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Biomedical subjects

J W McDonald

Publications and source records attributed to J W McDonald.

At least 19 recordsLinked to original sources
PubMed2001

Evidence for highly charged ion Coulomb crystallization in multicomponent strongly coupled plasmas.

Multicomponent non-neutral ion plasmas in a Penning trap consisting of Be(+) and highly charged Xe ions, having different mass-to-charge ratios than Be(+), are cooled to form strongly coupled plasmas by applying a laser-based collisional cooling scheme. The temperature of the plasma was determined from a Doppler broadened transition in Be(+). For the Xe ions, which are centrifugally separated from the Be, the Coulomb coupling parameter was estimated to be approximately 1000. Molecular dynamics simulations of the ion mixture show ordered structures, indicating crystallization of the Xe.

Journal Article↗
PubMed2000

A comparison of methotrexate with placebo for the maintenance of remission in Crohn's disease. North American Crohn's Study Group Investigators.

BACKGROUND: Patients with Crohn's disease often have relapses. Better treatments are needed for the maintenance of remission. Although methotrexate is an effective short-term treatment for Crohn's disease, its role in maintaining remissions is not known. METHODS: We conducted a double-blind, placebo-controlled, multicenter study of patients with chronically active Crohn's disease who had entered remission after 16 to 24 weeks of treatment with 25 mg of methotrexate given intramuscularly once weekly. Patients were randomly assigned to receive either methotrexate at a dose of 15 mg intramuscularly once weekly or placebo for 40 weeks. No other treatments for Crohn's disease were permitted. We compared the efficacy of treatment by analyzing the proportion of patients who remained in remission at week 40. Remission was defined as a score of 150 or less on the Crohn's Disease Activity Index. RESULTS: Forty patients received methotrexate, and 36 received placebo. At week 40, 26 patients (65 percent) were in remission in the methotrexate group, as compared with 14 (39 percent) in the placebo group (P=0.04; absolute reduction in the risk of relapse, 26.1 percent; 95 percent confidence interval, 4.4 percent to 47.8 percent). Fewer patients in the methotrexate group than in the placebo group required prednisone for relapse (11 of 40 [28 percent] vs. 21 of 36 [58 percent], P=0.01). None of the patients who received methotrexate had a severe adverse event; one patient in this group withdrew because of nausea. CONCLUSIONS: In patients with Crohn's disease who enter remission after treatment with methotrexate, a low dose of methotrexate maintains remission.

Adult↗
PubMed2000

Embryonic stem cells differentiate into oligodendrocytes and myelinate in culture and after spinal cord transplantation.

Demyelination contributes to the loss of function consequent to central nervous system (CNS) injury. Enhanced remyelination through transplantation of myelin-producing cells may offer a pragmatic approach to restoring meaningful neurological function. An unlimited source of cells suitable for such transplantation therapy can be derived from embryonic stem (ES) cells, which are both pluripotent and genetically flexible. In this paper we show that oligodendrocyte cultures can be reliably produced from retinoic acid-induced ES cells and that these oligodendrocytes can myelinate axons in vitro. Methods were further developed for generating highly enriched cultures of oligodendrocytes through an additional culturing step, producing an intermediate "oligosphere" stage. To test whether ES cells can survive, migrate, and differentiate into mature myelin-producing cells in areas of demyelination in the adult CNS, ES cells were transplanted into the dorsal columns of adult rat spinal cord 3 days after chemical demyelination. In the demyelination site, large numbers of ES cells survived and differentiated primarily into mature oligodendrocytes that were capable of myelinating axons. Furthermore, when oligosphere cells were transplanted into the spinal cords of myelin-deficient shiverer (shi/shi) mutant mice, the ES cell-derived oligodendrocytes migrated into the host tissue, produced myelin and myelinated host axons. These studies demonstrate the ability of ES cell-derived oligodendrocytes to myelinate axons in culture and to replace lost myelin in the injured adult CNS. Transplantation of ES cells may be a practical approach to treatment of primary and secondary demyelinating diseases in the adult CNS.

Animals↗
PubMed2000

Association models for a multivariate binary response.

