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Biomedical subjects

D W Coombs

Publications and source records attributed to D W Coombs.

At least 19 recordsLinked to original sources
PubMed1997

Subchronic inhalation studies of styrene in CD rats and CD-1 mice.

Groups of 10 male and 10 female Charles River (CRL) CD (Sprague-Dawley-derived) rats were exposed to styrene vapor at 0, 200, 500, 1000, or 1500 ppm 6 hr per day 5 days per week for 13 weeks. Styrene had no effect on survival, hematology, or clinical chemistry. Males at 1500 ppm weighed 10% less after 13 weeks and males and females at 1000 and 1500 ppm consumed more water than controls. Histopathologic changes were confined to the olfactory epithelium of the nasal mucosa. Groups of 20 male and 20 female CRL CD-1 and B6C3F1 mice were exposed to styrene vapor at 0, 15, 60, 250, or 500 ppm 6 hr per day 5 days per week for 2 weeks. Mortality was observed in both CD-1 and B6C3F1 mice exposed to 250 or 500 ppm; more female mice, but not males, died from exposure to 250 ppm than from 500 ppm. Groups of 10 male and 10 female CRL CD-1 mice were exposed to styrene vapors at 0, 50, 100, 150, or 200 ppm 6 hr per day 5 days per week for 13 weeks. Two females exposed to 200 ppm died during the first week. Liver toxicity was evident in the decedents and in some female survivors at 200 ppm. Changes were observed in the lungs of mice exposed to 100, 150, or 200 ppm and in the nasal passages of all treatment groups, those exposed to 50 ppm being less affected. Satellite groups of 15 male rats and 30 male mice were exposed as described above for 2, 5, or 13 weeks for measurement of cell proliferation (BrdU labeling). No increase in cell proliferation was found in liver of rats or mice or in cells of the bronchiolar or alveolar region of the lung of rats. No increase in labeling index of type II pneumocytes was seen in mouse lungs, while at 150 and 200 ppm, an increased labeling index of Clara cells was seen after 2 weeks and in occasional mice after 5 weeks. Large variations in the labeling index among animals emphasize the need for large group sizes. For nasal tract effects, a NOAEL was not found in CD-1 mice, but in CD rats, the NOAEL was 200 ppm. For other effects, the NOAEL was 500 ppm in rats and 50 ppm in mice.

Administration, Inhalation↗
PubMed1996

Inhalation teratology and reproduction studies with 1,1-dichloro-2,2,2-trifluoroethane (HCFC-123).

HCFC 123 is one of the chemicals being developed as a replacement for CFC 11 in refrigerant and solvent applications. Supplementing earlier rat teratology studies, a rabbit inhalation teratology study was conducted. In addition, one-generation and two-generation inhalation reproduction studies were conducted. In the teratology study, the pregnant rabbits were exposed to levels of 0 (control), 500, 1500, and 5000 ppm, 6 hr per day from Days 6 through 18 of gestation. Slight body weight losses and reduced food consumption were seen in does in all three exposure level groups. This response followed an exposure-related pattern. There were no other signs of maternal toxicity. There was also no evidence of treatment-related effects on the kits. A probe one-generation reproduction study was conducted. In this study four groups of 12 male and 12 female rats were exposed to vapors of HCFC 123 6 hr per day, 7 days per week from 4 weeks prior to mating through weaning of their offspring. The exposure levels for this study were 0 (control), 300, 1000, and 5000 ppm. There were no effects on mating and fertility, or on pup survival or birth weight. A two-generation study was subsequently conducted. In this study, five groups of 32 male and female rats were exposed to HCFC 123 from 6 weeks of age through weaning. From the offspring of these animals, groups of 28 males and females were selected for the F1 generation. These animals were exposed to HCFC 123 from weaning (4 weeks of age) through weaning of the F1 generation. All exposures were 6 hr per day, 7 days per week. The exposure levels for this study were 0 (control), 30, 100, 300, and 1000 ppm. There were no effects on any of the fertility or reproductive indices measured. As with prior studies, decreases in serum triglyceride levels were seen. Pup survival and birth weight were unaffected by treatment. Pup body weight gain was lower in all treatment groups during nursing, following an exposure-related pattern. Since weight gain for the F1 animals was normal following weaning, this depression of body weight gain may be related to the depression of serum triglycerides. In addition, liver weights of the adult rats exposed to levels of 100 ppm and higher of HCFC 123 were higher than controls, histological examination revealed only hepatic enlargement and vacuolation. It was concluded that exposure to HCFC 123 did not cause reproductive effects although it did effect the body weight gain of the offspring during lactation.

