Biomedical subjects

G Jeffery

Publications and source records attributed to G Jeffery.

At least 19 recordsLinked to original sources

PubMed2006

Age-related changes in the thickness of the human lamina cribrosa.

OBJECTIVE: To measure the human lamina cribrosa thickness (LCT) in vitro in fully hydrated specimens and to determine whether there is any association between thickness and age or sex. METHODS: 45 fixed human optic nerves, age range 9-90 years, were dissected from the globe and frozen sectioned. The study was divided into two parts: the first investigated the overall change in LCT and cribrosal beam thickness (CBT) with age, and the second divided eyes into two specific age groups (38-49 and 78-87 years) and assessed differences with respect to age and sex. RESULTS: LCT ranged from 345.4 to 555.9 microm between the samples. A positive relationship was found between LCT and age (LCT = 2.41xage+365.5, 95% confidence interval (CI) for slope 1.31 to 3.52; r(2) = 0.30, p<0.001). A regional difference in CBT was observed, with beams being thickest at the posterior cribrosa (mean 14.8 (standard deviation (SD) 2.2) microm) and thinnest at the anterior cribrosa (9.8 (SD 2.4) microm). CBT increased with increasing age. Differences related to sex were also found, with females having relatively thinner LCT than males, irrespective of age, but this was not statistically significant. CONCLUSIONS: This study shows an increase in human LCT with increasing age. This changing structural property of the lamina cribrosa may have implications for its functioning with respect to compliance and reversibility, and has particular relevance to glaucoma, where increasing age has been identified as a strong risk factor for the development of the disease.

Adolescent↗

PubMed2005

The achiasmia spectrum: congenitally reduced chiasmal decussation.

AIM: To describe the clinical spectrum of achiasmia, a congenital disorder of reduced relative decussation at the optic chiasm. METHODS: A retrospective case note and patient review of nine children (four boys). Achiasmia was defined by the combination of a characteristic asymmetry of the monocular visual evoked potential (VEP) response to flash and neuroimaging showing reduced chiasmal size. RESULTS: Three of the children had an associated skull base encephalocele with agenesis of the corpus callosum. In two patients achiasmia was associated with septo-optic dysplasia. Three patients had no neuroimaging abnormalities other than reduced chiasmal size and have no known pituitary dysfunction. One child had multiple physical deformities but the only brain imaging abnormality was reduced chiasmal size. CONCLUSIONS: Some children with disorders of midline central nervous system development, including septo-optic dysplasia and skull base encephaloceles, have congenitally reduced chiasmal decussation. Reduced relative decussation may co-exist with overall chiasmal hypoplasia. Children with an apparently isolated chiasmal decussation deficit may have other subtle neurological findings, but our clinical impression is that most of these children function well.

Abnormalities, Multiple↗

PubMed2002

Distribution of metabotropic glutamate receptors in the superior colliculus of the adult rat, ferret and cat.

The distribution of different metabotropic glutamate receptors (mGluRs 1a, 1b, 1c, 2/3, 4 and 5) has been compared in the superior colliculus of the rat, cat and ferret using immunohistochemical techniques and light microscopy. We found that although there are differences in labelling patterns between the species, there are also substantial similarities. In general, there was only light staining for the various mGluR1 splice variants, whereas labelling for the other Group I receptor, mGluR5, was heavier and with a pattern which suggested that at least some label arose from retinal afferents to the superficial superior colliculus. A further consistent feature in all species was labelling of astrocytes in the optic nerve/optic tract, superficial superior colliculus and brain at the collicular level with the antibody directed towards the Group II receptors, mGluR2 and mGluR3. Staining for the Group III receptor, mGluR4, was dense in the superficial superior colliculus in all species, with characteristics suggesting nerve fibre staining. mGluR4 staining was seen in the cat optic nerve/optic tract. One source of mGluR4 staining in the superior colliculus may thus be retinal axons, although other sources cannot be entirely excluded. These results demonstrate that distributions of mGluRs in these species have significant similarities but also some differences, suggesting that within the superior colliculus there may be some preservation of functional roles for some of the different receptor types. This is particularly so for the Group II and Group III receptors, which appear to have specific and distinct roles in the modulation of visual responses.

Animals↗

PubMed2001

Effects of interleukin-12 on the immune response to a multipeptide vaccine for resected metastatic melanoma.

