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Biomedical subjects

D Muir

Publications and source records attributed to D Muir.

At least 19 recordsLinked to original sources
PubMed2002

Global distribution of halogenated dimethyl bipyrroles in marine mammal blubber.

Four halogenated dimethyl bipyrroles (HDBPs), hypothesized to be naturally produced, were quantitated in marine mammal blubber from a number of species obtained from various locations worldwide. HDBPs were found in samples from all locations studied. Concentrations of total HDBPs (SigmaHDBPs) ranged from 0.4 ng/g lipid weight in ringed seals (Phoca hispida) from the White Sea to 2,540 ng/g lipid weight in Dall's porpoise (Phocoenoides dalli) from the northwestern North Pacific Ocean. At their highest levels, SigmaHDBPs made up 11% of the total quantitated organohalogen body burden of adult male Dall's porpoises. In two beluga (Delphinapterus leucas) data subsets, it was found that males contained significantly higher concentrations of SigmaHDBPs than females. No significant effects of age or sex on SigmaHDBPs were observed in harbor seal (Phoca vitulina) and bowhead whale (Balaena mysticetus) data subsets. The geographical distribution of concentrations did not resemble that of the ubiquitous anthropogenic organohalogen, polychlorinated biphenyl congener CB-153. Higher concentrations of HDBPs and different patterns of congeners were observed in samples from Pacific as opposed to non-Pacific Ocean influenced environments. Concentrations of HDBPs in beluga from the Arctic and St. Lawrence River were similar. Their high abundance in north Pacific Ocean biota and widespread occurrence suggest that HDBPs undergo extensive transport from a source located primarily in the Pacific Ocean. Evidence from HDBP congener patterns indicates that both ocean currents and atmospheric transport likely play a role in the movement of HDBPs. These results imply that HDBPs and anthropogenic organohalogens have different sources and support the natural production hypothesis.

Adipose Tissue↗
PubMed2001

Axonal regeneration into acellular nerve grafts is enhanced by degradation of chondroitin sulfate proteoglycan.

Although the peripheral nerve has the potential to regenerate after injury, degenerative processes may be essential to promote axonal growth into the denervated nerve. One hypothesis is that the nerve contains growth inhibitors that must be neutralized after injury for optimal regeneration. In the present study, we tested whether degradation of chondroitin sulfate proteoglycan, a known inhibitor of axon growth, enhances the growth-promoting properties of grafts prepared from normal donor nerves. Excised segments of rat sciatic nerve were made acellular by freeze-killing before treatment with chondroitinase ABC. Chondroitinase-dependent neoepitope immunolabeling showed that chondroitin sulfate proteoglycan was thoroughly degraded throughout the treated nerve segments. In addition, neuronal cryoculture assays revealed that the neurite-promoting activity of acellular nerves was significantly increased by chondroitinase treatment. Control and chondroitinase-treated acellular nerves were then used as interpositional grafts in a rat nerve injury model. Axonal regeneration into the grafts was assessed 4 and 8 d after implantation by growth-associated protein-43 immunolabeling. At both time points, the number of axons regenerating into acellular grafts treated with chondroitinase was severalfold greater than in control grafts. Growth into the chondroitinase-treated grafts was pronounced after only 4 d, suggesting that the delay of axonal growth normally associated with acellular grafts was attenuated as well. These findings indicate that chondroitinase treatment significantly enhanced the growth-promoting properties of freeze-killed donor nerve grafts. Combined with the low immunogenicity of acellular grafts, the ability to improve axonal penetration into interpositional grafts by preoperative treatment with chondroitinase may be a significant advancement for clinical nerve allografting.

Animals↗
PubMed2001

Tumorigenic properties of neurofibromin-deficient neurofibroma Schwann cells.

