Biomedical subjects

G M Halliday

Publications and source records attributed to G M Halliday.

At least 91 records · Page 5Linked to original sources

PubMed1999

Topical all-trans retinoic acid augments ultraviolet radiation-induced increases in activated melanocyte numbers in mice.

We have previously shown that daily application of 0.05% retinoic acid to the backs of lightly pigmented, hairless HRA:Skh-2 mice increases melanogenesis resulting from exposure to solar-simulated ultraviolet radiation. In this study we show that as early as 1 wk following commencement of treatment, there is a 2- fold increase in the number of epidermal 3,4-dihydroxyphenylalanine positive melanocytes in retinoic acid and ultraviolet radiation treated HRA:Skh-2 mice compared with mice that received ultraviolet radiation only. This increased to a 2.9-fold difference by 6 wk. Retinoic acid also augmented ultraviolet radiation-stimulated melanogenesis, with a 4-fold increase being observed after only 2 wk. These findings were also seen in C57BL mice. Ultraviolet radiation and retinoic acid needed to be applied to the same skin site for the augmentation in melanocyte activation to occur. Ultraviolet B rather than ultraviolet A was mainly responsible for melanogenesis and the retinoic acid primarily increased ultraviolet B-induced melanogenesis. Furthermore, retinoic acid on it's own, in the absence of ultraviolet radiation caused a small but statistically significant increase in 3,4-dihydroxyphenylalanine positive melanocyte numbers and melanogenesis. Thus topical retinoic acid is a potent modulator of melanocyte activation. Alone it is able to increase the number of activated epidermal melanocytes and make melanocytes more sensitive to activation by ultraviolet B.

Animals↗

PubMed1999

Low-dose UVA and UVB have different time courses for suppression of contact hypersensitivity to a recall antigen in humans.

This study investigates the relative effects of low-dose solar-simulated ultraviolet, ultraviolet A, and ultraviolet B radiation on the elicitation of contact hypersensitivity to nickel in nickel-allergic volunteers. A xenon arc lamp with changeable filters was used to irradiate groups of volunteers daily, on separate areas of their lower backs, with both solar-simulated ultraviolet (ultraviolet B, ultraviolet AII + ultraviolet AI) and ultraviolet A (same ultraviolet AII content but twice the ultraviolet AI as the solar-simulated ultraviolet spectrum) for 1 and 2 d; 3, 4, and 5 d; and from 1 to 4 wk. A fourth group was irradiated for 1-5 d with the ultraviolet B component of solar-simulated ultraviolet. Following the final irradiation in each group, nickel-containing patches were applied to both ultraviolet-treated sites and adjacent, unirradiated control sites. Erythema caused by nickel contact hypersensitivity at each site was quantitated 72 h later with a reflectance erythema meter. By comparing the nickel reactions of irradiated and unirradiated skin, ultraviolet immunosuppression was assessed with the different spectra and durations of ultraviolet exposure. We found significant immunosuppression with daily doses of ultraviolet B and ultraviolet A equivalent to approximately 6 min of summer sun exposure, and that ultraviolet A and ultraviolet B exerted their maximal immunosuppressive effects at different times. Solar-simulated ultraviolet-induced immunosuppression was significant after one exposure, near-maximal after two exposures and remained elevated thereafter. Ultraviolet B-induced immunosuppression was lower than that induced by solar-simulated ultraviolet, but followed a similar time-course. In contrast, ultraviolet A-induced immunosuppression was transient, peaking after three exposures. Immune responses returned towards normal with subsequent ultraviolet A exposure, suggesting that an adaptive mechanism may prevent immunosuppression by continued ultraviolet A irradiation.

Adolescent↗

PubMed1999

Specific temporoparietal gyral atrophy reflects the pattern of language dissolution in Alzheimer's disease.

