PubMed Health⌕ Search

Biomedical subjects

R E MacLaren

Publications and source records attributed to R E MacLaren.

At least 19 recordsLinked to original sources
PubMed2006

Retinal repair by transplantation of photoreceptor precursors.

Photoreceptor loss causes irreversible blindness in many retinal diseases. Repair of such damage by cell transplantation is one of the most feasible types of central nervous system repair; photoreceptor degeneration initially leaves the inner retinal circuitry intact and new photoreceptors need only make single, short synaptic connections to contribute to the retinotopic map. So far, brain- and retina-derived stem cells transplanted into adult retina have shown little evidence of being able to integrate into the outer nuclear layer and differentiate into new photoreceptors. Furthermore, there has been no demonstration that transplanted cells form functional synaptic connections with other neurons in the recipient retina or restore visual function. This might be because the mature mammalian retina lacks the ability to accept and incorporate stem cells or to promote photoreceptor differentiation. We hypothesized that committed progenitor or precursor cells at later ontogenetic stages might have a higher probability of success upon transplantation. Here we show that donor cells can integrate into the adult or degenerating retina if they are taken from the developing retina at a time coincident with the peak of rod genesis. These transplanted cells integrate, differentiate into rod photoreceptors, form synaptic connections and improve visual function. Furthermore, we use genetically tagged post-mitotic rod precursors expressing the transcription factor Nrl (ref. 6) (neural retina leucine zipper) to show that successfully integrated rod photoreceptors are derived only from immature post-mitotic rod precursors and not from proliferating progenitor or stem cells. These findings define the ontogenetic stage of donor cells for successful rod photoreceptor transplantation.

Animals↗
PubMed2006

EIAV vector-mediated delivery of endostatin or angiostatin inhibits angiogenesis and vascular hyperpermeability in experimental CNV.

We evaluated the efficacy of equine infectious anaemia virus (EIAV)-based lentiviral vectors encoding endostatin (EIAV.endostatin) or angiostatin (EIAV.angiostatin) in inhibiting angiogenesis and vascular hyperpermeability in the laser-induced model of choroidal neovascularisation (CNV). Equine infectious anaemia virus.endostatin, EIAV.angiostatin or control (EIAV.null) vectors were administered into the subretinal space of C57Bl/6J mice. Two weeks after laser injury CNV areas and the degree of vascular hyperpermeability were measured by image analysis of in vivo fluorescein angiograms. Compared with EIAV.null-injected eyes, EIAV.endostatin resulted in a 59.5% (P<0.001) reduction in CNV area and a reduction in hyperpermeability of 25.6% (P<0.05). Equine infectious anaemia virus.angiostatin resulted in a 50.0% (P<0.05) reduction in CNV area and a 23.9% (P<0.05) reduction in hyperpermeability. Equine infectious anaemia virus.endostatin, but not EIAV.angiostatin significantly augmented the frequency of apoptosis within the induced CNV as compared with injected controls. TdT-dUTP terminal nick end labeling analysis 5 weeks post-injection, and histological and retinal flatmount analysis 12 months post-injection revealed no evidence of vector- or transgene expression-related deleterious effects on neurosensory retinal cells, or mature retinal vasculature in non-lasered eyes. Highly expressing EIAV-based vectors encoding endostatin or angiostatin effectively control angiogenesis and hyperpermeability in experimental CNV without long-term deleterious effects, supporting the use of such a strategy in the management of patients with exudative age-related macular degeneration.

Angiogenesis Inhibitors↗
PubMed2002

Spontaneous foreign body extrusion following perforating eye injury.

A structured approach to the management of a perforating ballistic eye injury is illustrated in this case, where initial treatment was limited to simple corneal wound closure and antibiotic prophylaxis. A pellet had passed completely through the globe but the retina remained attached, and it was decided to manage the case conservatively. Two retained foreign bodies were extruded spontaneously some months after the injury when suture removal and delayed cataract surgery led to a virtually perfect visual outcome. The patient has had no further complications at least three years after initial injury. The management of this civilian case illustrates some basic concepts in treating ballistic eye injuries that may be applicable in a military setting.

Adult↗
PubMed1999

Re-establishment of visual circuitry after optic nerve regeneration.

In mammals there are a few circumstances in which axotomised ganglion cell axons can regenerate. For instance, in vitro explants of retina can be encouraged to regenerate axons into appropriate culture media. Similarly, axotomised ganglion cells can regenerate into a peripheral nerve graft surgically connected to the optic nerve head, and during early development axons are able to regenerate across the retina to re-enter the optic nerve. This is certainly encouraging, but we are a long way from applying these observations to clinical practice. We need to know whether regenerating axons also retain a functional capacity for navigation. We must ask whether a regenerated projection is likely to be topographic rather than disordered. In this brief review we will look at some selected models of ganglion cell regeneration in order to examine this question of navigation in more detail. This is an important issue: the capacity to re-establish appropriate rather than random connections after ganglion cell regeneration would most likely be necessary for any meaningful return of visual function.

Animals↗
PubMed1998

Regeneration and transplantation of the optic nerve: developing a clinical strategy.

