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Biomedical subjects

R M Walker

Publications and source records attributed to R M Walker.

At least 37 records · Page 2Linked to original sources
PubMed1997

Early effects of CI-924 on hepatic peroxisome proliferation, microsomal enzyme induction, PCNA, and apoptosis in B6C3F1 mice and Wistar rats.

The lipid lowering agent 5,5'[[1,1'-biphenyl]-2,5-diylbis(oxy)]bis[2,2-dimethylpentanoic acid] (CI-924) is a peroxisome proliferator in rats and mice, but increased the incidence of hepatic tumors in mice only. Male and female B6C3F1 mice and albino Wistar rats were treated with CI-924 at doses of 0, 25 and 75 mg/kg for 1, 3, 7 and 28 days. Our aim was to identify species differences potentially related to tumorigenicity and to establish the time course of early events related to or associated with peroxisome proliferation. After 24 h of exposure to CI-924 in the diet there were increases in carnitine acyl transferase and CYP4A1 activity in mice at 25 and 75 mg/kg. In rats, carnitine acyl transferase activity was increased after 24 h and CYP4A1 activity increased after 3 days at 75 mg/kg. Acyl CoA oxidase activity was increased at both doses in male and female rats and mice by 3 days. In general the changes in enzyme activity were of greater magnitude in rats. In contrast to the rapid peroxisome proliferation, increases in the amount of PCNA were observed in CI-924 treated rats and mice at later times after administration and only at 75 mg/kg. PCNA was increased to a similar extent in both rats and mice, while apoptosis was decreased at both doses of CI-924 after 3 days in female rats, 7 days in male rats, and was largely unchanged in mice. It was concluded that the sequence of peroxisome proliferation was generally similar in rats and mice. Early changes in cell proliferation and programmed cell death were not directly correlated with subsequent CI-924-induced hepatotumorigenicity.

Animals↗
PubMed1997

Pressure-flow studies in the diagnosis of bladder outlet obstruction: a study comparing suprapubic and transurethral techniques.

OBJECTIVE: To compare suprapubic and transurethral methods of measuring intravesical pressure in a group of men undergoing investigation for lower urinary tract symptoms (LUTS), to identify which urodynamic variables are affected by the presence of an urethral catheter during the voiding phase, and consequently whether there is any change in the grading of bladder outflow obstruction (BOO) using the commonly recognised grading systems. PATIENTS AND METHODS: Thirty-five men with LUTS underwent both suprapubic and transurethral pressure-flow studies during a single session. Standard pressure flow variables were measured in all patients with both methods, enabling calculation of obstruction using the commonly used grading systems, i.e. the Abrams-Griffith number, linear passive urethral resistance ratio (LPURR) and urethral resistance algorithm (URA). RESULTS: There were statistically significant differences between the methods in the mean values of maximum flow rate and the detrusor pressure at that maximum: 60% of men were in the same LPURR class with either method. Using the transurethral method, 26% of patients increased the LPURR class by one and 6% by two classes. Using the Abrams-Griffiths nomogram, 17% moved from a classification of equivocal to obstructed and 3% from unobstructed to equivocal. Using the criterion of a value of URA > 29, 57% were obstructed using the suprapubic and 74% using the transurethral method. CONCLUSION: According to the method used, there were differences in the classification of obstruction between the suprapubic and transurethral routes; transurethral studies tended to indicate greater obstruction. The interpretation of urodynamic studies should take into account the technique used and where the route is transurethral, the smallest catheter available should be used.

Adult↗
PubMed1996

Life values, resuscitation preferences, and the applicability of living wills in an older population.

OBJECTIVES: To determine whether life values are related to resuscitation preferences and living will completion in an older population and to assess beliefs about the applicability of living wills. DESIGN: Individual structured interviews. SETTING: An independent retirement community. PARTICIPANTS: One hundred thirty-two subjects older than 63 years of age. MEASUREMENTS: Resuscitation preferences were elicited in five hypothetical scenarios. Subjects with living wills were asked whether their living will would play a role in the scenarios. Subjects rated the importance of 13 life value statements. RESULTS: The percentage of subjects desiring CPR in each scenario was as follows: current condition (66%); acute illness (33%); terminal disease (8%); functional impairment (8%); and dementia (7%). The percentage of those with a living will who thought their living wills would play a role in the scenarios was as follows: acute illness (84%); terminal disease (93%); functional impairment with intact cognition (66%); and dementia (91%). Factor analysis of the life value statements revealed five meaningful factors: quality of life; capacity/autonomy; family relations; physical comfort; and treatment philosophy. Multiple correlations were found between four of five life value factors and hypothetical resuscitation preferences or the presence of a living will. CONCLUSION: Subjects misinterpreted the applicability of living wills in nonterminal illness scenarios. A relationship between life values and resuscitation preferences was noted, which emphasizes the importance of eliciting and including life values when discussing advance directives.