The aim of this study was to determine the topography and degree of atrophy in speech and language-associated cortical gyri in Alzheimer's disease. The post-mortem brains of 10 patients with pathologically confirmed Alzheimer's disease and 21 neurological and neuropathological controls were sectioned in serial 3 mm coronal slices and grey and white matter volumes were determined for specific cortical gyri. All Alzheimer's disease patients had prospectively documented impairments in verbal and semantic memory with concomitant global decline. The cortical regions of interest included the planum temporale, Heschl's gyri, the anterior superior temporal gyri, the middle and inferior temporal gyri, area 37 at the inferior temporoparietal junction, areas 40 and 39 (supramarginal and angular gyri) and Broca's frontal regions. Although most patients had end-stage disease, the language-associated cortical regions were affected to different degrees, with some regions free of atrophy. These included Broca's regions in the frontal lobe and Heschl's gyri on the superior surface of the temporal lobe. In contrast, the inferior temporal and temporoparietal gyri (area 37) were severely reduced in volume. The phonological processing regions in the superior temporal gyri (the planum temporale) were also atrophic in all Alzheimer's disease patients while the anterior superior temporal gyri were only atrophic in female patients. Such atrophy may underlie the more severe language impairments previously described in females with Alzheimer's disease. The present study is the first to analyse the volumes of language-associated gyri in post-mortem patients with confirmed Alzheimer's disease. The results show that atrophy is not global but site-specific. Atrophied gyri appear to reflect a specific network of language and semantic memory dissolution seen in the clinical features of patients with Alzheimer's disease. Females showed greater atrophy than males in the anterior superior temporal gyri.

Aged↗

PubMed1999

Regression of melanoma, but not keratoacanthoma, is associated with increased HLA-B22 and decreased HLA-B27 and HLA-DR1.

Sixty three Caucasian patients with either melanoma, keratoacanthoma or squamous cell carcinoma were human leucocyte antigen (HLA) typed. The regressing tumour groups were compared with their non-regressing counterparts, and the patient groups were compared with a control Caucasian population. Melanoma patients showing histological regression were more likely to be HLA-B22 positive, and HLA-B27 and -DR1 negative, than those without features of regression. When compared with a control population, the group of melanoma patients were more likely to be HLA-B22 positive. Comparison of the group of keratoacanthomas, a self-regressing tumour, and the group of squamous cell carcinomas, a non-regressing tumour, did not show any significant differences in HLA typing.

Carcinoma, Squamous Cell↗

PubMed1999

Effect of inhibitors of oxygen radical and nitric oxide formation on UV radiation-induced erythema, immunosuppression and carcinogenesis.

We investigated whether supplementation of a sunscreen containing the UVB absorber 2-ethyl-hexyl-methoxycinnamate (cinnamate) with oxygen radical inhibitors (ORI) would improve protection from sunburn, immunosuppression and carcinogenesis. Mice were exposed to solar-simulated UV radiation (ssUV) containing a mixture of UVB and UVA. In initial studies, the ORI 2,2'-dipyridyl and N(G)-monomethyl-L-arginine acetate (L-NMMA) were shown to prevent UVA-induced suppression of contact sensitivity (CS) in mice. Addition of these inhibitors to the sunscreen did not affect the sun protection factor (SPF), but lowered the level of edema when mice were exposed to ssUV. Combination of both inhibitors with the sunscreen, however, increased the SPF from 5 to 5.5. The immune protection factor (IPF) of the sunscreen was only 1.18, but addition of neither dipyridyl nor L-NMMA singly or in combination measurably improved immune protection. However, the ORI improved the ability of the sunscreen to prevent carcinogenesis. The results indicate that reactive oxygen or nitrogen species produced in response to UV radiation are important for erythema, immunosuppression and carcinogenesis, and addition of inhibitors improves the protective capacity of sunscreens.

2,2'-Dipyridyl↗

PubMed1999

Measurement of in vivo sunscreen immune protection factors in humans.

This study investigates the level of protection provided by sunscreens against solar-simulated UV radiation-induced immunosuppression in humans. The in vivo immune protection factors (IPF) of two broad-spectrum sunscreens were determined by assessing their ability to prevent UV-induced suppression of nickel contact hypersensitivity (CHS) in 15 nickel-allergic volunteers. Each volunteer was irradiated on unprotected skin of the back with different doses of UV daily for 4 days. Multiples of these UV doses were concurrently delivered to sunscreen-treated sites on the contralateral back. Nickel patches were then applied to both irradiated sites and adjacent, unirradiated control sites. Nickel-induced erythema at each site was measured 72 h later with a reflectance spectrometer. Comparison of the nickel reactions of irradiated and unirradiated skin revealed linear UV dose-responses for immunosuppression in both unprotected and sunscreen-treated skin. The minimum level of immunosuppression that can be reliably detected with this method is 20%. Therefore, the UV dose that reduces mean nickel CHS by 20% is the minimal immune suppression dose (MISD). Sunscreen IPF were determined by dividing the mean MISD of sunscreen-treated skin by that of unprotected skin. The sunscreens, with sun protection factors of 9 and 24, had IPF of 6.5 and > 25, respectively.

