Biomedical subjects

J P Keogh

Publications and source records attributed to J P Keogh.

At least 19 recordsLinked to original sources

PubMed2000

Patterns and predictors of employer risk-reduction activities (ERRAs) in response to a work-related upper extremity cumulative trauma disorder (UECTD): reports from workers' compensation claimants.

BACKGROUND: Despite being preventable, work-related upper extremity cumulative trauma disorders (UECTDs) remain problematic. This study is unique in its focus on predictors of employer risk-reduction activities (ERRAs) in response to a UECTD case. METHODS: Workers' compensation claimants (N = 537) completed a telephone survey about employer risk-reduction activities, workplace characteristics, safety programs, and physician recommendations for job modifications. RESULTS: Only 52% of respondents reported employer actions to investigate or reduce UECTD risk. Engineering and pace changes were prominent for keyboard workers and transfer to another job for manufacturing workers. Safety programs and physician recommendations increased the likelihood of risk-reduction activities. CONCLUSIONS: An opportunity to intervene post-injury to reduce risks for the injured worker and prevent new UECTD cases is being missed. Physician recommendations are strongly associated with specific ERRAs thought to be most effective. Educating employers and physicians about ergonomics could result in prevention of UECTDs.

Adult↗

PubMed2000

The impact of occupational injury on injured worker and family: outcomes of upper extremity cumulative trauma disorders in Maryland workers.

BACKGROUND: Surveys have identified a dramatically rising incidence of work-related upper extremity cumulative trauma disorders (UECTDs). Outcome studies have addressed time lost from work and cost of compensation; omitting other significant consequences. We assess health, functional and family outcomes. METHODS: We identified 537 Workers' Compensation UECTD claimants. A computer-assisted telephone questionnaire was used to elicit symptom prevalence, functional impairment, depressive symptoms (CES-D scale), employment status. RESULTS: One to 4 years post-claim, respondents reported persistent symptoms severe enough to interfere with work (53%), home/recreation activities (64%) and sleep (44%). Only 64% of responses to the activities of daily living scale items indicated "normal" function. Job loss was reported by 38% of respondents, and depressive symptoms by 31%. CONCLUSIONS: Work-related UECTDs result in persisting symptoms and difficulty in performing simple activities of daily living, impacting home life even more than work. Job loss, symptoms of depression, and family disruption were common.

Activities of Daily Living↗

PubMed2000

Health effects of depleted uranium on exposed Gulf War veterans.

A small group of Gulf War veterans possess retained fragments of depleted uranium (DU) shrapnel, the long-term health consequences of which are undetermined. We evaluated the clinical health effects of DU exposure in Gulf War veterans compared with nonexposed Gulf War veterans. History and follow-up medical examination were performed on 29 exposed veterans and 38 nonexposed veterans. Outcome measures employed were urinary uranium determinations, clinical laboratory values, and psychiatric and neurocognitive assessment. DU-exposed Gulf War veterans with retained metal shrapnel fragments are excreting elevated levels of urinary uranium 7 years after first exposure (range 0.01-30.7 microg/g creatinine vs 0.01- 0.05 microg/g creatinine in the nonexposed). The persistence of the elevated urine uranium suggests on-going mobilization from a storage depot which results in a chronic systemic exposure. Adverse effects in the kidney, a presumed target organ, are not present at this time, though other effects are observed. Neurocognitive examinations demonstrated a statistical relationship between urine uranium levels and lowered performance on computerized tests assessing performance efficiency. Elevated urinary uranium was statistically related to a high prolactin level (>1.6 ng/ml; P=0.04). More than 7 years after first exposure, DU-exposed Gulf War veterans with retained metal fragments continue to excrete elevated concentrations of urinary uranium. Effects related to this are subtle perturbations in the reproductive and central nervous systems.

Adult↗

PubMed1999

Disposition of ropinirole in animals and man.

