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Biomedical subjects

J Ritchie

Publications and source records attributed to J Ritchie.

At least 19 recordsLinked to original sources
PubMed2005

Melanocortin-1 receptor gene variants affect pain and mu-opioid analgesia in mice and humans.

BACKGROUND: A recent genetic study in mice and humans revealed the modulatory effect of MC1R (melanocortin-1 receptor) gene variants on kappa-opioid receptor mediated analgesia. It is unclear whether this gene affects basal pain sensitivity or the efficacy of analgesics acting at the more clinically relevant mu-opioid receptor. OBJECTIVE: To characterise sensitivity to pain and mu-opioid analgesia in mice and humans with non-functional melanocortin-1 receptors. METHODS: Comparisons of spontaneous mutant C57BL/6-Mc1r(e/e) mice to C57BL/6 wildtype mice, followed by a gene dosage study of pain and morphine-6-glucuronide (M6G) analgesia in humans with MC1R variants. RESULTS: C57BL/6-Mc1r(e/e) mutant mice and human redheads--both with non-functional MC1Rs--display reduced sensitivity to noxious stimuli and increased analgesic responsiveness to the mu-opioid selective morphine metabolite, M6G. In both species the differential analgesia is likely due to pharmacodynamic factors, as plasma levels of M6G are similar across genotype. CONCLUSIONS: Genotype at MC1R similarly affects pain sensitivity and M6G analgesia in mice and humans. These findings confirm the utility of cross species translational strategies in pharmacogenetics.

Adolescent↗
PubMed2003

Effect of in vivo lymphocyte-depleting strategies on development of lymphoproliferative disorders in children post allogeneic bone marrow transplantation.

T cell depletion (TCD) of marrow is a proven method of graft-versus-host disease (GVHD) prophylaxis in allogeneic bone marrow transplantation (BMT). Nonetheless, TCD is associated with an increased risk of developing post transplant lymphoproliferative disorder (PTLD). Between 1986 and 1998, 241 pediatric patients at the University of Iowa underwent BMT using ex vivo TCD of marrow from mismatched related or matched unrelated donors. Additional GVHD prophylaxis included antithymocyte globulin (ATG) or anti lymphocyte globulin (ALG) post transplant (in vivo TCD). A total of 30 cases of PTLD were identified based upon a combination of clinical, histological, and immunological features. Nearly all cases occurred within 3 months post BMT. A statistically significant increase in PTLD incidence was noted for patients treated with ATG vs ALG (33 vs 9%). While grade I-II acute GVHD was more common in patients receiving ATG vs ALG, no difference in grade III-IV GVHD or overall survival was noted between the two groups. Assessment of immune recovery at various times post BMT revealed significantly fewer T cells in the ATG-treated group, suggesting the deleterious effect of ATG may be due to excessive depletion of donor-derived Epstein-Barr virus-specific cytotoxic T cells. Thus, caution should be exercised in the use of anti-T-cell antibody therapy for additional GVHD prophylaxis in the setting of TCD BMT.

Antilymphocyte Serum↗
PubMed2002

Cardiovascular autonomic function in systemic lupus erythematosus.

AIM: To determine whether cardiovascular autonomic function is impaired in systemic lupus erythematosus (SLE). METHODS: A case-control study of 23 patients with SLE was performed. Autonomic symptoms were assessed using a standard questionnaire. Cardiovascular autonomic function was measured using 10 non-invasive investigations. There were significant differences between patients and controls in three out of 24 parameters measured during the different tests (P < 0.002). These were reduction in systolic blood pressure at 5 min on head-up tilt, and heart rate responses to isometric exercise and cutaneous cold. Eleven out of 23 patients had an abnormal heart rate, blood pressure or Valsalva response (value below the age corrected 5th centile) while testing compared with six of the controls. Plasma adrenaline and noradrenaline levels were significantly lower in patients vs controls in both the supine (P < 0.05) and tilt position (P < 0.01). Twenty-one of the 23 patients had one or more symptoms that may be attributable to abnormalities in autonomic function. There was no significant association between the number of symptoms and presence of autonomic dysfunction. Cardiovascular autonomic impairment may be demonstrated in some patients with SLE. Symptoms attributable to autonomic dysfunction are common in SLE and autonomic assessment may be required.

Adult↗
PubMed2001

Thabo Mbeki and the AIDS 'jury'.

This paper examines the debate regarding efforts by the South African government to control the spread of HIV infections, with particular reference to events surrounding the 13th International AIDS conference. We posit that the reaction of the medical, pharmaceutical, and media sectors to the stance by the President Mbeki on HIV control amounts to an over-simplification of a very complex issue. Empathy and sincere partnership are required to address South Africa's worsening AIDS situation.

