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Biomedical subjects

J S Walker

Publications and source records attributed to J S Walker.

At least 37 records · Page 2Linked to original sources
PubMed1998

Intercellular adhesion molecule-1 expression in adjuvant arthritis in rats: inhibition by kappa-opioid agonist but not by NSAID.

OBJECTIVE: To quantify intercellular adhesion molecule-1 (ICAM-1) expression in normal and adjuvant arthritic rats and to determine the extent to which ICAM-1 expression in arthritic animals is altered by treatment with a prototype nonsteroidal antiinflammatory drug (NSAID) and a kappa-opioid agonist. METHODS: Unilateral hind paw inflammation was induced by intradermal injection of Freund's complete adjuvant (FCA) into the right hind paw of female Lewis rats. Polyarthritis was induced by intradermal injection of FCA into the base of the tail of female dark Agouti rats. The NSAID naproxen [5 mg/kg intraperitoneally (ip)] or the kappa-opioid PD117302 (15 mg/kg ip) was administered twice daily throughout the experiment (21 days). ICAM-1 expression was quantified using monoclonal antibodies against rat ICAM-1 that bind to the endothelium in proportion to the degree of adhesion molecule expression. RESULTS: ICAM-1 expression was significantly upregulated in the joints of affected limbs of animals with both unilateral hind paw inflammation and polyarthritis. In animals treated with PD 117302 and naproxen there was a significant attenuation of arthritis; however, only treatment with PD117302 was able to significantly inhibit the upregulation of ICAM-1 expression in arthritic joints. CONCLUSION: ICAM-1 expression is upregulated in experimental arthritis. It appears that the kappa-opioid PD117302, but not the NSAID naproxen, inhibits the upregulation of ICAM-1 in arthritic joints, suggesting these agents act via different mechanisms. The ability of the kappa-agonist, PD117302, to inhibit both the inflammation and upregulation of ICAM-1 in arthritic joints emphasizes the potential of kappa-agonists as antiarthritic agents.

Animals↗
PubMed1997

Nonsteroidal antiinflammatory drugs in rheumatoid arthritis and osteoarthritis: support for the concept of "responders" and "nonresponders".

OBJECTIVE: A range of functional, biochemical, and psychological indicators was used to test the concept of "responders"/"nonresponders" and to seek predictors of response to 2 nonsteroidal antiinflammatory drugs in 9 patients with rheumatoid arthritis (RA) and 11 with osteoarthritis (OA). METHODS: In a balanced, randomized, double-blind, latin-square study design that involved four 4-week treatment periods, patients received ketoprofen or piroxicam (each for 2 of the 4 periods). Clinical and laboratory responses (pain, tenderness, swelling, patient and physician global assessments, acute-phase protein levels, and disability) were assessed in the last 2 weeks of each period. Responders were those who showed >30% improvement in at least 5 of 7 measures of disease activity. Mood was also assessed. RESULTS: At baseline, variables were higher in RA than in OA patients. The drugs produced clear improvements in patients' visual analog scale scores, physicians' overall assessments, and patients' responses to the McGill Pain Questionnaire, as well as plasma prostaglandin concentrations. In patients with either RA or OA, responders could be distinguished from nonresponders; about one-third of patients were unambiguous responders. In RA, there were responder/nonresponder differences in lymphocyte counts, erythrocyte sedimentation rate (ESR), and levels of tumor necrosis factor alpha, but no differences were seen in OA patients. However, caution in interpretation of the data is necessary because of the small number of patients. Responders had improved mood scores compared with nonresponders in both disease groups. Baseline ESR and white blood cell counts were correlated with responder status in RA patients. CONCLUSION: This study provides support for the responder/nonresponder concept. It also indicates that in RA, pretreatment ESR and lymphocyte counts are possibly useful indicators of therapeutic response.

Adult↗
PubMed1997

Myosin isoforms and functional diversity in vertebrate smooth muscle.

The expression of fast and slow myosin isoforms in individual cells is associated with differences in shortening velocities and power output in fully differentiated vertebrate striated muscle. This paradigm in which shortening velocity is determined by the myosin isoform (and load) is inappropriate for smooth muscle. Smooth muscle tissues express multiple myosin heavy and light chain isoforms, and it is not currently possible to separate and identify chemically distinct native myosin hexamers (i.e., isoforms). It is not known if different isoforms are localized in subpopulations of cells or in specific cellular domains nor whether they combine preferentially to form a small number of native myosin hexamer isoforms. Potentially, thick filaments are aggregates of many different combinations of heavy and light chain isoforms that may or may not exhibit different kinetics. Shortening velocities in smooth muscle are regulated by Ca(2+)-dependent crossbridge phosphorylation of the myosin regulatory light chains. Much of the observed diversity in power output in smooth muscle may be attributed to regulatory mechanisms modulating crossbridge cycling rates rather than contractile protein isoform expression.