1. The disposition and metabolic fate of ropinirole, a novel compound indicated for the symptomatic treatment of Parkinson's disease, was studied in the mouse, rat, cynomolgus monkey and man, following oral and intravenous administration of ropinirole hydrochloride. 2. In all species, nearly all of the p.o. administered dose (94%) was rapidly absorbed from the gastrointestinal tract following administration of 14C-ropinirole hydrochloride. In rat and monkey, the compound distributed rapidly beyond total body water and was shown to cross the blood-brain barrier. Blood clearance of the compound was high, approximately equal to one-half the hepatic blood flow in the monkey and similar to the hepatic blood flow in rat. Terminal phase elimination half-lives for the compound were relatively short (0.5 and 1.3 h in rat and monkey respectively), although there was evidence of a second elimination phase in the monkey with an elimination half-life of approximately 5-11 h. Plasma concentrations of ropinirole after the intravenous dose were not determined in the mouse and were below the lower limit of quantification in man (0.08 ng/ml) at the doses used in the studies described in this paper. 3. In both animals and man, ropinirole was extensively metabolized. In the rat, the major metabolic pathway was via hydroxylation of the aromatic ring to form 7-hydroxy ropinirole. In mouse, monkey and man, the major pathway was via N-depropylation. The N-despropyl metabolite was metabolized further to form 7-hydroxy and carboxylic acid derivatives. Metabolites formed in all species were generally metabolized further by glucuronidation. 7-Hydroxy ropinirole is the only metabolite of ropinirole previously shown to possess significant dopamine agonist activity in vivo. In all species, the major route of excretion of ropinirole-related material after oral or intravenous administration of the compound was renal (60-90% of dose).

Absorption↗

PubMed1999

Elevated urine uranium excretion by soldiers with retained uranium shrapnel.

The use of depleted uranium in munitions has given rise to a new exposure route for this chemically and radioactively hazardous metal. A cohort of U.S. soldiers wounded while on or in vehicles struck by depleted uranium penetrators during the Persian Gulf War was identified. Thirty-three members of this cohort were clinically evaluated, with particular attention to renal abnormalities, approximately 3 y after their injury. The presence of retained shrapnel was identified by x ray, and urine uranium concentrations were measured on two occasions. The absorption of uranium from embedded shrapnel was strongly suggested by measurements of urine uranium excretion at two time intervals: one in 1993/1994 and one in 1995. Mean urine uranium excretion was significantly higher in soldiers with retained shrapnel compared to those without shrapnel at both time points (4.47 vs. 0.03 microg g(-1) creatinine in 1993/1994 and 6.40 vs. 0.01 microg g(-1) creatinine in 1995, respectively). Urine uranium concentrations measured in 1995 were consistent with those measured in 1994/1993, with a correlation coefficient of 0.9. Spot urine measurements of uranium excretion were also well correlated with 24-h urine collections (r = 0.95), indicating that spot urine samples can be reliably used to monitor depleted uranium excretion in the surveillance program for this cohort of soldiers. The presence of uranium in the urine can be used to determine the rate at which embedded depleted uranium fragments are releasing biologically active uranium ions. No evidence of a relationship between urine uranium excretion and renal function could be demonstrated. Evaluation of this cohort continues.

Amputation, Surgical↗

PubMed1997

Relationship between gastric mucus synthesis, secretion and surface gel erosion measured in amphibian stomach in vitro.

