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Biomedical subjects

W Clarke

Publications and source records attributed to W Clarke.

At least 19 recordsLinked to original sources
PubMed1996

Inhibition of cyclic 3'-5'-guanosine monophosphate-specific phosphodiesterase selectively vasodilates the pulmonary circulation in chronically hypoxic rats.

While it is known that nitric oxide (NO) is an important modulator of tone in the hypertensive pulmonary circulation, the roles of cyclic 3'-5'-guanosine monophosphate (cGMP) and cGMP-phosphodiesterase (PDE) are uncertain. We found that isolated lung perfusate levels of cGMP were over ninefold elevated in hypertensive vs. normotensive control rats. 98-100% of lung cGMP hydrolytic activity was cGMP-specific PDE5, with no significant decrease in PDE activity in hypertensive lungs, suggesting that the elevation in cGMP was due to accelerated production rather than reduced degradation. In pulmonary hypertensive rat lungs, in vitro, cGMP-PDE inhibition by E4021[1-(6-chloro-4-(3,4-methylbenzyl) amino-quinazolin-2-yl)piperdine-4-carboxylate], increased perfusate cGMP threefold, reduced hypoxic vasoconstriction by 58 +/- 2%, and reduced baseline pulmonary artery pressure by 37 +/- 5%. In conscious, pulmonary hypertensive rats, intravenous administration of E4021 reduced hypoxic vasoconstriction by 68 +/- 8%, pulmonary artery pressure by 12.6 +/- 3.7% and total pulmonary resistance by 13.1 +/- 6.4%, with no significant effect on cardiac output, systemic pressure, and resistance. Comparison of E4021 to inhaled nitric oxide demonstrated that cGMP-PDE inhibition was as selective and as effective as inhaled NO.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1995

Synthesis of (+)-(R)- and (-)-(S)-trans-8-hydroxy-2-[N-n-propyl-N-(3'-iodo-2'-propenyl)] aminotetralin: new 5-HT1A receptor ligands.

(R,S)-trans-8-Hydroxy-2-[N-n-propyl-N-(3'-iodo-2'- propenyl)amino]tetralin 7, a new radioiodinated ligand based on 8-OH-DPAT, was reported as a potential ligand for 5-HT1A receptors. The optically active (+)-(R)- and (-)-(S)-7 were prepared to investigate the stereoselectivity of (R,S)-7. Racemic intermediate 8-methoxy-2-N-n-propyltetralin was reacted with the acyl chloride of (-)-(R)-O-methylmandelic acid to form a mixture of (S,R)- and (R,R)-diastereoisomers, which were separated by flash column chromatography. After removing the N-acyl group from the diastereoisomers, the desired (+)-(R)- or (-)-(S)-7 was obtained by adding an N-iodopropenyl group. In vitro homogenate binding studies showed the stereoselectivity of this new compound for 5-HT1A receptors. (+)-(R)-7 isomer displayed 100-fold higher affinity than the (-)-(S)-7 isomer. Biochemical study indicated that (+)-(R)-7 potently inhibited forskolin-stimulated adenylyl cyclase activity in hippocampal membranes (Emax and EC50 were 24.5% and 5.4 nM, respectively), while (-)-(S)-7 showed no effect at 1 microM. The radioiodinated (+)-(R)- and (-)-(S)-[125I]7 were confirmed by coelution with the resolved unlabeled compound on HPLC (reverse phase column PRP-1, acetonitrile/pH 7.0 buffer, 80/20). The active isomer, (+)-(R)-[125I]7, displayed high binding affinity to 5-HT1A receptors (Kd = 0.09 +/- 0.02 nM). In contrast, the (-)-(S)-7 isomer displayed a significantly lower affinity to the 5-HT1A receptor (Kd > 10 nM).(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclase Inhibitors↗
PubMed1995

A multicenter evaluation of blood glucose awareness training-II.

