevalence of depression increases with age, as does the prevalence of higher levels of the cytokine interleukin-6 (IL-6). This analysis was performed to determine the association between increased levels of this cytokine and depression in a population-based sample. DESIGN: Cross-sectional cohort study. SETTING: Rural and urban counties in North Carolina. PARTICIPANTS: Community-dwelling older people. MEASUREMENTS: The association between IL-6 and other biologic variables with self-report depression was examined in 1686 persons aged 70 years and older in the third in-person survey wave (1991) of the Duke Established Population for Epidemiologic Studies of the Elderly (EPESE). Bivariate associations were established by the Spearman correlation, adjusted for age. A stepwise linear logistic regression model was used to derive a final model to assess multivariable effects on CES-D scores. RESULTS: Depression was correlated with IL-6 (P = .011), D-Dimer (P = .017), alpha-1-globulin (P = .023), alpha-2-globulin (P = .002), and beta globulin (P = .012). After controlling for age, race, and gender, IL-6 levels remained the only biologic variable significantly associated with depression (P = .035). CONCLUSION: These data suggest that the inflammatory marker, IL-6, is associated with depression in older people in this cross-sectional study. These results are compatible with the hypothesis of cytokine (IL-6) stimulation in geriatric depression as part of an overall immunoendocrine dysregulation.
OBJECTIVE: To test the hypothesis that bone mineral density (BMD), a marker of cumulative estrogen exposure, is associated with cognitive function in nondemented older women. DESIGN: A prospective cohort study. SETTING: Clinical centers in Baltimore, Maryland, Minneapolis, Minnesota, the Monongahela Valley near Pittsburgh, Pennsylvania, and Portland, Oregon. PARTICIPANTS: We evaluated 8333 older community-dwelling women enrolled in the Study of Osteoporotic Fractures who were not taking estrogen replacement. MEASUREMENTS: Calcaneal and hip BMD were measured at baseline and at follow-up (4-6 years later); vertebral fractures were ascertained radiologically at year 6. Women were administered a modified Mini-Mental State Exam, Trails B, and Digit Symbol at baseline and at follow-up. RESULTS: Compared with women with higher bone mineral density, women with low baseline BMD had up to 8% worse baseline cognitive scores (P = .001) and up to 6% worse repeat cognitive scores (P = .001), even after multivariate adjustments. For 1 SD decrease in baseline hip BMD or calcaneal BMD, women had a 32% (95% CI, 19-47%) or a 33% (95% CI, 20-48%) greater odds of cognitive deterioration (worst 10th percentile of change). Women with vertebral fractures had lower cognitive test scores and a greater odds of cognitive deterioration than those without fractures (OR = 1.29; 95% CI, 1.03-1.60). CONCLUSIONS: Women with osteoporosis, whether measured by baseline BMD, reductions in BMD, or vertebral fractures, have poorer cognitive function and greater risk of cognitive deterioration. Our findings suggest a link between two of the most common conditions affecting older women. Further understanding of this association may be important for new treatment and prevention directions.
OBJECTIVE: Infection with the hepatitis C virus (HCV) becomes chronic in 85% of the infected individuals. We studied risk factors that may predict clearance of HCV. METHODS: A case-control study compared the association between risk factors and viral clearance. Viral clearance was defined as presence of a positive HCV antibody test plus negative HCV test by polymerase chain reaction (PCR). Forty-four cases and 214 controls with persistent viremia were identified in a database of patients evaluated at the Gastroenterology Clinic of the University of New Mexico. RESULTS: Of all 258 HCV-antibody-positive patients, 17% had a negative test by PCR. The multivariate logistic regression revealed that a history of parenteral exposure and a long time interval since the most recent exposure were both associated with an increased likelihood of persistent viremia, whereas subjects who had been monogamous for longer time periods were more likely to have cleared HCV from their serum. A low serum level of ferritin also conferred protection against persistent viremia. Case and control subjects did not differ with respect to their demographic characteristics, occurrence of comorbid disease, previous medical history, occurrence of sexually transmitted diseases, blood group, and risky health or sexual practices. CONCLUSIONS: These data suggest that route of exposure and time when exposure occurred are important in the development of persistent HCV infection.