PURPOSE: Forty-eight patients with high-risk re-sected stage III or IV melanoma were immunized with two tumor antigen epitope peptides derived from gp100(209-217)(210M) (IMDQVPSFV) and tyrosinase(368-376)(370D) (YMDGTMSQV) emulsified with incomplete Freund's adjuvant (IFA). Patients received peptides/IFA with or without interleukin (IL)-12 30 ng/kg to evaluate the toxicities and immune responses in either arm with time to relapse and survival as secondary end points. PATIENTS AND METHODS: Immunizations were administered every 2 weeks for 8 weeks, then every 4 weeks for 12 weeks, and then once 8 weeks later. A leukapheresis to obtain peripheral-blood mononuclear cells for immune analyses was done before and after vaccination. Skin testing with peptides and recall reagents was performed before and after vaccinations. RESULTS: Local pain and granuloma formation, fever, and lethargy of grade 1 or 2 were observed. Transient vaccine-related grade 3-but no grade 4-toxicity was observed. Thirty-four of 40 patients developed a positive skin test response to the gp100 peptide but none to tyrosinase. Immune responses were measured by release of gamma-interferon in an enzyme-linked immunosorbent assay (ELISA) by effector cells in the presence of peptide-pulsed antigen-presenting cells or by an antigen-specific tetramer flow cytometry assay. Thirty-three of 38 patients demonstrated an immune response by ELISA after vaccination, as did 37 of 42 patients by tetramer assay. Twenty-four of 48 patients relapsed with a median follow-up of 20 months, and 10 patients in this high-risk group have died. CONCLUSION: These data suggest a significant proportion of patients with resected melanoma mount an antigen-specific immune response against a peptide vaccine and indicate that IL-12 may increase the immune response and supporting further development of IL-12 as a vaccine adjuvant.

Adolescent↗

PubMed2001

Asymmetric segregation of Numb in retinal development and the influence of the pigmented epithelium.

Asymmetric segregation of cell-fate determinants during cytokinesis plays an important part in controlling cell-fate choice in invertebrates. During Drosophila neurogenesis, for example, asymmetric segregation of the Numb protein, which inhibits Notch signaling, is necessary for the two daughter cells of a division to have different fates. In vertebrates, the role of asymmetric segregation of cell-fate determinants is uncertain, and the way the process might be regulated is unknown. We have studied the orientation of cell divisions and the distribution of Numb in the developing rat retina. We show that, whereas most retinal neuroepithelial cells divide with their mitotic spindles oriented parallel to the plane of the neuroepithelium, a substantial minority divides with their spindles oriented perpendicularly. The proportion of these vertically dividing cells changes during development, peaking around the day of birth. Numb appears to be inherited only by the apical daughter cell when a neuroepithelial cell divides vertically. Similarly, in dissociated cell cultures, some retinal neuroepithelial cells divide asymmetrically and distribute Numb to only one of the two daughter cells, suggesting that the dissociated cells can retain their polarity in vitro. Using retinal explant cultures, we find that the retinal pigment epithelium apparently promotes vertical divisions in the neural retina. To our knowledge, this is the first evidence that asymmetric segregation of cell-fate determinants may contribute to cell diversification in the mammalian retina and that an epithelium controls this process by influencing the plane of division in the adjacent neural retina.

Animals↗

PubMed2001

Growth dynamics of the developing lateral geniculate nucleus.

Segregated binocular maps in the lateral geniculate nucleus (LGN) develop from stages where they initially completely overlap. Here, we show that segregation occurs at different rates across the depth of the nucleus and that the volume of the ipsilateral projection does not decrease significantly during this period, rather LGN volume expands markedly and its shape changes. Hence, we have examined the differential growth of the ferret LGN during the process of segregation by using novel shape modelling techniques. These have facilitated quantification of its three-dimensional structure at successive developmental stages as well as the definition of growth vectors which illustrate shape change. This has been undertaken in direct representations of the LGN and those normalised for size and orientation. Spatiotemporal aspects of shape change have then been compared with different measurements of its cellular population. Initial stages of segregation are associated with a large expansion of the rostrocaudal axis of the nucleus along which segregation takes place, and an expansion of caudal regions that will eventually contain the binocular representation. Later stages are associated with dorsoventral expansions and a consolidation of the rostrocaudal axis. The pace of shape change peaks toward the end of the period of segregation when the nucleus has adopted approximately 50% of its adult shape. After segregation, nuclear growth is mainly isotropic. The mature shape of the nucleus is achieved before it reaches its full size and while cell density and cell sizes are still changing.

Age Factors↗

PubMed2001

Variegated expression and delayed retinal pigmentation during development in transgenic mice with a deletion in the locus control region of the tyrosinase gene.

