Biomedical subjects

I D Duncan

Publications and source records attributed to I D Duncan.

At least 19 recordsLinked to original sources

PubMed1997

Microtubule organization and stability in the oligodendrocyte.

The oligodendrocyte is the glial cell responsible for the formation and maintenance of CNS myelin. Because the development of neuronal morphology is known to depend on the presence of highly organized microtubule arrays, it may be hypothesized that the properties of microtubules influence the form and function of oligodendrocytes. The goals of the present study were to define the physical attributes of microtubules in oligodendrocytes maintained in vitro. The results of electron and confocal microscopy indicate that microtubules are present throughout the cell bodies and large and small processes of oligodendrocytes and are rarely associated with discrete microtubule-organizing centers. A modified "hooking" protocol demonstrated that the polarity orientation of microtubules is uniformly plus-end distal in small oligodendrocyte processes, compared with a nonuniform, predominantly plus-end distal orientation in large processes. Oligodendrocytes were exposed to the microtubule-depolymerizing drug nocodazole to examine microtubule stability in these cells. The results suggest that oligodendrocyte microtubules can be resolved into at least three distinct microtubule populations that differ in their kinetics of depolymerization in the presence of nocodazole. These findings suggest that the properties of the oligodendrocyte microtubule array reflect the functions of the different regions of this highly specialized cell.

Animals↗

PubMed1997

Induction of sodium channel clustering by oligodendrocytes.

As oligodendrocytes wrap axons of the central nervous system (CNS) with insulating myelin sheaths, sodium channels that are initially continuously distributed along axons become segregated into regularly spaced gaps in the myelin called nodes of Ranvier. It is not known whether the regular spacing of nodes results from regularly spaced glial contacts or is instead intrinsically specified by the axonal cytoskeleton. Contact with Schwann cells induces clustering of sodium channels along the axons of peripheral neurons in vitro and in vivo. Similarly, it has been suggested that astrocyte contact induces clustering of sodium channels along CNS axons. Here we show that oligodendrocytes are necessary for clustering of sodium channels in vitro and in vivo. The induction, but not the maintenance, of sodium-channel clustering along the axons of highly purified rat retinal ganglion cells in culture depends on a protein secreted by oligodendrocytes. Surprisingly, the oligodendrocyte-induced clusters are regularly spaced at the predicted interval in the absence of glial-axonal contact. Mutant rats that are deficient in oligodendrocytes develop few axonal sodium channel clusters in vivo. These results demonstrate a crucial role for oligodendrocytes in inducing clustering of sodium channels.

Animals↗

PubMed1997

Invasive cervical cancer after conservative therapy for cervical intraepithelial neoplasia.

BACKGROUND: Conservative outpatient therapy for cervical intraepithelial neoplasia (CIN) by ablative or excisional techniques is widely used. The main objective of this treatment is the prevention of invasive cervical cancer. We assessed the rate of invasive disease and the duration of the risk of developing invasive cervical cancer after such treatment. METHODS: Four UK centres have used life-table methods to analyse the long-term results of conservative treatment of CIN. We combined and updated data from these studies to investigate the rate of invasive disease after treatment and the duration of that risk. FINDINGS: The data comprised 44 699 woman-years of follow-up, with 2116 women under observation 8 years after treatment. 33 women developed invasive cancer, 14 of whom had microinvasion. The cumulative rate of invasion 8 years after treatment was 5.8 per 1000 women and the rate of invasive cancer during this period was 85 (95% CI 60-119) per 100,000 woman-years. The risk of developing cancer did not change throughout the 8 years of follow-up. INTERPRETATION: These data show that conservative outpatient therapy in women with CIN reduces the risk of invasive cancer of the cervix by 95% during the first 8 years after treatment. However, even with careful, long-term follow-up, the risk of invasive cervical cancer among these women is about five times greater than that among the general population of women throughout that period. Careful follow-up is essential for at least 10 years after conservative treatment of CIN.

