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Biomedical subjects

J W Lynch

Publications and source records attributed to J W Lynch.

At least 55 records · Page 3Linked to original sources
PubMed1998

Zinc potentiation of the glycine receptor chloride channel is mediated by allosteric pathways.

Molecular mechanisms of zinc potentiation were investigated in recombinant human alpha1 glycine receptors (GlyRs) by whole-cell patch-clamp recording and [3H]strychnine binding assays. In the wild-type (WT) GlyR, 1 microM zinc enhanced the apparent binding affinity of the agonists glycine and taurine and reduced their concentrations required for half-maximal activation. Thus, in the WT GlyR, zinc potentiation apparently occurs by enhancing agonist binding. However, analysis of GlyRs incorporating mutations in the membrane-spanning domain M1-M2 and M2-M3 loops, which are both components of the agonist gating mechanism, indicates that most mutations uncoupled zinc potentiation from glycine-gated currents but preserved zinc potentiation of taurine-gated currents. One such mutation in the M2-M3 loop, L274A, abolished the ability of zinc to potentiate taurine binding but did not inhibit zinc potentiation of taurine-gated currents. In this same mutant where taurine acts as a partial agonist, zinc potentiated taurine-gated currents but did not potentiate taurine antagonism of glycine-gated currents, suggesting that zinc interacts selectively with the agonist transduction pathway. The intracellular M246A mutation, which is unlikely to bind zinc, also disrupted zinc potentiation of glycine currents. Thus, zinc potentiation of the GlyR is mediated via allosteric mechanisms that are independent of its effects on agonist binding.

Cell Line↗
PubMed1998

Macro-to-micro links in the relation between income inequality and mortality.

A growing literature points to links between income inequality and mortality. Any examination of the link should distinguish, both theoretically and empirically, between shifts in inequality that result from changes in the bottom and top of the income distribution. When state-level data from the U.S. censuses of 1980 and 1990 were used to measure differences in mortality, the results indicated that inequality measures reflecting depth of poverty show stronger correlations with mortality than do inequality measures reflecting heights of affluence. In addition, longitudinal data from the Panel Study of Income Dynamics were used to related state-level inequality measures to individual-level data on mortality. This comparison revealed significant associations between degree of income inequality in state of residence and individual risk of death only for nonelderly individuals with middle-class incomes in 1990.

Health Status Indicators↗
PubMed1998

Does low socioeconomic status potentiate the effects of heightened cardiovascular responses to stress on the progression of carotid atherosclerosis?

OBJECTIVES: This study examined whether heightened cardiovascular reactivity and low socioeconomic status had synergistic effects on the progression of carotid atherosclerosis in a population of eastern Finnish men. METHODS: Data from the Kuopio Ischemic Heart Disease Risk Factor Study were used to measure 4-year progression of intima-media thickness in 882 men according to cardiovascular reactivity and socioeconomic status. Associations were examined in relation to risk factors and were stratified by baseline levels of atherosclerosis and prevalent ischemic heart disease. RESULTS: The effect of reactivity on atherosclerotic progression depended on socioeconomic status. Men who had heightened cardiovascular responsiveness to stress and were born into poor families, received little education, or had low incomes had the greatest atherosclerotic progression. CONCLUSIONS: An understanding of associations between individual risk factors and disease should be based on etiologic hypotheses that are conceived at the population level and involve fundamental social and economic causes of disease. This study demonstrates how examining the interaction of an individual biological predisposition will low socioeconomic status over the life course is etiologically informative for understanding the progression of atherosclerotic vascular disease.

Arteriosclerosis↗
PubMed1998

Income inequality and mortality in metropolitan areas of the United States.

OBJECTIVES: This study examined associations between income inequality and mortality in 282 US metropolitan areas. METHODS: Income inequality measures were calculated from the 1990 US Census. Mortality was calculated from National Center for Health Statistics data and modeled with weighted linear regressions of the log age-adjusted rate. RESULTS: Excess mortality between metropolitan areas with high and low income inequality ranged from 64.7 to 95.8 deaths per 100,000 depending on the inequality measure. In age-specific analyses, income inequality was most evident for infant mortality and for mortality between ages 15 and 64. CONCLUSIONS: Higher income inequality is associated with increased mortality at all per capita income levels. Areas with high income inequality and low average income had excess mortality of 139.8 deaths per 100,000 compared with areas with low inequality and high income. The magnitude of this mortality difference is comparable to the combined loss of life from lung cancer, diabetes, motor vehicle crashes, human immunodeficiency virus (HIV) infection, suicide, and homicide in 1995. Given the mortality burden associated with income inequality, public and private sector initiatives to reduce economic inequalities should be a high priority.

