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Biomedical subjects

M Underwood

Publications and source records attributed to M Underwood.

At least 19 recordsLinked to original sources
PubMed1999

Development of novel benzimidazole riboside compounds for treatment of cytomegalovirus disease.

Benzimidazole ribosides are a new class of compounds with novel mechanisms of action against CMV. One compound in this series, BDCRB, inhibits CMV DNA processing by the UL89 gene product (putative terminase), but rapid metabolism to an inactive compound makes it unsuitable for development as a medicine. Another benzimidazole analogue, 1263W94, has many characteristics that make it an attractive candidate for development, including high potency in vitro, selectivity, good oral bioavailability, and lower toxicity than therapies currently available for treatment of CMV disease. Initial clinical trials have provided encouraging results, including good tolerability and linear pharmacokinetics over a wide dose range. Ongoing and planned clinical trials that will study the safety and tolerability of repeated dosing and evaluate the in vivo antiviral activity and ocular penetration of 1263W94, will help to determine the potential of this drug as an improved therapy for CMV disease.

Antiviral Agents↗
PubMed1999

Influence of normothermic systemic perfusion temperature on cold myocardial protection during coronary artery bypass surgery.

OBJECTIVE: To determine the effect of normothermic systemic perfusion on myocardial injury when using cold cardioplegic techniques in patients undergoing coronary artery bypass surgery. METHOD: Sixty six patients with stable angina pectoris were prospectively randomized into three groups according to cardiopulmonary bypass temperature: hypothermia (28 degrees C, n = 22), moderate hypothermia (32 degrees C, n = 22) and normothermia (37 degrees C, n = 22). All patients received cold antegrade crystalloid cardioplegia and topical cooling with saline at 4 degrees C. Serum samples were collected for troponin T and I estimation preoperatively, 4 hours after removal of the aortic cross clamp, and 12, 24, 36 and 48 hours postoperatively. In addition, serial electrocardiographic studies were undertaken on days 1, 3 and 5. RESULTS: Patients were similar with regard to preoperative and intraoperative characteristics Four patients showed ECG changes typical of perioperative myocardial infarction but remained clinically well (28 degrees C, one; 32 degrees C, one; 37 degrees C, two). In the remaining 62 patients, serum troponin T increased significantly from a mean baseline value of 0.02 ng/ml to 1.5+/-0.9 ng/ml 4 hours after removal of the aortic cross-clamp (P<0.0001). Similarly, troponin I increased from 0.06 ng/ml to 0.63+/-0.47 ng/ml 12 hours after reperfusion (P<0.0001). Serum concentrations of both markers subsequently declined with time but remained higher than preoperative values at 48 hours. There were no differences between the three groups with respect to peak and cumulative serum troponin release. Normothermic cardiopulmonary bypass did not compromise the efficacy of cold myocardial protection when assessed by serum troponin concentrations in low risk patients undergoing coronary revascularization.

Aged↗
PubMed1999

The effect of chronic mechanical circulatory support on neuroendocrine activation in patients with end-stage heart failure.

OBJECTIVE: To evaluate if the improvement of patients supported with a Novacor was associated with a normalization in neuroendocrine activity. METHODS: Six patients had a Novacor implanted for end-stage heart failure. Four patients were transplanted after a mean of 4.5 months (range 3-6). One patient was weaned after 5 months and one died of a cerebral haemorrhage 5 weeks after implantation. Analysis of neuroendocrine activity was made prior to implantation and after 14, 30, 60 and 90 days. Levels of aldosterone, renin, cortisol, testosterone and T3 were measured using radio-immunoassays. Twenty-four hour urinary collections were made for assessment of adrenaline and noradrenaline excretion. RESULTS: Renin activity fell to normal after 14 days (16 +/- 3.0 ng/ml per h to 4.28 +/- 2.1 ng/ml per h, P < 0.05) and was maintained at 90 days. A similar picture was seen with aldosterone (1.5 +/- 0.4 nM to 0.12 +/- 0.07 nM, P < 0.05). Norepinephrine (67.46 +/- 14.1 microg/24 h) and epinephrine 12.9 +/- 2.5 microg/24 h) fell to normal physiological levels during the same time period. Cortisol levels were above normal pre-implantation but fell by day 30 (665.25 +/- 80.0 nM to 461.8 +/- 43.0 nM, P < 0.01). T3 and testosterone were lower than normal pre-implantation (T3 50 +/- 9.5 ng/dl vs. 90-200 ng/dl, testosterone 6.83 +/- 1.7 nM vs. 13-35 nM). T3 normalized after 90 days (81 +/- 11.7 ng/dl) and testosterone after 60 days (16.3 +/- 1.7 nM). CONCLUSION: Neuroendocrine function is abnormal in patients with cardiac failure who require circulatory support. The Novacor improved this, but metabolic recovery was delayed. The positive effect on the neuroendocrine axis, in the absence of activation of other endocrine systems, suggests that prolonged support may be well tolerated.