Animals↗
PubMed1996

Effect of mu-opioids morphine and buprenorphine on the development of adjuvant arthritis in rats.

OBJECTIVE AND DESIGN: On the basis that endogenous opioids play a role in the physiological response to inflammation, this study tests the anti-arthritic effects of a mu-opioid agonist, morphine and the partial mu-agonist, buprenorphine. MATERIAL: Male Lewis rats were used. TREATMENT: Rats were inoculated subcutaneously with 0.05 ml of Freund's complete adjuvant (5 mg/ml) into the right hind paw to produce adjuvant arthritis. Morphine (either 10 to 60 mg/kg/day s.c. bolus or 60 mg/kg/day s.c. infusion) and buprenorphine (0.65 +/- 0.06 mg/kg/day, orally), respectively, were administered for 3 days during the primary inflammatory phase of adjuvant arthritis. METHODS: The progression of adjuvant arthritis was monitored every three days by body weight change and hind limb oedema (ipsilateral and contralateral). On day 21 the animals were sacrificed and histology and radiography of the contralateral limb were performed. In rats receiving Freund's adjuvant and no drug treatment, the incidence of arthritis was 89%. Effect was expressed as the pooled severity index (PSI) derived from the arithmetic average of the volume, histology and radiography scores in the contralateral hind limb. RESULTS: Buprenorphine had no effect on experimental arthritis (PSI control vs treated: 242 +/- 28 vs 253 +/- 28%). In contrast, morphine by subcutaneous injection twice daily (10 to 60 mg/kg/day) but not by subcutaneous infusion (60 mg/kg/day) was found to attenuate the progression of adjuvant arthritis in a dose-dependent manner. This indicates that the anti-arthritic effects of morphine are opioid receptor mediated (ED50, 58 +/- 9 mg/kg) and suggests that the local concentration reached effective levels only after subcutaneous injection. It is also possible that the high doses of morphine were anti-inflammatory through effects at the kappa receptor. However, these high doses of morphine produced death in one third of the rats, the calculated lethal dose (LD50, 63 +/- 2 mg/kg) being close to the effective dose. CONCLUSION: Anti-arthritic effects of morphine are opioid receptor mediated but morphine use for this indication is restricted by its adverse effects.

Analgesics, Opioid↗
PubMed1996

Vascular abdominal emergencies.

Vascular emergencies are an uncommon but significant cause of abdominal pain, back pain, hemorrhagic shock, and death in adults. This article reviews abdominal vascular anatomy, risk factors, signs and symptoms, abdominal vascular thrombosis, mesenteric ischemia and infarction, and abdominal vascular emboli and aneurysms.

Abdomen↗
PubMed1996

The site of anti-arthritic action of the kappa-opioid, U-50, 488H, in adjuvant arthritis: importance of local administration.

