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Biomedical subjects

R G MacKenzie

Publications and source records attributed to R G MacKenzie.

At least 55 records · Page 3Linked to original sources
PubMed1989

A-69024: a non-benzazepine antagonist with selectivity for the dopamine D-1 receptor.

A-69024 HBr, 1-(2-bromo-4,5-dimethoxybenzyl)-7-hydroxy-6-methoxy-2-methyl-1,2,3,4- tetrahydroisoquinoline hydrobromide, is a selective antagonist of the dopamine D-1 receptor. A-69024 HBr shows an apparent affinity toward the D-1 receptor (identified using [125I]SCH 23390) of 12.6 (4.15-38.3) nM (mean (90% CL), n = 3); the apparent affinity toward the D-2 receptor (identified using [3H]spiroperidol is 1 290 (1,200-1,380) nM (n = 3); using [125I]lysergic acid diethylamine to identify the 5-HT1C receptor gives apparent affinity of 17,800 (9,700-32,600) nM (n = 3). In assays of adenylate cyclase activity, A-69024 HBr antagonizes the D-1 receptor with a calculated affinity of 43.9 (17.5-110) nM (n = 5), while the molecule antagonizes the D-2 receptor with a calculated affinity greater than 400 nM. Behavioral studies demonstrate that A-69024 HBr (5 mg/kg s.c.) is able to block both amphetamine-induced locomotor activity and apomorphine-induced stereotypy. Furthermore, A-69024 HBr blocks SF&F 38393-, but not quinpirole-, induced rotation in rats having unilateral 6-hydroxydopamine lesions of the substantia nigra. When administered at behaviorally effective doses. A-69024 HBr neither increases the concentration of serum prolactin nor potentiates dihydroxyphenylalanine (DOPA) accumulation in the caudate-putamen of rats pretreated with the DOPA decarboxylase inhibitor NSD 1015. Because A-69024 is a dopamine receptor antagonist discriminating between the D-1 and D-2 receptors, it may be a useful research tool.

Adenylyl Cyclases↗
PubMed1989

Prior training and recommendations for future training of clinical research faculty members.

A survey was conducted of the first authors of half of the research papers published in 18 leading peer-reviewed medical journals over a six-month period in 1986. The first authors of every other article (that is, alternate articles) published during this period were sent a questionnaire that assessed their previous research training and their recommendations for training of clinical research faculty members. Of the 772 physicians sent the questionnaire, 482 responded. Of these, 57% had had some research training in medical school, 52% had received such training during residency, and 87% had received it during their fellowships. Fifty-six percent had taken a formal statistics course, 31.4% had taken some computer training, and 87% had received research supervision in a nonstructured format (that is, no formal course work). Introductory biostatistics was the only formal course in any of the seven subject areas listed in the questionnaire that more than one-third of the respondents had taken, yet at least two-thirds recommended that researchers take formal courses in all of the seven areas listed. The investigators recommend for medical students and postgraduate trainees a graduated experience of research training and exposure that includes formal courses.

Adult↗
PubMed1988

Neural modulation of the stimulatory regulatory protein of adenylate cyclase in rat brown adipose tissue.

We reported previously that cold exposure increases by 2- to 3-times the maximal responsiveness of interscapular brown adipose tissue (IBAT) adenylate cyclase to stimulation by norepinephrine or fluoride and that the sensitizing effect of cold is the result of an increase in neural transmission to the tissue because it is abolished by prior surgical denervation of IBAT. The present report examined further the molecular basis of the sensitization of IBAT adenylate cyclase. Cold exposure increased the maximal responsiveness of adenylate cyclase to stimulation by guanylyl-5'-imidodiphosphate without altering the apparent affinity of the enzyme for the nucleotide. In addition, cold exposure increased the maximal extent of cholera toxin-mediated ADP-ribosylation of the alpha subunit of the stimulatory regulatory protein of adenylate cyclase (Gs alpha) in proportion to the increase in adenylate cyclase activity, but did not alter pertussis toxin-mediated labeling of the inhibitory regulatory protein. Direct measurement of Gs alpha by immunoblotting, however, revealed that sensitized membranes did not contain more Gs alpha protein. These results indicate that neural stimulation of IBAT produced by cold exposure alters the proportion of existing Gs molecules that are functional. The additional observation that sensitized adenylate cyclase activity did not reconstitute into cyc- S-49 lymphoma membranes suggests that the ability of neural stimulation to increase Gs function in IBAT might depend upon the interaction of Gs with factors that are unique to membranes of cold-exposed rats.