Acquired Immunodeficiency Syndrome↗
PubMed2001

Study of plasma factors associated with neutrophil activation and lipid peroxidation in preeclampsia.

Neutrophil activation occurs in women with preeclampsia and is resolved after delivery. The present study examined whether circulating factors in plasma of women with preeclampsia caused neutrophil activation and lipid peroxidation. Twenty-one women with proteinuric preeclampsia were matched for age and gestational age with 19 normal pregnant women. Plasma was collected from all subjects before delivery and at 6 weeks postpartum and incubated with autologous white-cell buffy coat collected at the postpartum visit. Neutrophil activation was assessed by level of CD11b and CD18 expression after incubation with autologous antepartum or postpartum plasma. Lipid peroxidation was assessed by measurement of F(2)-isoprostanes in plasma, plasma-white cell incubates, and urine. Neutrophil CD11b and CD18 expression was not differentially altered by incubation with plasma from either women with preeclampsia or normal pregnant women and was similar between groups when incubation was performed with plasma collected after delivery. In preeclampsia, plasma F(2)-isoprostanes were significantly increased before and after delivery compared with controls. Plasma F(2)-isoprostanes were increased 2-fold after incubation of plasma with buffy coat, but preeclamptic women had higher levels compared with those of controls when either pregnant or postpartum plasma was used. In pregnant preeclamptics, plasma F(2)-isoprostanes were positively correlated with lymphocyte count. Six weeks after delivery, plasma F(2)-isoprostanes in the preeclamptic women were significantly positively associated with lymphocyte count and cholesterol and negatively associated with albumin. In conclusion, the present study does not suggest that a stable circulating factor causes neutrophil activation in preeclampsia. However, lipid peroxidation is elevated before and after delivery in women with preeclampsia, which suggests that these women may have an underlying predisposition to increased oxidative stress that may be driven by or contribute to a persistent low-grade inflammatory response.

Adult↗
PubMed2001

Users in the driving seat or sitting alongside map-reading?

The government agenda is clear. At the highest level users are involved in policy making. We as service providers need to show evidence that users views are elicited and used to improve the quality of care. The tool bag of techniques used to elicit users views will be explored--questionnaires, structured interviews, focus groups and innovative cognitive techniques such as perception score cards. We explore the continuum of user-led qualitative techniques to provider-led quantitative approaches. Building a framework of techniques which cover the diverse needs of people using a speech and language therapy (SLT) service is a challenge. A greater challenge is using the views of users to bring about meaningful change.

Humans↗
PubMed2001

Role of ovarian hormones in the pathogenesis of impaired detrusor contractility: evidence in ovariectomized rodents.

PURPOSE: Although detrusor hyperactivity with impaired contractility is a common urodynamic finding in elderly subjects, to our knowledge its pathogenesis remains unknown. Biopsy studies indicate that subjects with detrusor hyperactivity and impaired contractility have ultrastructural evidence of dysjunction and degeneration patterns in isolated detrusor hyperactivity and impaired contractility, respectively. Based on the known cellular effects of estrogen we postulated that declines in ovarian hormone production may contribute to the pathogenesis of detrusor hyperactivity with impaired contractility. MATERIALS AND METHODS: Mature 13 to 14-month-old female Fisher 344 rats were studied 4 months after bilateral ovariectomy or sham surgery. Detrusor structure was evaluated by electron microscopy and contractility was evaluated by muscle strip studies. RESULTS: After bilateral ovariectomy detrusor smooth muscle decreased by 25% with a 12% decrease in the number of nucleated muscle profiles and degenerative changes in many axons. Muscle strips from bilaterally ovariectomized animals generated 40% to 50% less tension per strip in response to carbachol than strips of equal size from sham operated animals with no apparent change in muscarinic receptor affinity. CONCLUSIONS: Bilateral ovariectomy resulted in many changes of the degeneration ultrastructural pattern but in none of the characteristic features of the dysjunction pattern. Our results indicate that the mature rodent detrusor and its innervation are sensitive to prolonged ovarian hormonal deficiency, contributing to impaired contractility in rodents. Future studies are required to establish whether estrogen has a role in the degeneration ultrastructural pattern or impaired contractility in humans.

Animals↗
PubMed2000

Upregulation of an opioid-mediated antinociceptive mechanism in transgenic mice over-expressing substance P in the spinal cord.

