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Biomedical subjects

J S Walker

Publications and source records attributed to J S Walker.

At least 19 recordsLinked to original sources
PubMed2002

The in vivo effects of tumour necrosis factor blockade on the early cell mediated immune events and syndrome expression in rat adjuvant arthritis.

Anti-TNF therapy is effective in rheumatoid arthritis (RA); however, its mechanisms of action are incompletely understood. T cell-driven mechanisms are thought to play an important role in RA and the effects of TNF blockade on these mechanisms are unclear. Adjuvant arthritis (AA) is a T cell dependent model of inflammatory arthritis. The aims of this study were to investigate the effects of TNF blockade on in vivo T cell cytokine expression and to clarify the role of TNF in the inguinal lymph nodes (ILN) in early arthritis. AA was induced in male DA rats. Rats received either 3 mg/kg or 10 mg/kg PEG sTNF-RI at days 0, 2 and 4 postinduction or 10 mg/kg anti-TNF antibody on day of arthritis induction. Control rats received either saline or normal sheep serum. Paw volume was assessed every 3-4 days. Rats were sacrificed on days 0, 6, 13 and 21 postinduction. Ankles were removed for quantitative radiology and histology. Synovium and ILN were removed for cell culture and to determine mRNA expression of cytokines using semiquantitative RT-PCR. TNF and IFN-gamma protein production was measured using a bioassay and an ELISA. TNF blockade did not suppress mRNA expression of T cell cytokines in the ILN of rats in the early phase of AA, suggesting ongoing T cell activity. TNF protein production by ILN cells in culture was reduced in PEG sTNF-RI treated rats, although mRNA expression was increased in the ILN prior to culture. Early administration of PEG sTNF-RI did not attenuate AA, in contrast to an anti-TNF antibody, which suppressed disease. A shorter half-life for the PEG sTNF-RI compared with the anti-TNF antibody or the development of anti-PEG sTNF-RI antibodies may account for these results.

Animals↗
PubMed2002

Effects of a PEGylated soluble TNF receptor type 1 (PEG sTNF-RI) on cytokine expression in adjuvant arthritis.

OBJECTIVE: To investigate the effects of TNF blocking therapy on synovial immune activity in rat adjuvant arthritis (AA) by measuring mRNA expression of key macrophage and T cell cytokines during PEG sTNF-RI treatment (10mg/kg) on days 8, 10 and 12. METHODS: Paw volume was assessed every 3-4 days. Ankles were removed for quantitative radiology and histology and synovial membrane removed to determine cytokine mRNA expression using semi-quantitative RT-PCR. T cells in joints were quantified by immunohistochemistry. RESULTS: Paw volume was significantly decreased in rats treated with PEG STNF-RI from days 12 to 17. Histology scores and synovial T cell numbers were reduced on days 13 and 17 and radiology scores significantly reduced on day 13. Expression of synovial TNF, IFN-gamma, IL-17, IL-2 and IL-4 mRNA was unchanged in treated rats and TGF-beta expression was significantly increased at day 13. CONCLUSIONS: PEG sTNF-RI attenuates AA and disease recurs after treatment ceases, similar to human rheumatoid arthritis. Continued TNF production and/or ongoing T cell activity, may explain the recrudescence of disease once treatment is stopped.

Animals↗
PubMed2001

Effects of nitric oxide synthase inhibition on ciliary blood flow, aqueous production and intraocular pressure.

A prior study found that inhibition of nitric oxide synthase with L-NAME causes a large, rapid decrease in IOP in anesthetized rabbits. In this follow-up study we sought to determine if this hypotensive effect was due to decreased aqueous production, possibly caused by ciliary vasoconstriction. Two protocols were performed in anesthetized rabbits. In the first protocol, mean arterial pressure (MAP) and IOP were measured by direct cannulation, and aqueous flow was measured by fluorophotometry, before and after L-NAME (5 mg kg(-1), i.v., n = 7). In the second protocol, ciliary blood flow was measured transclerally by laser Doppler flowmetry while MAP was varied mechanically over a wide range before and after L-NAME (5 mg kg(-1), i.v., n = 8). L-NAME caused a significant increase in MAP and decreases in IOP, ciliary blood flow and aqueous flow. L-NAME also caused a significant downward shift in the ciliary pressure-flow relation over the entire pressure range examined. The results indicate that L-NAME causes ciliary vasoconstriction and decreases aqueous production, suggesting that the L-NAME ocular hypotensive effect may be due in part to a blood flow-dependent decrease in aqueous production. However, assuming no uveoscleral outflow and constant episcleral venous pressure and outflow facility, the decrease in aqueous flow accounts for 66% of the drop in IOP, suggesting an additional effect of L-NAME on aqueous outflow.