1. Currently available pharmacological therapies treat arthritis inadequately. We have previously found that the kappa (kappa)-opioid, U-50,488H (trans-(+/-)- 3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl) cyclohexyl]- benzene-acetamide methane sulphonate), possesses anti-arthritic effects. In light of the finding that opioid receptors in the periphery are upregulated during inflammation, kappa-opioids may represent a novel therapy for arthritis. The primary aim and unique feature of the present study is to investigate whether opioids exert their anti-arthritic effects in the periphery. Thus, the dose-effect relationship of a kappa-opioid agonist, U-50,488H was compared after both local and distant administration. Further, we tested whether the anti-arthritic effects of this drug are stereospecific and receptor-mediated by use of opioid antagonists. 2. Using an adjuvant model of arthritis in male Lewis rats, arthritis was judged by oedema, radiography and histological changes in the contralateral ankle of the hind limb. Treatment with (+/-)-U-50,488H for 3 days during disease onset and 3 days during established disease significantly attenuated arthritis, but the effects of (+/-)-U-50,488H on radiology and histology varied according to treatment time. Administration of (+/-)-U-50,488H during disease onset had a more marked effect on radiography, suggesting that treatment with that drug should be started early to prevent progressive joint destruction. Further, it was found that (+/-)-U-50,488H, administered for 3 days during the disease onset, either by direct subcutaneous injection into the inflamed paw or at a more distant site into the back of the neck, dose-dependently attenuated arthritic damage as measured by an index which pooled all three variables. More importantly however, (+/-)-U-50,488H was approximately fourfold more potent as an 'anti-arthritic' agent after local compared to distant subcutaneous injection (ED50; local vs distant: 5.8 +/- 1.6 vs 19.5 +/- 0.8 mg kg-1). 3. Equivalent doses of the (-)-enantiomer (20 mg kg-1day-1) and the racemate (+/-) of U-50,488H (40 mg kg-1day-1), elicited a similar attenuation of arthritic parameters while the (+/-)-enantiomer exacerbated arthritis, suggesting that the anti-arthritic activity lies solely with the (-)-enantiomer. 4. Both the peripherally selective antagonist, naloxone methiodide, and the kappa-selective antagonist, MR2266 ((-)-5,9 alpha-diethyl-2-(3-furylmethyl)-2'-hydroxy-6,7-benzomorphan), were able to reverse fully the peripheral anti-arthritic effects of U-50,488H, indicating that it exerts its effects through peripheral kappa-opioid receptors. 5. Taken together, these results not only confirm our previous findings that demonstrate anti-arthritic effects of U-50,488H but they indicate that the opioid attenuation of experimental arthritis is mediated via peripheral kappa-receptors in the arthritic joint. Peripherally acting kappa-opioid agonists should lead to new therapies for arthritis.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1996

Inferior glenohumeral dislocation (luxatio erecta humeri).

A 67-year-old woman was seen in the emergency department because of severe pain and inability to move her left shoulder after falling on an abducted left arm. The fall was the result of a near-syncopal episode. On examination, the left arm was hyperabducted and elevated approximately 80 degrees from the horizontal plane. Furthermore, the patient was unable to move her left arm. Radiographs of the shoulder revealed an inferior dislocation of the glenohumeral joint. Closed reduction in the emergency department was successful. This rare but classic case of inferior glenohumeral dislocation (luxatio erecta humeri) serves to emphasize that a heightened awareness for this injury is necessary if it is to be recognized and treated appropriately. It is important to obtain orthopedic consultation or follow-up (or both) for this injury, because of the high incidence of accompanying tears of the rotator cuff. Neurovascular compromise is also commonly associated with this dislocation. The neurologic injuries are more common than the vascular injuries but tend to resolve after reduction.

Accidental Falls↗
PubMed1995

Pain due to nerve damage: are inflammatory mediators involved?

Damage to peripheral nerves often results in pain and hyperalgesia. We suggest that nerve damage causes an inflammatory response in which cells associated with the nerve release inflammatory mediators such as eicosanoids; these mediators may contribute to the hyperalgesia which results from nerve injury. The cell types most likely to be responsible include macrophages and postganglionic sympathetic neurones. A better understanding of the mechanisms involved should lead to improved therapies for neuropathic pain.

Animals↗
PubMed1995

Anti-inflammatory effects of kappa-opioids in adjuvant arthritis.

Current therapies for arthritis are unsatisfactory and cause serious side effects and morbidity. It has been postulated that opioid drugs may block inflammatory mediators and attenuate the joint damage in adjuvant arthritis. However, the importance of opioid receptor subtypes involved in inflammation remains to be determined because data are conflicting in this regard. The present investigation was designed to test the effects of both a kappa-agonist, (+/-)U50488H and a kappa-antagonist, MR2266 on the progression of experimental arthritis. To produce adjuvant arthritis, male Lewis rats were inoculated subcutaneously (s.c.) with 0.05 ml of Freund's complete adjuvant (10 mg/ml) into the right hind paw. The kappa-opioid agonist, (+/-)U50488H (20 mg/kg/d s.c.) and the kappa-opioid antagonist, MR2266 (20 mg/kg/d s.c.) were administered for 3 days during the primary inflammatory phase of adjuvant arthritis. There were four treatment groups; group I were non-arthritic controls and received paraffin oil vehicle and opioid injections; group II were arthritic controls and received adjuvant and saline injections; group III received adjuvant and agonist and group IV received adjuvant and antagonist. The progression of adjuvant arthritis from day 0 to 24 was monitored by body weight change, hind limb size (ipsilateral and contralateral) and a total severity score for each clinical observation of gait, coat and limb condition. On day 24 histology and radiography of the contralateral limb was performed. There was less soft-tissue swelling, as judged by time-averaged % change in the volume of the contralateral limb, in both agonist (mean +/- se: 82 +/- 5) and antagonist (77 +/- 4) treated rats compared to untreated arthritic controls (99 +/- 5, p < 0.05). Other clinical measures of severity were not different between untreated and opioid-treated arthritic rats. However, the joint damage as judged by radiography was lower in kappa agonist treated rats (2.6 +/- 0.5, p < 0.05) compared to untreated controls (4.1 +/- 0.5) and antagonist treatment (4.4 +/- 0.5). Microscopic pathological scores were also significantly lower in agonist (2.8 +/- 0.3, p < 0.05) compared to both antagonist treated rats (4.2 +/- 0.1) and vehicle-treated controls (3.6 +/- 0.2). The results of this study show that kappa-opioid receptor agonists but not antagonists attenuate the progression of experimental arthritis. These observations have important implications for the evaluation and use of kappa-opioid agents in the management of arthritis.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1995

