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Biomedical subjects

R Milner

Publications and source records attributed to R Milner.

At least 55 records · Page 3Linked to original sources
PubMed1997

Inhibition of oligodendrocyte precursor motility by oligodendrocyte processes: implications for transplantation-based approaches to multiple sclerosis.

Transplantation of oligodendrocyte precursor cells represents a promising approach to the treatment of the chronic demyelinated lesions of multiple sclerosis. In view of the multi-focal nature of the disease it will be necessary for the transplanted oligodendrocyte precursor cells to migrate through normal white matter between lesions. Work in other systems has shown that differentiated oligodendrocytes within white matter express molecules inhibitory for axon outgrowth. In light of this we have examined the effect of oligodendrocytes on the migration of oligodendrocyte precursors in vitro using time lapse video microscopy. We find that oligodendrocytes induce collapse and loss of motility in oligodendrocyte precursor processes, with this effect being lost as oligodendrocytes undergo programmed cell death. We conclude that the inhibitory factors present on differentiated oligodendrocytes may prevent effective migration between lesion in vivo, and that strategies to overcome this inhibition may be required for successful repair.

Animals↗
PubMed1997

Expression of alpha vbeta3 and alpha vbeta8 integrins during oligodendrocyte precursor differentiation in the presence and absence of axons.

We have shown previously that switching of the alpha v-associated beta1 and beta5 integrin subunits during differentiation of myelin-forming oligodendrocytes may regulate important aspects of cell behaviour such as migration (Milner et al., 1996: J Neurosci 16:7240-7252). In this study we have examined the developmental regulation of other alpha v-associated beta subunits in oligodendroglial cell cultures and also the control of their expression by neurons, using xenocultures to distinguish glial and neuronal integrins. We have found that oligodendroglia express alpha vbeta8 in addition to the previously-described alpha vbeta1, alpha vbeta3, and alpha vbeta5. Beta8 and beta3 together comprise the 80kD band seen in alpha v immunoprecipitations that represents the most abundant alpha v-associated beta subunit and show reciprocal patterns of expression during development. Alpha vbeta8 is expressed at high levels on oligodendrocyte precursors and differentiated oligodendrocytes but diminishes during the intermediate stages of differentiation. Alpha vbeta3, in contrast, shows an opposite pattern of expression, with the highest levels seen at the intermediate stages of differentiation and little expression on either oligodendrocyte precursors and differentiated oligodendrocytes. The expression of alpha vbeta3 is not altered by coculture with neurons, unlike that of alpha vbeta8, in which the decrease seen at the intermediate stages of differentiation is less marked in the presence of neurones. Our results confirm that switching of alpha v-associated beta subunits is an important feature of oligodendrocyte differentiation and suggest that alpha vbeta8 and alpha vbeta3 have distinct functions during myelination.

Animals↗
PubMed1996

A role in migration for the alpha V beta 1 integrin expressed on oligodendrocyte precursors.

Myelination of the CNS requires the migration of oligodendrocyte precursors throughout the CNS from restricted regions within the ventricular and subventricular zones. In light of the significant effects of cell-extracellular matrix (ECM) interactions on cell migration in other developing systems, we have analyzed the role of integrins in oligodendrocyte precursor migration. We have shown previously that oligodendrocyte precursors in vitro express a limited repertoire of integrins, including alpha 6 beta 1, alpha v beta 3, and that differentiation is associated with downregulation of alpha v beta 1 and upregulation of alpha v beta 5. Using a migration assay based on the movement of cells away from an agarose drop containing a high-density cell suspension, we find that RGD peptides (that block alpha v but not alpha 6 integrins) and anti-beta 1 antibodies block migration on an astrocyte-derived ECM, whereas anti-beta 3 antibodies have little effect. These results suggest that alpha v beta 1 but not alpha 6 beta 1 plays a role in oligodendrocyte precursor migration, and this is confirmed by the use of blocking monoclonal antibodies that distinguish these two integrins. In keeping with the results of others, we find that differentiated oligodendrocytes lose migratory potential and that the timing of this loss correlates with downregulation of alpha v beta 1. Taken together with the work of others showing that ECM ligands for alpha v beta 1 are expressed within the CNS, we propose that this integrin plays a significant role in the migration of oligodendrocyte precursors in vivo and that its downregulation during differentiation could be an important factor regulating the migratory phenotype of these cells.