Adenosine Diphosphate Ribose↗
PubMed1987

The clinical utility and evaluation of drug screening techniques.

A better understanding of the methods of drug detection, their sensitivities, and limitations increases the efficiency of medical decision making for better patient care. Many of the sociomedical and medicolegal questions are yet to be answered through court challenge. The physician must remember his or her role as a clinician, and practice the art in a fashion that best serves the interest of his or her teenage patient.

Adolescent↗
PubMed1987

Recognizing the adolescent drug abuser.

Adolescents are at high risk for using and abusing illicit drugs. Guidelines for recognizing drug abusers are presented as well as a staging process for progression of drug use. The family physician is in an ideal position to identify young users/abusers and to assist them and their families in obtaining much needed assistance.

Adolescent↗
PubMed1986

Streptozotocin-induced diabetes reduces brain serotonin synthesis in rats.

The rate of brain 5-hydroxytryptamine (serotonin) synthesis and turnover in streptozotocin-diabetic rats was assessed using three separate methods: the rate of 5-hydroxytryptophan accumulation following decarboxylase inhibition with Ro 4-4602; the decline in 5-hydroxyindoleacetic acid levels following monoamine oxidase inhibition with pargyline; and the rate of 5-hydroxyindoleacetic acid accumulation following blockade of acid transport with probenecid. Each of the three methods revealed that 5-hydroxytryptamine synthesis and turnover is decreased by 44-71% in diabetic rats with plasma glucose levels of between 500 and 600 mg%. In addition, the levels of free and bound plasma tryptophan were measured and the levels of the free amino acid were found to be the same in control and diabetic rats. Since diabetic rats exhibit a 40% decrease in brain tryptophan, the free tryptophan level in plasma does not predict brain tryptophan levels in diabetic rats. These data are discussed within the context of psychiatric disturbances experienced by diabetic patients.

5-Hydroxytryptophan↗
PubMed1985

Management of localized non-Hodgkin's lymphoma.

Non-Hodgkin's lymphomas (NHLs) are a heterogeneous group of disorders that vary widely in response to therapy. In Canada the modified Rappaport classification is used to categorize NHL. To facilitate the reporting and comparison of treatment results all cases should also be categorized in the terminology of the National Cancer Institute's working formulation. The choice of therapy should be guided by specific prognostic factors: stage and bulk of the disease, patient's age, presence of systemic symptoms and histologic subtype. Of these, the last appears to be the most important. Radiotherapy (RT) is the treatment of choice in localized low-grade lymphomas with favourable prognoses, while bimodal therapy (RT and chemotherapy [CT]) is warranted in presentations with unfavourable prognoses. Regional irradiation alone is indicated in intermediate-grade lymphomas with good prognoses (i.e., pathological stage I or II or clinical stage IA or IIA localized disease of small bulk in young patients). All other patients require CT followed by RT. The results of CT alone are encouraging but remain experimental. Aggressive therapy with multidrug regimens that include central nervous system prophylaxis is the foundation for successful treatment of high-grade NHL such as lymphoblastic lymphoma and diffuse small-noncleaved-cell lymphomas. Low-dose RT should be given to sites of bulky disease.

Adult↗
PubMed1985

Chronic neuroleptic treatment increases D-2 but not D-1 receptors in rat striatum.

In vitro binding of [3H]cis(Z)-flupentixol (FPT) to rat striatal membranes was evaluated as an assay for D-1 receptors. It was found that under the appropriate assay conditions [3H]FPT bound to a single saturable site which was most abundant in striatum and bound dopaminergic agonists in the potency order that these drugs demonstrate for adenylate cyclase. These data support previous work suggesting that [3H]FPT labels the D-1 receptor. Next, rats received haloperidol or fluphenazine for 54 days and striatal dopamine receptors were assayed 72 h later. The drug treatments increased the density of D-2 receptors as measured by [3H]spiperone binding by 40% and 25% respectively. However, no change was observed in D-1 receptor density. We conclude that effects of chronic neuroleptic treatment that depend upon increased dopamine receptor density are mediated via the D-2 receptor subtype.

Adenylyl Cyclases↗
PubMed1985

Neural control of adenylate cyclase responsiveness in brown adipose tissue.