Dermal and plexiform neurofibromas are peripheral nerve sheath tumors that arise frequently in neurofibromatosis type 1. The goal of the present study was to examine the tumorigenic properties of neurofibromin-deficient human Schwann cells (SCs) that were found to represent a subset of SCs present in approximately half of the total neurofibromas examined. Highly enriched SC cultures were established from 10 dermal and eight plexiform neurofibromas by selective subculture using glial growth factor-2 and laminin. These cultures had low tumorigenic potential in classical in vitro assays yet several unique preneoplastic properties were frequently observed, including delayed senescence, a lack of density-limited growth, and a strong propensity to spontaneously form proliferative cell aggregates rich in extracellular matrix. Western blot analysis failed to detect full-length neurofibromin in any of the neurofibroma SC cultures, indicating that neurofibromin-deficient SCs had a substantial growth advantage. Immunohistochemical staining of the originating tumors showed the majority were comprised principally of neurofibromin-negative SCs, whereas the remainder contained both neurofibromin-negative and neurofibromin-positive SCs. Lastly, engraftment of neurofibromin-deficient SC cultures into the peripheral nerves of scid mice consistently produced persistent neurofibroma-like tumors with diffuse and often extensive intraneural growth. These findings indicate that neurofibromin-deficient SCs are involved in neurofibroma formation and, by selective subculture, provide a resource for the development of an in vivo model to further examine the role of these mutant SCs in neurofibroma histogenesis.

Adolescent↗
PubMed2000

Predictive value of the ultrasensitive HIV viral load assay in clinical practice.

The aim of this study was to determine whether an HIV viral load of <50 copies/ml (c/ml), in the first available plasma sample to have shown a viral load of <400 c/ml, in patients on antiretroviral therapy, is correlated with longer term suppression of viral load (at <400 c/ml) compared to a viral load of 50-399 c/ml, and secondly, to compare the results obtained by ultrasensitive and standard viral load assays carried out on the same sample. A total of 98 HIV-positive patients on antiretroviral therapy with a viral load of <400 c/ml and at least one subsequent viral load measurement, were selected. For each patient, the first available specimen showing a viral load of <400 c/ml was tested using the Roche Amplicor ultrasensitive viral load assay, and patients were followed up subsequently for a median period of 52 weeks. Whether patients achieved an ultrasensitive viral load (USVL) of <50 c/ml or not made very little difference to the proportion of patients in each group showing continued response to treatment (52% vs. 45% respectively). The only variable that was shown to significantly predict longevity of response was the number of antiretroviral drugs used. Secondly, a standard viral load of <400 c/ml but with a detectable signal above background levels, was strongly predictive of a USVL of >50 c/ml. Overall, the findings suggest that the advantage in predictive value of the ultrasensitive over the standard HIV viral load assay, shown previously in clinical trials, may be limited in clinical practice.

Anti-HIV Agents↗
PubMed2000

MMP-2 and MMP-9 increase the neurite-promoting potential of schwann cell basal laminae and are upregulated in degenerated nerve.

Compared to degenerated nerves, the ability of normal adult peripheral nerve to support axonal regeneration is poor and may be attributed to the inhibition of endoneurial laminin by chondroitin sulfate proteoglycan (CSPG). In cryoculture assays, neuritic growth of neonatal and adult peripheral neurons was increased on sections of normal nerve by pretreatment with CSPG-degrading enzymes, including the matrix metalloproteinases MMP-2 and MMP-9. Axonal regeneration is known to occur within the Schwann cell basal laminae of degenerated nerve. Similarly, deconvolution microscopy revealed that neuritic growth on nerve tissue sections occurred principally on the lumenal surface of enzymatically modified basal laminae. Compared to normal nerve, there was a marked increase in the neurite-promoting activity of the degenerated nerve, and this activity was not increased significantly by subsequent MMP treatment. Additionally, the expression and activation of MMP-2 and MMP-9 were elevated in degenerated nerve, suggesting that degradation of inhibitory CSPG by the MMPs contributes to the growth-promoting properties of degenerated nerve.

Age Factors↗
PubMed2000

Combined alpha interferon and ribavirin for the treatment of hepatitis C in patients with hereditary bleeding disorders.

Patients with hereditary bleeding disorders who received non-virally inactivated plasma-derived clotting factor concentrates before the mid-1980s invariably became infected with hepatitis C virus (HCV). Therapy with interferon alpha (IFN-alpha) alone has been disappointing in this group. We conducted an open-label study, using a combination of IFN-alpha2b (3 million units three times per week) and ribavirin 1-1.2 g/d in 28 patients with hereditary bleeding disorders. Twenty-one of the 28 patients had liver biopsy-confirmed chronic hepatitis (median histological activity index 5; range 1-10) and all patients were HCV RNA positive by PCR. Virological response rate to therapy at 3 months was 82% (23 out of 28). Three HIV co-infected patients showed an early virological response with loss of HCV RNA, but two subsequently relapsed after 3 and 6 months of therapy. Four patients stopped treatment early (one at 4, one at 7 and two at 9 months) because of treatment-related side effects, although three of these have maintained a virological response. Seventeen patients completed the 48-week course. Twenty of the 28 (71%) treated have had a durable virological response with a median follow-up of 16 months (range 1-24). Combination therapy represents a significant advance in the treatment of hepatitis C in patients with hereditary bleeding disorders.

