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Biomedical subjects

J Stewart

Publications and source records attributed to J Stewart.

At least 235 records · Page 13Linked to original sources
PubMed1996

Second primary cancers following cancers of the kidney and prostate in New South Wales (Australia), 1972-91.

Data from the New South Wales (NSW) (Australia) Central Cancer Registry for the period 1972-91 were examined to determine the risk of second primary cancers following an initial invasive cancer of the renal parenchyma (ICD-9 code 189.0), renal pelvis (code 189.1), or prostate (code 185). Eligible cases were restricted to those who had survived for at least two months after diagnosis of the first primary cancer. Expected numbers of cancers were obtained by assuming that subjects experienced the same cancer incidence as prevailed in the corresponding general population and applying gender-, age-, and calendar-specific rates to the appropriate person-years at risk. The relative risk (RR) of a second primary cancer was taken to be the ratio of observed to expected numbers of second cancers. Following prostatic cancer, there was an overall deficit of cancers at all sites combined (RR = 0.79, 95 percent confidence interval [CI] = 0.75-0.84), and no site had a significantly raised RR. Taking this into consideration, there appeared to be a reciprocal relationship of increased risk of prostatic cancer (RR = 1.7, CI = 1.2-2.3) following an initial cancer of the renal parenchyma and of renal parenchymal cancer (RR = 1.2, CI = 0.8-1.7) after cancer of the prostate. An increased risk of bladder cancer occurred following renal parenchymal (RR = 3.4, CI = 1.1-8.0, for women only) as well as after renal pelvic cancer (men: RR = 8.7, CI = 5.4-13; women: RR = 39, CI = 26-56). A tobacco-related pattern of excess risk was seen after renal pelvic cancer but not after cancer of the renal parenchyma. These data illustrate that an excess of second primary cancers may reflect shared etiologic factors or increased medical surveillance.

Aged↗
PubMed1996

Effects of opioid and dopamine receptor antagonists on relapse induced by stress and re-exposure to heroin in rats.

The effects of blockade of opioid and dopamine receptors on relapse to heroin-seeking induced by footshock stress and re-exposure to heroin were examined in a reinstatement procedure. Male rats were trained to self-administer heroin (100 micrograms/kg per infusion, IV; four 3-h sessions/day for 8-11 consecutive days). Extinction sessions were given for 5-7 days during which saline was substituted for heroin. In nine groups, the effects on relapse induced by footshock (10 min, 0.5 mA, 0.5 s on with a mean off period of 40 s), heroin priming (0.25 mg/kg), and saline priming were studied after pretreatment with either naltrexone (1 or 10 mg/kg, SC), the D1-like receptor antagonist SCH 23390 (0.05 or 0.1 mg/kg, IP), the D2-like receptor antagonist raclopride (0.25 or 0.5 mg/kg, IP), the mixed dopamine antagonist flupenthixol decanoate (3 or 6 mg/kg, IM), or IP injection of saline (control condition). Naltrexone, flupenthixol, raclopride, and the highest dose of SCH 23,390 attenuated heroin-induced relapse: only the mixed DA receptor antagonist, flupenthixol, attenuated foot-shock-induced relapse. These results, and those from microdialysis showing that heroin elicits greater locomotor activity and DA release in the nucleus accumbens than footshock, suggest that the neurochemical events underlying stress- and heroin-induced relapse are not identical.

Animals↗
PubMed1996

Inverse analysis of empirical matrices of idiotypic network interactions.

The concept of shape space proposed by Perelson and Oster (1979, J. Theor. Biol. 81, 645-670) has been a useful tool for the theoretical immunologists, who have invoked it to model idiotypic binding, which plays a significant role in mathematical models of immune networks. The actual construction of such a space from its definition requires specialized experimental information, which is not completely available. In this article, we discuss, with illustrative examples, how graphical representations similar to the idea of shape space can be derived by analyzing real affinity matrices, and the relative merits of such representations to approximations that might be obtained by the approach of Perelson and Oster. We also give directions for future research with a view toward applications.

Animals↗
PubMed1996

Stress reinstates cocaine-seeking behavior after prolonged extinction and a drug-free period.