Adult↗

PubMed1997

Normal temporal and spatial distribution of oligodendrocyte progenitors in the myelin-deficient (md) rat.

A point mutation in exon 3 of the proteolipid protein (PLP) gene of the myelin-deficient (md) rat leads to a failure of oligodendrocyte maturation and early death of oligodendrocytes, resulting in dysmyelination. It has been suggested that an alternative-splice isoform of PLP, known as DM-20, might be expressed in oligodendrocyte progenitors in the embryonic central nervous system (CNS), raising the possibility that early development of the oligodendrocyte lineage might also be affected in the md rat. To test this suggestion, we visualized oligodendrocyte progenitors in the embryonic md rat spinal cord and brain by in situ hybridization with a probe to the platelet-derived growth factor alpha receptor (PDGFR). We could detect no abnormalities in the time of first appearance of oligodendrocyte precursors, nor in their subsequent proliferation and dispersal throughout the CNS. These data strongly suggest that the PLP mutation in the md rat primarily or exclusively affects the later stages of oligodendrocyte lineage.

Animals↗

PubMed1997

Myelination of the canine central nervous system by glial cell transplantation: a model for repair of human myelin disease.

There is a lack of effective means of promoting remyelination of the central nervous system (CNS) in humans with chronic demyelinating disease. We have investigated the ability of transplanted glia to myelinate areas of the CNS equivalent to focal demyelinated lesions in multiple sclerosis (MS). In these studies we show that transplantation of oligodendrocytes or their progenitors into the CNS of a neonatal or adult canine myelin mutant results in repair of large areas similar in size to many MS plaques. Progenitor or pre-progenitor cells of the oligodendrocyte lineage have the greatest capacity for myelination following grafting, although cells of neonatal origin may also be used. Such an approach may therefore have therapeutic value in the repair of focal lesions in human myelin disease.

Age Factors↗

PubMed1997

Schwann cell invasion of the central nervous system of the myelin mutants.

Schwann cells are excluded from the CNS during development by the glial limiting membrane, an area of astrocytic specialisation present at the nerve root transitional zone, and at blood vessels in the neuropil. This barrier, however, can be disrupted and, with the highly migratory nature of Schwann cells, can result in their invasion and myelination of the CNS in many pathological situations. In this paper we demonstrate that this occurs in a number of myelin mutants, including the myelin deficient (md) and taiep rats and the canine shaking (sh) pup. While it is still relatively uncommon in the rodent mutants, the sh pup shows extensive Schwann cell invasion along the neuraxis. This invasion involves the spinal cord, brain stem, and cerebellum and increases in amount and distribution with age. In situ hybridisation studies using a Pzero riboprobe suggest that the likely origin of these cells in the sh pup is the nerve roots, primarily the dorsal roots. Paradoxically, Schwann cell myelination of the CNS increases with time in the sh pup despite a marked, progressive gliosis involving the glia limitans and neuropil. Thus the mechanism by which these cells migrate into the CNS through the gliosed nerve root transitional zone or from vasa nervorum remains unknown. Extensive Schwann cell CNS myelination may have therapeutic significance in human myelin disease.

Animals↗

PubMed1996

Efficient and sustained transgene expression in mature rat oligodendrocytes in primary culture.

In order to evaluate the characteristics and efficiency of gene transfer in primary cultures of oligodendrocytes, four different techniques including particle bombardment (Accell gene gun), cationic liposome-mediated transfection (lipofection), calcium phosphate co-precipitation and retroviral infection were compared using the LacZ and luciferase reporter genes. Highly purified postnatal adult rat oligodendrocytes were obtained by sequential immunopanning, plated in culture, and transfected using various reporter and promoter genes. The most efficient expression of LacZ and luciferase genes was found with particle mediated gene delivery. The transgene expression level obtained with gene gun delivery was at least two- to 100-fold greater than three other tested gene transfer methods. Comparison of the relative strength of four viral and two cellular promoters in these primary oligodendrocytes cultures demonstrated that the CMV promoter was the strongest. Using a human growth hormone (hGH) reporter gene, a long-term transgene expression pattern in primary oligodendrocytes was demonstrated to be sustained in culture for the entire experimental period (4 weeks) after particle-mediated gene transfer. These results demonstrate that expression of a foreign gene can be effectively achieved in primary cultures of adult oligodendrocytes, especially by using the particle bombardment method. The results also suggest that the current ex vivo gene transfer system may be used to manipulate oligodendrocytes for future application in gene therapy studies.