Adolescent↗
PubMed1998

Weight gain and the risk of developing insulin resistance syndrome.

OBJECTIVE: Obesity and weight gain have been associated independently with hypertension, hyperinsulinemia, and dyslipidemia; however, prior research has not looked at the relation between weight gain from early adulthood to middle age and the development of this cluster of risk factors, known as insulin resistance syndrome. RESEARCH DESIGN AND METHODS: The association between weight gain over 30 years (defined as the difference between measured weight in middle age and participant recall of their weight at age 20) and the odds of developing insulin resistance syndrome at middle age was examined in a population-based sample of 2,272 eastern Finnish men. RESULTS: Each 5% increase in weight over the reported weight at age 20 was associated with nearly a 20% greater risk of insulin resistance syndrome by middle age, after adjustment for age and height. Moreover, there was a strong graded association between categories of weight gain and risk of insulin resistance syndrome. Men with weight increases of 10-19%, 20-29%, or > or =30% since age 20 were 3.0, 4.7, or 10.6 times more likely to have insulin resistance syndrome, respectively, by middle age, compared with men within 10% of their weight at age 20. Adjustments for age, height, physical activity, smoking, education, and parental history of diabetes did not alter these findings. CONCLUSIONS: The odds of having developed the hemodynamic and metabolic abnormalities that characterize insulin resistance syndrome by middle adulthood were increasingly higher the greater the weight gain over the preceding 30 years. This study adds to the literature identifying deleterious effects of weight gain from young to middle adulthood.

Adult↗
PubMed1997

Cumulative impact of sustained economic hardship on physical, cognitive, psychological, and social functioning.

BACKGROUND: Although the relation between low income and poor health is well established, most previous research has measured income at only one time. METHODS: We used income information collected in 1965, 1974, and 1983 from a representative sample of adults in Alameda County, California, to examine the cumulative effect of economic hardship (defined as a total household income of less than 200 percent of the federal poverty level) on participants who were alive in 1994. RESULTS: Because of missing information, analyses were based on between 1081 and 1124 participants (median age, 65 years in 1994). After adjustment for age and sex, there were significant graded associations between the number of times income was less than 200 percent of the poverty level (range, 0 to 3) and all measures of functioning examined except social isolation. As compared with subjects without economic hardship, those with economic hardship in 1965, 1974, and 1983 were much more likely to have difficulties with independent activities of daily living (such as cooking, shopping, and managing money) (odds ratio, 3.38; 95 percent confidence interval, 1.49 to 7.64), activities of daily living (such as walking, eating, dressing, and using the toilet) (odds ratio, 3.79; 95 percent confidence interval, 1.32 to 9.81), and clinical depression (odds ratio, 3.24; 95 percent confidence interval, 1.32 to 7.89) in 1994. We found little evidence of reverse causation -- that is, that episodes of illness might have caused subsequent economic hardship. CONCLUSIONS: Sustained economic hardship leads to poorer physical, psychological, and cognitive functioning.

Activities of Daily Living↗
PubMed1997

Concentration dependence of sodium permeation and sodium ion interactions in the cyclic AMP-gated channels of mammalian olfactory receptor neurons.

The dependence of currents through the cyclic nucleotide-gated (CNG) channels of mammalian olfactory receptor neurons (ORNs) on the concentration of NaCl was studied in excised inside-out patches from their dendritic knobs using the patch-clamp technique. With a saturating concentration (100 microM) of adenosine 3',5'-cyclic monophosphate (cAMP), the changes in the reversal potential of macroscopic currents were studied at NaCl concentrations from 25 to 300 mM. In symmetrical NaCl solutions without the addition of divalent cations, the current-voltage relations were almost linear, reversing close to 0 mV. When the external NaCl concentration was maintained at 150 mM and the internal concentrations were varied, the reversal potentials of the cAMP-activated currents closely followed the Na+ equilibrium potential indicating that PCl/PNa approximately 0. However, at low external NaCl concentrations (< or = 100 mM) there was some significant chloride permeability. Our results further indicated that Na+ currents through these channels: (i) did not obey the independence principle; (ii) showed saturation kinetics with K(m)s in the range of 100-150 mM and (iii) displayed a lack of voltage dependence of conductance in asymmetric solutions that suggested that ion-binding sites were situated midway along the channel. Together, these characteristics indicate that the permeation properties of the olfactory CNG channels are significantly different from those of photoreceptor CNG channels.

Animals↗
PubMed1997

Is combined modality therapy necessary for advanced Hodgkin's disease?