Adult↗
PubMed2000

The growth of Listeria monocytogenes in cheese packed under a modified atmosphere.

The effect of modified atmosphere Packaging (MAP) on the growth of Listeria monocytogenes in mould ripened cheeses was studied at refrigeration temperatures (2-8.3 degrees C) over a storage period of 6 weeks. Control experiments in cling film with no atmospheric modification produced a lag time before growth of up to 1 week and rapid subsequent growth. MAP with a CO2 concentration of less than 20% allowed growth to occur but when O2 was incorporated; the lag time was reduced from 3 to 2 weeks and subsequent growth was also faster, producing an increase in cell numbers of 1.4 log cycles over the incubation period. N2-MAP in the absence of O2 increased the lag time to 3 weeks and slowed growth, while the inclusion of CO2 extended the lag to 3 weeks and slowed subsequent growth even more. In MAP with 80:10:10 (v/v/v) N2:CO2:O2, there was a lag period of 2-3 weeks before growth of L. monocytogenes occurred, while the total viable aerobic count (TVAC) decreased by 2-3 log cycles and the total Lactobacillus count showed little change. It was concluded that MAP was not suitable for preventing the growth of L. monocytogenes in such cheeses.

Carbon Dioxide↗
PubMed2000

Mitochondrial DNA analysis of Sporothrix schenckii in South Africa and Australia.

Clinical isolates of Sporothrix schenckii were investigated for mitochondrial DNA (mtDNA) types using restriction fragment length polymorphism patterns with HaeIII. The 62isolates in South Africa comprised Types 3 (9.7%), 4 (1.6%), 11 (9.7%), 17 (77.4%) and 23 (1.6%) while the 23 Australian isolates comprised Types 3 (26.0%), 4 (56.5%), 7 (8.6%) and 21 (8.6%). In a phylogenetic tree based on the sequence divergence of mtDNA, the mtDNA types were clustered into two groups, A and B. The results suggested that isolates in South Africa mainly belong to Group A and isolates in Australia mainly belong to Group B.

Australia↗
PubMed2000

Bcl-2 immunoreactive cells with immature neuronal phenotype exist in the nonepileptic adult human brain.

Bcl-2, a cell death suppressor protein, is expressed during brain development but is largely down-regulated in the adult central nervous system. We previously reported strong expression of bcl-2 in small, "oligodendrocyte-like" cells (OLC) found in glioneuronal hamartias. These hamartias are microscopic cell rests found in temporal lobe resections from patients with intractable epilepsy and are considered a form of cerebral microdysgenesis. However, a causative relationship between these rests and seizures is not clear. We now report the identification, lineage characterization, and postnatal ontogeny of hamartia-like cell rests in temporal lobes of nonepileptic humans. Postmortem temporal lobes from 28 patients without history of neurologic disease (mean age = 53 years; range = 20 to 83 years) were studied. Microscopic cellular aggregates containing immature-appearing, bcl-2-immunoreactive cells (BIC) (identical to OLC) were observed in 23 of 28 (82%) temporal lobes from nonepileptic individuals. BIC were strongly immunoreactive for neuronal-specific class III beta tubulin, neuronal nuclear antigen, and MAP-2, but were consistently negative for neurofilament proteins and Ki67. Such cells were localized to subventricular regions of the caudal amygdala and often extended into the adjacent subcortical white matter and periamygdaloid cortex. BIC became less abundant with advancing age. These findings suggest that hamartia-like rests containing immature postmitotic neurons are normally present in the human brain and that glioneuronal hamartias may not always represent a maldevelopmental lesion associated with epilepsy.

Adult↗
PubMed2000

Culture of cytogenetically abnormal schwann cells from benign and malignant NF1 tumors.