Adenoviridae↗

PubMed1996

Glial cell transplantation and remyelination of the central nervous system.

Glial cell transplantation has proved to be a powerful tool in the study of glial cell biology. The extent of myelination achieved by transplanting myelin-producing cells into the CNS of myelin mutants, or into focal demyelinating lesions has raised hope that such a strategy may have therapeutic applications. Oligodendrocytes or Schwann cells could be used for repair. It is likely that the immature stages of the oligodendrocyte lineage have the best phenotypic characteristics for remyelination when transplanted, either as primary cells or as immortalized cells or cell lines. Prior culturing and growth factor treatment provides opportunities to expand cell populations before transplantation as dissociated cell preparations. Cell lines are attractive candidates for transplantation, but the risk of transformation must be monitored. The application of this technique to human myelin disorders may require proof that migration, division and stable remyelination of axons by the transplanted cells can occur in the presence of gliosis and inflammation.

Animals↗

PubMed1996

Is there any value in the long term follow up of women treated for endometrial cancer?

OBJECTIVE: To evaluate the clinical benefit of routine follow up of women after treatment for endometrial adenocarcinoma. DESIGN: Retrospective case analysis. PARTICIPANTS: All cases diagnosed and treated for endometrial adenocarcinoma in Tayside, Scotland during 1982 to 1984 inclusive. METHODS: Case-note and cancer registration document review. RESULTS: Of 102 patients, 97 had complete follow up for 10 years or until death. Recurrent disease was diagnosed in 17 women, only six of whom were asymptomatic at the time of diagnosis. There was no difference in survival between cases with symptomatic and asymptomatic recurrences. No recurrences were diagnosed more than six years after initial diagnosis. CONCLUSIONS: The diagnosis of asymptomatic recurrent endometrial carcinoma was not associated with improved long term survival. This small study showed no evidence of improved survival from the current practice of routine clinical review following treatment for endometrial adenocarcinoma. The effect of follow up on patient anxiety remains to be assessed.

Adenocarcinoma↗

PubMed1996

Molecular analysis of glial cell development in the canine 'shaking pup' mutant.

The shaking pup, a canine mutant, carries a point mutation in the myelin proteolipid protein (PLP) gene that causes dysmyelination of the central nervous system (CNS) with resultant tremor, seizures, and other persistent neurological deficits. The developmental potential of glial cells in the shaking pup CNS and peripheral nervous system (PNS) was evaluated by quantitative analysis of the expression of several glial-specific genes. All of the myelin-associated genes demonstrated developmental patterns of expression similar to those observed in the controls, but at significantly reduced levels. Expression of the genes for the major CNS myelin proteins, PLP and the myelin basic protein, are most dramatically affected in the shaking pup, although reduced expression levels are observed for other oligodendrocyte-specific genes such as 2',3'-cyclic nucleotide 3'phosphodiesterase and glucose phosphate dehydrogenase. The pattern of gene expression in the shaking pup indicates that the oligodendrocytes experience an inhibition in development after the myelination program has begun. There appears to be little evidence for an astrocytic response to the dysmyelinating condition at the RNA level, but we present evidence for ectopic expression of P0 mRNA in the CNS. Expression of the P0 and PLP genes in the sciatic nerve appears to be normal, reinforcing previous reports that PNS myelination is unaffected by the mutation in the PLP gene.

