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J W Lynch

Publications and source records attributed to J W Lynch.

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

A pore-lining glutamic acid in the rat olfactory cyclic nucleotide-gated channel controls external spermine block.

Spermine is a potent, voltage-dependent blocker of the olfactory cyclic nucleotide-gated channel from both the intracellular and extracellular sides. However, its sites of action are unknown. This study investigated the external spermine binding site in the rat CNCalpha3 subunit. Neutralization of a glutamic acid residue (E342Q) in the P-loop region eliminated voltage-dependence of block by externally applied spermine. The charge-conservative E342D mutation had little effect on spermine block. Thus, E342 forms the binding site for externally applied spermine. However, spermine remained a potent voltage-independent blocker of the E342Q mutant channel, suggesting that the mutation either created a novel binding site outside the membrane electrical field or that it dramatically changed the properties of the existing pore site.

Animals↗
PubMed2000

Relation between income inequality and mortality in Canada and in the United States: cross sectional assessment using census data and vital statistics.

OBJECTIVE: To compare the relation between mortality and income inequality in Canada with that 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, was calculated and these measures were examined in relation to all cause mortality, grouped by and adjusted for age. SETTING: The 10 Canadian provinces, the 50 US states, and 53 Canadian and 282 US metropolitan areas. RESULTS: Canadian provinces and metropolitan areas generally had both lower income inequality and lower mortality than US states and metropolitan areas. In age grouped regression models that combined Canadian and US metropolitan areas, income inequality was a significant explanatory variable for all age groupings except for elderly people. The effect was largest for working age populations, in which a hypothetical 1% increase in the share of income to the poorer half of households would reduce mortality by 21 deaths per 100 000. Within Canada, however, income inequality was not significantly associated with mortality. CONCLUSIONS: Canada seems to counter the increasingly noted association at the societal level between income inequality and mortality. The lack of a significant association between income inequality and mortality in Canada may indicate that the effects of income inequality on health are not automatic and may be blunted by the different ways in which social and economic resources are distributed in Canada and in the United States.

Canada↗
PubMed2000

Standing at work and progression of carotid atherosclerosis.

OBJECTIVES: The association between the amount of standing at work and the progression of carotid intima media thickness (IMT) was studied among 584 active working men participating in the Kuopio Ischemic Heart Disease Risk Factor Study. METHODS: Ultrasound measurements of atherosclerotic changes in the carotid arteries were performed at the beginning of the study and after 4 years. Analyses of changes in IMT included adjustments for risk factors and stratification by base-line levels of atherosclerosis and prevalent ischemic heart disease (IHD). RESULTS: Significant relationships were found between the amount of standing at work and atherosclerotic progression. After adjustment for the heaviness of the work, psychosocial job factors, income, and biological and behavioral risk factors, the mean change in maximum IMT for those standing not at all, a little, a lot, and very much was 0.24, 0.25, 0.28, and 0.33 mm, respectively. For men with IHD the respective changes were 0.08, 0.15, 0.37, and 0.75 mm -- a 9-fold difference between the no-exposure and high-exposure group. For the men with carotid stenosis, the respective difference was 3-fold. CONCLUSIONS: These findings provide the first empirical support in a population study for the role of hemodynamic factors in the progression of atherosclerosis induced by long-term standing. Men with carotid stenosis or IHD appear especially vulnerable to the adverse effects associated with standing at work. Reducing the duration of standing at work should be considered both in the occupational rehabilitation of such patients and in the primary prevention of atherosclerosis.

Adult↗
PubMed1999

Rectification of the olfactory cyclic nucleotide-gated channel by intracellular polyamines.

