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Biomedical subjects

J P Clark

Publications and source records attributed to J P Clark.

At least 19 recordsLinked to original sources
PubMed2006

Brain-derived neurotrophic factor and neurotrophin receptors modulate glutamate-induced phase shifts of the suprachiasmatic nucleus.

Light information reaches the suprachiasmatic nucleus (SCN) through a subpopulation of retinal ganglion cells. Previous work raised the possibility that brain-derived neurotrophic factor (BDNF) and its high-affinity tropomyosin-related receptor kinase may be important as modulators of this excitatory input into the SCN. In order to test this possibility, we used whole-cell patch-clamp methods to measure spontaneous excitatory currents in mouse SCN neurons. We found that the amplitude and frequency of these currents were increased by BDNF and decreased by the neurotrophin receptor inhibitor K252a. The neurotrophin also increased the magnitude of currents evoked by application of N-methyl-d-aspartate and amino-methyl proprionic acid. Next, we measured the rhythms in action potential discharge from the SCN brain slice preparation. We found that application of K252a dramatically reduced the magnitude of phase shifts of the electrical activity rhythm generated by the application of glutamate. By itself, BDNF caused phase shifts that resembled those produced by glutamate and were blocked by K252a. The results demonstrate that BDNF and neurotrophin receptors can enhance glutamatergic synaptic transmission within a subset of SCN neurons and potentiate glutamate-induced phase shifts of the circadian rhythm of neural activity in the SCN.

Animals↗
PubMed2005

HIV protein, transactivator of transcription, alters circadian rhythms through the light entrainment pathway.

Patients infected with the human immunodeficiency virus (HIV), and other mammals infected with related lentiviruses, exhibit fatigue, altered sleep patterns, and abnormal circadian rhythms. A circadian clock in the hypothalamic suprachiasmatic nucleus (SCN) temporally regulates these functions in mammals. We found that a secretary HIV transcription factor, transactivator of transcription (Tat), resets the murine circadian clock, in vitro and in vivo, at clinically relevant concentrations (EC(50) = 0.31 nM). This effect of Tat occurs only during the subjective night, when N-methyl-D-aspartate (NMDA) receptor [D-2-amino-5-phosphonovaleric acid (0.1 mM)] and nitric oxide synthase (N(G)-nitro-L-arginine methyl ester, 0.1 mM) inhibitors block Tat-induced phase shifts. Whole cell recordings of SCN neurons within the brain slice revealed that Tat did not activate NMDA receptors directly but potentiated NMDA receptor currents through the enhancement of glutamate release. Consistent with this presynaptic mechanism, inhibitors of neurotransmission block Tat-induced phase shifts, such as tetrodotoxin (1 microM), tetanus toxin (1 microM), P/Q/N type-calcium channel blockers (1 microM omega-agatoxin IVA and 1 microM omega-conotoxin GIVA) and bafilomycin A(1) (1 microM). Thus the effect of Tat on the SCN may underlie lentiviral circadian rhythm dysfunction by operating as a disease-dependent modulator of light entrainment through the enhancement of excitatory neurotransmission.

Action Potentials↗
PubMed2000

Rate of heart failure and 1-year survival for older people receiving low-dose beta-blocker therapy after myocardial infarction.