Aged↗
PubMed1995

Living wills and resuscitation preferences in an elderly population.

BACKGROUND: Living wills are considered clear and convincing evidence of a person's preferences for end-of-life treatment. Unfortunately, living wills often use vague language that forces physicians and others to infer specific treatment choices, like the choice to forgo cardiopulmonary resuscitation (CPR). To test the validity of such inferences we examined the relationship between living will completion and CPR preference. We also examined whether CPR choices were fixed or could be influenced by detailed information on CPR. METHODS: We interviewed 102 retired elderly persons, many of whom had living wills. We obtained CPR preferences in five hypothetical scenarios before and after providing CPR information. We then analyzed differences in desire for CPR between the group of subjects with living wills and the group without. RESULTS: In each scenario there were subjects in both groups who desired CPR. The group with living wills desired less CPR in scenarios involving functional impairment and cognitive impairment, but not in scenarios involving current health, severe illness, and terminal illness. After receiving CPR information, both groups changed their preferences such that intergroup differences were no longer seen. CONCLUSIONS: Preferences for CPR among subjects with living wills are not homogeneous, but distributed across the clinical scenarios. Therefore, one cannot infer CPR preference from the mere presence of a living will. Cardiopulmonary resuscitation information can influence preferences even among persons with living wills, implying that preferences are neither fixed nor always based on adequate information. Physicians should view vaguely worded documents as unreliable expressions of treatment preference that should not supplant informed discussion.

Aged↗
PubMed1995

Peroxisome proliferation and microsomal enzyme induction by the hypolipidemic CI-924 in rats and mice: relationship to tumorgenicity.

CI-924 (5'5'-[1,1'-biphenyl]-2,5-diylbis(oxy)]bis [2,2-dimethyl-pentanoic acid]), a lipid lowering agent, was previously shown to be hepatotumorigenic in male and female B6C3F1 mice but not in male and female albino Wistar rats. To determine if the difference between the species in tumorigenic response correlated with the extent of peroxisome proliferation or microsomal changes the effects of CI-924 on liver were characterized in rats and mice. CI-924 doses of 0, 25, 75, and 150 mg/kg were administered in the diet for 4 weeks to B6C3F1 mice and albino Wistar rats. Peroxisomal beta-oxidation activity was significantly increased in all groups at doses of 25 mg/kg or higher and was induced up to 25 times in male rats. Peroxisomal carnitine acyltransferase and acyl-CoA oxidase activities were also increased, with the greatest induction observed in male rats. Catalase activity quadrupled in rats and doubled in mice. Serum liver enzyme activities were unchanged with the exception of 5'nucleotidase which was elevated in mice and decreased in male, but not female, rats. Glutathione S-transferase decreased in the males of both species and glutathione peroxidase increased in the mice. Cytochrome P450 4A1 increased in both species at doses of 25 mg/kg or greater and correlated with increased lauric acid hydroxylation. The high degree of peroxisome proliferation in male rats was unexpected in light of the lack of tumorgenicity demonstrated in a previous 2-year study and these results indicate that early peroxisome proliferation alone is not always a good predictor of hepatocarcinogenicity.

Animals↗
PubMed1995

The lack of advance directives among hospice patients.

This study reported a lower than expected prevalence of advance directives among hospice patients. The presence of an advance directive was related to certain sociodemographic factors, diagnosis, and previous physician-patient advance directive discussions. Barriers that precluded the completion of an advance directive primarily involved a lack of physician-patient advance directive discussions or a lack of patient understanding. This study confirmed the importance of physician-patient discussion toward completion of an advance directive. Improving physician-patient communication about this issue should increase the prevalence of advance directive completion among hospice patients.

Advance Care Planning↗
PubMed1994

Inhibition of mitochondrial respiration in vivo is an early event in acetaminophen-induced hepatotoxicity.