Deletion of the tyrosinase locus control region (LCR) in transgenic mice results in variegated expression in the skin. Here we investigate the pigmentation pattern of other tissues that express tyrosinase: iris, choroid, and retina in the same animals. A mosaic distribution of pigmentation appears in the iris and choroid. Interestingly, a markedly different mosaic pattern is found in the retina, where central areas contain little or no melanin while pigmentation rises to normal levels towards periphery. Further, there is a temporal delay in the initiation and accumulation of pigment in retinal pigmented epithelium (RPE) cells during development, and patterns of adult retinal melanisation in these mice appear arrested at a stage found in early embryogenesis in wild-type mice. These results demonstrate that the tyrosinase LCR is needed for the correct establishment and maintenance of this expression domain throughout development, but particularly during the later stages of retinal melanisation.

Alleles↗

PubMed2001

Oxygen modulates cell death in the proliferating retina.

Many factors probably regulate the process of natural cell death during development. It is present in both the early undifferentiated retina and later following differentiation. Melanin production plays a role in regulating retinal development and when it is absent, cell proliferation and death are enhanced. Here we examine the effects of hyperoxia on this process, as oxygen has been shown to reduce cell death among differentiated photoreceptors late in development. However, in this study we examine its effects much earlier in pigmented and albino pigmentation phenotypes, when most cells are still actively dividing and are not committed to a specific fate. Newborn mice were exposed to high oxygen levels for 24 h and then returned to normal air for varying periods and their retinae examined. Hyperoxia had a dramatic effect on the number of dying cells, reducing them by almost 60% in pigmented animals and by over 80% in albinos. Following the return to normal air there was a gradual increase in their number over 360 min back to normal levels in pigmented mice; however, in albinos there was a complete rebound in levels of cell death within 40 min, reflecting the increased metabolic stress present in albino retinae due to their abnormal levels of proliferation. These results highlight the important role played by oxygen during early natural cell death in the retina and reveal the different developmental conditions present in the retinae of the two pigmentation phenotypes examined.

Albinism↗

PubMed2001

Architecture of the optic chiasm and the mechanisms that sculpt its development.

At the optic chiasm the two optic nerves fuse, and fibers from each eye cross the midline or turn back and remain uncrossed. Having adopted their pathways the fibers separate to form the two optic tracts. Research into the architecture and development of the chiasm has become an area of increasing interest. Many of its mature features are complex and vary between different animal types. It is probable that numerous factors sculpt its development. The separate ganglion cell classes cross the midline at different locations along the length of the chiasm, reflecting their distinct periods of production as the chiasm develops in a caudo-rostral direction. In some mammals, uncrossed axons are mixed with crossed axons in each hemi-chiasm, whereas in others they remain segregated. These configurations are the product of different developmental mechanisms. The morphology of the chiasm changes significantly during development. Neurons, glia, and the signals they produce play a role in pathway selection. In some animals fiber-fiber interactions are also critical, but only where crossed and uncrossed pathways are mixed in each hemi-chiasm. The importance of the temporal dimension in chiasm development is emphasized by the fact that in some animals uncrossed ganglion cells are generated abnormally early in relation to their retinal location. Furthermore, in albinos, where many cells do not exit the cell cycle at normal times, there are systematic chiasmatic abnormalities in ganglion cell projections.

Albinism↗

PubMed2000

Oa1 knock-out: new insights on the pathogenesis of ocular albinism type 1.

Ocular albinism type I (OA1) is an X-linked disorder characterized by severe reduction of visual acuity, strabismus, photophobia and nystagmus. Ophthalmologic examination reveals hypopigmentation of the retina, foveal hypoplasia and iris translucency. Microscopic examination of both retinal pigment epithelium (RPE) and skin melanocytes shows the presence of large pigment granules called giant melanosomes or macromelanosomes. In this study, we have generated and characterized Oa1-deficient mice by gene targeting (KO). The KO males are viable, fertile and phenotypically indistinguishable from the wild-type littermates. Ophthalmologic examination shows hypopigmentation of the ocular fundus in mutant animals compared with wild-type. Analysis of the retinofugal pathway reveals a reduction in the size of the uncrossed pathway, demonstrating a misrouting of the optic fibres at the chiasm, as observed in OA1 patients. Microscopic examination of the RPE shows the presence of giant melanosomes comparable with those described in OA1 patients. Ultrastructural analysis of the RPE cells, suggests that the giant melanosomes may form by abnormal growth of single melanosomes, rather than the fusion of several, shedding light on the pathogenesis of ocular albinism.

Albinism, Ocular↗

PubMed2000

Retinal cell addition and rod production depend on early stages of ocular melanin synthesis.

