Lung function in alpha1-antitrypsin heterozygotes (Pi type MZ).
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Biomedical subjects
Publications and source records attributed to D M Cooper.
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Behavioral effects of cyclo (Leu-Gly) (cLG), administered either acutely or chronically, were assessed in combination with haloperidol in the rat. cLG administered chronically, produced a significant reduction in the increase in apomorphine-induced stereotypy produced by chronic haloperidol infusion. On the other hand, the same dose of cLG which reduced this induction of dopamine receptor supersensitivity due to chronic haloperidol treatment, failed to produce a change in the potency of haloperidol in blocking conditioned avoidance responding in the rat. Furthermore, degeneration-induced supersensitivity of dopamine neurons, produced by unilateral destruction of the nigrostriatal pathway, was not reduced by acute or chronic treatment with cLG as measured by apomorphine-induced rotation. These data suggest that cLG may decrease motor system side effects thought to be caused by chronic antipsychotic administration without affecting the therapeutic efficacy of the antipsychotic agent.
Transforming growth factor-beta(2) promotes healing in a variety of animal models and exhibits clinical effects thought to be mediated by connective tissue formation. Two clinical trials were conducted to evaluate the safety and effect of transforming growth factor-beta(2) purified from bovine bone and delivered topically to venous stasis ulcers three times per week for up to 6 weeks by means of a lyophilized collagen vehicle. The first was an open-label trial comparing transforming growth factor-beta(2) purified from bovine bone (0.5 microg/cm(2)) with a placebo consisting of lyophilized collagen vehicle-without active drug. After no safety issues arose in that trial, a prospectively randomized, closed-label, observer-blinded, three-armed trial was conducted to compare bovine transforming growth factor-beta(2) (2.5 microg/cm(2)) with the collagen matrix placebo vehicle and with a standard dressing. Standardized elastic compression was applied to all test extremities. The rate of reduction of ulcer area as measured by planimetry was the primary measure of effect. No serious safety-related events occurred in either trial. Clinical evaluation suggested that improvement in the quality and quantity of granulation tissue appeared to precede epithelialization of ulcers treated with bovine transforming growth factor-beta(2). In both studies, treatment with bovine transforming growth factor-beta(2) appeared to have a positive effect on the rate of ulcer closure, whereas ulcers in the control groups continued to exhibit impaired healing. In the open-label study, the mean rate of closure of ulcers treated with bovine transforming growth factor-beta(2) was significantly greater than that of ulcers treated with placebo. There was likewise enhanced reduction in ulcer area in the ulcers treated with bovine transforming growth factor-beta(2) in the second trial. However, because of a higher variability in patient response and a greater placebo effect, the difference was not significant. The placebo was not worse than the standard care arm, thereby showing that the vehicle is not injurious to healing. The combined results of the two trials suggest that, at doses of 0.5 to 2.5 microg/cm(2), bovine transforming growth factor-beta(2) is safe as a topically applied agent in a collagen matrix vehicle and can have a positive effect on closure of venous stasis ulcers. Large multicenter trials appear to be indicated to evaluate fully the potential utility of transforming growth factor-beta(2) in accelerating closure of chronic dermal ulcers.
New treatments for chronic wounds require carefully performed clinical trials with significant endpoints. Total wound closure is the only endpoint currently accepted by the Food and Drug Administration. This study describes a scale that measures ease of wound closure and applies it to a four-arm prospectively randomized, blinded pressure ulcer trial of recombinant human platelet-derived growth factor-BB. Following validation of interrater reliability, 83 evaluable subjects' photographs were given a weekly ease of closure score by four raters blinded to treatment. The change of ease of closure score was correlated with the change of wound area and volume. Each ease of closure score was given a procedural cost. Results showed ease of closure did not directly correlate with either wound area or volume, suggesting that it was measuring additional information. The mean change in ease of closure score was 6 for subjects treated with 100 microg recombinant human platelet-derived growth factor-BB daily; 5 for those treated with 300 microg growth factor daily or 100 microg recombinant human platelet-derived growth factor-BB bid; and 4 for those treated with placebo. The cost savings ranged from $7200 for the group receiving 100 microg recombinant human platelet-derived growth factor-BB daily to $6300 for the controls. Outcomes in all 4 groups were significantly improved from their starting evaluation (p < 0.001). Based on this study, ease of closure is a verifiable endpoint that can be related to cost efficiency and may be a measure of efficacy.