Morphological changes in mitochondria are observed early in the course of acetaminophen (AA)-induced hepatotoxicity, and mitochondrial dysfunction has been observed both in vivo and in vitro following exposure to AA. This study examined the early effects of AA exposure in vivo on mitochondrial respiration and evaluated the effectiveness of N-acetyl-L-cysteine (NAC) in protecting against respiratory dysfunction. Mitochondria were isolated from the livers of fasted, male CD-1 mice 0, 0.5, 1, 1.5 or 2 h after administration of a hepatotoxic dose of AA (750 mg/kg). Glutamate- and succinate-supported mitochondrial respiration were subsequently assessed by polarographic measurement of state 3 (ADP-stimulated) and state 4 (resting) rates of oxygen consumption and determination of the corresponding respiratory control ratios (RCR: state 3/state 4) and ADP:O ratios. Hepatotoxicity was assessed histologically and by measuring plasma alanine aminotransferase (ALT) activity. The earliest sign of mitochondrial dysfunction observed in this study was a significant decrease in the ADP:O ratio for the oxidation of glutamate 1 h post-dosing. At 1.5 and 2 h post-dosing the RCRs for both glutamate- and succinate-supported respiration were significantly decreased. All of the respiratory parameters measured in this study were significantly decreased, with the exception of succinate-supported state 4 respiration which was significantly increased, 2 h after AA administration. Thus, inhibition of mitochondrial respiration preceded overt hepatic necrosis, indicated by an elevation of ALT activity, which was not observed until 3 and 4 h post-dosing. In addition, mitochondrial respiratory dysfunction correlated with morphological alterations.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaminophen↗
PubMed1994

Effects of pregnancy and chronic exercise on respiratory responses to graded exercise.

Effects of cycle ergometer conditioning (heart rate 143 +/- 2 beats/min, 25 min/session, 3 sessions/wk) during the second and third trimesters of pregnancy were studied in 18 healthy previously sedentary women. A nonexercising control group (n = 9) was also studied. Graded exercise tests were conducted for both groups at approximately 17, 27, and 37 wk of gestation and at 20 wk postpartum. Both groups exhibited augmented ventilatory responses to exercise throughout pregnancy. Significant aerobic conditioning effects observed in the exercised group between entry and third trimester of pregnancy testing included a 17% increase in oxygen pulse at peak exercise, reduction in the respiratory exchange ratio during standard submaximal exercise, and an increase in work rate at the onset of blood lactate accumulation. Onset of blood lactate accumulation did not change significantly in the control group. Respiratory exchange ratio at peak exercise was higher in postpartum tests compared with those conducted in late gestation in both groups. Peak postexercise lactate levels were also significantly lower in second and third trimesters of pregnancy testing compared with postpartum in the control group. This effect appeared to be prevented by physical conditioning in the exercised group. The study results support the hypothesis that moderate aerobic conditioning increases maximal aerobic power and the capacity for sustained submaximal exercise. Chronic exercise also appeared to help to preserve anaerobic working capacity in late gestation.

Adult↗
PubMed1993

Toxicity of CI-949, a novel anti-allergy agent.

The toxicity of CI-949, an effective inhibitor of allergic mediator release in pharmacology models, was evaluated in rodents and dogs. Median lethal doses at 24-hr postdose ranged from 343 to 453 mg/kg in mice and 806 to 2058 mg/kg in rats. Delayed toxicity was observed at 300 mg/kg and greater in mice and at 500 mg/kg and greater in rats. Mortality and clinical intolerance occurred in rats at 200 and 400 mg/kg in the subacute studies, and at 100 and 150 mg/kg in the 13-week study. In rats, dose-dependent lymphoid tissue atrophy and depletion or necrosis of lymphocytes in lymphoid tissues were seen in deaths and moribund terminations. Although doses up to 60 mg/kg administrated for 2 weeks to dogs were well tolerated, 60 and 120 mg/kg in the 13-week dog study were poorly tolerated. Cutaneous sores, mucocutaneous purulent discharge, emesis, diarrhea, and weight loss were identified at these lethal doses. Histopathologic changes in dogs included myocardial, vascular and soft tissue inflammation, and gastric ulceration at 60 and 120 mg/kg, and thymic atrophy at 20 mg/kg and greater. Doses of 10 and 50 mg/kg were no-effect doses in 13-week repeated dose studies in dogs and rats, respectively. These results were used to support initial human clinical trials of CI-949.

Administration, Oral↗
PubMed1993

Resuscitation decision making in the elderly: the value of outcome data.