OBJECTIVE: Blood glucose awareness training (BGAT) teaches individuals with insulin-dependent diabetes to more accurately estimate/detect their blood glucose (BG) fluctuations. It has not, however, consistently resulted in improved ability to detect low BG. To assess an enhanced version of BGAT (BGAT-II), with more focus on increasing sensitivity to low BG events, a multicenter study was undertaken. Following up on previous findings that BGAT is most effective with individuals who are least accurate in estimating BG, this study explicitly recruited subjects who did and did not report reduced awareness of hypoglycemia. RESEARCH DESIGN AND METHODS: Seventy-eight subjects from three research sites participated in a repeated baseline design. Subjects' BG estimation accuracy and BG profiles were assessed 6 months before, immediately before, and immediately after BGAT-II. RESULTS: Post-treatment, BGAT-II led to better overall accuracy in detecting BG fluctuations and better detection of both low and high BG levels. This was achieved while the number of low readings of self-monitoring of blood glucose (SMBG) was reduced. Reduction in the number of low SMBG events was significant only for subjects reporting awareness of hypoglycemia. Detection of low BG was significant only for subjects reporting reduced awareness of hypoglycemia. Both groups demonstrated equivalent improvements in detection of high BG levels. CONCLUSIONS: BGAT may be an effective behavioral strategy for reversing hypoglycemic unawareness and an adjunct to intensive insulin therapy to reduce the occurrence of severe hypoglycemia.

Adult↗
PubMed1994

A potential 5-HT1A receptor antagonist: p-MPPI.

A potential 5-HT1A receptor antagonist, p-MPPI, 4-(2'-methoxy-)phenyl-1-[2'-(n-2"-pyridinyl)-p-iodobenzamido-]ethy l- piperazine, was developed. The [125I]p-MPPI demonstrated high affinity and selectivity toward 5-HT1A receptors; Kd = 0.36 nM and Bmax = 264 fmol/mg of protein in rat hippocampal membrane homogenates. The binding is not sensitive to GTP (300 microM) or Gpp(NH)p (100 microM). In forskolin-stimulated adenylyl cyclase assay using rat hippocampus, p-MPPI (up to 10 microM) showed no agonist activity as compared to that of (+/-)-8-OH-DPAT. At 100 nM it completely antagonized the inhibition of forskolin-stimulated adenylyl cyclase activity produced by 100 nM of (+/-)-8-OH-DPAT. This potential 5-HT1A antagonist may provide a powerful tool for studies of the pharmacology of the 5-HT1A receptor system.

Adenylyl Cyclases↗
PubMed1994

Parent-child relationships and the management of insulin-dependent diabetes mellitus.

Several dimensions of parent-child relationships were examined as predictors of adherence to treatment and metabolic control in a multi-informant study of 88 children and adolescents with insulin-dependent diabetes mellitus who were recruited from 2 endocrinology clinics. Ratings of parent-child discipline, warmth, and behavioral support were not significantly associated with diabetes outcome, but parent-child conflict was a consistent correlate of both adherence and metabolic control. Within a public hospital subsample, conflict was related to parent, child, and nurse ratings of adherence and to a physiological index of metabolic control. These results were partially replicated in a private practice sample where conflict was significantly related to parents' ratings of adherence and to metabolic control. Conflict accounted for unique variance in diabetes outcome beyond that associated with other measures of the parent-child relationship, but the relation between conflict and metabolic control was no longer significant when adherence ratings were entered into regression equations first.

Adolescent↗
PubMed1994

Long-term follow-up evaluation of blood glucose awareness training.