Abnormalities, Drug-Induced↗
PubMed1996

Effectiveness of an Indonesian model for rapid training of Guatemalan health workers in diarrhea case management.

The aim of this study was to assess the effectiveness of a newly developed method for rapid tiered training of health workers in improving community health worker knowledge and case management skills. The interactive "Kader" method, developed in West Java, Indonesia, was compared with traditional didactic training in a prospective trial with rural health workers ("Tecnicos") and village health promoters ("Promotores") for the Public Health Department in the state of Alta Verapaz, Guatemala. Twenty-five tecnicos received one day of training concerning diarrhea and dehydration. One group was trained using the interactive Kader method of Indonesia; the other with didactic methods. A sample of these tecnicos then trained 49 randomized promotores utilizing the same training method with which they were trained. The tecnicos and promotores in each group completed a case-based pre-test and post-test before and after their training sessions. Both tecnicos and promotores trained using the Kader tiered training approach demonstrated significantly greater improvement in their ability to correctly diagnose and recommend treatment for diarrhea of varying type and severity. Non-significant differences favoring the experimental groups were found in the tecnicos' and promotores' general knowledge regarding diarrhea prevention practices, signs of dehydration and preparation of oral rehydration solution. This pilot study suggests that the Kader method for rapid tiered training of health workers has applicability to the populations of other developing nations and can be recommended for large scale implementation and evaluation in the training of public health workers, village health promoters and families in Guatemala.

Adult↗
PubMed1995

Gender differences in autotomy following sciatic cryoneurolysis in the rat.

Gender differences reported in nociceptive and nerve injury research should be considered before conclusions about basic pathologic mechanisms are drawn. Holtzman male rats are routinely used in the mononeuropathy model produced by a peripheral nerve freeze lesion, sciatic cryoneurolysis (SCN). SCN reproducibly results in abnormal behaviors which include autotomy, the gnawing and scratching of the affected hindpaw. In the present studies, the incidence and severity of autotomy 1 to 21 days following SCN was compared in male and female Holtzman rats. Female Holtzman rats displayed a decreased incidence and severity of autotomy 7 days and beyond following SCN. This disparity was statistically different at 14 days (p < 0.01) and at 21 days (p < 0.05) by Newman-Keuls test. Morphometric comparison of the sciatic nerve at the lesion site in male and female rats 14 days post-SCN (time of peak autotomy behavior in this model) displayed differences in the fascicular percentage of edema (p < 0.01) and remyelinating axons (p < 0.05) between genders using Student's t-test. However, these percentage values did not correlate with either the incidence or severity of autotomy scores for those animals. Therefore, biochemical differences at and/or proximal to the peripheral nerve freeze lesion may be responsible for mechanisms which generate or relate to autotomy.

Animals↗
PubMed1995

Sciatic cryoneurolysis in rats: a model of sympathetically independent pain. Part 2: Adrenergic pharmacology.

The purpose of this study was to investigate the possibility that sympathetic exacerbation of neuropathic pain activity may be mediated in part by the development of abnormal peripheral adrenergic mechanisms at the site of peripheral nerve injury. We evaluated changes in mechanical stimulation withdrawal thresholds before and after the delivery of selected alpha-adrenergic agonists and antagonists to the immediate area of a prior nerve injury in rats that had developed continuous mechanical allodynia subsequent to sciatic cryoneurolysis (SCN). Allodynia was attenuated (thresholds increased) after administration of the alpha 1 antagonist prazosin, but not the alpha 2 antagonist idazoxan. Similar attenuation occurred with infusions of the alpha 2 agonist dexmedetomidine and at the lowest dose (2.0 micrograms) of the mixed alpha agonist clonidine. In contrast, allodynia was exacerbated (thresholds decreased) by infusion of the highest dose of clonidine (20 micrograms). Infusions of the alpha 2 agonist ST-91, a polar analog of clonidine, did not alter withdrawal thresholds. The findings suggest that a minimal peripheral adrenergic modulation of SCN-induced allodynia occurs via mechanisms that are not localized to the prior injury site. However, overall, the SCN model of neuropathic pain appears to be resistant to adrenergic interventions, providing further evidence that SCN in rats is a model of sympathetically independent pain (SIP).

Adrenergic alpha-Agonists↗
PubMed1995

Predictive validity of medical student choices of practice location.