In transgenic mice expressing ectopic substance P fibres in the spinal white matter, a normally innocuous mechanical stimulus induces hyperalgesia and allodynia which are reversed by substance P and N-methyl-D-aspartate receptor antagonists. This period of enhanced excitation is followed by a rebound overshoot in these animals. As previous evidence indicates opioid mechanisms in a similar rebound in normal animals, the present study was done to determine the effects of systemic administration of morphine and the opiate receptor antagonist, naloxone, on the stimulus-induced responses in the tail withdrawal reflex. Once baseline reaction times had been taken, different combinations of saline, naloxone and morphine were administered intraperitoneally to transgenic and control mice of either sex. A mechanical conditioning stimulus of 450g was then applied to the tip of the tail for 2s. This stimulus was innocuous in control mice given saline or naloxone, but provoked a nociceptive response in transgenic mice given these compounds. In control and transgenic mice, following morphine administration there was an antinociceptive effect. In control mice the subsequent mechanical stimulus had no effect. However, in transgenic mice the mechanical stimulus produced a further antinociception. Naloxone blocked the effect of morphine and the subsequent conditioning stimulus in both control and transgenic mice. The results indicate that while morphine is equally effective on the withdrawal reflex in both types of animal, in the transgenic mice morphine reveals an intrinsic, naloxone-sensitive antinociceptive mechanism. The data are interpreted to suggest that over-expression of substance P or some other factor in the spinal cord of transgenic mice is associated with the up-regulation or facilitation of an opiate-mediated intrinsic antinociceptive mechanism. This is a novel observation because the genetic manipulation in this transgenic mouse results in a transient over-expression of nerve growth factor during development that leads to the formation of ectopic primary afferent fibres in the spinal cord containing substance P. These fibres persist indefinitely after the nerve growth factor levels return to normal. Opioid mechanisms, which are likely of dorsal horn origin, do not fall under the direct influence of nerve growth factor mechanisms and therefore the intriguing possibility is raised that opioid mechanisms in the spinal cord are regulated at least in part by substance P-related mechanisms.

Analgesics, Opioid↗
PubMed2000

In vivo and in vitro induction of human cytochrome P4503A4 by dexamethasone.

PURPOSE: The aims of these experiments were to determine the effect of a therapeutic regimen of dexamethasone on cytochrome P4503A4 (CYP3A4) activity in healthy volunteers; and the concentration-effect relationship between dexamethasone and CYP3A4 activity in primary human hepatocyte cultures. METHODS: The effect of dexamethasone (8 mg administered by mouth two times a day for 5 days) on CYP3A4 activity in 12 healthy volunteers was assessed with the erythromycin breath test and urinary ratio of dextromethorphan to 3-methoxymorphinan. Concentration-effect of dexamethasone on CYP3A4-dependent testosterone 6-beta-hydroxylation was determined in human hepatocytes treated with 2 to 250 micromol/L dexamethasone. RESULTS: The percent of erythromycin metabolized per hour increased from 2.20% +/- 0.60% (mean +/- SD) at baseline to 2.67% +/- 0.55% on day 5 of dexamethasone (mean increase in hepatic CYP3A4 activity 25.7% +/- 24.6%; P = .004). The mean urinary ratio of dextromethorphan to 3-methoxymorphinan was 28 (4.8 to 109) and 7 (1 to 23) at baseline and on day 5 of dexamethasone (mean decrease = 49%; P = .06). Substantial intersubject variability was observed in the extent of CYP3A4 induction. The extent of CYP3A4 induction was inversely correlated with baseline erythromycin breath test (r2 = 0.58). In hepatocytes, dexamethasone 2 to 250 micromol/L resulted in an average 1.7-fold to 6.9-fold increase in CYP3A4 activity, respectively. The extent of CYP3A4 induction with dexamethasone in hepatocyte preparations was inversely correlated with baseline activity (r2 = 0.59). CONCLUSIONS: These data demonstrate that dexamethasone at doses used clinically increased CYP3A4 activity with extensive intersubject variability and that the extent of CYP3A4 induction was, in part, predicted by the baseline activity of CYP3A4 in both healthy volunteers and human hepatocyte cultures.

Administration, Oral↗
PubMed2000

Parental use of a paediatric emergency department as an ambulatory care service.

OBJECTIVE: This qualitative study explored the parental attitudes, perceptions and beliefs that play a role in the use of a tertiary paediatric emergency department (PED) when a child has a non-urgent illness. METHOD: Semi-structured, in-depth interviews of 25 parents of children with non-urgent illnesses were conducted in the waiting room of a tertiary PED in Western Sydney in 1998. Inductive analysis was used to identify dominant themes. RESULTS: Parents used their own system of triage to choose the appropriate service for their sick child. The perceived expertise of the tertiary PED, access and parental expectations all appeared to be major factors in parental use of a PED. CONCLUSIONS: The parental choice to attend a PED is a dynamic, complex and unique process and the parental views that underpin this process often diverge from those of health professionals about the most 'appropriate' use of a PED. IMPLICATIONS: A clearer understanding by health professionals of the factors influencing parental choice will promote more effective collaboration with parents and ultimately assist in the decision on the best management option for sick children.