PURPOSE: To determine whether single-modality therapy is optimal management for patients with Stage III-IV Hodgkin's disease. METHODS AND MATERIALS: All patients with advanced (Stage III and IV) Hodgkin's disease treated at the University of Florida from 1964 through 1989 (n = 141) were studied retrospectively for factors predictive of good outcome with single-modality therapy. Treatment modalities varied and were distributed as follows: combined-modality therapy (CMT), 55 patients; chemotherapy alone (CX), 50 patients; and radiotherapy alone (RT), 36 patients. RESULTS: Ten-year rates of freedom from relapse and overall survival for all Stage III patients were 66% and 59% compared with 36% and 35% for Stage IV patients. The RT subset was highly selected with the majority of patients having nonbulky Stage IIIA disease. Within the RT group, multivariate analysis identified the degree of splenic involvement and age as the factors most associated with freedom from relapse. In patients treated with CX, multivariate analysis identified bulky tumor (maximum transverse tumor dimension > 6 cm) as the most important prognostic factor for relapse. In patients without bulky disease (< or = 6 cm), the probabilities of freedom from relapse and overall survival at 10 years, respectively, according to treatment group were 53% and 58% for RT patients, 60% and 56% for CX patients, and 83% and 71% for CMT patients. For patients without bulky disease, the probability of freedom from relapse was significantly better for the CMT group than for CX patients (p = 0.03) or RT patients (p = 0.04), but there was no statistical difference in overall survival among the three groups. In patients with bulky disease (> 6 cm), the probabilities of freedom from relapse and overall survival at 10 years were 44% and 45% for RT patients, 9% and 0% for CX patients, and 72% and 58% for CMT patients. Freedom from relapse and overall survival were significantly better (p = 0.0001) for CMT patients compared with CX patients. Fatal hematopoietic disorders developed in 10 patients: 2 of 36 RT patients, 2 of 50 CX patients, and 6 of 55 CMT patients. Nine patients had received chemotherapy, and eight had six or more cycles of alkylator-based chemotherapy. CONCLUSION: This retrospective study suggests that combined-modality therapy is preferable to single-modality therapy in the majority of patients with advanced Hodgkin's disease.

Adolescent↗
PubMed1997

Is comprehensive lymphatic irradiation for low-grade non-Hodgkin's lymphoma curative therapy? Long-term experience at a single institution.

PURPOSE: This study reports 21 patients with Stage I-III low-grade non-Hodgkin's lymphoma who were treated with comprehensive lymphatic irradiation (CLI) at the University of Florida between 1966 and 1992. METHODS AND MATERIALS: Sites clinically involved with disease were treated with 30 Gy, whereas clinically uninvolved sites were treated with 25 Gy. Median follow-up for the group was 14 years (24.5 years for Stage III patients). RESULTS: Overall absolute survival rates at 5, 10, and 15 years were 84%, 68%, and 34%. Cause-specific survival rates at 5, 10, and 15 years were 84%, 68%, and 56%. Freedom-from-relapse rates at 5, 10, and 15 years were 75%, 58%, and 58%, with no relapses noted after 10 years. Bulky disease (>6 cm) was a significant indicator of poor prognosis for cause-specific survival (p = .01). CONCLUSION: These data support findings from other institutions suggesting a role for CLI as potentially curative therapy with acceptable toxicity and a short treatment time for patients with Stages I and II and limited Stage III disease.

Adult↗
PubMed1997

Interaction of workplace demands and cardiovascular reactivity in progression of carotid atherosclerosis: population based study.

OBJECTIVE: To examine the combined influence of workplace demands and changes in blood pressure induced by stress on the progression of carotid atherosclerosis. DESIGN: Population based follow up study of unestablished as well as traditional risk factors for carotid atherosclerosis, ischaemic heart disease, and other outcomes. SETTING: Eastern Finland. SUBJECTS: 591 men aged 42-60 who were fully employed at baseline and had complete data on the measures of carotid atherosclerosis, job demands, blood pressure reactivity, and covariates. MAIN OUTCOME MEASURES: Change in ultrasonographically assessed intima-media thickness of the right and left common carotid arteries from baseline to 4 year follow up. RESULTS: Significant interactions between workplace demands and stress induced reactivity were observed for all measures of progression (P < 0.04). Men with large changes in systolic blood pressure (20 mm Hg or greater) in anticipation of a maximal exercise test and with high job demands had 10-40% greater progression of mean (0.138 v 0.123 mm) and maximum (0.320 v 0.261 mm) intima-media thickness and plaque height (0.347 v 0.264) than men who were less reactive and had fewer job demands. Similar results were obtained after excluding men with prevalent ischaemic heart disease at baseline. Findings were strongest among men with at least 20% stenosis or non-stenotic plaque at baseline. In this subgroup reactive men with high job demands had more than 46% greater atherosclerotic progression than the others. Adjustment for atherosclerotic risk factors did not alter the results. CONCLUSIONS: Men who showed stress induced blood pressure reactivity and who reported high job demands experienced the greatest atherosclerotic progression, showing the association between dispositional risk characteristics and contextual determinants of disease and suggesting that behaviourally evoked cardiovascular reactivity may have a role in atherogenesis.