BACKGROUND: Many older people do not receive beta-blocker therapy after myocardial infarction or receive doses lower than those tested in trials, perhaps because physicians fear that beta-blockers may precipitate heart failure. We examined the relation between use of beta-blockers, the dose used, and hospital admission for heart failure and 1-year survival in a cohort of all older patients surviving myocardial infarction in Ontario, Canada. METHODS: We collected data on a cohort of 13,623 patients aged 66 years or older who were discharged from hospital after a myocardial infarction and who did not receive beta-blocker therapy or received low, standard, or high doses. We used Cox's proportional-hazards models to study the association of dose with admission for heart failure and survival with adjustment for factors including age, sex, and comorbidity. FINDINGS: Among 8232 patients with no previous history of heart failure, dispensing of beta-blocker therapy was associated with a 43% reduction in subsequent admission for heart failure (adjusted risk ratio 0.57 [95% CI 0.48-0.69]) compared with patients not dispensed this therapy. Among the 4681 patients prescribed beta-blockers, the risk of admission was greater in the high-dose than in the low-dose group (1.53 [1.01-2.31]). Among all 13,623 patients in the cohort, 2326 (17.1%) died by 1 year. Compared with those not dispensed beta-blocker therapy, the adjusted risk ratio for mortality was lower for all three doses (low 0.40 [0.34-0.47], standard 0.36 [0.31-0.42], high 0.43 [0.33-0.56]). INTERPRETATION: Compared with high-dose beta-blocker therapy, low-dose treatment is associated with a lower rate of hospital admission for heart failure and has a similar 1-year survival benefit. Our findings support the need for a randomised controlled trial comparing doses of beta-blocker therapy in elderly patients.

Adrenergic beta-Antagonists↗
PubMed2000

Exotic dancing and health.

The health and safety of women who work as exotic dancers are firmly embedded within the social organization of the strip club and the broader social, economic and political context of the work of exotic dancing. Exotic dancers in this study expressed health concerns associated with: the effects of costuming and appearance requirements; dirty work environments; problems due to stigmatization, sexual harassment and assault; and police disinterest or victim blaming. The balance between benefits and hazards related to exotic dancing is influenced not only by the personal choices made by dancers, but also by the organization of the strip club and the broader context within which exotic dancing takes place.

Adolescent↗
PubMed1999

Use of beta-blocker therapy in older patients after acute myocardial infarction in Ontario.

BACKGROUND: Despite its proven efficacy, beta-blocker therapy remains underused in elderly patients after myocardial infarction (MI). The objectives of this study were to identify undertreated groups of seniors and to determine whether older and frailer patients are being selectively dispensed low-dose beta-blocker therapy. METHODS: From a comprehensive hospital discharge database, all people aged 66 years or more in Ontario who survived an acute MI between April 1993 and March 1995 were identified and classified into those who did not receive beta-blocker therapy and those dispensed low, standard or high doses of this agent. Logistic regression models were used to study the effect of age, sex, comorbidity, potential contraindications to beta-blocker therapy and residence in a long-term-care facility on the odds of not being dispensed a beta-blocker. Among beta-blocker users, the odds of being dispensed low relative to standard or high doses of this agent were evaluated. RESULTS: Of the 15,542 patients, 7549 (48.6%) were not dispensed a beta-blocker. Patients 85 years of age or more were at greater risk of not receiving beta-blocker therapy (adjusted odds ratio [OR] 2.8, 95% confidence interval [CI] 2.5-3.2) than were those 66 to 74 years. Having a Charlson comorbidity index of 3 or greater was associated with an increased risk of not receiving beta-blocker therapy (adjusted OR 1.5, 95% CI 1.3-1.8) compared with having lower comorbidity scores. Patients who resided in a long-term-care facility were at increased risk of not being prescribed beta-blocker therapy (adjusted OR 2.6, 95% CI 2.0-3.4). Among the 5453 patients with no identifiable contraindication to beta-blocker therapy, women were significantly less likely than men to receive this agent (p = 0.005). Of the 6074 patients who received beta-blockers, 2248 (37.0%) were dispensed low-dose therapy. Patients aged 85 years or more had an increased risk of being dispensed low-dose therapy (adjusted OR 1.6, 95% CI 1.3-2.0) compared with those aged 66 to 74 years. Compared with those who had the lowest comorbidity scores, patients with the highest comorbidity scores were more likely to be dispensed low-dose beta-blocker therapy (adjusted OR 1.3, 95% CI 1.0-1.8). INTERPRETATION: Almost half of Ontario patients aged 66 or more who survived an MI, particularly those who were older or frailer, did not receive beta-blocker therapy. Among those dispensed beta-blocker therapy, older and frailer patients were more frequently dispensed low-dose therapy.