Dermal and plexiform neurofibromas are benign peripheral nerve sheath tumors that arise in neurofibromatosis type 1 (NF1). NF1 patients also have an increased risk of malignant peripheral nerve sheath tumors (MPNSTs), thought to arise in a subset of plexiform neurofibromas. Plexiform neurofibroma pathogenesis is poorly understood, despite the serious clinical problem posed by these tumors. The Schwann cell is hypothesized to be the cell type initially mutated and clonally expanded in plexiform neurofibromas. To test this hypothesis and search for genetic alterations involved in tumorigenesis, we established Schwann cell cultures from plexiform and dermal neurofibromas. Cytogenetic abnormalities were identified in 4/6 plexiform cultures (including one from a plexiform with a sarcomatous component) and 0/7 dermal neurofibroma Schwann cell cultures. There were no consistent chromosomal regions involved in the abnormal karyotypes, suggesting that plexiform tumors are heterogeneous and may bear a variety of primary and/or secondary genetic changes. This is the first study to show successful culturing of genetically abnormal Schwann cell lineages from plexiform neurofibromas. Thus, we present the strongest evidence yet to support the theory that the Schwann cell is the central component in the development of plexiform neurofibromas. This is a key finding for NF1 research, which will lead to further studies of the genetic and biochemical pathogenesis of these Schwann cell tumors. Genes Chromosomes Cancer 27:117-123, 2000.

Cell Division↗
PubMed2000

Chromosome 17 loss-of-heterozygosity studies in benign and malignant tumors in neurofibromatosis type 1.

Neurofibromatosis type 1 (NF1) is a common autosomal dominant condition characterized by benign tumor (neurofibroma) growth and increased risk of malignancy. Dermal neurofibromas, arising from superficial nerves, are primarily of cosmetic significance, whereas plexiform neurofibromas, typically larger and associated with deeply placed nerves, extend into contiguous tissues and may cause serious functional impairment. Malignant peripheral nerve sheath tumors (MPNSTs) seem to arise from plexiform neurofibromas. The NF1 gene, on chromosome segment 17q11.2, encodes a protein that has tumor suppressor function. Loss of heterozygosity (LOH) for NF1 has been reported in some neurofibromas and NF1 malignancies, but plexiform tumors have been poorly represented. Also, the studies did not always employ the same markers, preventing simple comparison of the frequency and extent of LOH among different tumor types. Our chromosome 17 LOH analysis in a cohort of three tumor types was positive for NF1 allele loss in 2/15 (13%) dermal neurofibromas, 4/10 (40%) plexiform neurofibromas, and 3/5 (60%) MPNSTs. Although the region of loss varied, the p arm (including TP53) was lost only in malignant tumors. The losses in the plexiform tumors all included sequences distal to NF1. No subtle TP53 mutations were found in any tumors. This study also reports the identification of both NF1 "hits" in plexiform tumors, further supporting the tumor suppressor role of the NF1 gene in this tumor type.

Adolescent↗
PubMed1999

Spatial and temporal trends and effects of contaminants in the Canadian Arctic marine ecosystem: a review.