Polyamine-induced inward rectification of cyclic nucleotide-gated channels was studied in inside-out patches from rat olfactory neurons. The polyamines, spermine, spermidine and putrescine, induced an 'instantaneous' voltage-dependent inhibition with Kd values at 0 mV of 39, 121 micron and 2.7 mM, respectively. Hill coefficients for inhibition were significantly < 1, suggesting an allosteric inhibitory mechanism. The Woodhull model for voltage-dependent block predicted that all 3 polyamines bound to a site 1/3 of the electrical distance through the membrane from the internal side. Instantaneous inhibition was relieved at positive potentials, implying significant polyamine permeation. Spermine also induced exponential current relaxations to a 'steady-state' impermeant level. This inhibition was also mediated by a binding site 1/3 of the electrical distance through the pore, but with a Kd of 2.6 mM. Spermine inhibition was explained by postulating two spermine binding sites at a similar depth. Occupation of the first site occurs rapidly and with high affinity, but once a spermine molecule has bound, it inhibits spermine occupation of the second binding site via electrostatic repulsion. This repulsion is overcome at higher membrane potentials, but results in a lower apparent binding affinity for the second spermine molecule. The on-rate constant for the second spermine binding saturated at a low rate (approximately 200 sec(-1) at +120 mV), providing further evidence for an allosteric mechanism. Polyamine-induced inward rectification was significant at physiological concentrations.

Animals↗
PubMed1999

The impact of radiotherapy dose and other treatment-related and clinical factors on in-field control in stage I and II non-Hodgkin's lymphoma.

PURPOSE/OBJECTIVE: To assess local (in-field) disease control, identify potential prognostic factors, and elucidate the optimal radiotherapy dose in various clinical settings of Stage I and II non-Hodgkin's lymphoma (non-CNS). MATERIALS & METHODS: A total of 285 consecutive patients with Stage I and II non-Hodgkin's lymphoma were treated with curative intent, including 159 with radiotherapy (RT) alone and 126 with combined-modality therapy (CMT). Of these, 72 patients had low-grade lymphomas (LGL), 92 had intermediate or high-grade lymphomas (I/HGL), and 21 had unclassified lymphomas. Clinical and treatment variables with potential prognostic significance for in-field disease control, freedom from relapse (FFR), and absolute survival (AS) were evaluated by univariate and multivariate analyses. RESULTS: The 5-, 10-, and 20-year actuarial AS rates were 73%, 46%, and 33% for patients with LGL and 64%, 44%, and 18% for patients with I/HGL, respectively. The 5-, 10-, and 20-year actuarial FFR rates were 62%, 59%, and 49% for patients with LGL and 66%, 57%, and 57% for patients with I/HGL, respectively. Significant prognostic factors identified by the multivariate analysis were age, tumor size, and histology for AS; tumor size and treatment for FFR; and only tumor size for in-field disease control. There were 95 total failures, with only 12 occurring infield. Most failures (65%) were in contiguous unirradiated sites. All 4 in-field failures in patients with LGL occurred after RT doses < 30 Gy, although none occurred in 10 patients with small-volume LGL of the orbit treated with doses < 30 Gy. The 8 in-field failures in patients with I/HGL were distributed evenly throughout the RT dose range; 5 occurred in patients treated with CMT, all with tumors > 6 cm, and 4 with less than a complete response (CR) to chemotherapy. CONCLUSION: Our analysis suggests that the overwhelming problem in the treatment of non-Hodgkin's lymphoma is not in-field failure but, rather, failure in contiguous unirradiated sites. A dose of 20-25 Gy may be sufficient for small-volume LGL of the orbit. A dose of 30 Gy is sufficient for LGL in general, as well as for patients with nonbulky (< or = 6 cm) I/HGL treated with CMT who have a CR. However, patients with I/HGL treated with CMT for tumors > 6 cm and/or without a CR may benefit from doses > or = 40 Gy.

Actuarial Analysis↗
PubMed1999

Non-Hodgkin's lymphoma of the head and neck: a 30-year experience at the University of Florida.