Animals↗
PubMed1996

Hunter-McAlpine craniosynostosis phenotype associated with skeletal anomalies and interstitial deletion of chromosome 17q.

Hunter-McAlpine syndrome is an autosomal dominant disorder consisting of variable manifestations including craniosynostosis, almond-shaped palpebral fissures, small mouth, mild acral-skeletal anomalies, short stature, and mental deficiency. We report on a 9-year-old boy with this phenotype with more severe skeletal abnormalities than previously described. Chromosomes showed del(17)(q23.1-->q24.2); the more severe phenotype may be explained by the deletion. The deletion also suggests the possibility that the gene for Hunter-McAlpine syndrome might map to that region.

Abnormalities, Multiple↗
PubMed1996

Analysis of integrin expression on oligodendrocytes during axo-glial interaction by using rat-mouse xenocultures.

To analyze the expression of cell-surface molecules on neurons or glia during myelination, we have developed a xenotypic coculture system in which mouse oligodendrocytes interact with rat dorsal root ganglion neurons. The axo-glial interactions in these cultures promote oligodendrocyte precursor cell proliferation, survival, and differentiation as in vivo, thus supporting the validity of the xenocultures as a model system to study myelination in which the molecules on the neurons or the glia can be distinguished using species-specific antibodies. We examined the expression of integrins, the major family of cell-surface extracellular matrix receptors, on oligodendrocytes during the early stages of myelination and found that, unlike Schwann cells, oligodendrocytes do not express alpha 6 beta 4 in association with myelin sheath formation. The pattern of integrin expression observed on oligodendrocytes in these cultures is similar to that seen in oligodendrocytes that differentiate in purified cultures, and it comprises alpha 6 beta 1, alpha v beta 5, and an as yet uncharacterized alpha v-associated beta subunit of 80 kDa. Changes in integrin expression associated with differentiation, therefore, do not depend on axonal contact, and beta 4 is not required for myelin sheath formation, although its expression may contribute to the individual properties of oligodendrocytes and Schwann cells.

Animals↗
PubMed1996

Erythropoietin therapy in neonates at risk of having bronchopulmonary dysplasia and requiring multiple transfusions.

OBJECTIVES: To determine whether treatment with recombinant human erythropoietin (r-HuEPO) reduces transfusion requirements in premature neonates at risk of having bronchopulmonary dysplasia and requiring multiple transfusions. STUDY DESIGN: A double-blind, randomized, controlled trial. SUBJECTS: Fifty-five infants appropriate in weight for gestational age (less than 1250 gm birth weight) who, at 10 days of age, were predicted to have a greater than 75% probability of having bronchopulmonary dysplasia. This criterion had previously been shown to identify infants requiring multiple transfusions. Twenty-seven infants were randomly assigned to receive r-HuEPO therapy and 28 to a control group. r-HuEPO was administered in a dosage of 20 U/kg body weight, subcutaneously, three times a week for 6 weeks. Control infants received sham treatment. RESULTS: Infants treated with r-HuEPO required significantly fewer transfusions than control infants during their entire hospital stay (mean 3.48 +/- 1.58 vs 5.68 +/- 2.30; p = 0.0001) and had a higher mean reticulocyte count (p < or = 0.0005) and a higher mean hemoglobin concentration (p < or = 0.005) during the treatment period. At follow-up, 4 months after term, there were no significant differences between the groups in mean reticulocyte count (p = 0.86) or mean hemoglobin concentration (p = 0.56). However, two infants in each group had low serum ferritin values indicative of depleted iron stores. CONCLUSIONS: Treatment with r-HuEPO effectively stimulated erythropoiesis in premature infants at high risk of having bronchopulmonary dysplasia and requiring multiple transfusions; the result was a reduction in transfusion requirements. This treatment, together with other strategies to reduce the need for transfusions, is appropriate in this population. Unrelated to r-HuEPO treatment, these infants may be at risk of having iron deficiency later in infancy.