Recent studies have added substantially to our knowledge of spatial and temporal trends of persistent organic pollutants and heavy metals in the Canadian Arctic marine ecosystem. This paper reviews the current state of knowledge of contaminants in marine biota in the Canadian Arctic and where possible, discusses biological effects. The geographic coverage of information on contaminants such as persistent organochlorines (OCs) (PCBs, DDT- and chlordane-related compounds, hexachlorocyclohexanes, toxaphene) and heavy metals (mercury, selenium, cadmium, lead) in tissues of marine mammal and sea birds is relatively complete. All major beluga, ringed seal and polar bear stocks along with several major sea bird colonies have been sampled and analysed for OC and heavy metal contaminants. Studies on contaminants in walrus are limited to Foxe Basin and northern Québec stocks, while migratory harp seals have only been studied recently at one location. Contaminant measurements in bearded seal, harbour seal, bowhead whale and killer whale tissues from the Canadian Arctic are very limited or non-existent. Many of the temporal trend data for contaminants in Canadian Arctic biota are confounded by changes in analytical methodology, as well as by variability due to age/size, or to dietary and population shifts. Despite this, studies of OCs in ringed seal blubber at Holman Island and in sea birds at Prince Leopold Island in Lancaster Sound show declining concentrations of PCBs and DDT-related compounds from the 1970s to 1980s then a levelling off during the 1980s and early 1990s. For other OCs, such as chlordane, HCH and toxaphene, limited data for the 1980s to early 1990s suggests few significant declines in concentrations in marine mammals or sea birds. Temporal trend studies of heavy metals in ringed seals and beluga found higher mean concentrations of mercury in more recent (1993/1994) samples than in earlier collections (1981-1984 in eastern Arctic, 1972-1973 in western Arctic) for both species. Rates of accumulation of mercury are also higher in present day animals than 10-20 years ago. Cadmium concentrations in the same animals (eastern Arctic only) showed no change over a 10-year period. No temporal trend data are available for metals in sea birds or polar bears. There have been major advances in knowledge of specific biomarkers in Canadian Arctic biota over the past few years. The species with the most significant risk of exposure to PCBs and OC pesticides may be the polar bear which, based on comparison with EROD activity in other marine mammals (beluga, ringed seal), appears to have elevated CYP1A-mediated activity. The MFO enzyme data for polar bear, beluga and seals suggest that even the relatively low levels of contaminants present in Arctic animals may not be without biological effects, especially during years of poor feeding.

Animals↗
PubMed1999

Spatial and temporal trends of contaminants in Canadian Arctic freshwater and terrestrial ecosystems: a review.

The state of knowledge of contaminants in Canadian Arctic biota of the freshwater and terrestrial ecosystems has advanced enormously since the publication of the first major reviews by Lockhart et al. and Thomas et al. in The Science of the Total Environment in 1992. The most significant gains are new knowledge of spatial trends of organochlorines and heavy metal contaminants in terrestrial animals, such as caribou and mink, and in waterfowl, where no information was previously available. Spatial trends in freshwater fish have been broadened, especially in the Yukon, where contaminant measurements of, for example, organochlorines were previously non-existent. A review of contaminants data for fish from the Northwest Territories, Yukon and northern Quebec showed mercury as the one contaminant which consistently exceeds guideline limits for subsistence consumption or commercial sale. Lake trout and northern pike in the Canadian Shield lakes of the Northwest Territories and northern Quebec generally had the most elevated levels. Levels of other heavy metals were generally not elevated in fish. Toxaphene was the major organochlorine contaminant in all fish analyzed. The concentrations of organochlorine contaminants in fish appear to be a function not only of trophic level but of other aspects of the lake ecosystem. Among Arctic terrestrial mammals, PCBs and cadmium were the most prominent contaminants in the species analyzed. Relatively high levels (10-60 micrograms g-1) of cadmium were observed in kidney and liver of caribou from the Yukon, the Northwest Territories and northern Quebec, with concentrations in western herds being higher than in those from the east. For the organochlorine contaminants, a west to east increase in zigma PCBs, HCB and zigma HCH was found in caribou, probably as a result of the predominant west to east/north-east atmospheric circulation pattern which delivers these contaminants from industrialized regions of central and eastern North America to the Arctic via long-range atmospheric transport. Radiocesium contamination of lichens and caribou has continued to decrease. Significant contamination by PCBs and lead of soils and vascular plants was observed in the immediate vicinity and within a 20-km radius of DEW line sites in the Canadian Arctic. There was also evidence for transfer of PCBs from plants to lemmings. There was no evidence, however, that large mammals such as caribou living in the general area of the DEW line sites had elevated levels of PCBs. There is very limited temporal trend information for most contaminants in biota of Arctic terrestrial and freshwater environments.

Animals↗
PubMed1999

Long-term actions of vector-derived nerve growth factor or brain-derived neurotrophic factor on choline acetyltransferase and Trk receptor levels in the adult rat basal forebrain.