We have shown previously, using an animal model of relapse, that acute exposure to intermittent footshock stress induces reinstatement of heroin-taking behavior in rats. Here we report that in rats trained to self-administer cocaine, exposure to acute intermittent footshock stress induces reinstatement of cocaine-taking behavior after prolonged extinction sessions and after a 4- to 6-week drug-free period; an effect comparable to that induced by a priming injection of cocaine. Animals were initially allowed to self-administer cocaine HCl (1.0 mg/kg per infusion, i.v.) during one 3-h session/day for 12 days. Subsequently, extinction conditions were introduced by substituting saline for cocaine so that lever-pressing resulted in i.v. infusions of saline rather than of drug. Extinction conditions were maintained until animals made 15 responses or less in the 3 h, after which animals were given saline infusions at the start of each daily session to establish baseline responding of ten responses or less. Subsequently, animals were tested for reinstatement of responding for saline infusions following a non-contingent injection of cocaine (2.0 mg/kg, i.v.) and exposure to intermittent footshock (10 min, 0.5 mA, 0.5 s on, mean off period of 40 sec). After an additional 4- to 6-week drug-free period, tests for reinstatement were repeated. Reinstatement of cocaine-taking behavior was observed in both sets of tests in response to footshock and cocaine. These results extend previous reports from this laboratory that footshock stress is an effective stimulus for reinstatement of drug-taking behavior in the rat.

Animals↗
PubMed1996

Acute and repeated activation of male sexual behavior by tail pinch: opioid and dopaminergic mechanisms.

We studied the effect of tail pinch on male sexual behavior and its neurochemical basis. Male rats were gonadectomized and maintained on low doses of testosterone propionate (20.0 micrograms/day). Tail pinch significantly increased the percentage of males that mounted, intromitted, and ejaculated within a 30-min test, and these increases were attenuated by both pimozide (1.0 mg/kg, i.p.) and by naloxone (0.5, 1.0, and 2.0 mg/kg, s.c.). Moreover, tail pinch in the presence of an estrous female led to significantly increased female-directed behavior 48 h later during a test without tail pinch. Repeated tail pinch tests led to progressively more sexual activity, and the development of this behavioral sensitization was prevented by naloxone. These findings suggest that tail pinch increases the salience of the incentive characteristics of the female. Furthermore, during subsequent tests, with or without tail pinch, the increased salience of the female remains, as measured by the continued increases in sexual activity. These acute and sensitized behavioral increases might result from tail pinch-induced activation of the midbrain dopamine system via an opioid mechanism; either preventing tail pinch-induced dopamine activation (by an opioid antagonist) or blocking the effects of dopamine activation (by a dopamine antagonist) attenuated the long-term facilitation of sexual behavior seen after pairing the female with tail pinch.

Animals↗
PubMed1996

A mobile lesion in the carotid artery.

The case of a 68 year old woman with a sudden onset of visual loss in the left eye is reported. Carotid duplex scanning revealed a 50-75% stenosis of the left internal carotid artery, with a floating tail of clot extending into the lumen of the artery. Emergency carotid endarterectomy, removing the plaque with the attached thrombus, was performed.

Aged↗
PubMed1996

Serum bactericidal activity in a secondary school population following an outbreak of meningococcal disease: effects of carriage and secretor status.

Sera obtained from 106 children following an outbreak of Neisseria meningitidis (B:4:P1.15) were screened for bactericidal antibodies against isolates of meningococci and Neisseria lactamica. Most had high titres of antibodies to N. lactamica and N. meningitidis NG:4:- but not to capsulate isolates: B:4:P1.15; B:15:P1.16; B:4:-; C:4:-. Bactericidal activity was higher for both carriers and secretors but the differences were not significant. Bactericidal activity was not associated with total or specific IgA or IgM. Carriers had significantly higher levels of IgG to N. lactamica but not to NG:4:- in sera with bactericidal activity for each of the capsulate strains. Among non-carriers, higher levels of IgG to N. lactamica were associated with killing of B:4:P1.15 and B:4:-. Secretors' sera with bactericidal activity had significantly higher levels of IgG to N. lactamica compared with sera that were not bactericidal. This was not observed among non-secretors. Antibodies to the outbreak strain were adsorbed by all Neisseria isolates tested and absorption of sera with N. lactamica alone completely removed the bactericidal activity against the outbreak strain.