Hyperplasia of airway smooth muscle (ASM) contributes to the airway hyperresponsiveness that characterizes asthma. We have investigated the relationship between cAMP-induced growth arrest of ASM cells and thrombin-stimulated, extracellular-regulated protein kinase (ERK) activity, cyclin D1, and the restriction protein retinoblastoma. The beta(2)-adrenergic receptor agonist albuterol (100 nM) inhibited DNA synthesis after incubation with ASM for periods as brief as 1 h when these coincided with the timing of the restriction point. Inhibition of thrombin-stimulated DNA synthesis by albuterol (1-100 nM), 8-bromo-cAMP (300 microM), or prostaglandin E(2) (1 microM) was accompanied by a reduction in cyclin D1 protein levels. The ERK kinase inhibitor PD98059 (3-30 microM) attenuated thrombin-stimulated ERK phosphorylation and activity and the increase in cyclin D1 protein levels, as did albuterol (1-100 nM) or 8-bromo-cAMP (300 microM). In contrast, neither albuterol (100 nM) nor PD98059 (30 microM) reduced cyclin D1 mRNA levels between 4 and 20 h after thrombin addition, which suggests that elevation of cAMP regulates cyclin D1 by a post transcriptional mechanism. The proteasome inhibitor MG132 (30 and 100 nM) and the calpain I inhibitor N-acetyl-Leu-Leu-leucinal (10 microM) attenuated the reduction in thrombin-stimulated cyclin D1 levels in ASM exposed to albuterol (100 nM), 8-bromo-cAMP (300 microM), or the phosphodiesterase inhibitor isobutylmethylxanthine (100 microM). Thus, the cAMP-induced arrest of ASM in the G(1) phase of the cell cycle is associated with a proteasomal degradation of cyclin D1 protein and a reduced protein retinoblastoma phosphorylation that prevents passage through the restriction point.
We have previously shown that glucocorticoids inhibit mitogen-stimulated proliferation of human cultured airway smooth muscle (ASM) cells. The present study analyzed the effect of glucocorticoids on key regulatory pathways leading to passage of cells through the restriction point of the cell cycle, including those mediated by extracellular-regulated kinases (ERK) 1 and 2; the ERK upstream regulator MAPK kinase (MEK1); cyclin D1 levels; and levels and phosphorylation of retinoblastoma protein (pRb). Fluticasone propionate, a new inhaled glucocorticoid, was at least 10-fold more potent than dexamethasone in inhibiting thrombin-stimulated DNA synthesis and increases in cell number. Thrombin-stimulated increases in the levels and hyperphosphorylation of pRb were inhibited by glucocorticoids, which also reduced thrombin-stimulated cyclin D1 protein and messenger RNA (mRNA) levels. PD98059 (10 microM), an inhibitor of MEK1 activation, markedly attenuated thrombin stimulation of ERK activity and phosphorylation, DNA synthesis, and cyclin D1 levels. However, glucocorticoids had no effect on ERK activity or phosphorylation at 5 min, 2 h, or 12 h after addition of thrombin. In conclusion, glucocorticoid-induced reduction of cyclin D1 mRNA and protein levels, and of pRb phosphorylation, is sufficient to account for inhibition of ASM proliferation. Furthermore, these inhibitory effects of glucocorticoids on cyclin D1 and pRb occur on a component of the mitogen signaling cascade that is either downstream of or parallel to the ERK pathway.
BACKGROUND: Earlier work on the protective role of social support in onset and course of depressive disorder suggested that its provision might be relevant for outcome. AIMS: To evaluate volunteer befriending as an intervention among women with chronic depression in inner London. METHOD: A randomised controlled trial, with a waiting list control design, with outcome measured as Present State Examination (PSE)-based full or partial remission after one year. RESULTS: A statistically significant effect upon remission was found for befriending. Other treatments monitored naturalistically did not relate to remission, nor did initial duration of chronic episode or comorbidity, but there was an association with initial PSE score. The findings are discussed in relation to standard drug-trial results and to another befriending intervention with the elderly. CONCLUSIONS: The results are not unpromising. Additional trials with less restricted intake conditions, and in more naturalistic general practice settings, might confirm volunteer befriending as a useful adjunct to current treatments.