BACKGROUND: Outcome in previously untreated patients with non-Hodgkin's lymphoma of the head and neck needed to be assessed. METHODS: A retrospective review was performed of 79 patients with stage I or II non-Hodgkin's lymphoma of the head and neck treated between 1964 and 1994 with radiotherapy (RT) or combined modality therapy (CMT) at the University of Florida. Freedom from relapse, cause-specific survival, and absolute survival were analyzed by the Kaplan-Meier method. Patterns of failure were defined, and the relationship between dose and infield recurrence was studied. Histology was classified as low grade or intermediate/high grade. RESULTS: At 10 years, absolute survival for patients with low-grade lymphoma treated with RT was 45%; absolute survival for patients with intermediate/high-grade lymphoma was 41% for those treated with RT and 57% for those who received CMT. Twenty-seven patients had a recurrence of lymphoma after initial treatment. Twenty patients (74%) had recurrences outside the radiation treatment field; 90% of these failures were in predictable sites that would be included in comprehensive lymphatic irradiation fields (Waldeyer's ring, mantle, and whole abdomen). No clear dose response was observed. Multivariate analysis showed that patients with tumors <5 cm in diameter had improved cause-specific survival, absolute survival, and freedom from relapse compared with patients with tumors > or = 5 cm in diameter. CONCLUSIONS: Patients with non-Hodgkin's lymphoma in the head and neck with tumors > or = 5 cm in diameter appear to have a worse prognosis than those with smaller tumors. The patterns of failure suggest that initial treatment with comprehensive lymphatic irradiation fields could potentially eliminate the majority of treatment failures.

Adult↗
PubMed1999

Socioeconomic considerations in the primordial prevention of cardiovascular disease.

Economic policy is an important determinant of population health; it is part of health policy. True primordial prevention of cardiovascular disease (CVD) may require regulation of the domestic and international market forces which produce and distribute CVD risk factors and their determinants. Because the market does not bear the cost of the legacy of poor health that it generates, primordial prevention of CVD may need to concern itself with societal mechanisms for holding these market forces accountable. Indeed, this approach is now an important part of the public health lexicon for preventing smoking. No program of primordial prevention of smoking could possibly ignore the national and international economic interests of the tobacco industry. We need to start thinking about primordial prevention of CVD risk factors such as low physical activity, high-fat diet, and psychosocial stress in the same way.

Cardiovascular Diseases↗
PubMed1999

Extended Rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma.

BACKGROUND: Rituximab is a chimeric monoclonal antibody directed against the B-cell CD20 antigen which has been utilized for therapy of B-cell non-Hodgkin's lymphoma (NHL). A previous clinical trial demonstrated that treatment with four weekly doses of 375 mg/m2 of Rituximab in patients with relapsed or refractory low-grade or follicular B-cell non-Hodgkin's lymphoma was well tolerated and had significant clinical activity. PATIENTS AND METHODS: To assess the safety and efficacy of Rituximab treatment, an open-label, single-arm, multi-center, phase II study of eight consecutive weekly infusions of 375 mg/m2 Rituximab in patients with low-grade or follicular B-cell NHL who had relapsed or had failed primary therapy was conducted. Thirty-seven patients with a median age of 55 years were treated. RESULTS: Grade 1 or 2 adverse events were the majority of reported toxicities and occurred most frequently with the first infusion, decreasing with subsequent infusions. No patients developed a host antibody response (HACA) to Rituximab. The mean serum immunoglobulin levels for IgG, IgA, and IgM stayed within the normal range throughout the study. The majority of patients who were bcl-2 positive at baseline in peripheral blood became bcl-2 negative during treatment and remained negative at the time of B-cell recovery. In the 37 intent-to-treat patients, 5 (14%) had a complete response and 16 (43%) had a partial response for an overall response rate of 57%. Of 35 evaluable patients, 21 (60%) responded to treatment (14% CR and 46% PR). In responders, the median time to progression (TTP) and the median response duration have not been reached after 19.4+ months and 13.4+ months, respectively. CONCLUSIONS: The safety profile and efficacy achieved in this pilot study of extended treatment with Rituximab compares favorably with those seen with four weekly doses. Further studies are warranted to investigate whether this or other extended Rituximab schedules will result in increased efficacy in all or in certain subgroups of patients with low-grade or follicular NHL.

Adult↗
PubMed1999

Comparison of autologous peripheral blood stem cell dosing by ideal vs actual body weight.