OBJECTIVE: To assess the relationship between cardiopulmonary resuscitation (CPR) information and desire for CPR in an elderly population and to determine the influence of outcome data on desire for CPR in older persons. DESIGN: An interventional study utilizing an educational program. SETTING: Elderly independent retirement community. PARTICIPANTS: One hundred two persons, all more than 62 years old, who were neither demented nor depressed. INTERVENTION: Participants received an educational intervention consisting of descriptive CPR information and quantitative information about CPR outcomes. CPR information, survival estimates, and preferences were recorded prior to and after the intervention. MEASUREMENTS AND MAIN RESULTS: Subjects exhibited a high level of basic knowledge about CPR, which did not change with the intervention. While subjects consistently overestimated their chances of survival post CPR, these estimates decreased toward more realistic levels after the intervention (p < 0.001). CPR preferences changed in three of five hypothetical clinical scenarios after the intervention (p < 0.05). Those who were more realistic in their estimates of CPR survival desired less CPR in the hypothetical scenarios (p < 0.01). A trend in our data suggest that quantitative outcome information may have a greater influence on CPR preferences than has descriptive information (p = 0.07). CONCLUSIONS: CPR preferences changed after an educational intervention. An improved understanding of quantitative outcome data appears to influence the desire for CPR and therefore should be included in CPR discussions with older patients.

Advance Directives↗
PubMed1993

A new model of progressive pulmonary fibrosis in rats.

Sprague-Dawley rats were exposed for 6 h daily to 0.8 ppm of ozone and 14.4 ppm of nitrogen dioxide. Approximately 7 to 10 wk after the initiation of exposure, animals began to demonstrate respiratory insufficiency and severe weight loss. About half of the rats died between Days 55 and 78 of exposure; no overt ill effects were observed in animals exposed to filtered air, to ozone alone, or to nitrogen dioxide. Biochemical findings in animals exposed to ozone and nitrogen dioxide included increased lung content of DNA, protein, collagen, and elastin, which was about 300% higher than the control values. The collagen-specific crosslink hydroxy-pyridinium, a biomarker for mature collagen in the lung, was decreased by about 40%. These results are consistent with extensive breakdown and remodeling of the lung parenchyma and its associated vasculature. Histopathologic evaluation showed severe fibrosis, alveolar collapse, honeycombing, macrophage and mast cell accumulation, vascular smooth muscle hypertrophy, and other indications of severe progressive interstitial pulmonary fibrosis and end-stage lung disease. This unique animal model of progressive pulmonary fibrosis resembles the final stages of human idiopathic pulmonary fibrosis and should facilitate studying underlying mechanisms and potential therapy of progressive pulmonary fibrosis.

Administration, Inhalation↗
PubMed1991

DNR in the OR. Resuscitation as an operative risk.

Should do-not-resuscitate (DNR) orders be routinely rescinded when terminally ill patients undergo palliative surgery? If so, patients will be forced to balance the benefits of palliative surgery against the risks of unwanted resuscitation. If physicians are required to honor intraoperative DNR orders, they may feel unacceptably restrained from correcting adverse effects for which they feel responsible. This dilemma has been overlooked by DNR policies. This article argues for the permissibility of honoring intraoperative DNR orders. The patient's right to refuse treatment outweighs physicians' concerns about professional scrutiny over intraoperative deaths. Physicians' moral concerns about hastening patient death are important but may be assuaged by (1) emphasizing patients' acceptance of operative mortality risk; (2) viewing matters as analogous to surgery on Jehovah's Witnesses who refuse lifesaving transfusion; (3) viewing the patient's intraoperative death as a double effect, that is, an unintended negative effect that is linked to the performance of a good act (palliation); and (4) distinguishing this from assisted suicide.

Christianity↗
PubMed1991

Beneficial effects of hyperbaric oxygen therapy in Nocardia brasiliensis soft-tissue infection.

OBJECTIVE: To report the success of hyperbaric oxygen therapy in the treatment of Nocardia brasiliensis mycetoma. We believe this to be only the second report in the medical literature of hyperbaric oxygen therapy used in the therapy of nocardial disease. CLINICAL FEATURES: A 78-year-old man presented to a general hospital outpatient clinic after eight months with a painless swollen left foot. There was no significant medical history, no trauma had occurred, and no foreign body had been detected. The dorsum of the foot had a discharging sinus, from which N. brasiliensis was isolated. INTERVENTIONS: After unsuccessful treatment with surgical debridement and high-dose antibiotic therapy, hyperbaric oxygen therapy was administered in a multiplace recompression chamber (one hour of treatment at 1.8 atmospheres absolute followed by a 30 minute "ascent" to surface pressure). A total of 19 treatments were administered. OUTCOME: Successful healing of an N. brasiliensis mycetoma of the left foot. CONCLUSION: In this case of N. brasiliensis mycetoma involving the lower extremity, the conventional management of surgery and antibiotic therapy was unsuccessful, and only with the addition of hyperbaric oxygen therapy did clinical recovery occur.