Adult↗
PubMed1998

In vivo biodistribution of a radiotracer for imaging serotonin-1A receptor sites with PET:[11C]LY274601.

LY274601 [R-(+)8-thiomethyl-2-(di-n-propyl-amino)tetralin], a full agonist of the 5-HT1A receptor with high affinity and selectivity, was labeled with 11C and 3H, and its in vivo behavior was studied to evaluate [11C]LY274601 as a PET radiotracer for imaging 5-HT1A receptor sites in living brain. Following intravenous tail injection into mice, [11C]LY274601 showed high blood-brain barrier permeability and accumulated in regions known to have high densities of 5-HT1A receptor sites such as the brain stem including the raphe nuclei. The binding of the radiotracer in target tissues is blocked by pre-injection of the 5-HT1A receptor selective ligand 8-OH-DPAT (1 mg/kg, s.c.), suggesting that the binding is specific to 5-HT1A receptor sites. Using ex vivo autoradiography, the target tissues such as hippocampus CA1-4 fields, piriform cortex, dorsal raphe nucleus and lateral septum were visualized as hot spots. These tissues were observed to have binding 2-2.7 times greater than the cerebellum. The distribution of the radiotracer agrees well with the distribution of 5-HT1A receptors revealed by in vitro autoradiography with [3H]8-OH-DPAT. However, the radiotracer was metabolized quickly and cleared from target tissues with a half life of approximately 15 min. [11C]LY274601 showed high non-specific binding in regions with low number of 5-HT1A receptor sites such as cerebellum.

8-Hydroxy-2-(di-n-propylamino)tetralin↗
PubMed1998

Cluster randomization: a trap for the unwary.

Controlled trials that randomize by practice can provide robust evidence to inform patient care. However, compared with randomizing by each individual patient, this approach may have substantial implications for sample size calculations and the interpretation of results. An increased awareness of these effects will improve the quality of research based on randomization by practice.

Cluster Analysis↗
PubMed1996

Prevalence of gastroesophageal reflux symptoms in asthma.

STUDY OBJECTIVE: To determine the prevalences of symptomatic gastroesophageal reflux (GER), reflux-associated respiratory symptoms (RARS), and reflux-associated beta-agonist inhaler use in asthmatics. DESIGN: Questionnaire-based, cross-sectional analytic survey. SETTING: Outpatient asthma and clinical research clinics attached to the University of Calgary tertiary care centre and two family practices. PATIENTS: Asthma group consisted of 109 patients referred to an outpatient asthma clinic. First control group consisted of 68 patients visiting their family physicians. Second control group consisted of 67 patients with thyroid disease, hypercholesterolemia, or diabetes participating in drug trials. RESULTS: Among the asthmatics, 77%, 55%, and 24% experienced heartburn, regurgitation, and swallowing difficulties, respectively. Symptoms were less prevalent in the control groups. At least one antireflux medication was required by 37% of asthmatics (p < 0.001, vs controls). None of the asthma medications were associated with an increased likelihood of symptomatic GER. In the week prior to completing the questionnaire, 41% of the asthmatics noted RARS, including cough, dyspnea, and wheeze and 28% used their inhalers while experiencing GER symptoms. Inhaler use correlated with the severity of heartburn (r = 0.28, p < 0.05) and regurgitation (r = 0.40, p < 0.05) CONCLUSIONS: The questionnaire demonstrated a greater prevalence of GER symptoms, RARS, and reflux-associated inhaler use in asthmatics. This excessive inhaler use may explain how GER indirectly causes asthma to worsen.

Adult↗
PubMed1995

C-erbB-2 gene amplification: a molecular marker in recurrent bladder tumors?