In this retrospective study, we evaluated the predictability of PBSC dose for hematopoietic engraftment comparing that calculated by ideal body weight (IBW) vs another calculated by actual body weight (ABW) for each patient. Sixty-three consecutive patients treated similarly using one transplant protocol were analyzed. While all patients had data available on CFU-GM and nucleated cells (NC), data on CD34+ enumeration was present only in 34 patients. We found that 49% of the patients were greater than 25% over their IBW. In addition, least-squares linear regression was used to assess the strength of the linear relationship between the inverse of cell dose/kg of ABW or IBW and time to AGC or platelet engraftment and showed no difference in r2 values for platelet engraftment, while using dose/kg of IBW greatly improved the ability of NC (r2 improved from 0.19 for ABW to 0.35 for IBW) and CFU-GM (r2 improved from 0.35 for ABW to 0.53 for IBW) to predict time to AGC engraftment, but did not change the CD34 r2. Hazard ratios were estimated using Cox proportional hazards regression and in all instances were found greater than 1.0 indicating that the probability of engraftment increased as cell dose/kg ABW or IBW increased. Finally, our data showed that 10 patients (16%) could have had one less apheresis procedure performed to obtain their set target stem cell dose calculated per kg IBW rather than ABW. In conclusion, PBSC dose per kg IBW is as good or better predictor of engraftment of AGC and may lead to cost savings in a certain subset of patients.

Adolescent↗
PubMed1999

Building new function into glycine receptors: a structural model for the activation of the glycine-gated chloride channel.

1. The glycine receptor chloride channel mediates inhibitory neurotransmission and is a member of the ligand-gated ion channel superfamily, which includes the nicotinic acetylcholine receptor channel. 2. Activation of these channels involves a movement of the pore-lining second membrane-spanning domain with respect to the remainder of the protein. 3. The present review considers the evidence that the loops that connect this domain with the rest of the protein act as crucial components of the channel activation mechanism.

Chloride Channels↗
PubMed1999

Individual causal models and population system models in epidemiology.

A group of individuals behaves as a population system when patterns of connections among individuals influence population health outcomes. Epidemiology usually treats populations as collections of independent individuals rather than as systems of interacting individuals. An appropriate theoretical structure, which includes the determinants of connections among individuals, is needed to develop a "population system epidemiology." Infection transmission models and sufficient-component cause models provide contrasting templates for the needed theoretical structure. Sufficient-component cause models focus on joint effects of multiple exposures in individuals. They handle time and interactions between individuals in the definition of variables and assume that populations are the sum of their individuals. Transmission models, in contrast, model interactions among individuals over time. Their nonlinear structure means that population risks are not simply the sum of individual risks. The theoretical base for "population system epidemiology" should integrate both approaches. It should model joint effects of multiple exposures in individuals as time related processes while incorporating the determinants and effects of interactions among individuals. Recent advances in G-estimation and discrete individual transmission model formulation provide opportunities for such integration.

Causality↗
PubMed1999

Identification of a new ligand binding domain in the alpha1 subunit of the inhibitory glycine receptor.

Four discontinuous extracellular sequence domains have been proposed to form the ligand binding sites of the ligand-gated ion channel receptor superfamily. In this study, we investigated the role of 12 contiguous residues of the inhibitory glycine receptor that define the proposed "loop A" ligand binding domain. Using the techniques of site-directed mutagenesis and patch-clamp electrophysiology, four of the 12 residues were shown to have impaired ligand binding. Three mutants, 193A, A101H, and N102A, resulted in significant (17-44-fold) increases in the agonist EC50 values as compared with the wild-type glycine receptor, whereas Hill coefficients, ImaX values, and antagonist affinity remained largely unaffected. Consideration of receptor efficacy values indicates that these residues are involved in ligand binding rather than channel activation. A fourth mutant, W94A, failed to give rise to any glycine-activated currents, although cell-surface expression was observed, suggesting that this residue may also be involved in agonist binding. These data provide the most extensive characterization of the loop A ligand binding domain available to date and define two new residue locations, Ile93 and Asn102, as contributing to the four-loop model of ligand binding.

Alanine↗
PubMed1998

An analysis of odorant-induced currents in on-cell patches on mammalian olfactory receptor neurons.