We compared University of Alabama medical students' 1980-1981 practice location and specialty preferences with actual practice locations and specialties in 1991 with the following results. (1) Primary care physicians were located mostly in small or large communities, whereas larger than expected numbers of subspecialists practiced in smaller cities. (2) Actual proportions in primary care and surgical subspecialties were less than in earlier preferences; more than expected chose nonsurgical subspecialties. (3) Large city practice locations showed an increase in 1991 at the expense of earlier preferences for medium-sized cities. We suggest that the shift of primary care physicians to larger cities reflects concerns about the financial viability of small town practice, coupled with greater earnings in affluent suburbs. Excess numbers of subspecialists in smaller locations may be due to a perceived oversupply of subspecialists in larger cities.

Adult↗
PubMed1995

Evaluation of a self-help program to reduce alcohol consumption among pregnant women.

This study tested a cognitive-behavioral intervention for reducing alcohol consumption among economically disadvantaged pregnant women. The intervention included a 10-minute educational session and a nine-step self-help manual. Women attending public health maternity clinics completed a screening questionnaire, a pretest questionnaire, were randomly assigned to receive the self-help intervention or usual clinic care, and completed a posttest questionnaire. A higher alcohol quit rate was observed among the intervention participants (88%) than controls (69%). The effect was strongest for "light" drinkers, African-Americans, and non-Protestants. This approach may be useful in clinics where staff time is limited.

Alcohol Drinking↗
PubMed1994

Suicide in Alabama, 1980 to 1989.

Trends of US suicide rates show great variations among demographic groups over time. Although more attention has been directed to the increasing suicide rate among adolescents, persons aged 65 years and older continue to commit suicide at a higher rate than for any other age group. To examine the recent trend of suicide rates and compare the suicide pattern with that at the national level, we conducted a study using suicide data in Alabama from 1980 to 1989. For all age groups in Alabama in the 1980s, male suicide rates exceeded female rates. Of the four major race-sex groups, nonwhite females are an especially low-risk group, experiencing a rate of about 1.5/100,000 at all ages. There have been remarkable increases in suicide rates in the 1980s for males, especially for nonwhite males in Alabama. The results suggest that high-risk groups to be targeted for interventions are men over age 45 (especially white men over age 65), and divorced and widowed men and women.

Adolescent↗
PubMed1994

Comparative histopathology of epidural hydrogel and silicone elastomer catheters following 30 and 180 days implant in the ewe.

New catheter materials, termed Hydrogels, have been developed recently that are stiff until exposed to hydration. The purpose of this study was to compare the 30 and 180 day histopathology of catheters composed of a common silicone elastomer versus a Hydrogel elastomer blend (HEB). Epidural catheters composed of either silicone or HEB were implanted in 19 yearling ewes for either 30 or 180 days. The degree of fibrotic reaction in the epidural space, muscle and subcutaneous tissue was assessed using both histopathology and quantitative imaging analysis. A separate subset of three ewes were implanted with HEB epidural catheters connected to subcutaneously implanted ports through which twice weekly injections of saline were given. There was no evidence of significant neurotoxicology associated with either the silicone or the HEB catheter materials. However, the silicone elastomer group had a quantifiably greater degree of fibrosis than the HEB group of both implant durations. The mean cross sectional area (sq. mm) of epidural pericatheter fibrosis was significantly smaller in the HEB group compared with the silicone group (0.491 in the HEB group and 1.585 in the silicone group at 30 days [P = 0.02] and 0.28 and 1.401 at 180 days [P = 0.0001]. The HEB catheter was easily inserted with standard epidural needles facilitated by the inherent stiffness of the catheter prior to hydration. HEB catheters remained patent throughout 30 days of saline injections per implanted ports. Silicone catheters demonstrated increased fibrosis relative to the HEB catheter material in the epidural space and in subcutaneous tissue.

Anesthesia, Epidural↗
PubMed1994

Comparative spinal neuropathology of hydromorphone and morphine after 9- and 30-day epidural administration in sheep.

Despite extensive clinical use of epidural morphine and to a lesser extent hydromorphone, the neurotoxicologic effects of large-dose epidural administration have not been reported. We compared the impact on behavior, blood and cerebrospinal fluid (CSF) chemistry and hematology, and neuropathology of both epidural morphine (M) and hydromorphone (H) versus preservative-free normal saline (S) given to control animals. Silicone lumbar epidural catheters were implanted in adult sheep and attached to either a subcutaneous port (acute 9-day study) or continuous flow type implantable drug pump (chronic 30-day study) through which the ewes were repeatedly exposed to either the epidural test drug or to similar volumes of saline. The 9-day groups received 5 mL of epidural injections twice daily with the dose incrementally increased as follows: M (n = 6) 40 mg/d, 4 mg/mL; H (n = 6), 16 mg/d, 1.6 mg/mL; S (n = 3), preservative-free normal saline. The 30-day M and H groups were continuously infused epidurally with increasing concentrations eventually augmented with daily epidural boluses: M group (n = 3), 100 mg maximum daily dose, 25 mg/mL maximum concentration; H group (n = 3), 30 mg maximum daily dose, 10 mg/mL maximum concentration; S group (n = 3).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Spinal dynorphin immunoreactivity increases bilaterally in a neuropathic pain model.