Adrenergic Antagonists↗
PubMed1999

Age- and gender-related use of low-dose drug therapy: the need to manufacture low-dose therapy and evaluate the minimum effective dose.

OBJECTIVES: Low-dose drug therapy is promoted as a way to maximize benefit and minimize adverse drug effects when prescribing for older adults. This population-based study evaluates the age and sex-related use of two common therapies: thiazide diuretics, where evidence supports the use of low-dose therapy, and beta-blockers, where trials have not evaluated the minimum effective dose. DESIGN: Using linked administrative databases we identified all of the 120,613 persons dispensed a thiazide diuretic therapy and 12,908 myocardial infarction survivors dispensed beta-blocker therapy in Canada's largest province. We used logistic regression models to study the association of age and sex with dispensing of low-dose thiazide diuretic and beta-blocker therapy at doses lower than evaluated in trials. RESULTS: Of 120,613 older people dispensed a thiazide diuretic, 32,372 (26.8%) were dispensed a low dose. Patients 85 years of age or older, relative to the youngest group, were 30% more likely to be dispensed low-dose therapy (OR=1.31; 95% CI, 1.27 to 1.36; P < .001). Women were 8% more likely than men to be dispensed a low-dose thiazide diuretic (OR=1.08; 95% CI, 1.05 to 1.11; P < .001). Of 10,991 myocardial infarction survivors dispensed atenolol, metoprolol, propranolol, or timolol, 9458 (86.1%) were dispensed a lower-than-evaluated dose. Patients 85 years of age or older, relative to those in the youngest group, were more than twice as likely to be dispensed a lower-than-evaluated beta-blocker therapy dose (OR=2.28; 95% CI, 1.74 to 3.04; P < .001). No difference was noted in the use of beta-blocker therapy dose by sex (OR=1.0; 95% CI, .89 to 1.15; P = .95). CONCLUSIONS: Low-dose thiazide diuretic therapy prescribed widely to older people, particularly those of advanced age and women. The vast majority of myocardial infarction survivors were dispensed beta-blocker therapy at lower-than-evaluated doses. These findings highlight the need to manufacture low-dose thiazide diuretic therapy and to evaluate the minimum effective dose of beta-blocker therapy.

Adrenergic beta-Antagonists↗
PubMed1999

Novel terpenoid-type quinones isolated from Pycnanthus angolensis of potential utility in the treatment of type 2 diabetes.

Using an ethnomedical-based drug discovery program, two previously unknown compounds (SP-18904 and SP-18905) from Pycnanthus angolensis were isolated that lower glucose concentrations in mouse models of type 2 diabetes. SP-18904 and SP-18905 are terpenoid-type quinones that significantly lowered plasma glucose concentration (p <.05) when given orally to either ob/ob or db/db mice, both of which are hyperglycemic and hyperinsulinemic. The antihyperglycemic actions of SP-18904 and SP-18905 were associated with significant decreases in plasma insulin concentrations (p <.05), suggesting that both compounds lowered glucose by enhancing insulin-mediated glucose uptake. This was supported by the insulin suppression test in ob/ob mice. Studies in hyperglycemic, insulin-deficient mice and in vitro experiments on 3T3-L1 adipocytes further supported this conclusion. As such, these two terpenoid-type quinones represent a new class of compounds of potential use in the treatment of type 2 diabetes.

Adipocytes↗
PubMed1998

Reporting of gender-related information in clinical trials of drug therapy for myocardial infarction.