ABO Blood-Group System↗
PubMed1996

Apneustic breathing provoked by limbic influences.

We describe a 64-year-old man with cerebrovascular disease who had an acute stroke characterised by pseudobulbar palsy, facial weakness, and pyramidal signs. He developed frequent emotional outbursts followed by periods of apneusis. Between these episodes he breathed with a regular and unvarying rate and tidal volume. Autopsy showed extensive cortical, subcortical and pontine infarction. The respiratory pattern indicated a dissociation between voluntary and automatic pathways. The descending limbic pathways were preserved but an abnormal pattern of automatic breathing (ie, apneusis) occurred because of the presence of bilateral pontine infarction.

Acute Disease↗
PubMed1996

Phosphorylation and activation of smooth muscle myosin light chain kinase by MAP kinase and cyclin-dependent kinase-1.

Smooth muscle myosin light chain kinase (MLCK) features several consensus sites of phosphorylation by proline-directed protein serine/threonine kinases. The phosphorylation of MLCK by two proline-directed kinases isolated from sea star oocytes, i.e., p44mpk (Mpk, a mitogen-activated protein kinase homologue) and cyclin-dependent kinase-1 (CDK1, also known as p34cdc2), was investigated. Chicken gizzard MLCK was phosphorylated on seryl and threonyl residues by both Mpk and CDK1. Phosphorylation of MLCK to 0.6 mol Pi/mol by Mpk increased the Vmax of phosphotransferase activity towards a synthetic peptide corresponding to residues 11-23 of the 20-kDa light chain of myosin by 1.6-fold. Phosphorylation of MLCK to 1.0 mol Pi/mol by CDK1 increased the Vmax by 2.3-fold. Phosphorylation by either kinase had no significant effect on the concentration of calmodulin required for half-maximal activation of MLCK. Analysis of the phosphorylation of synthetic peptides containing consensus phosphorylation sites for Mpk and CDK1 indicated that the major site of phosphorylation in MLCK by Mpk was Ser-834, and by CDK1 was Thr-283. Both of these sites are located outside the calmodulin-binding site (residues 796-815), consistent with the observation that phosphorylation by Mpk or CDK1 was unaffected by the presence of bound Ca2+/calmodulin. These results indicate that MLCK activity may be regulated by phosphorylation catalyzed by proline-directed kinases, possibly directed at Thr-40 and Thr-43 at the amino terminus of MLCK.

Animals↗
PubMed1996

Phase II study of topotecan in patients with extensive-stage small-cell carcinoma of the lung: an Eastern Cooperative Oncology Group Trial.

PURPOSE: To determine the response rate and survival of chemotherapy-naive patients with extensive-stage small-cell lung cancer (SCLC) treated with topotecan, and to determine the relationship of topotecan pharmacokinetics with response and toxicity. PATIENTS AND METHODS: Forty-eight patients with previously untreated, extensive-stage SCLC received 2.0 mg/m2 of topotecan daily for 5 days. The first 13 patients were treated without colony-stimulating factor (CSF) support; the next 35 patients received 5 micrograms/kg of granulocyte-colony-stimulating factor (G-CSF) for 10 to 14 days starting on day 6. Cycles were repeated every 3 weeks for a maximum of four cycles. Patients who had a partial response to topotecan after four cycles, stable disease after two cycles, or progressive disease at any time received salvage chemotherapy with cisplatin and etoposide. Topotecan pharmacokinetics were measured using a four-point sampling scheme. RESULTS: Of 48 patients, none had a complete response and 19 had a partial response, for an objective response rate of 39% (95% confidence interval [CI], 25.2% to 53.0%). The median response duration was 4.8 months (95% CI, 3.0 to 7.3). After a median follow-up duration of 18.2 months, the overall median survival time was 10.0 months (95% CI, 8.2 to 12.7); the 1-year survival rate was 39% (95% CI, 25.2% to 53.0%). Eight of 34 patients (24%) who received salvage chemotherapy responded. Four of 17 patients who did not respond to first-line therapy with topotecan responded to cisplatin and etoposide. The most common toxicity was hematologic. Ninety-two percent of patients treated without G-CSF developed grade 3 or 4 neutropenia, compared with 29% who received G-CSF. However, the incidence of neutropenic fevers was similar between the two groups (8% and 11%, respectively), and one patient in each group died of neutropenic fevers. There were no differences in objective tumor response, duration of response, time to treatment failure, or survival between the 13 patients who entered the study before G-CSF administration was mandated and the 35 patients who entered after and received G-CSF. There was poor correlation between the WBC count and absolute neutrophil counts (ANCs) and both the area under the curve (AUC) and maximum concentration++ (Cmx) of total topotecan in plasma. There was no correlation between the tumor response and either AUC or Cmx of total topotecan. CONCLUSION: The activity of topotecan in extensive-stage SCLC noted in this study warrants further investigation of this agent in phase III clinical trials.