The level of prior adrenergic stimulation is known to affect the responsiveness of tissue to subsequent stimulation. We investigated the effects of cold exposure on sympathetic nerve activity in interscapular brown adipose tissue (IBAT) and the impact of those changes on the responsiveness of the adenylate cyclase system. Exposing rats to 4 degrees C for 3 days increased norepinephrine turnover in IBAT and increased the ability of norepinephrine to stimulate adenylate cyclase activity. This 2- to 3-fold increase in adenylate cyclase activity appeared to result from increased nerve transmission because it was abolished by prior surgical denervation of IBAT. Additional studies indicated that cold exposure did not affect the number of beta adrenergic receptors in IBAT. Moreover, cold exposure increased the maximal response of adenylate cyclase to fluoride and guanosine-5--(beta-gamma-imino)triphosphate stimulation by 2- to 3-fold. We conclude that increased nerve transmission produces supersensitivity of IBAT adenylate cyclase and this effect is mediated by a postreceptor modification of the adenylate cyclase system.

Adenylyl Cyclases↗
PubMed1984

High- and low-affinity states of striatal D2 receptors are not affected by 6-hydroxydopamine or chronic haloperidol treatment.

Specific D2 binding in rat striatum was characterized and then the effects of chronic disruption of dopaminergic activity on antagonist and agonist binding to these sites were studied. D2 receptors were defined as those sites capable of binding [3H]spiperone in the presence of cinanserin, a 5-HT2 antagonist, but not in the presence of (+)-butaclamol, a D2 and 5-HT2 blocker. Saturation, competition, and kinetic analyses suggested that D2 receptors are a homogeneous population exhibiting more complex interactions with agonists than antagonists. Antagonist binding was monophasic and guanine nucleotide-insensitive whereas agonist binding was biphasic and guanine nucleotide-sensitive. D2 receptor density was elevated by more than 40% following dopamine depletion by 6-hydroxydopamine or chronic receptor blockade by haloperidol. However neither treatment altered the affinities or magnitudes of the high- and low-affinity components associated with agonist binding to the D2 receptor.

Animals↗
PubMed1981

Metabolic effects of hypothalamic hyperphagia.

In order to test the hypothesis that the enhanced gluconeogenesis of hypothalamic obesity remains responsive to changed in food intake, we have measured gluconeogenesis in two modes of hypothalamic obesity under both hyperphagic and normophagic conditions. The results show that hyperphagia partially decreases gluconeogenesis and fully restores liver glycogen in both modes. The discussion section relates our present findings to the enhanced glucose utilization previously noted after VMH destruction and to the recent hypothesis that hyperphagia is a response to body protein depletion.

Animals↗
PubMed1981

Effects of ventromedial hypothalamic lesions on adipose tissue of weanling male rats.

In weanling male rats, destruction of the ventromedial hypothalamus causes increased carcass lipid deposition and decreased linear growth without changes in food intake or blood glucose levels. These changes are not dependent on altered pituitary function. Lipogenesis and glucose utilization are increased in vivo and in vitro, while gluconeogenesis is accelerated in vivo. The enhanced lipogenesis occurs before increased gluconeogenesis.

Adipose Tissue↗
PubMed1979

Hyperphagia following intraventricular p-chlorophenylalanine-, leucine- or tryptophan-methyl esters: lack of correlation with whole brain serotonin levels.

The methylester hydrochlorides of DL-p-chlorophenylalanine (PCPA), L-leucine and L-tryptophan were intraventricularly administered to rats. All compounds produced increased food intake compared to saline administration. PCPA and leucine administration significantly decreased serotonin levels by 15--18%, while no serotonin depletion occurred following tryptophan injections. The data suggest that intraventricular injections of large quantities of neutral amino acid methyl esters may cause hyperphagia in rats through non-serotonergic effects on brain function.

Animals↗
PubMed1978

Urolithiasis in adolescents.

The characteristics of 31 adolescent patients aged 11 to 20 years with urolithiasis were examined by means of a ten-year retrospective chart review. The majority of stones were found to be secondary to preexisting conditions, with the most common being bladder dysfunction (neurogenic or exstrophy). Exogenous corticosteroid therapy appeared to play a role in lithogenesis in five patients and was the only apparent contributing factor in an 11 1/2-year-old girl. Childhood inborn errors of metabolism accounted for the stones in four of the teenagers. An additional four adolescents did not have any definable biochemical, genetic, or anatomic abnormalities and, therefore, no obvious etiology.

Adolescent↗