BACKGROUND: Concern has been expressed that women are not adequately represented in clinical trials evaluating treatments for medical conditions they commonly experience. This study was designed to assess the reporting of data on women in recently published trials of drug therapy for myocardial infarction, including those funded by an agency with a gender-related policy. METHODS: All randomized controlled trials and meta-analyses of drug therapies for myocardial infarction published in The New England Journal of Medicine, The Lancet, The Journal of the American Medical Association, the Annals of Internal Medicine and the British Medical Journal from January 1992 to December 1996 were evaluated. On preliminary review 102 articles met the inclusion criteria; these were reviewed in detail, and 59 were excluded. Two reviewers independently extracted gender-related information from the 43 articles; discrepancies were resolved by consensus. RESULTS: Women presented up to 48% of the trial participants (mean 24.1%). In the trials funded by an agency with a gender-related policy, only 16.8% of participants, on average, were women. Of the 43 articles in the sample, only 14 (32%) provided gender-related results. Funding from an agency with gender-related policy did not affect the reporting of gender-related information. Subgroup analyses were provided for 14 (32%) of the 43 trials, including 2 (29%) of 7 trials funded by an agency with a gender-related policy. Of the 12 trials that included interaction analyses (excluding the 2 trials in which secondary analyses were conducted specifically to identify differences between women and men), 7 (58%) conducted an interaction analysis to determine if women responded differently than men; for one of these the interaction analysis was for a secondary outcome measure (drug safety). Only 5 (12%) of the 43 articles mentioned the differences between men and women in the Discussion section; 2 of these were studies that used secondary analyses to examine sex differences. Of the 5, only 1 was funded by an agency with a gender-related policy. INTERPRETATION: Women were poorly represented in the randomized controlled trials in this sample, regardless of whether the trials were funded by an agency with a gender-related policy. Structured reporting of gender-related information for clinical trials may improve the quality of information available about women and therefore facilitate the application of research findings to the care of women.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1990

Chemical induction of thymomas in AKR mice: interaction of chemical carcinogens and endogenous murine leukemia viruses. Comparison of N-methyl-N-nitrosourea and methyl methanesulphonate.

The time course of development of thymic lymphoma, which occurs spontaneously in mice of the AKR strain, is accelerated by the methylating agents N-methyl-N-nitrosourea (MNU) and methyl methanesulphonate (MMS). Since MNU is a potent mutagen inducing G----A transition mutations and MMS a relatively weak mutagen, it was of interest to examine the genetic alterations associated with each class of the chemically induced tumors and to compare these alterations with those found in the spontaneous tumors. The same spectrum of genetic alterations was found for MMS-induced and spontaneous thymomas. Both showed rearrangements of c-myc and Pim-1 genes that appeared to result from integration of recombinant mink cytopathic focus-forming (MCF) proviruses but failed to reveal evidence for activation of ras oncogenes, either by DNA transfection experiments or by hybridization of DNA to specific oligonucleotide probes. Some alteration in c-myc and Pim-1 genes were also found in MNU-induced tumors, but, mainly, these involved integration of ecotropic-like rather than recombinant MCF viruses. Furthermore, MNU-induced tumors frequently (in 24% of thymomas) contained G----A transition mutations, activating the Ki-ras oncogene at codon 12 position 2. Another feature that distinguishes the MNU-induced tumors from those occurring in untreated and MMS-treated mice was the consistently high level of c-myc mRNA that occurred in the absence of c-myc gene rearrangement. Taken together, the data indicate that the mechanisms of development of tumors following treatment with MNU and MMS are distinct, and that the effect of MMS is probably to speed up the process of viral leukemogenesis.

Animals↗
PubMed1983

Deterrence in the workplace: perceived certainty, perceived severity, and employee theft.

The phenomenon of employee theft is examined empirically, utilizing a deterrence paradigm. Employees selected randomly from three different industry sectors and metropolitan areas were asked to self-report their involvement in a number of property theft activities within the employment setting. Using a weighted least-squares logit regression analysis, the study found that the perception of both the certainty and severity of organizational sanctions were related to employee theft. Males reported more theft than did females, but contrary to previous research, no gender/certainty or gender/severity interactions were observed. The best-fit model did, however, contain two significant first-order interactions: age/certainty and age/severity. These interactions strongly suggest that younger employees are not as deterrable as their older peers, especially under conditions of both high certainty and high severity of punishment. While a number of possible explanations might account for differential deterrability according to age, a commitment to or stakes in conformity explanation is proposed.