1. The layer of adherent mucus that protects the surface of the stomach reflects a dynamic balance between biosynthesis of glycoprotein, secretion of preformed mucus and erosion of the adherent gel layer. The present study is the first in which all these processes have been measured concomitantly and was undertaken to define interrelationships between the three parameters. 2. A chambered sac preparation of amphibian gastric mucosa is described. Biosynthesis was determined by specific incorporation of radiolabelled sugars into purified glycoprotein. Mucus secretion was determined by measuring the thickness of the adherent gel and erosion of the surface layer was assessed from the appearance of soluble mucin in the luminal solution. 3. 16,16-Dimethyl-prostaglandin (PG) E2 stimulated glucosamine incorporation by 10-fold, but did not alter the rate of incorporation of galactose. There was a rapid two-fold increase in the thickness of the adherent mucus layer but no change in the rate of erosion. Dibutyryl-cAMP also stimulated mucus release but, unlike PG, increased glycoprotein labelling by galactose. 4. Both distention or the application of a cholinergic agonist increased adherent mucus thickness. Stimulation of mucus release in response to carbachol was accompanied by a decrease in glycoprotein labelling by galactose. In contrast, the adrenergic agent noradrenaline decreased secretion but did not influence labelling. 5. These results indicate that biosynthesis and secretion of gastric mucus are subject to differential regulation. Moreover, the profile of incorporation of sugars in response to secretagogues also differs, indicating the need for caution when interpreting effects on glycoprotein biosynthesis.

16,16-Dimethylprostaglandin E2↗

PubMed1996

Risk factors for lung cancer and for intervention effects in CARET, the Beta-Carotene and Retinol Efficacy Trial.

BACKGROUND: Evidence has accumulated from observational studies that people eating more fruits and vegetables, which are rich in beta-carotene (a violet to yellow plant pigment that acts as an antioxidant and can be converted to vitamin A by enzymes in the intestinal wall and liver) and retinol (an alcohol chemical form of vitamin A), and people having higher serum beta-carotene concentrations had lower rates of lung cancer. The Beta-Carotene and Retinol Efficacy Trial (CARET) tested the combination of 30 mg beta-carotene and 25,000 IU retinyl palmitate (vitamin A) taken daily against placebo in 18314 men and women at high risk of developing lung cancer. The CARET intervention was stopped 21 months early because of clear evidence of no benefit and substantial evidence of possible harm; there were 28% more lung cancers and 17% more deaths in the active intervention group (active = the daily combination of 30 mg beta-carotene and 25,000 IU retinyl palmitate). Promptly after the January 18, 1996, announcement that the CARET active intervention had been stopped, we published preliminary findings from CARET regarding cancer, heart disease, and total mortality. PURPOSE: We present for the first time results based on the pre-specified analytic method, details about risk factors for lung cancer, and analyses of subgroups and of factors that possibly influence response to the intervention. METHODS: CARET was a randomized, double-blinded, placebo-controlled chemoprevention trial, initiated with a pilot phase and then expanded 10-fold at six study centers. Cigarette smoking history and status and alcohol intake were assessed through participant self-report. Serum was collected from the participants at base line and periodically after randomization and was analyzed for beta-carotene concentration. An Endpoints Review Committee evaluated endpoint reports, including pathologic review of tissue specimens. The primary analysis is a stratified logrank test for intervention arm differences in lung cancer incidence, with weighting linearly to hypothesized full effect at 24 months after randomization. Relative risks (RRs) were estimated by use of Cox regression models; tests were performed for quantitative and qualitative interactions between the intervention and smoking status or alcohol intake. O'Brien-Fleming boundaries were used for stopping criteria at interim analyses. Statistical significance was set at the .05 alpha value, and all P values were derived from two-sided statistical tests. RESULTS: According to CARET's pre-specified analysis, there was an RR of 1.36 (95% confidence interval [CI] = 1.07-1.73; P = .01) for weighted lung cancer incidence for the active intervention group compared with the placebo group, and RR = 1.59 (95% CI = 1.13-2.23; P = .01) for weighted lung cancer mortality. All subgroups, except former smokers, had a point estimate of RR of 1.10 or greater for lung cancer. There are suggestions of associations of the excess lung cancer incidence with the highest quartile of alcohol intake (RR = 1.99; 95% CI = 1.28-3.09; test for heterogeneity of RR among quartiles of alcohol intake has P = .01, unadjusted for multiple comparisons) and with large-cell histology (RR = 1.89; 95% CI = 1.09-3.26; test for heterogeneity among histologic categories has P = .35), but not with base-line serum beta-carotene concentrations. CONCLUSIONS: CARET participants receiving the combination of beta-carotene and vitamin A had no chemopreventive benefit and had excess lung cancer incidence and mortality. The results are highly consistent with those found for beta-carotene in the Alpha-Tocopherol Beta-Carotene Cancer Prevention Study in 29133 male smokers in Finland.