Adult↗
PubMed1996

Urine acidification affects the activity of the organic base transporter in a nonstereoselective manner.

This investigation determined 1) the effect of urine acidification on renal clearance (Clrenal), total systemic clearance (Cltotal) and nonrenal clearance (Clnonrenal) of pindolol, 2) whether urine acidification affected the stereoselectivity of pindolol excretion and 3) the pharmacodynamic effects that may result from changes in the activity of the organic base transporter. The Clrenal, Cltotal and Clnonrenal values of pindolol isomers were determined during pindolol administration (10 mg twice daily; control phase) and during pindolol administration (10 mg twice daily) with NH4Cl, a systemic and urinary acidifier, (1.5 g every 6 hr). Eight healthy males (22-33 yr) randomly received this therapy for 3 days on two occasions. On day 4, urine and plasma were collected over 24 hr. R-(+) pindolol Clrenal values during control and NH4Cl were 203 +/- 82 and 480 +/- 248 ml/min, respectively (P = .03). S-(-) pindolol Clrenal values during control and NH4Cl were 279 +/- 81 and 593 +/- 294 ml/min, respectively (P = .005). NH4Cl increased R-(+) pindolol Clrenal by 173% +/- 136% (P = .003) and S-(-) pindolol Clrenal by 127% +/- 105% (P = .03). Stereoselective renal excretion of pindolol was unaffected by NH4Cl; the R(+)/S(-) pindolol Clrenal ratio was unchanged from control to NH4Cl (0.74 +/- 0.23 to 0.81 +/- 0.10, P = NS, respectively). NH4Cl, however, affected pindolol Clnonrenal in a stereoselective fashion; R-(+) pindolol Clnonrenal values increased (641 +/- 241 to 851 +/- 251 ml/min; P = .02), whereas S-(-) pindolol Clnonrenal values remained constant (354 +/- 116 vs. 370 +/- 213 ml/min). Changes in pindolol clearance values resulted in a significant reduction in beta-blocking activity assessed by isoproterenol testing. We conclude that increasing the urine proton gradient can increase the Clrenal value of organic bases by 2-fold in a manner that is not stereoselective. NH4Cl, however, did increase the Clnonrenal value of pindolol in a stereoselective manner. These data, therefore, indicate that the administration of a urine-acidifying agent can greatly enhance the elimination of organic bases and ultimately reduce the pharmacologic activity of the organic base.

Adult↗
PubMed1995

Natural tolerance in a simple immune network.

The following basic question is studied here: In the relatively stable molecular environment of a vertebrate body, can a dynamic idiotypic immune network develop a natural tolerance to endogenous components? The approach is based on stability analyses and computer simulation using a model that takes into account the dynamics of two agents of the immune system, namely B-lymphocytes and antibodies. The study investigates the behavior of simple immune networks in interaction with an antigen whose concentration is held constant as a function of the symmetry properties of the connectivity matrix of the network. Current idiotypic network models typically become unstable in the presence of this type of antigen. It is shown that idiotypic networks of a particular connectivity show tolerance towards auto-antigen without the need for ad hoc mechanisms that prevent an immune response. These tolerant network structures are characterized by aperiodic behavior in the absence of auto-antigen. When coupled to an auto-antigen, the chaotic attractor degenerates into one of several periodic ones, and at least one of them is stable. The connectivity structure needed for this behavior allows the system to adopt particular dynamic concentration patterns which do not lead to an unbounded immune response. Possible implications for the understanding of autoimmune disease and its treatment are discussed.