Increased spinal levels of dynorphin, an endogenous opioid kappa agonist, are seen in models of both chronic and acute hyperalgesia. This study determined the extent and localization of spinal immunoreactive dynorphin following sciatic cryoneurolysis (SCN), a neuropathic pain model produced by a peripheral nerve freeze lesion. SCN results in behaviors associated with neuropathic pain such as autotomy (the gnawing and scratching of the affected limb), touch-evoked and mechanical allodynia, and spontaneous nociceptive behavior. Following SCN, 4 rats that displayed autotomy and 3 rats that did not were randomly chosen for immunohistochemical staining of dynorphin-like immunoreactivity (DLIR). The area of DLIR above a standardized threshold level was quantified in both dorsal horns of each spinal cord section using a computer-assisted image analyzer to express DLIR in pixels. DLIR was observed both ipsilateral and contralateral to the injured peripheral nerve. In addition, the area of DLIR was significantly greater (P = 0.05) in rats that showed autotomy behavior (mean = 52.6 x 10(3) +/- 25.6) compared to rats with no autotomy (mean = 13.8 x 10(3) +/- 4.78). In sharp contrast to the ipsilateral dynorphin increases observed in other neuropathic pain models, we observe a bilateral increase at 21 days following SCN.

Animals↗
PubMed1993

Intrathecal catheterization alone reduces autotomy after sciatic cryoneurolysis in the rat.

There is substantial evidence that sciatic cryoneurolysis (SCN, freeze lesion of the sciatic nerve) is a neuropathic pain model in the rat. During characterization of this model, SCN was performed 4 days after either a sham operation or the insertion of an indwelling intrathecal catheter preparatory to selective spinal drug administration. Body weight and autotomy scores were recorded for the next 22 days until sacrifice. The catheter group experienced significant weight loss (7.5%) by 4 days but rapidly regained to parity with the sham group. Autotomy scores and the frequency of severe autotomy (score > 3) were less at day 22 in the catheter group as compared with the sham-control group (p < 0.005, p < 0.03, respectively). Intrathecal catheterization itself effects the degree of behavioral response to neurogenic pain and thus, should be controlled for in studies using nociceptive animal models.

Animals↗
PubMed1993

Low CSF pressure.

Explore the source record for details and available documents.

Analgesia, Epidural↗
PubMed1993

Acute toxicology of an enkephalinase inhibitor (SCH 32615) given intrathecally in the ewe.

Intrathecal application of the enkephalinase inhibitor, SCH 32615, yields antinociception in animal paradigms. Our purpose was to identify possible acute behavioral effects, neurotoxicity, or systemic toxicity of intrathecal SCH 32615 administration during 9 days in the ewe. Seventeen ewes were implanted with lumbar silicone intrathecal catheters and subcutaneous access ports for repeated injection. Baseline and serial daily behavioral assessments were made during 9 days of 2-mL intrathecal injection twice daily of either normal saline (SAL group) or a 20 mg/mL isotonic sterile solution of SCH 32615 (SCH group). Data were analyzed by treatment group (SCH versus SAL) by taking the group means of individual ewe cumulative scores during 9 days. At 15-18 h after the last injection, the ewes were euthanized and the spinal cords and leptomeninges were grossly examined and prepared for histological assessment. Histological evaluation of the lumbar (at catheter entrance site and catheter tip), thoracic, and cervical sections of all animals was performed by two neuropathologists. Several mild, reversible, and apparently nonprogressive behaviors (Stepping/Placing and Hindlimb Stretching/Splaying) were observed almost exclusively in SCH-treated ewes. These behaviors were interpreted as mild temporary irritative effects, without significant neuropathological sequelae. Pathological findings primarily consisted of mild, focal dural thickening and white matter compression. These changes were distributed equally between drug-treated and control groups and were attributable to catheter implantation and local compressive effects. There were no pathological bases identified in this study to preclude the clinical study of SCH 32615 within the dose range studied.

Animals↗
PubMed1993

The ganglioside GM1 decreases autotomy but not substance P depletion in a peripheral mononeuropathy rat model.