Bronchopulmonary Dysplasia↗
PubMed1996

A portable system for measuring bone mineral density in the pre-term neonatal forearm.

Current systems used to measure bone mineral content (BMC) in the neonate have the major drawback that the child must be well enough to be moved to the scanner. Consequently, low birth weight pre-term neonates, a group at particular risk of mineral compromise, cannot be measured. This paper describes a portable neonatal bone mineral device capable of measuring bone mineral in the incubator. It uses a radiation sensitive, charge coupled device (CCD) to acquire a bone mineral image enabling bone mineral to be measured at various sites. It measures bone mineral density (BMD) with a precision of 5.5 mg cm-2 in vivo, reduced to 7.5 mg cm-2 when repositioning between scans is taken into account. The procedure takes under 5 min with an image acquisition time of 30 s and an absorbed radiation dose to skin of 6 microSv. Calibration has been undertaken with aluminium foils of differing thickness to confirm the linearity of the system throughout the intended measurement range. A regression line fitted to the data demonstrated linearity and correlation between BMD and aluminium thickness with r = 0.99 (p < 0.0001). Preliminary measurements on pre-term neonates show values of BMD ranging from 43 to 115 mg cm-2 in babies aged 23-41 weeks post-conception. These figures are within the linear range of the system.

Absorptiometry, Photon↗
PubMed1995

Differentiation of the O-2A progenitor cell line CG-4 into oligodendrocytes and astrocytes following transplantation into glia-deficient areas of CNS white matter.

The in vitro properties of the CG4 cell line have led to its increasing use as a cell line with which to study the behaviour of the O-2A progenitor cell. In this study we have examined the in vivo behaviour of the CG4 cell line following transplantation into areas of adult rat spinal cord white matter which have been permanently depleted of glial cells by the combination of local X-irradiation and direct injection of 0.1% ethidium bromide. Twenty-one days after transplantation, both myelin-forming oligodendrocytes and glial fibrillary acidic protein-positive astrocytes were identified within the lesion, indicating that the CG4 cell line has bipotential differentiation properties when introduced into a pathological environment consisting of demyelinated axons but devoid of oligodendrocytes or astrocytes. In this respect, the CG4 cell line resembles other glial progenitor cell lines that have been transplanted into similar lesions. In some areas of the lesion, remyelination was observed that was similar in extent to that achieved by growth factor-expanded populations of O-2A progenitor cells. The transplant origin of the cell types within the lesion was confirmed by retroviral incorporation of the lacZ marker gene, the expression of which allowed their identification by histochemistry. In conclusion, the in vivo properties of the CG4 cell line make it a highly suitable line with which to study the behaviour of O-2A progenitors following transplantation into normal and damaged CNS.

Animals↗
PubMed1995

Perichondrial arthroplasty incorporating costal cartilage.

A technique of IP joint arthroplasty is described using costal cartilage with accompanying perichondrium. All patients presented following trauma to the IP joints; their ages ranging from 15 to 45 years. Five out of six cases showed improvement of symptoms and function following reconstruction of the traumatized joint.

Adolescent↗
PubMed1994

Randomised trial of intravenous immunoglobulin G, intravenous anti-D, and oral prednisone in childhood acute immune thrombocytopenic purpura.