Retinal mitosis is regulated by dopa, a melanin precursor present in the developing retinal pigment epithelium. Its absence results in retinal deficits including a failure of approximately 30% of the rod population to develop. Here, (3)H-thymidine labelling is used to analyse patterns of cell addition spanning the main period of retinal development in rat litters containing both pigmented and albino phenotypes. Many more thymidine-labelled cells are found in each cellular layer at maturity in albinos than in their pigmented littermates. Normal spatial patterns of photoreceptor addition are seen in albinos during cone production and for most of the subsequent period of rod addition. However, abnormal spatial patterns of cell addition occur across the retinal when rod production peaks. A delay in the centre to periphery gradient of cell addition is apparent in both nuclear layers. These data are related to deficits in the mature architecture of the albino retina. The results are consistent with there being significant cell cycle and/or exit point irregularities in hypopigmented retinae. It is probable that reduced dopa levels in albinos result in the cell cycle rate not slowing appropriately with development, which may lead to cells missing their exit points. This produces abnormal patterns of cell addition at key stages and delays in the gradient of retinal maturation along with a large cell loss at critical stages of rod production.

Aging↗

PubMed1999

Retinal mitosis is regulated by dopa, a melanin precursor that may influence the time at which cells exit the cell cycle: analysis of patterns of cell production in pigmented and albino retinae.

A melanin-associated agent seems to play a role in regulating retinal development. When absent, diverse deficits occur. There is evidence that this agent regulates patterns of mitosis. This study examines retinal development in pigmented and albino rats to identify the regulating agent and its mode of action. Throughout neurogenesis, many more mitotic profiles are found in albinos than pigmented animals. At the peak of retinal neurogenesis, approximately 50% more mitotic profiles are found in albinos than in matched pigmented animals, resulting in abnormal retinal thickening. Concurrently, increasing numbers of pyknotic nuclei are identified, such that later in development retinal thickness normalises. However, the crude centre-to-periphery pattern of cell production is preserved. Abnormal cell proliferation is found in a range of albino rat strains, but it is not present in their brains, confirming that the abnormality is ocular and melanin related. Dopa is a critical element in initial stages of melanin synthesis and is present in abnormally low levels in developing albino retinae. Furthermore, it is an antimitotic agent. Addition of dopa to albino eyes in vitro normalises patterns of cell production. These results are consistent with the hypothesis that dopa is a major regulator of retinal cell production and that it influences the capacity of cells to exit the cell cycle.

Albinism↗

PubMed1999

Visual abnormalities in albino wallabies: a brief note.

Abnormally reduced uncrossed retinofugal pathways and abnormally low retinal cell densities have been described in albinos of a number of species of eutherian mammal, but have not been studied in marsupials. The optic chiasm of marsupials differs from that of the eutherian brains that have been studied, with uncrossed fibres segregating from crossed fibres prechiasmatically in the marsupials, but not in the eutherians. We have examined the optic chiasm and the retina in albino and normally pigmented wallabies (Macropus rufogriseus) to determine whether the abnormalities found in eutherian albinos are also present in this marsupial. The uncrossed pathway of the albino wallaby is smaller than that of the pigmented animals and the cell density in the retinal ganglion cell layer is reduced at the area centralis. We conclude that the characteristic albino abnormalities are present in both groups of mammals in spite of the other known differences in the visual pathways. The albino mutation acts at the chiasm in a similar manner in both groups even though the determinants of the chiasmatic pathway differ.

Albinism↗

PubMed1999

Phase I trial of a MART-1 peptide vaccine with incomplete Freund's adjuvant for resected high-risk melanoma.