Animals↗

PubMed1996

Mature results of a randomized trial of two doses of cisplatin for the treatment of ovarian cancer. Scottish Gynecology Cancer Trials Group.

PURPOSE: In 1992, we reported the first results of a randomized study in ovarian cancer, comprising two doses of cisplatin and indicated a significant difference (P = .0008) in median survival. Four years later, we now describe the results of this trial. PATIENTS AND METHODS: After a median follow-up of 4 years and 9 months, 115 of 159 cases of advanced ovarian cancer, originally randomized to receive six cycles of cyclophosphamide 750 mg/m2 and either a high dose (HD) of 100 mg/m2 cisplatin or a low dose (LD) of 50 mg/m2 (LD) cisplatin, have now died. RESULTS: The overall survival for HD and LD patients is 32.4% and 26.6%, respectively, and the overall relative death rate is 0.68 (P = .043). This represents a reduction in overall benefit with longer follow-up compared with the first 2 years (relative death rate of 0.52). Toxicity, particularly neurotoxicity, is still evident in the fourth year (10/31 on HD compared with 1/24 on LD). CONCLUSION: Our recommended dose of cisplatin in combination schedule is therefore 75 mg/m2, representing the optimal balance between efficacy and toxicity.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1995

Myelin mutants: new models and new observations.

The myelin mutants have been extensively used as tools to study the complex process of myelination in the central and peripheral nervous system. A multidisciplinary approach to the study of these models ultimately allows a correlation to be made between phenotype and genotype. This correlation may then lead to the formation of new hypotheses about the functions of the products of genes involved in myelination. This review presents a number of new myelin mutants which have recently been described. The species involved include mouse, rat, rabbit, hamster, and dog models. The genetic defect has not been elucidated in all of these animals, but most have been characterized clinically and pathologically, and, in some cases, biochemically. In addition, a better known myelin mutant, the trembler mouse, is discussed. Recent molecular findings have brought this fascinating mutant to the forefront of the field of peripheral nervous system research. The range of abnormalities in the mutants described in this review includes defects in specific myelin proteins, suspected abnormalities in membrane formation, and apparent defects of the oligodendrocyte cytoskeleton. These findings underscore the complexity of the myelination process and highlight the numerous ways in which it can be disrupted.

Animals↗

PubMed1995

Gene expression and oligodendrocyte development in the myelin deficient rat.

The proteolipid proteins play a major role in the structure of the CNS myelin sheath, but they have also been implicated in the oligodendrocyte development leading to myelination. Mutations in the PLP gene result in severe dysmyelination and a paucity of mature oligodendrocytes. The myelin deficient (md) rat, carrying a Thr75-->Pro substitution present in both isoforms of proteolipid protein (PLP and DM20), is the most severely affected of the PLP mutants described to date. The expression of myelin associated genes was quantitated to determine the effect of the mutation on oligodendrocyte development in vivo. At 5 days postnatal, gene expression in the md rat approximated that in age-matched control rats, but as they matured, there was a progressive inhibition of gene expression in the md rats. The genes expressed late in the myelination program (PLP and MBP) were affected more dramatically than those expressed earlier in oligodendrocyte development (CNP and GPDH). The results indicate that the later stages of oligodendrocyte maturation and myelin elaboration are inhibited.

Animals↗

PubMed1995

Canine oligodendrocytes undergo morphological changes in response to basic fibroblast growth factor (bFGF) in vitro.

The mature oligodendrocyte, though able to divide under certain circumstances, has been regarded as incapable of changing into a phenotypically plastic cell type. To further explore this question, we developed an in vitro system in which a virtually pure population of early postnatal canine oligodendrocytes were cultured in a serum free, defined medium. We tested the oligodendrocytes' morphological and mitotic responses to concentration of basic Fibroblast Growth Factor (bFGF) ranging from 5 ng to 100 ng/ml. We found that bFGF effected both the morphology and mitotic potential of these cells. In addition, oligodendrocytes exposed to bFGF respond to 10% fetal bovine serum (FBS) by undergoing morphological changes that are quite different than naive oligodendrocytes exposed to 10% FBS, suggesting that bFGF causes some fundamental change in plasticity.