OBJECTIVE: Blood glucose awareness training (BGAT) has been found effective in teaching individuals with insulin-requiring diabetes to improve their ability to better recognize blood glucose (BG) fluctuations. This study investigated whether subjects who underwent BGAT a mean of 4.9 years previously were superior to past control subjects in terms of their ability to recognize BG fluctuations, and whether past BGAT subjects had fewer automobile crashes and lost work days and better glycosylated hemoglobin than control subjects. Additionally, the beneficial effects of providing booster training to past BGAT subjects also was evaluated. RESEARCH DESIGN AND METHODS: This study followed up 28 past BGAT subjects. Half of these subjects (n = 14) received a simple booster-training program. Twelve previous control subjects also were evaluated. Booster subjects were given a BGAT diary to complete for 2 weeks before evaluation. Evaluation for all subjects included completion of a retrospective questionnaire on work and driving history, blood drawing for a glycosylated hemoglobin analysis, and having subjects estimate and measure their BG levels 50-80 times during a 3- to 4-week period during their daily routine. RESULTS: At long-term follow-up, BGAT subjects had significantly fewer automobile crashes than control subjects. BGAT subjects receiving booster training were significantly more accurate at estimating their BG levels and were more aware of hypoglycemia. Post hoc analyses indicated that the ability to accurately estimate BG fluctuations correlated positively with follow-up glycosylated hemoglobin and the number of hypoglycemic and hyperglycemic symptoms participants demonstrated. Both BGAT and control subjects demonstrated significantly improved glycosylated hemoglobin relative to baseline measures. CONCLUSIONS: These data suggest that BGAT has long-term benefits, which can be enhanced with booster training. Specifically, BGAT and simple booster training may result in reduction of severe hypoglycemic episodes and automobile crashes in the long term.

Accidents, Traffic↗
PubMed1994

Antiemetic prophylaxis for strabismus surgery.

Droperidol can reduce the high incidence of vomiting after pediatric strabismus surgery; however, its use may be associated with sedation, delayed hospital discharge, dysphoria and extrapyramidal signs. Midazolam, a short-acting benzodiazepine with antiemetic properties, has few side effects and may be a suitable alternative. We prospectively compared the antiemetic effect of these two drugs in 393 healthy children aged 18 months to 14 years undergoing outpatient strabismus surgery. The children were randomly assigned to receive midazolam hydrochloride (50 micrograms/kg) (199 patients) or droperidol (50 micrograms/kg) (194 children). The incidence rates of vomiting in the two groups were 45% and 37% respectively, a nonsignificant difference. The incidence of vomiting was not affected by the duration of anesthesia, but the number of muscles repaired was a significant predictor of postoperative vomiting (p < 0.001).

Adolescent↗
PubMed1993

Natural history of presumed congenital Brown syndrome.

OBJECTIVE: To evaluate the stability of the ocular alignment in patients with presumed congenital Brown syndrome. DESIGN: A retrospective review of patients with Brown syndrome with an emphasis on nonsurgical cases. Follow-up of at least 1 year was required for inclusion in the study. SETTING: Patients were selected for this study from the pediatric ophthalmology services at the Ivey Institute of Ophthalmology, London, Ontario, and the Children's Hospital of Eastern Ontario, Ottawa. PATIENTS: A cohort of 71 patients with presumed congenital Brown syndrome. Two cases were bilateral. Eleven cases were excluded because of insufficient length of follow-up, leaving 60 patients with an average follow-up of 46 months. All patients were assessed and followed up by a pediatric ophthalmologist. RESULTS: Of 38 patients who had no hypotropia in primary position at presentation, only two (5%) patients experienced a worsening with the development of a small vertical strabismus during the follow-up period. Six (10%) of the entire group of 60 patients experienced a complete spontaneous resolution of the deficiency in elevation at 4, 6, 8, 10, 12, and 15 years of age. CONCLUSION: Among patients with congenital Brown syndrome, those who are orthotropic in the primary position tend to remain stable or improve over time without surgical intervention.

Child↗
PubMed1993

Interphysician agreement in the diagnosis of subtypes of acute ischemic stroke: implications for clinical trials. The TOAST Investigators.