Three separate experimental models of optic nerve regeneration have been presented--along the existing pathway in the presence of antibodies to neutralise inhibitory molecules, along peripheral nerve grafts and from retinal transplants. Each offers a theoretical clinical strategy for restoration of vision, if the mechanism of re-establishment of maps and reconnection to appropriate targets during regeneration can be determined. This is the process of axon guidance, and underlines the importance of our research into the molecular determinants that guide normal development of the visual system.

Animals↗
PubMed1997

Chiasmatic specificity in the regenerating mammalian optic nerve.

The mammalian central nervous system is capable of regenerating; however, there is no evidence that the regenerating axons can navigate along their normal pathways and reestablish topographically organized projections: essential for functional return of vision. Here retinal ganglion cells in the opossum Monodelphis were birthdated with tritiated thymidine on the sixth postnatal day (P6), before being lesioned in the temporal retina at P8. Retrograde tracing with horseradish peroxidase injected into the ipsilateral optic tract at P24 showed that the temporal crescent had reformed behind the retinal lesion. By comparisons of cell and thymidine counts from lesioned and control regions of retina, it was estimated that about 40% of the normal number of ganglion cells are able to regenerate into the ipsilateral optic tract following a lesion in the temporal retina at P8. A clear line of decussation (separation of ipsilateral and contralateral projections) reformed in the lesioned temporal retina and regenerating ganglion cells labeled with DiI were turned at appropriate points on passing through the optic chiasm. This is evidence of chiasmatic specificity with regard to lesioned retinal ganglion cells regenerating into the ipsilateral optic tract.

Animals↗
PubMed1996

Expression of myelin proteins in the opossum optic nerve: late appearance of inhibitors implicates an earlier non-myelin factor in preventing ganglion cell regeneration.

The pattern of appearance of myelin-associated proteins in the visual system of the Brazilian opossum Monodelphis domestica is described. Whole mounts of optic nerve, chiasm, and optic tract were sectioned horizontally and incubated with antibodies to myelin basic protein (MBP), proteolipid protein (PLP), myelin-associated glycoprotein (MAG), "Rip," and the neurite inhibitory protein (IN-1), followed by visualization with diaminobenzidine and a peroxidase-conjugated secondary antibody. PLP is first detectable 24 days after birth (P24) at the centre of the optic chiasm. MBP, MAG, Rip, and IN-1 appear first in the same area at P26. By P28 the distribution of all proteins is similar, occupying the entire chiasm, optic tracts, and prechiasmatic portion of the optic nerves. Protein expression progresses along the optic nerve to reach the lamina cribrosa by P34, coincident with the time of eye opening. A critical period in which the retinofugal pathway has a regenerative capacity has recently been observed in Monodelphis. This period ends at P12, 2 weeks before the appearance of the myelin-associated inhibitory proteins MAG and IN-1. These results therefore suggest that regeneration in the developing retinofugal projection of the opossum is restricted by an earlier non-myelin factor, which is in contrast to current literature on the spinal cord.

Animals↗
PubMed1996

Immunological instability of persistent adenovirus vectors in the brain: peripheral exposure to vector leads to renewed inflammation, reduced gene expression, and demyelination.

Nonreplicating adenovirus vectors are being developed as vehicles for the delivery of therapeutic genes in vivo. Whereas in many organs an antiviral T cell response eliminates the vector and damages local tissue, when adenovirus vectors are injected into the brain the subsequent immune attack can be ineffective, allowing the vector to persist. In the present study, E1-deleted human adenovirus vectors were injected into the caudate nucleus of rats. Two months later, expression of protein from the vector was still evident and little inflammation was seen. A subcutaneous injection of adenovirus vector at this time, however, led within 2 weeks to severe mononuclear inflammation and microglial activation in the caudate. This caused local demyelination and a decrease in detectable protein expression from the vector. Interestingly, intense microglial activation and numerous lymphocytes and monocytes were also seen in brain areas containing neurons capable of retrogradely transporting the adenovirus vector from the caudate. Control experiments established that this inflammation in distant brain areas was not a nonspecific consequence of degeneration. These experiments demonstrate that although adenovirus vectors can persist in the brain without causing chronic inflammation, they remain the potential target of a damaging cell-mediated immune response brought about by a subsequent peripheral exposure to vector. The finding of lymphocytes in brain areas that project to the caudate further shows that viral antigens that are retrogradely transported by neurons can also be the target of a T cell attack.

Adenoviridae↗
PubMed1996

Development and role of retinal glia in regeneration of ganglion cells following retinal injury.