Adult↗
PubMed1997

Identification of intracellular and extracellular domains mediating signal transduction in the inhibitory glycine receptor chloride channel.

Fast synaptic neurotransmission is mediated by transmitter-activated conformational changes in ligand-gated ion channel receptors, culminating in opening of the integral ion channel pore. Human hereditary hyperekplexia, or startle disease, is caused by mutations in both the intracellular or extracellular loops flanking the pore-lining M2 domain of the glycine receptor alpha1 subunit. These flanking domains are designated the M1-M2 loop and the M2-M3 loop respectively. We show that four startle disease mutations and six additional alanine substitution mutations distributed throughout both loops result in uncoupling of the ligand binding sites from the channel activation gate. We therefore conclude that the M1-M2 and M2-M3 loops act in parallel to activate the channel. Their locations strongly suggest that they act as hinges governing allosteric control of the M2 domain. As the members of the ligand-gated ion channel superfamily share a common structure, this signal transduction model may apply to all members of this superfamily.

Allosteric Regulation↗
PubMed1997

Odorant-induced currents in intact patches from rat olfactory receptor neurons: theory and experiment.

Odorant-induced currents in mammalian olfactory receptor neurons have proved difficult to obtain reliably using conventional whole-cell recording. By using a mathematical model of the electrical circuit of the patch and rest-of-cell, we demonstrate how cell-attached patch measurements can be used to quantitatively analyze responses to odorants or a high (100 mM) K+ solution. High K+ induced an immediate current flux from cell to pipette, which was modeled as a depolarization of approximately 52 mV, close to that expected from the Nernst equation (56 mV), and no change in the patch conductance. By contrast, a cocktail of cAMP-stimulating odorants induced a current flux from pipette into cell following a significant (4-10 s) delay. This was modeled as an average patch conductance increase of 36 pS and a depolarization of 13 mV. Odorant-induced single channels had a conductance of 16 pS. In cells bathed with no Mg2+ and 0.25 mM Ca2+, odorants induced a current flow from cell to pipette, which was modeled as a patch conductance increase of approximately 115 pS and depolarization of approximately 32 mV. All these results are consistent with cAMP-gated cation channels dominating the odorant response. This approach, which provides useful estimates of odorant-induced voltage and conductance changes, is applicable to similar measurements in any small cells.

Animals↗
PubMed1997

The glycine receptor.

The inhibitory glycine receptor (GlyR) is a member of the ligand-gated ion channel receptor superfamily. The GlyR comprises a pentameric complex that forms a chloride-selective transmembrane channel, which is predominantly expressed in the spinal cord and brain stem. We review the pharmacological and physiological properties of the GlyR and relate this information to more recent insights that have been obtained through the cloning and recombinant expression of the GlyR subunits. We also discuss insights into our understanding of GlyR structure and function that have been obtained by the genetic characterisation of various heritable disorders of glycinergic neurotransmission.

Amino Acid Sequence↗
PubMed1997

Why do poor people behave poorly? Variation in adult health behaviours and psychosocial characteristics by stages of the socioeconomic lifecourse.

Attempts to explain socioeconomic inequalities in health have often made reference to the observation that poor health behaviours and psychosocial characteristics cluster in low socioeconomic status (SES) groups. Causal interpretation of the association between SES, health behaviour, psychosocial orientations, and health inequalities has been hampered because these factors and SES have usually been measured at the same point in time. Data from the Kuopio Ischaemic Heart Disease Risk Factor Study were used to examine the associations between measures of SES reflecting different stages of the lifecourse, health behaviours, and psychosocial characteristics in adulthood in a population-based study of 2674 middle-aged Finnish men. Results show that many adult behaviours and psychosocial dispositions detrimental to health are consistently related to poor childhood conditions, low levels of education, and blue-collar employment. Poor adult health behaviours and psychosocial characteristics were more prevalent among men whose parents were poor. Increases in income inequality which place children into low SES conditions may well produce a negative behavioural and psychosocial health dividend to be reaped in the future. Understanding that adult health behaviour and psychosocial orientations are associated with socioeconomic conditions throughout the lifecourse implies that efforts to reduce socioeconomic inequalities in health must recognize that economic policy is public health policy.