To test interphysician agreement on the diagnosis of subtype of ischemic stroke, we sent subtype definitions and 18 case summaries (clinical features and pertinent laboratory data) to 24 neurologists who have a special interest in stroke, and asked them to determine the most likely subtype diagnosis. The overall agreement was 0.64 (Kappa [K] = 0.54). Interphysician agreement was highest for the diagnoses of stroke secondary to cardioembolism (K = 0.75) or to large-artery atherosclerosis (K = 0.69). Individual physicians varied widely; four agreed with the consensus diagnosis in all 18 cases, while six others disagreed with the consensus diagnosis in three to five cases. Our level of interphysician agreement is greater than that reported in other studies and was substantial. However, despite using subtype definitions and being given extensive information often not available in the acute setting, physicians still disagree about the etiology of stroke, particularly in regard to stroke due to small-artery occlusion or of undetermined etiology. Physicians seem reluctant not to attribute stroke to a specific etiology. The uncertainty about subtype diagnosis will affect interpretation of the results of clinical trials in patients selected by the subtype of ischemic stroke and also suggests that results of treatment as affected by subtype should be cautiously interpreted unless efforts to assure uniformity are included in the trial's operations. Refinement of algorithms for determining subtype of ischemic stroke do improve interphysician agreement. Such criteria should be applied strictly, and trials should include measures to assure the most uniform diagnosis of stroke subtype possible.

Aged↗
PubMed1993

Driving decrements in type I diabetes during moderate hypoglycemia.

Diabetic hypoglycemia produces cognitive-motor slowing, which is assumed to increase risk of automobile crashes. This study investigated driving decrements during and after hypoglycemia, and the patients' awareness of driving decrements. We used a randomized, single-blind, crossover design and conducted the study at the University of Virginia's General Clinical Research Center. We studied a volunteer sample of 27 consecutive adult type I diabetic patients who responded to newspaper ads. Two dropped out (final n = 25). Mean age (+/- SD) was 35.9 +/- 14 yr. Diabetes history was 14.6 +/- 10.5 yr, with HbA1 of 10.8 +/- 2.9%. Driving experience was 19 +/- 13.2 yr. Participants drove a state-of-the-art driving simulator on two consecutive days: Control day involved four euglycemia (mean blood glucose, 6.3 +/- 0.89 mM) driving tests; experimental day involved testing at euglycemia, mild hypoglycemia (mean blood glucose, 3.6 +/- 0.33 mM), moderate hypoglycemia (mean blood glucose, 2.6 +/- 0.28 mM), and again at euglycemia. Patients were blind to blood glucose manipulations and levels. Driving performance was not disrupted at mild hypoglycemia nor after recovery from moderate hypoglycemia. Moderate hypoglycemia disrupted steering, causing more swerving (P < 0.03), spinning (P < 0.03), time over midline (P < 0.05), and time off road (P < 0.01). It also resulted in an apparent compensatory slowing, with more very slow driving (P < 0.04). Global driving performance decrements were observed in 35% of the patients, only 50% of whom stated they would not drive under similar conditions. Driving decrements were unrelated to demographic, disease, or driving history variables.(ABSTRACT TRUNCATED AT 250 WORDS)

Accidents, Traffic↗
PubMed1992

Cholate solubilization of liver microsomal membrane components which promote NADPH-supported lipid peroxidation.

NADPH-supported lipid peroxidation monitored by malondialdehyde (MDA) production in the presence of ferric pyrophosphate in liver microsomes was inactivated by heat treatment or by trypsin and the activity was not restored by the addition of purified NADPH-cytochrome P450 reductase (FPT). The activity was differentially solubilized by sodium cholate from microsomes, and the fraction solubilized between 0.4 and 1.2% sodium cholate was applied to a Sephadex G-150 column and subfractionated into three pools, A, B, and C. MDA production was reconstituted by the addition of microsomal lipids and FPT to specific fractions from the column, in the presence of ferric pyrophosphate and NADPH. Pool B, after removal of endogenous FPT, was highly active in catalyzing MDA production and the disappearance of arachidonate and docosahexaenoate, and this activity was abolished by heat treatment and trypsin digestion, but not by carbon monoxide. The rate of NADPH-supported lipid peroxidation in the reconstituted system containing fractions pooled from Sephadex G-150 columns was not related to the content of cytochrome P450. p-Bromophenylacylbromide, a phospholipase A2 inhibitor, inhibited NADPH-supported lipid peroxidation in both liver microsomes and the reconstituted system, but did not block the peroxidation of microsomal lipid promoted by iron-ascorbate or ABAP systems. Another phospholipase A2 inhibitor, mepacrine, poorly inhibited both microsomal and pool-B'-promoted lipid peroxidation, but did block both iron-ascorbate-driven and ABAP-promoted lipid peroxidation. The phospholipase A2 inhibitor chlorpromazine, which can serve as a free radical quencher, blocked lipid peroxidation in all systems. The data presented are consistent with the existence of a heat-labile protein-containing factor in liver microsomes which promotes lipid peroxidation and is not FPT, cytochrome P450, or phospholipase A2.