The most serious complication of childhood acute immune thrombocytopenic purpura (ITP), intracranial haemorrhage, occurs in about 1% of children with platelet counts below 20 x 10(9)/L. We conducted a randomised study to explore three treatment options in this high-risk group. 146 children (> 6 months and < 18 years old) with typical acute ITP and platelet counts of 20 x 10(9)/L or lower were randomised to receive high-dose intravenous immunoglobulin G (IVIgG) 1 g/kg on 2 consecutive days (n = 34), 0.8 g/kg once (n = 35), intravenous anti-D 25 micrograms/kg on 2 consecutive days (n = 38), or oral prednisone 4 mg/kg per day with tapering and discontinuation of prednisone by day 21 (n = 39). The rate of response as reflected by the number of days with platelet counts at 20 x 10(9)/L or lower and the time taken to achieve a platelet count 50 x 10(9)/L or more was significantly faster for both IVIgG groups than for the anti-D group (p < 0.05); the difference between prednisone and IVIgG was significant (p < 0.05) only for the IVIgG 0.8 g/kg group, and responses to the two IgG groups were similar. These differences in response rates were reflected in the percentages of children with platelet counts of 20 x 10(9)/L or lower at 72 hours following the start of treatment: 3% (IVIgG 0.8 g/kg x 1), 6% (IVIgG 1 g/kg x 2), 18% (anti-D), and 21% (oral prednisone 4 mg/kg/day). Treatment-associated toxicities included a fall in haemoglobin with anti-D (to less than 100 g/L in 24% of cases); weight gain with oral prednisone; and fever, nausea, vomiting, and headache with IVIgG. On the basis of these results, intravenous anti-D cannot be recommended as initial therapy for children with acute ITP and platelet counts of 20 x 10(9)/L or lower. A single dose of 0.8 g/kg IVIgG offers the fastest recovery for the least treatment; additional IgG or oral prednisone can be reserved for the one-third of children who continue to have platelet counts of 20 x 10(9)/L or less at 48-72 hours after the start of treatment.

Adolescent↗
PubMed1994

Reliability of the Guide to Pregnancy Risk Grading of the Ontario Antenatal Record in assessing obstetric risk.

OBJECTIVE: To assess the reliability of the Guide to Pregnancy Risk Grading of the Ontario Antenatal Record through evaluation of inter- and intra-observer agreement on the grading of obstetric risk. DESIGN: Retrospective chart review. SETTING: Urban community teaching hospital in Hamilton, Ont. PATIENTS: Obstetric charts of 77 women were randomly selected from those of all women who delivered at the hospital or were transferred before delivery to the regional perinatal centre between Apr. 1, 1987, and Mar. 31, 1988. Six family physicians and two obstetricians participated as chart reviewers. MAIN OUTCOME MEASURES: Agreement beyond chance (kappa [kappa] statistic) between (a) different reviewers, (b) the same reviewer at different times and (c) the majority of reviewers (majority risk grade) and the antenatal record. MAIN RESULTS: The kappa value for interobserver agreement ranged from 0.48 (95% confidence interval [CI] 0.34 to 0.62) to 0.51 (95% CI 0.36 to 0.66). For intraobserver agreement it was 0.69 (95% CI 0.37 to 1.0). Agreement between the majority risk grade and the risk grade last recorded in the antenatal record had a kappa value of 0.58 (95% CI 0.54 to 0.61). CONCLUSION: The guide possesses only modest reliability. Efforts should be made to make descriptions of risk factors more explicit and to improve the training of health care providers in the use of the guide in order to prevent errors in pregnancy risk assessment and resulting inappropriate patient care and misdirection of health care resources.

Female↗
PubMed1994

Effect of local acid-base status on gastric mucosal blood flow and surface cell injury by bile acid.

Topical application of 5 mM sodium taurocholate (5 TC, pH 1.2) to canine gastric mucosa results in luminal hydrogen ion (H+) loss and surface epithelial cell (SEC) injury. However, gross mucosal injury does not occur because of a protective increase in gastric mucosal blood flow (GMBF). The mechanism of this blood flow response is unknown. To test the hypothesis that mucosal acid-base status influences mucosal blood flow and surface cell injury, three groups of dogs with vascularized chambered gastric mucosae were studied during two sequential 30-min periods. Mucosae were exposed during period I to topical acidified isotonic saline (ATS, pH 1.2), and during period II to topical 5 TC. During both periods, group A (n = 5) received close intraarterial (ia) NaCl (0.15 M), group B (n = 5) close ia HCO3 (0.32 M), and group C (n = 4) close ia HCl (0.2 N). Parameters evaluated during both ATS and 5 TC periods included the luminal accumulation of DNA (DNAE, a sensitive marker of SEC exfoliation), luminal H+ loss, and GMBF measured using radiolabeled microspheres. Gastric venous pH was also measured. It was found that, compared to the NaCl group, the HCO3 group had no increase in GMBF after 5 TC exposure. Simultaneously, however, SEC loss was reduced by 48%, 604 +/- 72 with NaCl versus 314 +/- 59 micrograms/30 min DNA with HCO3, P < 0.025. Infusion of ia HCl generated a large increase in GMBF without an increase in SEC injury compared to ia NaCl. Thus, mucosal acid-base status is an important modulator of mucosal blood flow which is itself critically important to gastric mucosal protection during bile acid induced injury.