NSAID: an update on their analgesic effects.

1. The non-steroidal anti-inflammatory drugs (NSAID) are a group of drugs that possess both analgesic and anti-inflammatory properties. They are used to treat a variety of painful and inflammatory disorders such as postoperative pain, dental surgery, headache, acute and chronic musculoskeletal pain. 2. There is now substantial evidence that NSAID produce analgesia by inhibiting prostaglandin (PG) synthesis both in the peripheral and central nervous system. However, other mechanisms of action should also be considered. There is a multiplicity of mediators capable of producing pain, and NSAID may act both on the peripheral and central nervous system to modulate such mediators. There is a growing body of evidence suggesting that NSAID can exert an effect on specific G-protein dependent functions. 3. There is significant intra- and interpatient variability in the response to NSAID. Development of tolerance after multiple doses may provide an explanation for the unsatisfactory response to NSAID in some patients. 4. It has been suggested that the rate of decline of drug effect is characteristic of analgesia itself and indicates that an endogenous substance mediates the analgesic effect; possible candidates include serotonin. 5. NSAID remain an important therapeutic option in the management of pain.

Analgesics↗
PubMed1994

Clinical response to non-steroidal anti-inflammatory drugs in urate-crystal induced inflammation: a simultaneous study of intersubject and intrasubject variability.

1. It is well known that an individual subject often responds preferentially to a particular nonsteroidal anti-inflammatory drug (NSAID) and clinical response to these drugs is characterised by considerable variability between individuals. Variability in response has often been attributed to the episodic nature of musculoskeletal disease. Few studies have studied intrasubject variability in response to these drugs using a multiple crossover design. A major difficulty has been the lack of objective, validated measures of inflammation sensitive to NSAIDs. The primary aim of the present study was to test the utility of urate-crystal induced inflammation as a tool to predict NSAID response in humans. 2. An inflammatory reaction was established in twenty-five healthy subjects with intradermal injection of urate crystals on four separate occasions separated by 1 week. Each subject was randomly assigned to receive either ibuprofen on two of these occasions (800 mg four times over 36 h) or matched placebo on the other two occasions using a double-blind, cross-over design. Decrease in the area under the wheal size-time curve was used to indicate anti-inflammatory response. 3. Peak inflammatory response was observed at about 32 h and had dissipated by 56 h post-urate injection. The logarithmic mean wheal area was significantly lower after ibuprofen (mean +/- s.e. mean; 6.74 +/- 0.09) compared with placebo (6.96 +/- 0.07 mm h); a difference of 20% (95% confidence interval for difference: 1 to 35%; P < 0.05). 4. There was marked intra- and intersubject variability in response to ibuprofen over the four treatment periods.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1994

Energetics of crossbridge phosphorylation and contraction in vascular smooth muscle.

Ca(2+)-dependent crossbridge phosphorylation is the primary mechanism governing crossbridge cycling in smooth muscle. A four-state crossbridge model in which phosphorylation is the only proposed regulatory mechanism was successful in predicting the mechanical properties of the swine carotid media including latch (sustained force with reduced crossbridge cycling). This model also predicts that the ATP consumption of crossbridge phosphorylation is approximately equal to that of crossbridge cycling and that ATP consumption will rise hyperbolically with increases in steady-state force. This review shows these predictions to be consistent with the available energetics data for the carotid media. The absolute energetic cost of covalent regulation is modest and less than the energy savings associated with latch. However, covalent regulation should reduce the total mechanical efficiency of smooth muscle relative to striated muscle.

Animals↗