Animals↗
PubMed1992

Studies of Org 10172 in patients with acute ischemic stroke. TOAST Study Group.

This report presents data from pilot studies of Org 10172 in the management of patients with acute ischemic stroke. The studies have established a potentially optimal dosage and treatment regimen and have provided information for the development of a large randomized trial. The trial of Org 10172 in acute stroke treatment is now underway in the United States.

Brain Ischemia↗
PubMed1991

Immunocytochemical staining of the RLM6 form of cytochrome P-450 in oligodendrocytes and myelin of rat brain.

We used immunocytochemical staining to localize the RLM6 form of cytochrome P-450 in rat brain. Immunofluorescence staining in vibratome sections was positive in cells that resembled oligodendrocytes, which are the cells that synthesize and maintain myelin. Double immunofluorescence staining with anti-RLM6, plus mouse monoclonal antibodies (MAb) against 2',3'-cyclic nucleotide-3'-phosphohydrolase or galactocerebrosides, showed localization of each of these oligodendrocyte "markers" in the same cells as RLM6. In vibratome sections from brains of adult rats there was faint RLM6 immunostaining in some of the myelinated fibers as well as in oligodendrocytes. In paraffin sections from adult rat brains, myelinated tracts were RLM6 positive, as were oligodendrocytes and myelinated fibers in the gray matter. Oligodendrocytes were also shown to contain glucose-6-phosphate dehydrogenase. We suggest that RLM6, which is constitutive to liver, is also constitutive to brain and, via the acetone monooxygenase reaction, which also utilizes NADPH, may contribute to the conversion of ketone bodies to substrates that could provide energy for the synthesis and maintenance of myelin.

2',3'-Cyclic Nucleotide 3'-Phosphodiesterase↗
PubMed1988

Acute digoxin overdose: use of digoxin-specific antibody fragments.

An acute ingestion of 6 to 7 mg digoxin as a suicidal gesture in a 76-year-old man with chronic heart disease is presented. The patient arrived in the emergency department approximately 5 hours after ingestion with a normal serum potassium and increasing numbers of multifocal premature ventricular contractions. Digoxin-specific antibody fragments were administered. The patient developed ventricular tachycardia and ventricular fibrillation and was eventually stabilized 35 minutes after the Fab fragments were infused. A review of the pharmacology and indications for use of digoxin-immune Fab fragments is also presented.

Aged↗
PubMed1988

Stability of reacted Chemstrip bG.

Reacted Chemstrip bG glucose reagent strips have been reported to retain their color changes for up to 7 days. Thus, patients could theoretically measure their blood glucose and mail their reacted test strips to their physicians for reanalysis. To test the stability of reacted Chemstrip bG blood glucose measurements, 268 Chemstrip bG test strips were reacted with blood obtained from 67 insulin-dependent diabetic patients, stored in desiccator vials, and read daily for 5 consecutive days with an Accu-Chek II blood glucose meter. Although Chemstrip bG blood glucose values significantly correlated with initial reference Beckman glucose analyzer glucose determinations for all 5 days, a steady significant decay in blood glucose readings over time was observed, and clinically accurate strip readings declined from 94% to 68%. Because this decay appeared consistent, correction factors were calculated with regression analyses. The correction factor for day 5 Accu-Chek II readings reduced measurement error by 77%. When applied to a different validation sample, this correction factor decreased day 5 error by 73%. Hence, it seems that correction factors may be applied to delayed readings of Chemstrips obtained with Accu-Chek II that would correct for the observed reduction in blood glucose readings. From these results, we conclude that delayed readings of Chemstrip bG test strips with the Accu-Chek II are not sufficiently accurate for clinical decision making or research purposes unless mathematically corrected.

Blood Glucose↗