Because of the difficulty of obtaining odorant-induced currents in mammalian olfactory receptor neurons using whole-cell recording, we have developed a mathematical model of the electrical circuit of the patch and rest-of-cell. This can be used to quantitatively analyze on-cell patch pipette currents in response to perfusion of the cell by solutions containing odorants or other compounds that can alter membrane conductance or cell potential. We have analyzed pipette currents from on-cell patches of olfactory receptor neurons (ORNs) dissociated from adult rats. Initially, we perfused the ORNs with a high (100 mM; control 10 mM) KCl solution, which immediately induced a current flux from cell to pipette of a magnitude to imply a depolarization of approximately 52 mV, close to the value predicted from the Nernst equation (56 mV), and no change in the patch conductance. In contrast, perfusion by a cocktail of five cyclic adenosine-3',5'-monophosphate (cAMP)-stimulating odorants (cineole, n-amyl acetate, methyl salicylate, limonene and alpha-pinene, each at a concentration of 1 mM), after a delay of 4-10 sec, induced a current flux from pipette into the cell. Data in normal [Ca2+] and [Mg2+] implied an average patch conductance increase of approximately 36 pS, a cell depolarization of approximately 13 mV and an odorant-induced single channel conductance of approximately 16 pS. In low [Ca2+] and no Mg2+ approximately 40% of cells responded to odorants, with an induced current flow from cell to pipette implying a patch conductance increase of approximately 115 pS and cell depolarization of approximately 32 mV. The results were consistent with the odorants gating cAMP-gated cation channels. This analytical approach, which enables estimates of odorant-induced voltage and conductance changes to be made from changes in pipette current, should also be of general use for comparing cell responses to different perfusing solutions.

Animals↗
PubMed1998

Nitric oxide inhibition of the rat olfactory cyclic nucleotide-gated cation channel.

The effects of nitric oxide (NO) and other cysteine modifying agents were examined on cyclic nucleotide-gated (CNG) cation channels from rat olfactory receptor neurons. The NO compounds, S-nitroso-cysteine (SNC) and 3-morpholino-sydnonomine (SIN-1), did not activate the channels when applied for up to 10 min. The cysteine alkylating agent, N-ethylmaleimide (NEM), and the oxidising agent, dithionitrobensoate (DTNB), were also without agonist efficacy. Neither SNC nor DTNB altered the cAMP sensitivity of the channels. However, 2-min applications of SIN-1, SNC and DTNB inhibited the cAMP-gated current to approximately 50% of the control current level. This inhibition showed no spontaneous reversal for 5 min but was completely reversed by a 2-min exposure to DTT. The presence of cAMP protected the channels against NO-induced inhibition. These results indicate that inhibition is caused by S-nitrosylation of neighboring sulfhydryl groups leading to sulfhydryl bond formation. This reaction is favored in the closed channel state. Since recombinantly expressed rat olfactory alpha and beta CNG channel homomers and alpha/beta heteromers are activated and not inhibited by cysteine modification, the results of this study imply the existence of a novel subunit or tightly bound factor which dominates the effect of cysteine modification in the native channels. As CNG channels provide a pathway for calcum influx, the results may also have important implications for the physiological role of NO in mammalian olfactory receptor neurons.

Animals↗
PubMed1998

Characterization of calcium-activated chloride channels in patches excised from the dendritic knob of mammalian olfactory receptor neurons.

We investigated the properties of calcium-activated chloride channels in inside-out membrane patches from the dendritic knobs of acutely dissociated rat olfactory receptor neurons. Patches typically contained large calcium-activated currents, with total conductances in the range 30-75 nS. The dose response curve for calcium exhibited an EC50 of about 26 microM. In symmetrical NaCl solutions, the current-voltage relationship reversed at 0 mV and was linear between -80 and +70 mV. When the intracellular NaCl concentration was progressively reduced from 150 to 25 mM, the reversal potential changed in a manner consistent with a chloride-selective conductance. Indeed, modeling these data with the Goldman-Hodgkin-Katz equation revealed a PNa/PCl of 0.034. The halide permeability sequence was PCl > PF > PI > PBr indicating that permeation through the channel was dominated by ion binding sites with a high field strength. The channels were also permeable to the large organic anions, SCN-, acetate-, and gluconate-, with the permeability sequence PCl > PSON > Pacetate > Pgluconate. Significant permeation to gluconate ions suggested that the channel pore had a minimum diameter of at least 5.8 A.

Animals↗