Adult↗
PubMed1981

Retroviral gp70 immune complexes in NZB x NZW F2 mice with murine lupus nephritis.

NZB x NZW (NZB x W) F1 hybrid mice spontaneously develop a disease most prominently characterized by immune complex glomerulonephritis (GN), which seems to be associated with both antibodies to DNA and to the serum retroviral envelope glycoprotein, gp70. To evaluate the contribution of each of these autoimmune responses to the pathogenesis of the GN, we studied NZB x W F2 mice in which the two responses appeared to segregate relatively independently. Use of this model permitted analysis of possible correlations between each response and the G.N. The presence of circulating anti-gp 70-complexed gp70 correlated significantly with the development of fatal GN and one could predict the course of renal disease by computing the rising serum levels of gp70 complexed with antibodies. In contrast, the presence of free antibodies to either double-stranded or single-stranded DNA was not significantly associated with the development of fatal GN. This association of anti-gp70 antibody production with these animals' early death from GN strongly suggests that the gene(s) governing production of antibodies to serum retroviral gp70 may be one of the major genes responsible for spontaneous renal disease segregated in NZB x W F2 generations.

Animals↗
PubMed1981

Actions of various muscarinic agonists on membrane potential, potassium efflux, and contraction of longitudinal muscle of guinea-pig intestine.

1 Depolarizations were recorded intracellularly in smooth muscle from the taenia of the guinea-pig caecum in response to the iontophoretic application of acetylcholine, carbachol, oxotremorine-M, methylfurmethide, hexyl trimethylammonium and tetramethylammonium (TMA). 2 No differences between the iontophoretic responses to agonists stable to cholinesterase were detected. 3 The latency and time to peak of acetylcholine-induced depolarizations were less than those to stable agonists, and the response was briefer and less complex in shape. These differences were reduced, or disappeared, upon inhibition of cholinesterase. 4 The rate of loss of 42K and changes in length were measured in superfused strips weighing about 10 mg of separated longitudinal muscle of guinea-pig ileum. 5 Acetylcholine, carbachol, methylfurmethide, butyltrimethylammonium and TMA contracted the muscle and increased the rate of loss of 42K. 6 Contrary to previous reports, no evidence of a selective action of any of these agonists on 42K loss was detected. TMA appeared to be a partial agonist in evoking 42K loss, although it produced a maximum contraction. 7 The maximum 42K efflux produced by acetylcholine was about 40% of the maximum evoked by application of carbachol or methylfurmethide. If cholinesterase was inhibited, the 42K efflux evoked by maximally effective concentrations of acetylcholine was comparable to that evoked by a stable agonist. 8 These results are consistent with the idea that the muscarinic agonists used interact in an essentially similar way with muscarinic receptors to produce their effects on membrane potential, permeability, and tension.

Acetylcholine↗
PubMed1981

Effects of histamine, high potassium and carbachol on 42K efflux from longitudinal muscle of guinea-pig intestine.

1. Shortening and rate of loss of (42)K were studied in strips of longitudinal muscle taken from guinea-pig ileum.2. Carbachol, histamine and raising the external potassium concentration, [K(+)](o), to 120 mm in the presence of atropine caused equal maximal shortenings of the muscle, but unequal maximal increases in (42)K efflux: maximal (42)K effluxes obtainable in response to raised [K(+)](o) and histamine were about (2/3) and (1/3) respectively of the maximal efflux in response to carbachol. In the absence of atropine the increase in (42)K efflux produced by 120 mm-[K(+)](o) was about 50% larger, probably because of the release of acetylcholine from nerve endings in the tissue.3. If inhibitors of histamine metabolism were applied, or a H(2)-receptor blocker (cimetidine), the maximum (42)K efflux produced by histamine was not increased. An analogue of histamine reputed to resist metabolic degradation did not produce a larger increase in (42)K efflux than histamine. The smaller maximal effect of histamine on (42)K efflux than carbachol may be because it can open fewer ion channels in the smooth muscle membrane.4. The ratio of the concentrations producing 50% maximal shortening and 50% maximal (42)K efflux was about 1:1.3 for raised [K(+)](o) but about 1:20 for histamine and carbachol. Depolarization by raising [K(+)](o) appears to be less effective in causing tension development than similar depolarizations produced by carbachol or histamine.5. The relative effects of carbachol, histamine and raised [K(+)](o) were discussed in the light of their similar depolarizing actions. Increases in (42)K efflux did not appear to be caused primarily either by contraction or by depolarization of the muscle. Access of the stimulant to cells and receptors other than those which are superficially situated was suggested as being an important factor in deciding the smaller increase in (42)K efflux seen with some stimulants. Histamine receptors may be fewer in number than muscarinic receptors and less able in their activated form to open channels through which potassium ions can escape.