Animals↗
PubMed2001

Cytokine expression and synovial pathology in the initiation and spontaneous resolution phases of adjuvant arthritis: interleukin-17 expression is upregulated in early disease.

The aim of this study was to understand the immune processes controlling the initiation and spontaneous resolution of adjuvant arthritis (AA). We investigated synovial T-cell recruitment and mRNA expression of IL-17 and other important disease related cytokines, IFN-gamma, IL-2, IL-4, TNF and TGF-beta in inguinal lymph node (ILN) and synovial membrane (SM). Arthritis severity was assessed by a numerical rating score and rats were sacrificed every 3--4 days postadjuvant induction. Further assessment involved quantitative radiology and histology of the ankle joints on each day, and the ILN and SM were removed for RNA extraction. Cytokine mRNA expression was measured using RT-PCR and densitometry. Paraffin sections of rat ankle joints were stained for T-cells (CD3) by immunohistochemistry. In the ILN, there was an increase in IL-17, TNF and IFN-gamma expression in the early stages of disease, with a secondary sustained increase in IFN-gamma expression. In the SM, there was expression of T-cell cytokines in early arthritis (day 13), and prolonged TNF and TGF-beta expression, which reflected disease progression. IL-4 mRNA expression increased in the later stages of AA. Synovial T-cell numbers transiently increased at day 6, and remained high from days 13--28. Increased pro-inflammatory cytokine expression, including IL-17, in the ILN reflects the initiating events in the early stage of disease. IL-17 may therefore play an important role in the pathogenesis of AA. The increase in IL-4 (an anti-inflammatory cytokine) in the SM in the later stages of AA suggests that IL-4 is involved in the spontaneous resolution of AA. The initial increase in IFN-gamma in the ILN may reflect a pro-inflammatory response, while the prolonged secondary increase may indicate activation of regulatory T-cells.

Animals↗
PubMed2001

The kappa-opioid agonist, asimadoline, alters cytokine gene expression in adjuvant arthritis.

OBJECTIVE: We have previously found that the kappa-opioid agonist, asimadoline, attenuates adjuvant arthritis in a dose-dependent, antagonist-reversible manner. To elucidate possible mechanisms, we investigated the effects of asimadoline (5 mg/kg/day i.p.) or vehicle on in vivo cytokine expression and T-cell recruitment in adjuvant arthritis. METHODS: Arthritis severity was assessed every 3-4 days for 21 days. Rats were killed on days 0, 13 and 21 post-induction and synovial membrane and inguinal lymph nodes were removed for mRNA extraction. Changes in cytokine mRNA expression were measured using reverse transcription-polymerase chain reaction (RT-PCR) and densitometry. T cells in joints were quantified by immunohistochemistry. RESULTS: Asimadoline significantly decreased arthritis severity at day 13, with a concomitant decrease in synovial membrane expression of cytokines interleukin-17 and transforming growth factor-beta (TGF-beta) mRNA at day 13, and no change in T cell numbers in the joints of arthritic rats. By contrast, in the inguinal lymph nodes, expression of tumour necrosis factor was increased at day 13 and TGF-beta mRNA was increased throughout. CONCLUSION: An altered balance, therefore, in the pro- and anti-inflammatory effects of TGF-beta by asimadoline might explain its striking anti-arthritic actions.

Acetamides↗
PubMed2001

Urinary ascariasis in a man with hematuria.

We present a case believed to be the first reported North American presentation of Ascaris lumbricoides within the urogenital tract. A young man came to the emergency department because of painless hematuria and having observed a 6-inch worm exit his urethra while urinating. The most common site for A lumbricoides infection is the gastrointestinal tract, specifically the area of the hepatopancreatic ducts. Worldwide, A lumbricoides infections are ubiquitous, but infections outside the alimentary tract are extremely rare.

Adult↗
PubMed2000

A dilution immunoassay to measure myosin regulatory light chain phosphorylation.