Models for a multivariate binary response are parameterized by univariate marginal probabilities and dependence ratios of all orders. The w-order dependence ratio is the joint success probability of w binary responses divided by the joint success probability assuming independence. This parameterization supports likelihood-based inference for both regression parameters, relating marginal probabilities to explanatory variables, and association model parameters, relating dependence ratios to simple and meaningful mechanisms. Five types of association models are proposed, where responses are (1) independent given a necessary factor for the possibility of a success, (2) independent given a latent binary factor, (3) independent given a latent beta distributed variable, (4) follow a Markov chain, and (5) follow one of two first-order Markov chains depending on the realization of a binary latent factor. These models are illustrated by reanalyzing three data sets, foremost a set of binary time series on auranofin therapy against arthritis. Likelihood-based approaches are contrasted with approaches based on generalized estimating equations. Association models specified by dependence ratios are contrasted with other models for a multivariate binary response that are specified by odds ratios or correlation coefficients.

Antirheumatic Agents↗
PubMed2000

Pulmonary alveolar proteinosis in association with household exposure to fibrous insulation material.

We report the case of a 35-year-old woman who developed pulmonary alveolar proteinosis requiring multiple lavage treatments, in association with household exposure to ventilation system dust comprised at least partially by a cellulose fire-resistant fibrous insulation material. Scanning electron microscopy with energy-dispersive x-ray analysis documented the presence of spectral peaks consistent with the insulation material in transbronchial biopsy tissue. The patient showed symptomatic improvement once exposure to the insulation material had ceased. We believe that this case demonstrates an unusual association with pulmonary alveolar proteinosis. This case emphasizes the broad differential diagnosis for this histologic injury pattern and the need to thoroughly investigate environmental exposures in patients with unexplained pulmonary disease.

Adult↗
PubMed1999

Lack of effect of intravenous administration on time to respond to azathioprine for steroid-treated Crohn's disease. North American Azathioprine Study Group.

BACKGROUND & AIMS: Azathioprine is effective for Crohn's disease but acts slowly. A loading dose may decrease the time to response. METHODS: A placebo-controlled study was conducted in patients with active Crohn's disease despite prednisone treatment. Patients were randomized to a 36-hour infusion of azathioprine, 40 mg/kg (51 patients), or placebo (45 patients) followed by oral azathioprine, 2 mg/kg, for 16 weeks. Prednisone was tapered over 5 weeks. The primary outcome measure was complete remission at week 8, defined by discontinuation of prednisone and a Crohn's Disease Activity Index of </=150 points. Erythrocyte concentrations of the azathioprine active metabolite, 6-thioguanine nucleotide, were measured. RESULTS: At week 8, 13 patients (25%) were in complete remission in the azathioprine-loaded group compared with 11 patients (24%) in the placebo group. The frequency of complete remission did not increase after 8 weeks in either group. Both groups achieved steady state of 6-thioguanine nucleotide by week 2, and no differences were found in mean concentrations between the groups. There were no significant differences in the frequency of adverse events between the groups. CONCLUSIONS: A loading dose does not decrease the time to response in patients with steroid-treated Crohn's disease beginning azathioprine therapy. Steady state of erythrocyte 6-thioguanine nucleotide and complete response occurred earlier than previously reported.

Administration, Oral↗
PubMed1999

Selective activation of group II mGluRs with LY354740 does not prevent neuronal excitotoxicity.

Recent reports have suggested a role for group II metabotropic glutamate receptors (mGluRs) in the attenuation of excitotoxicity. Here we examined the effects of the recently available group II agonist (+)-2-Aminobicyclo[3.1.0]hexane-2-6-dicarboxylic acid (LY354740) on N-methyl-D-aspartate (NMDA)-induced excitotoxic neuronal death, as well as on hypoxic-ischemic neuronal death both in vitro and in vivo. At concentrations shown to be selective for group II mGluRs expressed in cell lines (0.1-100 nM), LY354740 did not attenuate NMDA-mediated neuronal death in vitro or in vivo. Furthermore, LY354740 did not attenuate oxygen-glucose deprivation-induced neuronal death in vitro or ischemic infarction after transient middle cerebral artery occlusion in rats. In addition, the neuroprotective effect of another group II agonist, (S)-4-carboxy-3-phenylglycine (4C3HPG), which has shown injury attenuating effects both in vitro and in vivo, was not blocked by the group II antagonists (2 S)-alpha-ethylglutamic acid (EGLU), (RS)-alpha-methyl-4-sulphonophenylglycine (MSPG), or the group III antagonist (S)-alpha-methyl-3-carboxyphenylalanine (MCPA), suggesting that this neuroprotection may be mediated by other effects such as upon group I mGluRs.