Anticarcinogenic Agents↗

PubMed1996

Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease.

BACKGROUND: Lung cancer and cardiovascular disease are major causes of death in the United States. It has been proposed that carotenoids and retinoids are agents that may prevent these disorders. METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled primary prevention trial -- the Beta Carotene and Retinol Efficacy Trial -- involving a total of 18,314 smokers, former smokers, and workers exposed to asbestos. The effects of a combination of 30 mg of beta carotene per day and 25,000 IU of retinol (vitamin A) in the form of retinyl palmitate per day on the primary end point, the incidence of lung cancer, were compared with those of placebo. RESULTS: A total of 388 new cases of lung cancer were diagnosed during the 73,135 person-years of follow-up (mean length of follow-up, 4.0 years). The active-treatment group had a relative risk of lung cancer of 1.28 (95 percent confidence interval, 1.04 to 1.57; P=0.02), as compared with the placebo group. There were no statistically significant differences in the risks of other types of cancer. In the active-treatment group, the relative risk of death from any cause was 1.17 (95 percent confidence interval, 1.03 to 1.33); of death from lung cancer, 1.46 (95 percent confidence interval, 1.07 to 2.00); and of death from cardiovascular disease, 1.26 (95 percent confidence interval, 0.99 to 1.61). On the basis of these findings, the randomized trial was stopped 21 months earlier than planned; follow-up will continue for another 5 years. CONCLUSIONS: After an average of four years of supplementation, the combination of beta carotene and vitamin A had no benefit and may have had an adverse effect on the incidence of lung cancer and on the risk of death from lung cancer, cardiovascular disease, and any cause in smokers and workers exposed to asbestos.

Aged↗

PubMed1996

Lead poisoning in telephone cable strippers: a new setting for an old problem.

Lead poisoning among workers processing lead sheathed telephone cable was identified at five worksites. High blood lead levels (BLLs) were identified during the medical evaluation of symptomatic workers following employer mandated air monitoring and through employer mandated blood lead levels. Once high BLLs were identified, governmental agencies became involved at every site, either as a result of worker complaints to OSHA or as a registry reporting mechanism. Workplace evaluation revealed significant overexposure to lead, particularly among workers mechanically stripping the lead sheaths. After intervention by a government agency, four of the workplaces chose to stop lead cable processing. Because the ongoing replacement of lead sheathed telephone cable with fiber optics may be continuing in many areas of the country, there is concern that the clusters we have identified represents a widespread and little recognized setting for lead overexposure. Recommendations for preventing overexposure to lead in this setting are given.

Conservation of Natural Resources↗

PubMed1996

The fate of a thiazolidinedione antidiabetic agent in rat and dog.

1. The fate of [14C]BRL 49653C, a novel thiazolidinedione antidiabetic agent, has been studied following oral administration to the rat and dog. 2. Clearance was almost exclusively by metabolism, with only small amounts of unchanged BRL 49653 being excreted by either species. 3. Phase I metabolism resulted in ring hydroxylation, N-demethylation and oxidative removal of the pyridinylamino function to yield a phenoxyacetic acid derivative. 4. Sulphation of phase I metabolites occurred in both species, but glucuronidation was only observed in the rat. 5. The parent compound was the major circulating component in both species at early times, but at later times sulphate conjugates of phase 1 metabolites were predominant.

Animals↗

PubMed1994

Occupational lead poisoning: who should conduct surveillance and training?

This commentary challenges the current employer-controlled model for delivering occupational health services. Problems emanating from traditional employer-based medical surveillance and worker education programs for occupational lead poisoning are identified. A new public health model for delivering these services is proposed. This model utilizes a case-based and hazard-based method for bringing workplaces and employers into the program and features direct delivery of surveillance and training services by public health agencies.