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Nineteen patients with cystic fibrosis (CF) were studied to determine whether plasma fatty acids correlated with severity of their lung disease as assessed by pulmonary function testing. Results were compared with 19 normal subjects of similar age and sex. Linoleic acid content of all lipid fractions was significantly lower in CF patients than controls including cholesterol ester fraction (CF 31%, control 50%, p less than 0.001), triglyceride fraction (7.6 to 16.6%, p less than 0.001), and phospholipid fraction (13.9 to 21.7%, p less than 0.001). Mean 20:3 omega 9/20:4 omega 6 ratio for CF patients was higher in all lipid classes and was suggestive of essential fatty acid deficiency. Correlations were found to exist between most pulmonary function parameters and fatty acids of plasma phospholipids but not any other lipid class. Positive correlations were found between all ventilatory tests and total omega 3 polyunsaturated fatty acids and also 22:5 omega 3 and 22:6 omega 3. There was no correlation between total saturated fatty acids, total monounsaturates, total omega 6 fatty acids, or triene/tetraene ratios and pulmonary function. Positive correlations were found between pulmonary function parameters and certain omega 6 polyunsaturates including 20:4 and 22:4 but not 18:2.
BACKGROUND: Regular use of inhaled beta-adrenergic agonists may have adverse effects in some asthma patients. Polymorphisms of the beta(2)-adrenergic receptor (beta(2)-AR) can affect its regulation; however, results of smaller studies of the effects of such polymorphisms on response to beta-agonist therapy have been inconsistent. METHODS: We examined the possible effects of polymorphisms at codons 16 (beta(2)-AR-16) and 27 (beta(2)-AR-27) on response to albuterol by genotyping 190 asthmatics who had participated in a trial of regular versus as-needed albuterol use. RESULTS: During the 16-week treatment period, patients homozygous for arginine (Arg/Arg) at beta(2)-AR-16 who used albuterol regularly had a small decline in morning peak expiratory flow (AM PEF). This effect was magnified during a 4-week run-out period, when all patients returned to as-needed albuterol only. By the end of the study, Arg/Arg subjects who had used albuterol regularly had an AM PEF 30.5 +/- 12.1 liters/min lower (p = 0.012) than Arg/Arg patients who had used albuterol as needed only. Subjects homozygous for glycine at beta(2)-AR-16 showed no such decline. Evening PEF also declined in the Arg/Arg regular but not in as-need albuterol users. No significant differences between regular and as-needed treatment were associated with polymorphisms at beta(2)-AR-27. CONCLUSIONS: Polymorphisms of the beta(2)-AR may influence airway responses to regular inhaled beta-agonist treatment.
Instant nutritional assessment of the hospitalized patient is described based upon admission serum albumin levels and total lymphocyte counts. Abnormalities of these parameters are associated with markedly increased morbidity and mortality in a series of 500 consecutively admitted patient. It is suggested that instant nutritional assessment be performed on all hospitalized patients with appropriate alterations and therapy being made to allow for nutritional repletion.
The concept of pituitary refractory period for GH secretion has been previously described. To measure the length of this refractory period we performed an exercise provocation test for GH secretion immediately following multiple overnight GH blood sampling. In addition, we correlated the magnitude of the GH response to a single exercise input with mean overnight GH, IGF-I and circulating IGFBP levels. 23 healthy adolescent females (15-17 yr) performed 10-min constant cycle ergometry at a power normalized to each subject's aerobic and anaerobic capacity. GH was measured every 10 min starting 10 min before exercise and then for 60 min after the exercise bout. Mean nocturnal GH was calculated from overnight values obtained every 20 min over a 12-h period. Pre-exercise GHBP, IGF-I and IGFBPs 1-5 were assessed using standard techniques. In five subjects, a spontaneous GH peak had preceded the exercise test by 1 hour or less, and no response to exercise was found. In the remaining 18 subjects, a GH peak (6.8 +/- 1.3 ng/ml, p < 0.0001) was observed at 32 +/- 4 min after the onset of exercise. The GH response to exercise was not correlated with fitness, mean GH or IGF-I but was correlated with IGFBP-3 (r = 0.65, p < 0.05). Spontaneous GH pulses may acutely render the pituitary refractory to exercise stimuli. The length of this refractory period is approximately 1 hour. The data corroborate the idea that while relationships exist among the various components of the GH-IGF-I axis, no single factor identified to date fully reflects GH-IGF-I "tone".
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This study was designed to evaluate whether maintenance of a moist environment on the nipple skin during the first week of breast-feeding would improve damaged nipple skin condition, as indicated by the presence of eschar, erythema, and fissures, and reduce pain. Fifty White women applied a polyethylene film dressing with a perimeter adhesive system to a randomly determined nipple. The dressing was present at all times except during feeding. Subjects were assessed every 48 hours (four times) over 7 days. Serial photographic slides were obtained and assessed for skin characteristics. Nipple pain was self-rated with a verbal descriptor scale. Use of an occlusive film dressing on nipple skin during the first week of breast-feeding appeared to have limited influence on improvement in damaged skin condition. Summary scores indicated significant reduction in the amount of eschar on the surface of the nipple. There were no differences in erythema intensity or fissure severity. Use of a dressing significantly reduced nipple pain during the study period.
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