Animals↗
PubMed1999

Transplanted embryonic stem cells survive, differentiate and promote recovery in injured rat spinal cord.

Transplantation approaches using cellular bridges, fetal central nervous system cells, fibroblasts expressing neurotrophin-3 (ref. 6), hybridoma cells expressing inhibitory protein-blocking antibodies, or olfactory nerves ensheathing glial cells transplanted into the acutely injured spinal cord have produced axonal regrowth or functional benefits. Transplants of rat or cat fetal spinal cord tissue into the chronically injured cord survive and integrate with the host cord, and may be associated with some functional improvements. In addition, rats transplanted with fetal spinal cord cells have shown improvements in some gait parameters, and the delayed transplantation of fetal raphe cells can enhance reflexes. We transplanted neural differentiated mouse embryonic stem cells into a rat spinal cord 9 days after traumatic injury. Histological analysis 2-5 weeks later showed that transplant-derived cells survived and differentiated into astrocytes, oligodendrocytes and neurons, and migrated as far as 8 mm away from the lesion edge. Furthermore, gait analysis demonstrated that transplanted rats showed hindlimb weight support and partial hindlimb coordination not found in 'sham-operated' controls or control rats transplanted with adult mouse neocortical cells.

Animals↗
PubMed1999

Nuclear expression of p53, p21 and cyclin D1 is increased in bronchioloalveolar carcinoma.

AIMS: The objectives of this study were: (1) to determine, using immunohistochemistry, the level of expression of the cell cycle factors p53, p21 and cyclin D1 in a group of bronchioloalveolar carcinomas (BACs), and to compare these data to relevant published data for lung carcinoma; (2) to determine if higher expression rates for these factors in BAC were associated statistically with advanced clinical stage, greater tumour size, tobacco abuse, and/or BAC subtype; (3) to seek, using Fisher's exact t-test and paired data groups, any significant associations within the expression data for p53, p21 and cyclin D1. METHODS AND RESULTS: A panel of monoclonal antibodies against p53, p21 and cyclin D1 was applied to 19 bronchioloalveolar carcinomas (17 surgical pathology cases and two autopsies) from the tissue archives of St. Louis University. These immunohistochemical stains were graded on a semiquantitative scale according to the prevalence of nuclear staining within the tumour (< 10% positive cells = 0, 10-25% = 1+, 25-50% = 2+, 50-75% = 3+ and 75-100% = 4+). Six of 19 (32%) of BACs showed 1+ or greater p53 positivity, six of 19 (32%) showed 1+ or greater nuclear cyclin D1 positivity, and nine of 19 (47%) of BACs showed 1+ or greater p21 nuclear positivity. A statistically significant correlation was found between p53 and cyclin D1 expression (P = 0.046, Fisher's exact t-test), but not between p53 and p21, or between p21 and cyclin D1. No statistically significant association was found between the cell cycle factor expression data and subtype of BAC (mucinous vs. nonmucinous), tumour diameter, clinical stage or tobacco-use history. CONCLUSIONS: BACs show p53 immunostain positivity at a frequency similar to that published for p53 mutations in lung adenocarcinomas in general. Cyclin D1 and p21 nuclear expression characterizes a significant proportion of BACs, with cyclin D1 and p53 expression showing a statistically significant association. Aberrations in p53, p21, and cyclin D1 expression may be important in the development of a significant proportion of BACs.

Adenocarcinoma, Bronchiolo-Alveolar↗
PubMed1998

Multiple classes of the oligodendrocyte lineage are highly vulnerable to excitotoxicity.

We have recently shown that galactocerebroside (Gal-C)-expressing oligodendrocytes are highly vulnerable to (AMPA)/kainate receptor-mediated death. Here we examined the vulnerability of cells at different developmental stages of the oligodendrocyte lineage to AMPA/kainate receptor-mediated excitotoxicity. Oligodendrocyte precursor cells, pre-oligodendrocytes and mature oligodendrocytes were killed by 24 h exposures to low concentrations of kainate (30-100 microM). Death was attenuated by the AMPA/kainate receptor antagonist 6-nitro-7-sulfamoylbenzo(f)quinoxaline-2,3-dione (NBQX). The high vulnerability of oligodendrocytes and their precursors to AMPA/kainate receptor excitotoxicity may represent an important mechanism of white matter damage resulting from trauma or ischemia in the perinatal and adult central nervous system (CNS).

Animals↗
PubMed1998

Extracellular acidity potentiates AMPA receptor-mediated cortical neuronal death.