Environmental Monitoring↗

PubMed1994

Cytotoxicity of heavy metals in the human small intestinal epithelial cell line I-407: the role of glutathione.

Cytotoxicities of metal salts were determined in the intestinal epithelial cell line I-407 in microwell culture plates over 48 h using the widely utilized and accepted neutral red uptake procedure. Rank order cytotoxicities induced by the metal salts (in terms of LC50 values) were found to be HgCl2 (32 microM) > CdCl2 (53 microM) > CuCl2 (156 microM) > T12SO4 (377 microM) > Pb(NO3)2 (1.99 mM). Combined administration of the two most toxic metals at their LC50's showed that their toxicities were not additive or synergistic. The role of glutathione in determining toxicity induced by the metal salts in these cells was assessed by inhibition of its synthesis. Buthionine sulfoximine pretreatment at 1 mM, which was not toxic to the cells, caused sustained reduction in cellular glutathione content (to 13.8% after 48 h) and increased toxicities induced by HgCl2 (5.7-fold) and CuCl2 (1.44-fold) as shown by reductions in the LC50 values. Toxicity induced by the other metals remained unaffected. Administration of glutathione with either HgCl2 or CdCl2 did not protect the cells against their toxicity, and in the case of cadmium its toxicity was exacerbated. N-Acetylcysteine diminished toxicity induced by mercury but not cadmium.

Cadmium↗

PubMed1993

Pharmacological alterations of cellular transglutaminase activity and invasiveness in human colorectal carcinoma cells.

Human colorectal tumor cells expressing differing metastatic potential and tissue transglutaminase (TGA) activity were tested for the ability of various pharmacological agents to enhance TGA activity. The most effective stimulant was tetradecanoylphorbol-13-acetate (TPA), which in human colon carcinoma cells (SW620) caused a 5-fold, protein synthesis dependent increase in activity over 3 days. In WiDr and SW480 cells TGA activity was less susceptible to induction by TPA, possibly owing to the higher basal levels of TGA. Retinoic acid and a synthetic retinoid, [RO 15-1570; (E)-4-[2(5,6,7,8-tetramethylnaphthalene-2-yl)propen-1-yl] benzenesulphonyl-ethane)], also induced TGA activity to a lesser extent in SW620 cells, whereas other differentiation inducers [sodium butyrate and hexamethylene bis-acetamide (HMBA)] were ineffective. In LS174T cells, TGA activity was resistant to induction by all of the agents. The synthetic retinoid (RO 15-1570) inhibited in vitro invasiveness of SW620 cells, however, TPA treatment or addition of exogenous TGA did not inhibit invasiveness of these cells. Hence, the invasive behavior of a metastatic human colon tumor cell line (SW620) does not appear to be dependent on the TGA activity which the cells express. The anti-invasive activity of the retinoid in SW620 cells therefore may be mediated by some other mechanism.

Adenocarcinoma↗

PubMed1993

Effects of exogenous transglutaminase on spreading of human colorectal carcinoma cells.

Using pre-confluent cultures of a human colon tumor cell line deficient in transglutaminase (LS174T cells), we have investigated the effect of adding exogenous transglutaminase (TGA) on cell spreading. The cells were plated at either 4.5 x 10(5) cells per well (low-seeded cultures) or 9 x 10(5) cells per well (high-seeded cultures) in 24-well dishes and treated for either 1 or 4 days (low- and high-seeded cultures respectively) under following conditions: Chee's Essential Medium (CEM) + 10% fetal calf serum (FCS); CEM + 10% FCS + TGA; CEM + 10% FCS + dithiothreitol (DTT) + CaCl2; CEM + 10% FCS + DTT + CaCl2 + TGA. Photomicrography of the cells after these treatments revealed that in both low- and high-seeded cultures, TGA inhibited the spreading of the cells both in the presence and absence of DTT and calcium. Individual colony sizes were significantly smaller in the presence of TGA. This phenomenon may be related to the ability of TGA to promote cell interactions with the underlying tissue matrices and metastasis.