Adult↗
PubMed1997

A clinical tool for rating response to civil commitment for substance abuse treatment.

OBJECTIVE: The objectives of this study were to develop a measure to assess patients' response to civil commitment, to test this measure on two groups of dually diagnosed patients (medically ill alcoholics and patients with dual mental and substance use disorders), and to identify patient characteristics associated with a positive response to commitment. METHODS: The outcome of 38 male veterans civilly committed to inpatient substance abuse treatment for an average of six months was rated by their treating clinicians. Raters used the Commitment Response Form (CRF), a scale anchored to behavioral descriptions that was developed for the study and that measures outcome in five areas: patients' attitude toward recovery, substance use, medical condition, engagement in substance abuse treatment, and independence of functioning. Each patient's medical records were reviewed by two clinical staff members who made independent retrospective ratings and a joint rating using the CRF. They also made independent and joint dichotomous ratings of whether the patient was a positive responder or a nonresponder to civil commitment. RESULTS: The CRF showed superior reliability when compared with the dichotomous rating of outcome. The scale demonstrated reasonable psychometric properties. Mean scale scores did not differ significantly by patient group; slightly more than half were rated as having a good to excellent overall response. Better outcome was associated with longer periods of previous abstinence from alcohol and a higher level of education. CONCLUSIONS: Use of a scale anchored to behavioral descriptions improved reliability of outcome determinations by clinical staff. Civil commitment resulted in good to excellent outcome in many but not all committed patients.

Adult↗
PubMed1996

Do cardiovascular risk factors explain the relation between socioeconomic status, risk of all-cause mortality, cardiovascular mortality, and acute myocardial infarction?

Much remains to be understood about how low socioeconomic status (SES) increases cardiovascular disease and mortality risk. Data from the Kuopio Ischemic Heart Disease Risk Factor Study (1984-1993) were used to estimate the associations between acute myocardial infarction and income, all-cause mortality, and cardiovascular mortality in a population-based sample of 2,272 Finnish men, with adjustment for 23 biologic, behavioral, psychologic, and social risk factors. Compared with the highest income quintile, those in the bottom quintile had age-adjusted relative hazards of 3.14 (95% confidence interval (CI) 1.77-5.56), 2.66 (95% CI 1.25-5.66), and 4.34 (95% CI 1.95-9.66) for all-cause mortality, cardiovascular mortality, and AMI, respectively. After adjustment for risk factors, the relative hazards for the same comparisons were 1.32 (95% CI 0.70-2.49), 0.70 (95% CI 0.29-1.69), and 2.83 (95% CI 1.14-7.00). In the lowest income quintile, adjustment for risk factors reduced the excess relative risk of all-cause mortality by 85%, that of cardiovascular mortality by 118%, and that of acute myocardial infarction by 45%. These data show how the association between SES and cardiovascular mortality and all-cause mortality is mediated by known risk factor pathways, but full "explanations" for these associations will need to encompass why these biologic, behavioral, psychologic, and social risk factors are differentially distributed by SES.

Adult↗
PubMed1996

Inequality in income and mortality in the United States: analysis of mortality and potential pathways.

OBJECTIVE: To examine the relation between health outcomes and the equality with which income is distributed in the United States. DESIGN: The degree of income inequality, defined as the percentage of total household income received by the less well off 50% of households, and changes in income inequality were calculated for the 50 states in 1980 and 1990. These measures were then examined in relation to all cause mortality adjusted for age for each state, age specific deaths, changes in mortalities, and other health outcomes and potential pathways for 1980, 1990, and 1989-91. MAIN OUTCOME MEASURE: Age adjusted mortality from all causes. RESULTS: There was a significant correlation (r = -0.62 [corrected], P < 0.001) between the percentage of total household income received by the less well off 50% in each state and all cause mortality, unaffected by adjustment for state median incomes. Income inequality was also significantly associated with age specific mortalities and rates of low birth weight, homicide, violent crime, work disability, expenditures on medical care and police protection, smoking, and sedentary activity. Rates of unemployment, imprisonment, recipients of income assistance and food stamps, lack of medical insurance, and educational outcomes were also worse as income inequality increased. Income inequality was also associated with mortality trends, and there was a suggestion of an impact of inequality trends on mortality trends. CONCLUSION: Variations between states in the inequality of the distribution of income are significantly associated with variations between states in a large number of health outcomes and social indicators and with mortality trends. These differences parallel relative investments in human and social capital. Economic policies that influence income and wealth inequality may have an important impact on the health of countries.

Adolescent↗