The extracellular acidity that accompanies brain hypoxia-ischemia is known to reduce both NMDA and AMPA-kainate receptor-mediated currents and NMDA receptor-mediated neurotoxicity. Although a protective effect of acidic pH on AMPA-kainate receptor-mediated excitotoxicity has been assumed, such has not been demonstrated. Paradoxically, we found that lowering extracellular pH selectively increased AMPA-kainate receptor-mediated neurotoxicity in neocortical cell cultures, despite reducing peak elevations in intracellular free Ca2+. This injury potentiation may, at least in part, be related to a slowed recovery of intracellular Ca2+ homeostasis, observed after AMPA-kainate receptor activation, but not after NMDA receptor activation or exposure to high K+. The ability of acidic pH to selectively augment AMPA-kainate receptor-mediated excitotoxicity may contribute to the prominent role that these receptors play in selective neuronal death after transient global ischemia.

Acids↗
PubMed1998

Role of glutamate receptor-mediated excitotoxicity in bilirubin-induced brain injury in the Gunn rat model.

Severe hyperbilirubinemia in neonates with prematurity and/or systemic illnesses such as hemolytic disease, acidosis, and hypoxemia enhances their risk for developing cerebral palsy, paralysis of ocular upgaze, and deafness. This neurologic syndrome has been associated with selective neuronal vulnerability in the basal ganglia, certain brainstem nuclei, and Purkinje cells. However, the mechanism by which bilirubin damages neurons remains unclear. In these studies, we found that intracerebral injection of N-methyl-D-aspartate (NMDA), an excitotoxic analogue of glutamate, caused greater injury in jaundiced 7-day-old Gunn (jj) rat pups than in nonjaundiced heterozygous (Nj) littermate controls. NMDA injection caused even greater injury when protein-bound bilirubin was displaced with the sulfonamide drug sulfadimethoxine in jaundiced homozygous pups. In additional experiments, the acute signs of bilirubin-mediated neuronal injury, induced in homozygous (jj) Gunn rats by treatment with sulfonamide, were reduced by concurrent treatment with the NMDA-type glutamate channel antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohept-5,10-imine (MK-801, dizocilpine). The results suggest that bilirubin may cause encephalopathy and neuronal injury, at least in part, through an NMDA receptor-mediated excitotoxic mechanism. This conclusion is consistent with clinical observations that bilirubin encephalopathy is synergistically worsened by hypoxemia, which also shares an excitotoxic mechanism of neuronal injury.

Animals↗
PubMed1998

Oligodendrocytes from forebrain are highly vulnerable to AMPA/kainate receptor-mediated excitotoxicity.

Little is known of the molecular mechanisms that trigger oligodendrocyte death and demyelination in many acute central nervous system insults. Since oligodendrocytes express functional alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate-type glutamate receptors, we examined the possibility that oligodendrocyte death can be mediated by glutamate receptor overactivation. Oligodendrocytes in primary cultures from mouse forebrain were selectively killed by low concentrations of AMPA, kainate or glutamate, or by deprivation of oxygen and glucose. This toxicity could be blocked by the AMPA/kainate receptor antagonist 6-nitro-7-sulfamoylbenzo(f)quinoxaline-2,3-dione (NBQX). In vivo, differentiated oligodendrocytes in subcortical white matter expressed AMPA receptors and were selectively injured by microstereotaxic injection of AMPA but not NMDA. These data suggest that oligodendrocytes share with neurons a high vulnerability to AMPA/kainate receptor-mediated death, a mechanism that may contribute to white matter injury in CNS disease.

Animals↗
PubMed1998

Mixed (neutrophil-rich) interstitial pneumonitis in biopsy specimens of lung allografts: a clinicopathologic evaluation.