Twenty-five patients with high-risk resected stages IIB, III, and IV melanoma were immunized with a vaccine consisting of the minimal epitope, immunodominant 9-amino acid peptide derived from the MART-1 tumor antigen (AAGIGILTV) complexed with incomplete Freund's adjuvant. The last three patients received the MART-1(27-35) peptide with incomplete Freund's adjuvant mixed with CRL 1005, a block copolymer adjuvant. Patients were immunized with increasing doses of the MART-1(27-35) peptide in a Phase I trial to evaluate the toxicity, tolerability, and immune responses to the vaccine. Immunizations were administered every 3 weeks for a total of four injections, preceded by leukapheresis to obtain peripheral blood mononuclear cells for immune analyses, followed by a post-vaccine leukapheresis 3 weeks after the fourth vaccination. Skin testing with peptide and standard delayed-type hypersensitivity skin test reagents was also performed before and after vaccinations. Local pain and granuloma formation were observed in the majority of patients, as were fevers or lethargy of grade 1 or 2. No vaccine-related grade III/IV toxicity was observed. The vaccine was felt to be well tolerated. Twelve of 25 patients were anergic to skin testing at the initiation of the trial, and 13 of 25 developed a positive skin test response to the MART-1(27-35) peptide. Immune responses were measured by release of IFN-gamma in an ELISA assay by effector cells after multiple restimulations of peripheral blood mononuclear cells in the presence of MART-1(27-35) peptide-pulsed antigen-presenting cells. An ELISPOT assay was also developed to measure more quantitatively the change in numbers of peptide-specific effector cells after vaccination. Ten of 22 patients demonstrated an immune response to peptide-pulsed targets or tumor cells by ELISA assay after vaccination, as did 12 of 20 patients by ELISPOT. Nine of 25 patients have relapsed with a median of 16 months of follow-up, and 3 patients in this high-risk group have died. Immune response by ELISA correlated with prolonged relapse-free survival. These data suggest a significant proportion of patients with resected melanoma mount an antigen-specific immune response against a peptide vaccine and support further development of peptide vaccines for melanoma.

Antigens, Neoplasm↗

PubMed1998

First evidence of diversity in eutherian chiasmatic architecture: tree shrews, like marsupials, have spatially segregated crossed and uncrossed chiasmatic pathways.

In the optic chiasm of mammals, axons either cross the midline to the opposite side of the brain or remain uncrossed. In the eutherian species studied to date, uncrossed axons in the caudal nerve are found in all regions. In the chiasm, they are dispersed through the hemichiasm, with many axons approaching the midline and then turning back to enter the same side of the brain as the originating eye. In marsupials, by contrast, uncrossed axons never approach the midline; instead, they remain grouped in the lateral nerve and chiasm. The impression gained from these data is that there is a major difference in chiasmatic architecture between eutherian and marsupial mammals. Therefore, the mechanisms by which axons choose their route through the chiasm was also thought to differ between the two major groups of mammals. However, the present study shows that the chiasm of a highly visual eutherian mammal, the tree shrew, is similar to that found in marsupials, with uncrossed axons confined to lateral regions and not approaching the midline. However, unlike marsupials, in the tree shrew, optic fascicles in the chiasm are often separated by thick collagen bundles. It is probable that the chiasmatic structure described to date for eutherian mammals is not ubiquitous, as was previously thought, and theories explaining the mechanisms by which axons chose their route through the chiasm during development will have to be expanded.

Animals↗

PubMed1998

Reduced retinal deficits in an albino mammal with a cone rich retina: a study of the ganglion cell layer at the area centralis of pigmented and albino grey squirrels.

In all albino mammals studied the central retina is underdeveloped and there is a rod deficit. Central ganglion cell density is approximately 25% below normal. This is not seen in birds, which have a come dominated retina. Here we examine the ganglion cell layer in a cone rich mammal, the squirrel Sciurus carolinensis leucotis. Central cell densities were only < 5% lower in the albinos than in pigmented squirrels. Squirrels are the only known albino mammal to survive successfully in the wild, reinforcing the notion that their visual deficits are minor. The relative immunity of these albino retinae from this deficits may be related to different patterns of cell production between rod and cone dominated eyes.

Albinism, Oculocutaneous↗

PubMed1998

The retinal pigment epithelium as a developmental regulator of the neural retina.

Melanin-related agents regulate the development of the mammalian neural retina, because in albinos there are a range of retinal deficits including abnormal connections between the eye and brain, an underdeveloped central retina and a rod deficit. These deficits may arise because gradients of retinal development in the albino are delayed and the retina is abnormally proliferative, but also goes through a subsequent period of excessive cell death. This may be caused by a reduction in ocular DOPA in albinos as this is in the synthetic pathway of melanin and is a known cell cycle regulator.

Albinism, Ocular↗

PubMed1998

Axon deviation in the human lamina cribrosa.

AIMS: To examine the course taken by individual retinal ganglion cell axons through the human lamina cribrosa. METHODS: Retinal ganglion cell axons were labelled using the retrograde tracer horseradish peroxidase applied directly to the optic nerve in two normal human eyes removed during the course of treatment for extraocular disease. RESULTS: A majority of axons took a direct course through the lamina cribrosa but a significant minority, in the range 8-12%, deviated to pass between the cribrosal plates in both central and peripheral parts of the optic disc. CONCLUSIONS: It is postulated that these axons would be selectively vulnerable to compression of the lamina cribrosa in diseases such as glaucoma in which the intraocular pressure is increased.

Aged↗