The effect of the ganglioside GM1 on autotomy, a nociceptive behavioral marker for neuropathic pain, and substance P depletion was determined in a rat model of peripheral mononeuropathy, sciatic cryoneurolysis (SCN). SCN is produced by the application of a cryoprobe to the common sciatic nerve using a freeze-thaw-freeze cycle. Due to structural sparing of the nerve, regenerative processes are not precluded. After this peripheral nerve insult, behavioral and neurochemical changes occur that support the use of SCN as a neuropathic pain model. These changes include: autotomy with coincident transient weight loss and paling of eye color suggestive of increased sympathetic activity, spontaneous nociceptive behaviors, touch-evoked allodynia, prolonged mechanical allodynia, ipsilateral decrease of immunoreactive substance P, and increases in spinal cord dynorphin expression. Incidence and severity of autotomy were assessed after the intraperitoneal administration of GM1 (1, 10, and 20 mg/kg) or saline injected daily for 2 days before SCN, the day of surgery, and for 14 days after surgery. In a subset of two rats from each treatment group, transcardiac perfusion was performed and spinal cords were processed for substance P immunoreactivity. GM1 at 10 and 20 mg/kg doses significantly attenuated autotomy as compared with saline-treated rats (P = 0.007 and 0.0001, respectively). However, GM1, at the doses studied, failed to alter the spinal substance P depletion 21 days after SCN. These results indicate that the ganglioside GM1 may have a role in the clinical management of neuropathic pain after peripheral nerve injury.

Animals↗
PubMed1993

Neurotoxicology of chronic infusion of the ganglioside GM1 in the ewe: phase I. intrathecal administration.

Gangliosides, including GM1, provide a measure of improved functional recovery after ischemic, toxic, and traumatic brain injuries in animal studies. Since systemically injected GM1 has provided equivocal results in a variety of human neurodegenerative conditions, the possibility exists that intrathecal or intracerebroventricular delivery might provide more effective concentrations along the neuroaxis. In preparation to consider clinical trials, the potential neurotoxicologic effects of chronic intrathecal GM1 were studied in ewes. Preliminary in vitro tests first demonstrated the stability and compatibility of GM1 in implanted pumps. Two groups of adult ewes were then implanted with either Therex or Infusaid continuous flow implantable pumps and chronic intrathecal catheters. Ewes were infused intrathecally with either preservative-free normal saline (n = 5) or GM1 (n = 7) 100 micrograms-10,000 micrograms/d for up to 24 wk. No abnormal behavioral responses were noted. Cerebrospinal fluid analyzed for GM1 concentrations by thin layer chromatography revealed no evidence of GM1 accumulation. After the animals were killed, spinal cords were removed, fixed, sectioned, and stained. Histologic analysis revealed no generalized pattern of neuronal damage, demyelination, gliosis, or axonopathy to distinguish intrathecal normal saline or GM1. In both treated and control groups, the only consistent finding was a pericatheter-associated compression of white matter with axonal dilation, vacuolation, and occasional neuronal loss. Catheter tracts in both groups were also associated with variable leptomeningeal fibroproliferative changes in adjacent dura and pia, at times in conjunction with more generalized duromeningeal thickening. In summary, chronic intrathecal GM1 in doses up to 10 mg/d had no definable neuropathologic consequences.

Animals↗
PubMed1992

Analgesic effects of intrathecally-administered 3 alpha-hydroxy-5 alpha-pregnan-20-one in a rat mechanical visceral pain model.

Recent studies in animals have demonstrated that the steroid, 3 alpha-hydroxy-5 alpha-pregnan-20-one (3A5P), is a potent analgesic when given intracerebroventricularly. Several studies in humans report that spinal steroids are effective in the treatment of chronic low-back pain when given in combination with morphine. The spinal antinociceptive effect of steroids, in particular a progesterone metabolite has not been studied in a visceral pain model. The experiments in the following study were designed to test, first, if the intrathecally-administered (i.t.) steroid, 3A5P, has analgesic properties in a mechanical visceral nociceptive assay, and second, if the intrathecal coadministration of this steroid and morphine is more effective than either therapy alone. Our mechanical visceral pain model (VPM) consists of a chronic indwelling duodenal balloon catheter implanted in the rat. The balloon is inflated to elicit a writhing response. Protection values are defined as the percentage of rats in each group which did not writhe. In this model, 3A5P was found to provide a dose-independent, though significant (p less than 0.01), antinociception when administered alone (33-67% protection vs. 0-25% for controls). Yet, protection offered by the coadministration of 3A5P and morphine (79%) was not significantly greater than that offered by morphine alone (85%). Unlike a dose and time-dependent response observed in a thermal cutaneous nociceptive assay, the antinociception of 3A5P was not dose-dependent when challenged with a mechanical visceral noxious stimulus.

Analgesics↗