Trophic factor gene therapy may provide a rational treatment strategy for neurodegenerative disease. Recombinant adeno-associated virus vectors, incorporating a neuron-specific promoter driving bicistronic expression of green fluorescent protein and either nerve growth factor or brain-derived neurotrophic factor, transduced 10,000-15,000 neurons in the medial septum for periods of at least six months. Both cholinergic and non-cholinergic neurons expressed green fluorescent protein. Nerve growth factor and brain-derived neurotrophic factor vectors produced up to 50% increases in immunohistochemical detection of the acetylcholine-synthesizing enzyme in septal neurons ipsilateral to the injection. Increased levels of this enzyme, choline acetyltransferase, persisted for six months with the brain-derived neurotrophic factor vector. The nerve growth factor vector increased Trk receptor immunoreactivity in a volume of brain exceeding that of the transduced cells. Counterstaining for the neuronal marker, NeuN, or Nissl substance did not reveal any vector toxicity at any time-point. It therefore appears that the lasting effects of vector-mediated trophic factor gene transfer will offer a new approach for modulating septal cholinergic transmission and Trk receptor activity.

Animals↗
PubMed1999

Diffusion tensor MR imaging and comparative histology of glioma engrafted in the rat spinal cord.

MR imaging using contrast material derived from the diffusion of tissue water was tested for its ability to provide a nondestructive histologic analysis of tumor morphology. An apparent diffusion tensor MR image of a glioma engrafted within a rat spinal cord was generated in which fiber orientation in three dimensions was displayed in color. This imaging method clearly separated tumor from host white and gray matter and corresponded well with conventional histologic microscopy.

Animals↗
PubMed1998

Neuronal matrix metalloproteinase-2 degrades and inactivates a neurite-inhibiting chondroitin sulfate proteoglycan.

Chondroitin sulfate proteoglycans (CSPGs) are implicated in the regulation of axonal growth. We previously reported that the neurite-promoting activity of laminin is inhibited by association with a Schwann cell-derived CSPG and that endoneurial laminin may be inhibited by this CSPG as well [Zuo J, Hernandez YJ, Muir D (1998) Chondroitin sulfate proteoglycan with neurite-inhibiting activity is upregulated after peripheral nerve injury. J Neurobiol 34:41-54]. Mechanisms regulating axonal growth were studied by using an in vitro bioassay in which regenerating embryonic dorsal root ganglionic neurons (DRGn) were grown on sections of normal adult nerve. DRGn achieved slow neuritic growth on sections of normal nerve, which was reduced significantly by treatment with metalloproteinase inhibitors. Similar results were obtained on a synthetic substratum composed of laminin and inhibitory CSPG. DRGn expressed the matrix metalloproteinase, MMP-2, which was transported to the growth cone. Recombinant MMP-2 inactivated the neurite-inhibiting CSPG without hindering the neurite-promoting potential of laminin. Similarly, neuritic growth by DRGn cultured on normal nerve sections was increased markedly by first treating the nerve sections with MMP-2. The proteolytic deinhibition by MMP-2 was equivalent to and nonadditive with that achieved by chondroitinase, suggesting that both enzymes inactivated inhibitory CSPG. Additionally, the increases in neuritic growth resulting from treating nerve sections with MMP-2 or chondroitinase were blocked by anti-laminin antibodies. From these results we conclude that MMP-2 provides a mechanism for the deinhibition of laminin in the endoneurial basal lamina and may play an important role in the regeneration of peripheral nerve.

Animals↗
PubMed1998

Degradation of chondroitin sulfate proteoglycan enhances the neurite-promoting potential of spinal cord tissue.

The contribution of chondroitin sulfate proteoglycan (CSPG) in the suppression of axonal growth in rat spinal cord has been examined by means of an in vitro bioassay in which regenerating neurons are grown on tissue section substrata. Dissociated embryonic chick dorsal root ganglionic neurons were grown on normal and injured adult spinal cord tissue sections treated with chondroitinases. Neuritic growth on normal spinal cord tissue was meager. However, both the percentage of neurons with neurites and the average neurite length were substantially greater on sections treated with chondroitinase ABC. Enzymes that specifically degraded dermatan sulfate or hyaluronan were ineffective. Neuritic growth was significantly greater on injured (compared to normal) spinal cord and a further dramatic increase resulted from chondroitinase ABC treatment. Neurites grew equally within white and gray matter regions after chondroitinase treatment. Observed increases in neurite outgrowth on chondroitinase-treated tissues were largely inhibited in the presence of function-blocking laminin antibodies. These findings indicate that inhibitory CSPG is widely distributed and predominant in both normal and injured spinal cord tissues. Additionally, inhibitory CSPG is implicated in negating the potential stimulatory effects of laminin that might otherwise support spinal cord regeneration.

Animals↗