Animals↗

PubMed1995

Acute dispersion of glial cells following transplantation into the myelin-deficient rat spinal cord.

Evaluation of glial cell migration following transplantation can be difficult as the force of the injection itself may cause the cells to become immediately dispersed. In this study we evaluated the extent of spread of cells after injection of 1 microliter of a dissociated cell suspension (50,000 cells/microliter) into the dorsal columns of the thoracolumbar spinal cord in the neonatal myelin-deficient (md) rat. Spinal cords were examined at 0, 4, and 24 h after injection to determine the dispersion of cells away from the initial site of deposition. Examination of skip-serial sections collected at 50-microns intervals rostral and caudal to the site of transplantation showed that the injection could result in a spread of transplanted cells up to 1,600 microns. Migration should therefore be defined as the detection of cells beyond the rostral-caudal boundaries defined by the injection deposition. Cell dispersion should be taken into account when evaluating the results of migration in previous and future experiments concerning glial cell transplantation.

Animals↗

PubMed1995

Oligodendrocyte survival and function in the long-lived strain of the myelin deficient rat.

This study has examined cellular and molecular aspects of glial cell function in a newly described long-lived myelin deficient rat mutant. In contrast to the shorter-lived mutants which died at 25-30 days, the longer-lived mutant rats lived to 75-80 days of age. Despite living longer, these mutants had a similar frequency of seizures to their younger counterparts. In the spinal cord and optic nerves of the older mutants, myelinated fibres in similar numbers to those seen in the younger myelin deficient rats were present. However, the total glial cell numbers were markedly reduced with few remaining normal appearing oligodendrocytes, and very few microglia compared to the younger mutants. In addition, little or no cell death or division was seen in the longer-lived rats. However, there was some evidence of ongoing myelination and the persistence of immature oligodendrocytes or their progenitors in the older mutant. There was some continued myelin gene expression, although this was at much reduced levels compared to normal, with proteolipid protein and myelin basic protein being most affected. In situ hybridization analysis for proteolipid protein mRNA showed that few proteolipid protein expressing oligodendrocytes remained in the 70-80-day-old mutant. Polymerase chain reaction analysis of exon 3 of the long-lived mutant revealed the same point mutation as described in the younger myelin deficient rat.

Animals↗

PubMed1995

Cold coagulation.

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Age Factors↗

PubMed1995

Screening for cervical neoplasia in Dundee and Angus: 10 years on.

OBJECTIVE: To evaluate the effect of changed cervical screening policies on a steady population with low migratory tendencies. DESIGN: A retrospective analysis study. SETTING: Dundee and Angus, Scotland. SUBJECTS: All women who developed cervical carcinoma between 1957 and 1992. MAIN OUTCOME MEASURES: The incidence of and mortality from cervical cancer after the introduction of organised cervical screening in 1962, according to age, stage, histology and screening history. RESULTS: The initial fall in incidence of cervical cancer seen in women between 35 and 54 years after the introduction of cervical screening was not sustained during the last 10 years of our study and appears to have been transferred to women aged 55 years and older instead. After 1976 an increase in the incidence of cervical cancer was seen in women under 35 years. The reduction in mortality from cervical cancer appears to have reached a plateau since 1976. No effect of cervical screening was seen on the incidence of adenocarcinoma of the cervix. CONCLUSIONS: The effect of changed cervical screening policies has been shown for a small population for a period of 35 years. The incidence of the higher stages of squamous cervical cancer continues to fall. The increase in incidence of cervical cancer in women under 35 years confirms similar trends seen in other countries. A background mortality rate refractory to further intensification of screening appears to have been reached. Adenocarcinoma of the cervix appears to gain in importance as cervical screening policies are shown to have their effect on its squamous counterpart.

Adenocarcinoma↗