Adolescent↗
PubMed1999

Clinical expression of Menkes disease in a girl with X;13 translocation.

Menkes disease is a rare X-linked recessive disorder of copper metabolism, characterised by progressive neurological degeneration, abnormal hair and connective tissue manifestations. We report on a girl with classic Menkes disease, carrying a de novo balanced translocation 46,X,t(X;13)(q13.3; q14.3). The translocation breakpoints at Xq13.3 and 13q14.3 coincide with the Menkes disease and Wilson disease loci, respectively.

Adenosine Triphosphatases↗
PubMed1999

Paw withdrawal threshold in the von Frey hair test is influenced by the surface on which the rat stands.

The effect of testing surface on the rat hind paw withdrawal threshold in the von Frey hair test is investigated in this study. The data indicate that wire mesh, which is typically used to apply von Frey hairs, may have an effect on the paw withdrawal threshold. For example, in control rats tested on the wire mesh, variability in the withdrawal threshold was observed between the left and the right hind paws (51.04+/-12.29 and 64.31+/-9.37 g, respectively) and on different days of testing (35.24+/-9.54 and 45.83+/-12.97 g for the left and right hind paws, respectively, 7 days later). In an attempt to reduce this variability, a customized platform was used to measure the von Frey hair-induced paw withdrawal in the rat. It consists of an opaque, flat-surfaced plastic platform with holes through which von Frey hairs are inserted and applied to the plantar surface of the paw. In control rats tested with von Frey hairs using this customized platform, variability in the paw withdrawal thresholds between the left and right hind paws in single rats over time as well as between different rats was reduced (49.86+/-6.97 and 49.29+/-6.56 g for the left and right hind paws, respectively, on day 0; 48.29+/-5.82 and 53.00+/-4.59 g for the left and right hind paws, respectively, 7 days later). Furthermore, in rats in which a 2 mm polyethylene cuff was used to constrict the left common sciatic nerve, the ipsilateral as well as the contralateral hind paw withdrawal thresholds were decreased (2.45+/-0.65 and 26.09+/-5.86 g, respectively, 7 days later). In similar rats tested on the wire mesh, the ipsilateral but not the contralateral paw withdrawal threshold decreased (12.80+/-2.21 and 65.00+/-10.28 g, respectively, at 7 days). The data suggest that the flat surface and opaque properties of the customized platform enable accurate, reliable and repeatable measurements of ipsilateral and contralateral paw withdrawal threshold using von Frey hairs in normal and nerve-injured rats.

Animals↗
PubMed1999

Nerve constriction in the rat: model of neuropathic, surgical and central pain.

In preparation for a series of electrophysiological experiments in a model of neuropathic pain, the present spinal reflex study was done to determine the optimal time after sciatic nerve constriction in the rat for tactile allodynia and to determine also the appropriate 'control' for the nerve constriction model. Therefore, this study focused on the magnitude and time course of change in paw withdrawal threshold following unilateral sciatic nerve constriction in the rat. Male Sprague-Dawley rats (375-425g) were used. Nerve constriction was done by placing a 2 mm polyethylene cuff (PE-90) around the left sciatic nerve (n=8). A second group of rats (n=8) received unilateral sham surgery and a third group (n=8) was unoperated. The ipsi- and contralateral hind paw withdrawal thresholds in each of the 3 groups were measured using von Frey hairs. In unoperated rats, the withdrawal threshold of each of the hind paws remained unchanged at approximately 50 g throughout the entire time course of the study, which lasted 145 days. However, in cuff-implanted rats, the withdrawal threshold of the nerve-injured hind paw decreased as soon as 1 day after surgery, reached as low as 1 to 2 g by 5 days and remained low throughout the test period. Threshold in sham-operated rats showed a bilateral decrease starting on days 1-3, which stabilised at about 30 g until about day 40, after which values returned gradually toward the unoperated withdrawal thresholds. In nerve-constricted rats the withdrawal threshold of the hind paw contralateral to the cuff followed the same change seen in sham-operated rats until about day 37, after which the withdrawal threshold matched that of the cuff-implanted hind paw. The data show that the cuff-induced sciatic nerve constriction produces a sustained hypersensitivity to normally innocuous tactile sensory input and that a relatively constant ipsilateral mechanical hyperalgesia can be found from days 5-27. It is also demonstrated that the contralateral hind paw and either hind paw in sham-operated rats are inappropriate as 'controls'. The data in this study suggest that three distinct types of allodynia are expressed. Ipsilateral allodynia may be representative of a model of neuropathic pain. The contralateral allodynia may be a model of central pain, as it likely arises from changes in central sensory processing. Allodynia in sham-operated rats was also expressed bilaterally and may be a model of long-term postoperative pain.

Analysis of Variance↗