Aged↗
PubMed1991

Preclinical toxicity studies of an adenosine agonist, N-(2,2-diphenylethyl) adenosine.

N-(2,2-Diphenylethyl)adenosine (DPEA) has been identified as a potential antipsychotic agent acting via stimulation of adenosine receptors. The projected human therapeutic dose, based on animal studies, is 2-3 mg/kg. DPEA has been tested for potential toxicity in mice, rats, dogs and monkeys. Following single oral doses, median lethal dose values were approximately 10-fold greater in rats than in mice, although similar clinical signs including reduced activity, prostration, and necrosis of the tail were seen in both species. DPEA was well tolerated at daily doses up to 40 mg/kg in rats for 2 weeks. A no observed effect level (NOEL) was not identified in the dog or monkey studies. Reduced activity, dacryorrhea, ptosis, hypothermia, necrosis of the tail, and death occurred in rats given 120 and 160 mg/kg. Pathologic changes consisted of pancreatitis, gastric erosion/ulceration, lymphocyte depletion of the thymus, and pulmonary congestion and hemorrhage at 80 mg/kg or greater. In dogs, sporadic emesis was noted at 12.5 mg/kg and greater, and significant pathologic changes consisted of coronary arteritis associated with myocardial lesions and lymphocyte depletion at 25 and 50 mg/kg, pancreatic acinar necrosis at 50 mg/kg, and renal tubular degeneration at 12.5 mg/kg and greater. Emesis and depression were noted at 25 and 50 mg/kg in monkeys. Renal tubular dilatation and degeneration at 25 and 50 mg/kg were noted in the monkeys. These studies demonstrated that DPEA produced a range of adverse effects in common laboratory animal species.

Adenosine↗
PubMed1990

Preclinical toxicology of the anticonvulsant calcium valproate.

The oral toxicity of the anticonvulsant calcium valproate with selected comparisons to valproic acid and sodium valproate was evaluated in mice, rats and Beagle dogs. Median lethal doses of the three forms of valproate in rodents ranged from 1100 to 3900 mg/kg. Clinical signs in acute studies and reductions in body weight or body weight gain and food consumption at high doses in rats and dogs during 2-, 13- and 52-week studies were considered to be central nervous system related. In the 13-week study in rats (calcium valproate at 200, 400, 800, 1200 and 1600 mg/kg and sodium valproate at 1200 mg/kg), reduced plasma globulin levels and low white blood cell counts due to suppressed neutrophil maturation were noted at doses of 800 mg/kg and higher. Platelet counts were reduced at 1200 and 1600 mg/kg. Testicular atrophy occurred at 1200 and 1600 mg/kg. In dogs given calcium valproate at 100, 200 and 400 mg/kg for 13 weeks, testicular atrophy was seen at 400 mg/kg and mild hepatocellular changes at all doses. In rats given calcium valproate at 125, 250 and 500 mg/kg for 1 year, reduced plasma protein and globulin levels and a dose-dependent increased incidence and severity of atrophic pancreatitis were noted at 250 and 500 mg/kg. Calcium valproate, given for 1 year to dogs at doses of 50, 100 and 200 mg/kg, was well tolerated. These studies indicated that calcium valproate has a toxicity profile similar to other forms of valproate.

Animals↗
PubMed1989

Renal and hepatic toxicity of a benzopyran-4-one in the Cynomolgus monkey.

The administration of PD 119819, a novel benzopyran-4-one brain dopamine autoreceptor agonist, to Cynomolgus monkeys was followed by deposition of needle-like drug crystals in the bile canaliculi, hepatocytes, proximal renal tubules and renal parenchyma. The crystals were associated with a granulomatous inflammation, and histological and biochemical evidence of hepatic and renal cell damage. Although metabolism differences may be the reason why primates, but not rodents, developed these changes, this form of crystallization appeared to be primarily a result of the insolubility of PD 119189 at alkaline pH.

5'-Nucleotidase↗