We examined the quantitation of myosin regulatory light chain phosphorylation (MRLCP) by Western blot and found both offset and saturation errors. The desirable characteristics of an MRLCP assay are that the dynamic range be 60- to 100-fold and that the detection threshold be known and preferably very small relative to total MRLC concentration. No technique examined provided all these characteristics. However, accurate measurements can be obtained by including serial dilutions of the sample to provide a fractional calibration scale in terms of the dephosphorylated light chain and by using interpolation of the phosphorylated band signal intensity to provide values for the relative phosphorylation ratio. We found that this method offers several advantages over methods that rely on signal ratios from single samples: The dilution ratio method is less subject to errors from differences in protein load, it offers estimates of the error in the individual measurement, and has some redundancy that increases the likelihood of obtaining a valid measurement despite gel or membrane artifacts.

Animals↗
PubMed2000

The importance of the hypothalamo-hypophyseal-adrenal axis to the anti-inflammatory actions of the kappa-opioid agonist PNU-50,488H in rats with adjuvant arthritis.

Possible contributions of the hypothalamo-hypophyseal-adrenal axis to the development of adjuvant-induced arthritis and therapeutic actions of the prototypical kappa-opioid agonist PNU-50,488H (PNU-50) were studied in DA rats. Paw edema, nociception, histological and radiological joint damage, and tumor necrosis factor-alpha release by peritoneal macrophages were measured in adrenalectomized (ADX) and sham-operated (SHO) arthritic animals (drug-treated and untreated groups). Disease developed earlier in ADX rats (paw edema was first apparent 11 days postadjuvant compared with day 13 in SHO animals) and remained more severe in that group. Twice-daily PNU-50 treatment completely prevented the development of edema in the SHO group but was effective in the ADX animals only on day 18. PNU-50 substantially reduced the pooled severity index (combined quantitative edema, histological and radiological assessments) at day 18 in both SHO and ADX rats and to an equal extent. During disease development, the paws of SHO, but not ADX, rats became hyperalgesic; paradoxically, ADX animals were hyperalgesic during PNU-50 treatment, but the drug produced analgesia in SHO animals. Compared with cells harvested from healthy animals, macrophages from arthritic rats released about twice as much tumor necrosis factor-alpha after lipopolysaccharide stimulation. It was concluded that the hypothalamo-hypophyseal-adrenal axis influences the development of adjuvant arthritis and plays a partial role in the therapeutic action of the kappa-agonist PNU-50.

Adrenal Cortex Hormones↗
PubMed1999

Zinc alleviates thermal hyperalgesia due to partial nerve injury.

Zinc has recently been shown to alleviate inflammatory hyperalgesia. In the present study, we showed that intrathecal, intraplantar or systemic injection of zinc chloride significantly relieved thermal hyperalgesia in rats with sciatic nerve injury. Alleviation of thermal hyperalgesia was dose dependent in each case, although higher doses were required for i.p. injections (ED50 = 13.6 nmole) than for intrathecal (ED50 = 0.05 nmole) or intraplantar injections (ED50 = 0.3 nmole). Neither intrathecal nor intraplantar zinc chloride influenced thermal nociception in normal rats without nerve injury. The results provide the first evidence that zinc alleviates neuropathic hyperalgesia.

Animals↗
PubMed1999

Zinc alleviates thermal hyperalgesia due to partial nerve injury.

Zinc has recently been shown to alleviate inflammatory hyperalgesia. In the present study, we showed that intrathecal, intraplantar or systemic injection of zinc chloride significantly relieved thermal hyperalgesia in rats with sciatic nerve injury. Alleviation of thermal hyperalgesia was dose dependent in each case, although higher doses were required for i.p. injections (ED50 = 13.6 nmol) than for intrathecal (ED50 = 0.05 nmol) or intraplantar injections (ED = 0.3 nmol). Neither intrathecal nor intraplantar zinc chloride influenced thermal nociception in normal rats without nerve injury. The results provide the first evidence that zinc alleviates neuropathic hyperalgesia.

Animals↗
PubMed1999

Hyperalgesia due to nerve injury: role of prostaglandins.