Acid-Base Equilibrium↗
PubMed1994

Capsaicin-induced gastric hyperemia and protection are NO- dependent.

Topical treatment of gastric mucosa with capsaicin (cap) increases gastric mucosal blood flow (GMBF) and protects the mucosa from injury by acidified bile salts. The purpose of this study was to test the hypothesis that this hyperemia related "cytoprotection" is mediated by nitric oxide. Male Sprague-Dawley rats were anesthetized and the glandular stomach (blood supply intact) was chambered between two plastic rings. Animals were divided into four groups. All groups received a 5-min topical saline exposure. Groups 1 and 2 received iv saline or nitro-L-arginine methyl ester (L-NAME, 25 mg/kg iv), a specific nitric oxide inhibitor, 5 min prior to baseline treatment, followed by a 15-min preinjury period of saline and a 15-min injury period of 10 mM acidified taurocholate (ATC, pH 1.2). Groups 3 and 4 were treated as above except topical cap (160 microM) was used during the preinjury period. GMBF was measured with a laser Doppler flowmeter (ml/min/100 g tissue). Injury was assessed grossly (grade 0-3), histologically (grade 0-3), and by measuring DNA content of a 5-min N-acetylcysteine wash (DNAE). Baseline GMBF of 30 +/- 1.5 significantly decreased to 15 +/- 1.2 in group 1 versus group 2 (P < 0.05). When topical ATC was used GMBF increased to 59 +/- 4.9 and 25 +/- 2.8, respectively. Injury by grade and DNAE was not significantly different between these groups. GMBF during cap exposure was 42 +/- 4 and 22 +/- 2 in groups 3 and 4, respectively. Graded histologic and gross injuries were significantly worse in group 4 compared to group 3 (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Blood-borne virus infections among Australian injecting drug users: implications for spread of HIV.

To describe the epidemiology of infection with hepatitis C virus (HCV), hepatitis B virus (HBV) and human immunodeficiency virus (HIV) among injecting drug users (IDUs) in Australia, in relation to the potential for further spread of HIV in IDUs, a cross-sectional analysis was performed on data from a sample of injecting drug users, correlating markers of exposure to blood-borne viruses with sex, age, sexual orientation, primary current drug injected and duration of injecting in rural and metropolitan Victoria, Australia. The subjects were currently active IDUs from a wide spectrum of age, sex, sexual orientation, geographical location and social background, contacted and recruited through their social networks and from community agencies and prisons by trained peer workers who interviewed and collected blood from them in the field. Sera were tested for antibody to HIV, HCV and hepatitis B core antigen (HBcAg), for hepatitis B surface antigen (HBsAg), and for HCV RNA using reverse transcription and polymerase chain reaction (RT-PCR). At entry to the study, 4.5% (14/311) had antibody to HIV, 47% (146/308) to HBcAg and 68% (206/303) to HCV. Prevalence of HBsAg was 1.8% overall (5/282), and 50% (84/168) were positive for HCV RNA. By multivariate analysis, HIV seropositivity was strongly associated with a history of homosexual contact in males and with exposure to HBV but not to HCV. Those who reported their current primary injected drug to be amphetamines were at greater and continuing risk of HIV infection than were current heroin injectors, while the reverse applied for HCV.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