STUDY OBJECTIVES: Mixed interstitial pneumonitis (MIP), defined herein as a diffuse neutrophil-rich inflammatory infiltrate within the interstitial tissues, is an uncommon finding that is not a standard manifestation of acute or chronic rejection. This study examines the clinical significance of MIP in lung allograft recipients at St. Louis University Hospital. DESIGN: We retrospectively reviewed surgical pathology reports from a selected 50-month period, and identified MIP reported in 13 transbronchial biopsy specimens in lung transplant recipients, representing 4.7% of all lung allograft biopsy specimens seen during this 4-year period. Biopsy specimens with MIP were examined to confirm the presence of a neutrophil-rich interstitial infiltrate and other associated histopathologic findings. The culture results, cytopathologic findings, and clinical charts of the affected patients were also reviewed. MEASUREMENTS AND RESULTS: The detection of MIP at some point in a patient's posttransplant course was found to be associated with a significantly shorter (p < 0.01) survival, when compared to lung allograft recipients who did not show this finding. A total of seven lung allograft recipients (23% of total) showed MIP at some point in their posttransplant course. Four of the seven (57%) were actively smoking following lung transplantation, compared to 0 of 22 patients who did not show MIP. Six of the 13 MIP biopsy specimens were associated with positive cultures. In no case did MIP coexist with the conventional histologic patterns of acute or chronic rejection. MIP also did not correlate with levels of immunosuppressive therapy or with the incidence of rejection at other times in the patients' posttransplant courses. CONCLUSIONS: We found no evidence that MIP represents an unusual form of acute or chronic rejection. Instead, it appears to represent a response to acute injury, similar to other injury patterns (hyaline membranes, organizing pneumonia) in transplant recipients. Exposure to tobacco smoke is likely to have played a role in the development of MIP in at least some cases. Because patients with MIP had a significantly shorter posttransplant survival, MIP may usefully identify lung allograft recipients at risk for an adverse outcome.

Adolescent↗
PubMed1998

Incidental early detection of a splenic marginal zone lymphoma by polymerase chain reaction analysis of paraffin-embedded tissue.

Splenic marginal zone lymphoma (SMZL) most commonly presents with splenomegaly and stage IV disease. To our knowledge, there have been only two reported cases of SMZL without associated splenomegaly; one was detected incidentally after a bicycle accident. This previously reported case represented an early-stage SMZL with monoclonality confirmed by immunohistochemistry. We report a case of early-stage SMZL detected incidentally following a motor vehicle accident; monoclonality was confirmed by polymerase chain reaction analysis of paraffin-embedded tissue owing to the inability of confirmation by immunohistochemical techniques. We describe our findings and emphasize the importance of recognizing early stages of SMZL in incidental splenectomies by polymerase chain reaction analysis of paraffin-embedded tissue. Frozen tissue is not generally available in such cases.

Accidents, Traffic↗
PubMed1997

Neuronal and glial apoptosis after traumatic spinal cord injury.

Cell death was examined by studying the spinal cords of rats subjected to traumatic insults of mild to moderate severity. Within minutes after mild weight drop impact (a 10 gm weight falling 6.25 mm), neurons in the immediate impact area showed a loss of cytoplasmic Nissl substances. Over the next 7 d, this lesion area expanded and cavitated. Terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate-biotin nick end labeling (TUNEL)-positive neurons were noted primarily restricted to the gross lesion area 4-24 hr after injury, with a maximum presence at 8 hr after injury. TUNEL-positive glia were present at all stages studied between 4 hr and 14 d, with a maximum presence within the lesion area 24 hr after injury. However 7 d after injury, a second wave of TUNEL-positive glial cells was noted in the white matter peripheral to the lesion and extending at least several millimeters away from the lesion center. The suggestion of apoptosis was supported by electron microscopy, as well as by nuclear staining with Hoechst 33342 dye, and by examination of DNA prepared from the lesion site. Furthermore, repeated intraperitoneal injections of cycloheximide, beginning immediately after a 12.5 mm weight drop insult, produced a substantial reduction in histological evidence of cord damage and in motor dysfunction assessed 4 weeks later. Present data support the hypothesis that apoptosis dependent on active protein synthesis contributes to the neuronal and glial cell death, as well as to the neurological dysfunction, induced by mild-to-moderate severity traumatic insults to the rat spinal cord.

Animals↗
PubMed1997

Susceptibility to apoptosis is enhanced in immature cortical neurons.

The susceptibility of cortical neurons to two forms of apoptotic death was compared with susceptibility to excitotoxic death during development in vitro (DIV 4-21). Murine cortical cultures were exposed for 48 h to the phosphatase inhibitor cyclosporine, the protein kinase inhibitor staurosporine or the excitotoxin N-methyl-D-aspartate (NMDA). Susceptibility to apoptosis induced by staurosporine or cyclosporine was maximal between DIV 4-10 and declined from DIV 10 through 18. The opposite pattern was observed with susceptibility to NMDA receptor-mediated excitotoxic necrosis, which was minimal at DIV 6 and progressively increased through DIV 21.

Animals↗