The hypothesis that prostaglandins contribute to hyperalgesia resulting from nerve injury was tested in rats in which the sciatic nerve was partially transected on one side. Subcutaneous injection of indomethacin (a classic inhibitor of cyclo-oxygenase) into the affected hindpaw relieved mechanical hyperalgesia for up to 10 days after injection. Subcutaneous injection of meloxicam or SC-58125 (selective inhibitors of cyclo-oxygenase-2) into the affected hindpaw also relieved mechanical hyperalgesia, but with a shorter time-course. Subcutaneous injection of SC-19220 (an EP1 prostaglandin receptor blocker) into the affected hindpaw produced significant relief of mechanical and thermal hyperalgesia. Comparable injections into the contralateral paw or abdomen had no effect on mechanical or thermal hyperalgesia, suggesting that the effects we observed were local rather than systemic. We conclude that prostaglandins, probably prostaglandin E1 or E2, contribute to the peripheral mechanisms underlying hyperalgesia following nerve injury. These data provide further evidence that inflammatory mediators contribute to neuropathic pain, and may warrant further study of peripherally administered non-steroidal anti-inflammatory drugs as a possible treatment for such pain in patients.

Animals↗
PubMed1999

Involvement of substance P in the anti-inflammatory effects of the peripherally selective kappa-opioid asimadoline and the NK1 antagonist GR205171.

We have previously shown that kappa-opioids have antiarthritic properties. In this study, using two differently acting drugs (the peripherally selective kappa-agonist, asimadoline, and the NK1-antagonist, GR205171), we have examined possible roles of the neuropeptide substance P (SP) in the pathogenesis and maintenance of experimental arthritis in rats. The anti-inflammatory actions and the time dependence of these drugs were compared, and concentrations of SP determined in joint tissue. In untreated animals, SP levels in ankle joint tissue increased late in the disease (by day 21) but substantially lagged behind development of clinical disease. Prolonged (days 1-21 or days 12-18) but not early, short-term (days 1-3) treatment with the NK1-antagonist GR205171 (1 mg/kg/day i.p.) significantly attenuated joint damage; SP levels showed multiphasic dose dependence over the 21-day treatment. The data suggest that GR205171 antagonizes the action of SP by presynaptic as well as postsynaptic mechanisms. Treatment with asimadoline (5 mg/kg/day i.p. ) produced marked (and sustained) attenuation of the disease with all three time regimes. The effect of asimadoline on SP levels was time dependent: reduction of SP content after 3 days but an increase after 12 or 21 days treatment, paradoxically with clinical improvement in each case. Drug-induced changes in SP content could follow from changed release or synthesis from either neural or immune cells. The results suggest that both drugs have potential therapeutic value at different stages of inflammatory joint disease.

Acetamides↗
PubMed1999

Gender differences in pain.

A literature survey reveals clear evidence of sex differences in the incidence of painful conditions and their severity, both being greater in women. The possible causes of this sexual dimorphism are discussed. Sex-role stereotyping may be relevant and there is evidence to indicate that, perhaps through their roles as carers, women seek and utilize more medical services than men. Less clear-cut evidence for anatomical and physiological differences is reviewed, together with documentation of hormonal (and reproductive cycle) influences on the operation of those systems.

Journal Article↗
PubMed1998

Dizziness.

Dizziness is a common but difficult symptom to evaluate because, due to its subjective nature, it is virtually impossible to measure objectively. In essence, dizziness means different things to different people. The most useful historical information is the patient's own description of the dizziness, its characterization, and the effects of position on the patient's symptoms. After taking a detailed history, the clinician should perform a thorough physical examination with emphasis on determining whether the dizziness is vestibular or nonvestibular in origin. Patient disposition is determined by the prognosis of the underlying cause and the presence of support mechanisms.

Adult↗
PubMed1998

Effect of the peripherally selective kappa-opioid agonist, asimadoline, on adjuvant arthritis.