Animals↗
PubMed1981

Evidence that histamine and carbachol may open the same ion channels in longitudinal smooth muscle of guinea-pig ileum.

1. Membrane potential was recorded intracellularly by micro-electrode in separated longitudinal muscle of guinea-pig ileum. Electrotonic potentials were evoked in longitudinal strips by passing current between large external electrodes in the partition chamber.2. Histamine increased the frequency of action potential discharge at low concentrations and depolarized the membrane. At higher concentrations it caused substantial depolarization and action potential discharge was abolished. Carbachol had similar actions but the maximal depolarization by carbachol (using 10(-4)m) was some 4-5 mV greater than maximal depolarization by histamine (using 10(-4)m).3. The change in size of evoked electrotonic potentials was used to estimate the effects of carbachol and histamine on the conductance of the smooth muscle membrane. The equilibrium potentials for histamine and carbachol depolarizations were estimated from their relative effects on potential and conductance and were found to be not significantly different; measurements of the effects on conductance showed that 10(-4)m-histamine increased conductance about 8-fold whilst 10(-4)m-carbachol had a much greater effect on conductance. This difference could explain the differing maximal depolarizing effects of these agents if both were assumed to open channels having the same ionic selectivity (i.e. equilibrium potential).4. The efflux of (42)K was studied in separated strips of longitudinal ileal muscle from guinea-pig. In the presence of a concentration of carbachol (2 x 10(-5)m or 10(-4)m) having a maximal effect on (42)K efflux rate, histamine (10(-4)m) did not increase efflux further although 120 mm-potassium did so. Experiments with the irreversible muscarinic receptor blocker, propylbenzilylcholine mustard, indicated that the number of muscarinic receptors did not limit the (42)K efflux response to carbachol and it was suggested that the response was limited by the availability of ion channels which could be opened by activated muscarinic receptors.5. Contractions to histamine and carbachol in 120 mm-potassium depolarizing solution were followed upon washing by a relaxation below basal tension. Carbachol, but not histamine, showed a pronounced and long lasting secondary contraction following this relaxation.6. These results are consistent with the idea that activated histamine and activated muscarinic receptors open the same ion channels in the smooth muscle membrane to produce depolarization, increased action potential discharge and contraction, although muscarinic receptors can open more of these. However, there was evidence that the opening of these channels is not the only pathway between receptor activation and contraction.

Animals↗
PubMed1978

Saccharin, cyclamate, and human bladder cancer. No evidence of an association.

An epidemiologic study designed to elucidate the possible roles of the artificial sweeteners saccharin and cyclamate in human urinary bladder cancer was recently completed. The previous intake of each of these substances among 519 patients with histopathologically confirmed bladder cancer and an equal number of matching controls in metropolitan Baltimore did not differ significantly in frequency, quantity, or duration. These normal findings persisted after simultaneous adjustment for the effects of smoking, occupation, age, diabetes mellitus, and a number of other potentially confounding factors. They are substantiated by the failure of the relative risk of bladder cancer to increase with increasing exposure to artificial sweeteners. It is concluded that neither saccharin nor cyclamate is likely to be carcinogenic in man, at least at the moderate dietary ingestion levels reported by the patient sample.

Cyclamates↗