C-erbB-2 gene amplification and protein overexpression have been implicated as prognostic markers for patients with recurrent progressive bladder tumors. This event has been investigated as a potential diagnostic indicator in archival samples of transitional cell carcinoma of the bladder. Two hundred thirty-six bladder tumors from 89 patients with recurrent disease (mean follow-up, 4 years), 20 tumors from patients with no evidence of bladder tumor recurrence (mean follow-up, 7 years) and 10 normal bladder controls (patients with no history of transitional cell carcinoma) were studied. A differential PCR was used to provide a semiquantitative estimate of C-erbB-2 gene amplification. Protein overexpression was assessed immunohistochemically. Sixteen of 89 patients with recurrent disease had evidence of C-erbB-2 gene amplification. No C-erbB-2 gene amplification was seen in the nonrecurrent tumors or normal bladder controls. Of the 89 patients with recurrent bladder tumors, 43 had evidence of progressive disease, and of these, 14 patients exhibited C-erbB-2 gene amplification, indicating a strong association with gene amplification and progressive disease (P < 0.0005). Gene amplification in these patients was seen only after disease progression had occurred. Protein overexpression was seen in 50% of patients with recurrent and 45% of patients with nonrecurrent disease. No protein overexpression was seen in normal controls. Protein overexpression could not be linked to disease progression. C-erbB-2 gene amplification and protein overexpression were of predictive value in multivariate analysis for overall bladder cancer death; however stage and grade remained the most important independent prognostic variables. C-erbB-2 gene amplification and protein overexpression were of no value as independent markers for the prediction of disease recurrence or progression. It appears from these results that the role of C-erbB-2 as a diagnostic marker may far outweigh its usefulness as a prognostic indicator.

Aged↗
PubMed1993

Balance improvements in older women: effects of exercise training.

BACKGROUND AND PURPOSE: Loss of lower-extremity strength increases the risk of falls in older persons. The purpose of this study was to test the hypothesis that a vigorous program of lower-extremity strengthening, walking, and postural control exercises would improve the single-stance balance of healthy older women and lower their risk of falls and fall-associated injuries. SUBJECTS: From a total of 38 respondents, 21 women were randomly assigned to either a treatment group (combined training, n = 12) or a control group (flexibility training, n = 9). The subjects ranged in age from 62 to 75 years (mean = 68, SD = 3.5). METHODS: A randomized control trial compared the effects of two exercise programs on static balance. The combined training group exercised three times per week on knee extension and sitting leg press machines, walked briskly for 20 minutes, and performed postural control exercises, which included simple tai chi movements. The flexibility training group performed postural control exercises weekly. Measurements of balance were obtained on a force platform in double and single stance, at baseline and following 6 months of exercise training. RESULTS: Double-stance measurements were unchanged after training. The mean displacement of the center of pressure in single stance improved 17% in the combined training group and did not change in the flexibility training group. A repeated-measures analysis of variance revealed that the difference in improvement between the combined training and flexibility training groups was not significant. DISCUSSION AND CONCLUSION: This is the first intervention trial to demonstrate improvements in single-stance postural sway in older women with exercise training. Additional studies with more subjects will be needed to determine whether a combined training program of resistance training, walking, and postural exercises can improve balance more than a program of postural control exercises alone.

Accidental Falls↗
PubMed1993

Exercise to improve gait velocity in older persons.

The effect of 12 weeks of resistance and balance training on strength and gait measures in older persons was tested in a randomized control trial. Thirty-one residents of two life-care communities volunteered (mean age, 82.1 years). The exercise group (E) trained three times per week, performing resistance training to fatigue for knee extension, hip abduction, ankle dorsiflexion, hip extension, and knee flexion, and postural control exercises. The control group (C) met weekly for flexibility exercises performed sitting in a chair. The exercise group achieved significant improvements in muscle strength and gait velocity (p < .05). Knee extension one maximum repetition increased 32% (24% to 40%, 95% confidence interval [CI]), from 55 +/- to 72 +/- 4N.m. Isokinetic knee extension torque increased 25% (3% to 47%) from 40 +/- 5 to 50 +/- 5N.m at 120 degrees s-1. Usual gait velocity increased 8% (3% to 13%) in E from 1.04 +/- .07 to 1.12 +/- .06m/s. There was a trend of improvement in maximal gait speed 4% (0 to 8%) from 1.43 +/- 0.1 to 1.49 +/- 0.1m/s, p = 0.054. Gait and strength measures in C were unchanged. A short-term exercise program that trained strength and balance achieved a clinically significant improvement in gait velocity.

Aged↗