Calcium Chloride↗

PubMed1992

Enhancement of gastric mucosal epidermal growth factor and platelet-derived growth factor receptor expression by sucralfate.

1. The effect of an anti-ulcer agent, sucralfate, on the expression of gastric mucosal epidermal growth factor (EGF) and platelet derived growth factor (PDGF) receptors was investigated. 2. Gastric mucosal cell membranes, isolated from the stomach of groups of rats, one receiving twice daily for 3 consecutive days a dose of 100 mg/kg sucralfate, and the other only the vehicle, were used as source for EGF and PDGF receptors. 3. Binding assays revealed the presence of both types of receptors, activation of which led to the elevation of tyrosine kinase activity as evidenced by a marked increase in membrane protein tyrosine phosphorylation patterns. 4. The specific receptor binding in the control group was 2.46 fmol/mg protein for EGF and 1.46 fmol/mg protein for PDGF, whereas the respective binding values in the sucralfate treated group increased by 61 and 65%. 5. The results suggest that sucralfate is capable of enhancement of epithelial proliferative activities through the stimulation of gastric mucosal EGF and PDGF receptors.

Animals↗

PubMed1991

Transglutaminase activity in human colorectal carcinomas of differing metastatic potential.

Transglutaminase (TGA) activity in four human colorectal carcinoma cell lines of differing metastatic potential, and the effects of mild proteolysis on this activity, was investigated. Rank order of metastatic activity measured in nude mice (intrasplenic injection) was found to be LS174T greater than SW620 greater than WiDr greater than SW480. Rank orders of TGA activity were SW480 greater than WiDr greater than SW620 greater than LS174T. Proteolysis of cell lysates increased LS174T TGA activity 42-fold, SW620 2-fold without affecting WiDr or SW480 activity. Hence a negative association exists between metastatic potential and TGA activity in human colorectal carcinoma cells. Furthermore, a positive association exists between proteolytic activation of TGA and metastatic potential.

Animals↗

PubMed1991

Chromatographic measurement of mucin production in cultures of gastric mucous cells.

The use of a miniature column chromatographic assay (using Sepharose CL-4B columns) for measuring mucin production in guinea pig gastric mucous cell cultures is described. The assay was based upon the ability of radiolabelled precursors ([14C]serine and [3H]galactose) to incorporate with high specificity into mucins which thereby appeared in the excluded material. Rates of excluded material radiolabelling by both precursors were constant for incubations up to 24 hours, and substantially reduced by cycloheximide co-incubation (25 microM). Labelled excluded material was completely degraded by mild alkaline borohydride treatment, only partially degraded by HNO2 (pH 1.5), and not degraded by chondroitinase ABC. Thus the major radiolabelled product measured in this system was mucin, although we found that it was less glycosylated than gastric mucins obtained from other sources. In addition, the technique employed to separate and measure mucin production proved rapid and consistent.

Animals↗

PubMed1991

Transforming growth factor-alpha binds to the epidermal growth factor receptor in gastric mucosa.

The ability of transforming growth factor-alpha (TGF-alpha) to interact with the gastric mucosal epidermal growth factor (EGF) receptor was investigated using a mucosal membrane preparation. TGF-alpha inhibited specific binding of [125I]EGF to its receptor, but the IC50 for TGF-alpha was at least 100 fold greater than that observed for unlabeled EGF. Cross-linking studies revealed no attachment of [125I]TGF-alpha to EGF-receptor size components, and the unlabeled TGF-alpha was only weakly effective in inhibiting cross-linking of [125I]EGF to the 170 kDa receptor. However, when the cytosolic fraction was reconstituted with the membrane preparation, an enhancement in binding of [125I]TGF-alpha to the EGF receptor occurred in a manner dependent on the concentration of cytosolic protein. Hence the binding characteristics of TGF-alpha to the EGF receptor in gastric mucosa are different from those for EGF.

Animals↗