Animals↗
PubMed1995

Interaction of tyrosine-based sorting signals with clathrin-associated proteins.

Tyrosine-based signals within the cytoplasmic domain of integral membrane proteins mediate clathrin-dependent protein sorting in the endocytic and secretory pathways. A yeast two-hybrid system was used to identify proteins that bind to tyrosine-based signals. The medium chains (mu 1 and mu 2) of two clathrin-associated protein complexes (AP-1 and AP-2, respectively) specifically interacted with tyrosine-based signals of several integral membrane proteins. The interaction was confirmed by in vitro binding assays. Thus, it is likely that the medium chains serve as signal-binding components of the clathrin-dependent sorting machinery.

Adaptor Proteins, Vesicular Transport↗
PubMed1995

Northern practices offer a challenge but few MDs willing to make the move.

Manitoba's Norway House offers a ruggedly beautiful location and a challenging medical practice, but the physical and professional appeal has not been strong enough to entice physicians to make a long-term commitment to the community, which has needed medical service since September 1994. A physician who left there this spring said concerns about practice restrictions convinced him to move south.

Manitoba↗
PubMed1995

Intra-VTA injections of the mu-opioid antagonist CTOP enhance locomotor activity.

In this paper we report on the effects of microinjections of the mu-opioid antagonist CTOP (D-Pen-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2) into the ventral tegmental area (VTA) on activity and ingestive behavior in the rat. Intra-VTA CTOP (0.015, 0.15, and 1.5 nmol per side) dose-dependently increased activity, whereas it had no effect on feeding and drinking behavior. These results are consistent with previous reports that intra-VTA injections of CTOP enhance extracellular dopamine levels in the nucleus accumbens. Furthermore, we propose a model of VTA mu-opioid mechanisms that might account for these surprising effects of intra-VTA CTOP.

Analysis of Variance↗
PubMed1995

Pulmonary surfactant protein SP-A with phospholipids in spread monolayers at the air-water interface.

Spread monolayers of pulmonary surfactant protein SP-A, alone or mixed with phospholipid(s), were formed at the air-water interface. Binary monolayers of SP-A plus dipalmitoylphosphatidylcholine (DPPC) showed positive deviations from ideal behavior of the mean areas in the films consistent with partial miscibility and interaction between the protein and lipid. During compression of SP-A/DPPC films which contained > or = 5 wt % SP-A, properties were displayed which were consistent with the protein being partially squeezed out at surface pressures of about 30 mN/m. Some protein appeared to remain in the monolayers even when they were compressed to high surface pressures of about 65-70 mN/m, and it was possibly included in the collapse phase(s) that was (were) formed at 72 mN/m. During dynamic cyclic compression-expansion of SP-A/DPPC monolayers initially formed at low surface pressures, SP-A enhanced the respreading of the films compressed beyond collapse compared to the respreading after collapse of films containing DPPC alone. Spread monolayers of SP-A plus either dipalmitoylphosphatidylglycerol (DPPG) or a mixture of DPPC plus DPPG (7:3, mol/mol) displayed additivity of the mean areas in the films, consistent with complete immiscibility (or ideal miscibility, an unlikely effect) between the protein and lipid components. Electrostatic repulsion between SP-A and DPPG, both negatively charged at physiological pH, possibly governed the behavior of these lipid-protein films. Calcium ions in the subphase did not alter the properties of SP-A/DPPC films, whereas they improved the ability of SP-A to mix with DPPG and DPPC/DPPG. Binding of calcium to the negatively charged DPPG and SP-A may account for association of the protein with DPPG and DPPC/DPPG in the monolayers in the presence of the divalent ions.

1,2-Dipalmitoylphosphatidylcholine↗