AIMS/BACKGROUND: Recent observations have shown that the glial scar resulting from a surgical lesion of the immature retina differs from elsewhere in the central nervous system, in that it permits the through growth and reconnection of regenerating axons. This study in the opossum examines in detail the development and reaction to injury of retinal glia at different developmental stages, and specifically examines the distribution of the gliosis related inhibitory molecule, chondroitin sulphate proteoglycan (CSPG), making comparisons with a control site of gliosis in the cerebral cortex. METHODS: A linear slit was cut into the retina or cortex with a fine tungsten probe. After a variable time delay, immunocytochemistry of the resulting gliosis was employed to detect astrocytes with glial fibrillary acidic protein (GFAP), Müller cells with vimentin, and CSPG with CS-56 antibodies. GFAP was also used at different ages to examine the normal development of astrocytes in the retina of this species. RESULTS: Astrocytes entered the retina 12 days after birth (P12), closely associated with blood vessels in the nerve fibre layer. In experiments at all ages studied, cellular continuity was re-established across the lesioned retina, which did not result in a significant astrocyte proliferation or CSPG expression. In contrast, cortical injury led to the development of a cystic cavity surrounded by astrocytes and CSPG. Müller cells expressed GFAP but not CSPG in the lesioned retina. CONCLUSION: Successful regrowth of ganglion cells through a retinal lesion may be partly the result of the scarcity of astrocytes in the retina, which results in minimal gliosis, or of their apparent inability to express inhibitory molecules.

Animals↗
PubMed1995

A critical period for axon regrowth through a lesion in the developing mammalian retina.

Although the central nervous system of mature mammals is incapable of regeneration, certain elements present in the developing system must permit and promote the growth of new axons to their initial targets. We investigate whether the environment of a developing visual system is capable of supporting regeneration in the Brazilian opossum Monodelphis domestica, in which the retinofugal system develops postnatally. Retinae were lesioned up to the 16th postnatal day and analysed for regeneration after a further 7-10 days. Anterograde tracing with Dil showed axons to have regrown from the axotomized area of retina directly through the lesion. Retrograde tracing with horseradish peroxidase injected into the superior colliculus confirmed that axons from the lesioned area of retina had grown to an appropriate position in the midbrain. The proportion of retinae in which axonal continuity was restored across the lesion decreased as the visual system matured, falling to zero after the 12th postnatal day. Thus a critical period exists in the postnatal opossum in which a retinal lesion permits axon passage. Correlating these results to the known pattern of retinofugal pathway development provides an insight into factors that may restrict this critical period to the 12th postnatal day, and suggests that at least some of the axotomized neurons are regenerating.

Animals↗
PubMed1995

Retinal haemorrhage in Himalayan mountaineers.

The fundi of 14 climbers were monitored on ascent to 6000 metres over a 15 day period in the Nepal Himalaya. A total of 4 climbers experienced symptomless haemorrhages. These haemorrhages were not secondary to changes in haemoglobin concentration, nor did they appear correlated to the use of acetazolamide. The risk of developing retinal haemorrhage was, however, significantly greater in the better acclimatized individuals. Possible reasons for this relationship are discussed.

Acetazolamide↗
PubMed1993

Use of an accident and emergency department observation ward in the management of head injury.

The management of 405 patients presenting with head injury to an accident and emergency department was assessed. Sixty-nine patients were admitted, although this number should have been 127 according to current guidelines on the management of head injury. Only three attenders were admitted inappropriately according to these guidelines. An accident and emergency observation ward was open on weekdays only; at weekends, patients with head injury were admitted to a general surgical ward. When the observation ward was open, 51 of the 76 patients (67 per cent) presenting with admission criteria were admitted. When closed, only 15 of the 51 patients (29 per cent) with these criteria were admitted. Guidelines were applied effectively to reduce the number of unnecessary admissions, but there was a significant number of patients with minor head injury who were discharged inappropriately. This number was much reduced when an observation ward was available.

Craniocerebral Trauma↗
PubMed1993

Skull X-ray after head injury: the recommendations of the Royal College of Surgeons Working Party report in practice.

In 1986 a Royal College of Surgeons Working Party published guidelines, based on over 15 years of clinical research both here and in the U.S.A., on when to perform skull X-rays on a head injury patient. In this retrospective study the recorded details of 405 patients who presented to an accident and emergency (A&E) department over a 3-month period in 1991 are analysed, and the Report criteria applied to each one to assess whether the guidelines are being followed in performing a skull X-ray. According to these guidelines, 191 of these patients (47.2%) should have been X-rayed, however, only 83 were. Only one patient was thought to have been X-rayed inappropriately. The Report criteria most commonly thought by the A&E doctors not to warrant skull X-ray, were loss of consciousness, amnesia, dizziness, blurred vision, headache, and alcohol intoxication. The reasons why these criteria are being ignored are examined, and together with reference to recent studies, slight alterations to the Working Party guidelines are suggested to make them more applicable to everyday situations of head injury encountered in a casualty department.

Adolescent↗
PubMedDate not supplied

A glial palisade delineates the ipsilateral optic projection in Monodelphis.

In developing marsupials, the path taken through the optic chiasm by ipsilaterally projecting retinal ganglion cells is complicated. Just prior to entry into the chiasm, ganglion cells destined for the ipsilateral optic tract separate from the remainder of axons by turning abruptly downwards to take a position in the ventral part of the optic nerve. In this report, it is shown that a discrete population of about 10-15 large glial cells transiently form a linear array across the prechiasmatic part of the optic nerve, precisely at this axon turning point. The distinct morphology of these cells and their novel location may reflect a specialized role in axon guidance.

Animals↗