1. Opioids, though widely used as analgesics, have not been seriously considered as therapy for rheumatoid arthritis. The present study evaluated the dose-effect and time-dependence relationships of a new peripherally selective kappa agonist, asimadoline, in rats with adjuvant arthritis. 2. The arthritis was assessed by a pooled severity index combining the comprehensive criteria of oedema, radiography and histological changes, in the hind limbs. Asimadoline was extremely effective in attenuating joint damage (by up to 80%) when administered parenterally (0.5 to 10 mg kg(-1) day(-1), i.p.) throughout the disease or during its early phase; treatment was less successful if confined to the latter stages. Ten fold higher doses were effective orally. 3. Equimolar doses of a peripherally-selective antagonist, naloxone methiodide, and the kappa-selective antagonist, MR2266, fully reversed the peripheral anti-arthritic effects of asimadoline (5 mg kg(-1) day(-1)), indicating that asimadoline acts through peripheral kappa-opioid receptors. However, an equivalent dose of MR2266 did not fully reverse the anti-arthritic effects of the highest dose of asimadoline (40 mg kg(-1) day(-1)), suggesting a loss of kappa-selectivity at this dose. 4. Asimadoline also exhibited analgesic effects (mechanical nociceptive thresholds) in arthritic but not non-arthritic rats, indicating that inflammation is necessary for asimadoline-induced analgesia. 5. These data confirm our previous findings that kappa-opioids possess anti-arthritic properties and that these effects are mediated via peripheral kappa-receptors. The present results are new in showing that the peripherally acting kappa-opioid agonist, asimadoline, is a potent anti-arthritic agent. Such novel drugs, essentially lacking central side effects, herald new treatments for rheumatoid arthritis.

Acetamides↗
PubMed1998

Inhibitory mechanisms for cross-bridge cycling: the nitric oxide-cGMP signal transduction pathway in smooth muscle relaxation.

Relaxation follows sequestration of Ca2+ mobilized by an excitatory stimulus in striated muscle. Removal of excitatory stimuli also relaxes smooth muscle in vitro after reductions in the myoplasmic [Ca2+] and dephosphorylation of the myosin regulatory light chains. However, there are several experimental procedures that produce relaxation in the presence of excitatory stimuli and elevated Ca(2+)-dependent cross-bridge phosphorylation. Of potential widespread physiological importance are treatments that increase myoplasmic [cGMP] owing to the ubiquity of nitric oxide (NO) as a signalling molecule for endothelial-mediated vasodilation and inhibitory nerves in most types of smooth muscle. Several mechanisms are implicated in the NO-cGMP mediated relaxation. Most studies support reductions in myoplasmic Ca2+. However, there is evidence that increases in cGMP also lower the Ca(2+)-sensitivity of cross-bridge phosphorylation. This would contribute to a decline in force through actions on the myosin light chain kinase/phosphatase system. In addition, changes in the dependence of force on phosphorylation are observed in tissues partially relaxed by treatments that elevate cGMP. This demonstrates that either the attachment and cycling of phosphorylated cross-bridges is impaired or blocked, or that the formation of dephosphorylated, force-generating cross-bridges ('latch-bridges') is reduced. Protein kinase G-catalysed phosphorylation of either a thin filament protein that blocks attachment of cross-bridges or a protein that inhibits myosin light chain phosphatase may explain the NO-induced relaxation with elevated cross-bridge phosphorylation.

Animals↗
PubMed1998

Experimental pain in healthy human subjects: gender differences in nociception and in response to ibuprofen.

UNLABELLED: We used electrically induced pain in healthy young subjects to study gender differences in nociception and the analgesic efficacy of ibuprofen. Cutaneous stimulation of the earlobe allowed measurement of pain detection thresholds and maximal pain tolerance. Drug and placebo were each administered twice using a double-blind, randomized, multiple cross-over design. Male subjects had greater stimulus thresholds (lower nociception) compared with female subjects (18 +/- 0.3 vs 15 +/- 0.3 volts, mean +/- SEM; n = 10 in each group) and a greater pain tolerance (24 +/- 0.4 vs 21 +/- 0.4 volts). Response variability was also greater in the male subjects, yet only the men exhibited a statistically significant analgesic response to ibuprofen (deltavolts; ibuprofen versus placebo: 2.80 +/- 0.33 vs -0.18 +/- 0.34; P < 0.05, n = 10). None of these results could be attributed to pharmacokinetic differences. The finding that ibuprofen was less effective in women than in men has potential clinical significance, especially as a factor in the response variability to nonsteroidal antiinflammatory drugs. IMPLICATIONS: In this study, we examined ibuprofen, a widely used nonsteroidal antiinflammatory drug, for its ability to reduce experimental pain. We found that it had such properties in healthy young male subjects but not in young female subjects. This is a paradox because many of the painful conditions for which nonsteroidal antiinflammatory drugs are used (e.g., rheumatoid arthritis) occur more often in women.

Adolescent↗