Adult↗

PubMed1998

UVA-induced immunosuppression.

It has previously been demonstrated that chronic low-dose solar-simulated ultraviolet (UV) radiation can induce both local and systemic immunosuppression as well as tolerance to a topically applied hapten. Epidermal cells from UV-irradiated mice inhibit spontaneous regression of tumours indicating that UV-induced immunosuppression is likely to permit the outgrowth of developing UV-induced skin tumours. We have used a chronic low-dose UV-irradiation protocol to investigate the effects of UVA on the skin immune system of C3H/HeJ mice. Irradiation with UVA + B significantly suppressed the local and systemic primary contact sensitivity (CS) response to the hapten TNCB. Furthermore UVA + B reduced Langerhans cell (LC) and dendritic epidermal T cell (DETC) numbers in chronically UV-irradiated mice. UVA-irradiation induced local, but not systemic, immunosuppression and reduced LC (32%) but not DETC from the epidermis compared to the shaved control animals. Treatment of mice with UVA + B or UVA radiation also induced an impaired secondary CS response, and this tolerance was transferable with spleen cells. Therefore exposure of C3H/HeJ mice 5 days per week for 4 weeks with UVA can induce local immunosuppression and tolerance. One of the mechanisms by which UVA affects biological systems is production of reactive oxygen species. We have also shown that Vitamin E, an inhibitor of lipid peroxidation, prevents UV-induced immunosuppression and loss of LC. It is possible that the UVA in UV radiation induces epidermal lipid peroxidation which stimulates LC migration from the epidermis, thus contributing to UV-induced immunosuppression. Hence, inhibition of epidermal lipid peroxidation by Vitamin E may provide some protection to the skin immune system from these effects of UV.

Animals↗

PubMed1998

Two novel presenilin-1 mutations (Ser169Leu and Pro436Gln) associated with very early onset Alzheimer's disease.

Mutations in the presenilin-1 (PS-1) gene account for the majority of early onset autosomal-dominant familial Alzheimer's disease (FAD) cases. We identified three missense mutations in the coding sequence of the PS-1 gene in three early onset (EO), FAD pedigrees. Alzheimer's disease was confirmed in one pedigree by autopsy. Mutation analysis of PCR products amplified from genomic DNA templates of affected individuals showed two novel mutations resulting in Ser169Leu and Pro436Gln and one known mutation resulting in Glu318Gly. The two new mutations are located within predicted transmembrane domains three (TM-3) and seven (TM-7), and are associated with a very early age of onset which is consistent with a marked loss of function of the protein. The age of onset in the pedigree with Glu318Gly mutation was similar to that reported previously in a separate pedigree with this mutation.

Adult↗

PubMed1998

Bioactive tumour necrosis factor alpha but not granulocyte-macrophage colony-stimulating factor correlates inversely with Langerhans's cell numbers in skin tumours.

Langerhans' cells (LCs) are thought to play an important role in presentation of tumour antigens for the induction of anti-tumour immunity. Epidermis overlying some transplanted murine skin tumours contains increased numbers of LCs; however, alterations in LC numbers are not related to tumour antigenicity or host immunity, suggesting that another factor(s), such as tumour-produced cytokines, influences LC density. It has been postulated that dendritic epidermal T cells (DETCs) play a role in immunosurveillance within the normal epidermis. Two cytokines which potentially alter LC numbers or function include granulocyte-macrophage colony-stimulating factor (GM-CSF) and tumour necrosis factor-alpha (TNF-alpha). GM-CSF maintains LC viability in culture, and there are reports that it can increase LC density. There is evidence that TNF-alpha induces LC to migrate from the epidermis. In the present study, LC densities in regressor and non-regressor murine skin tumours and overlying epidermis were enumerated, and bioactive GM-CSF and TNF-alpha present in the tumours were measured. We found significantly increased epidermal LC numbers above non-regressor, but not regressor, tumours. DETC numbers were significantly increased above some tumours. Although all tumour types produced TNF-alpha, the regressors, which did not increase LC numbers, produced the most TNF-alpha. In contrast, tumour production of GM-CSF did not correlate with any pattern of alteration of LC density or tumour growth. Tumour production of neither cytokine nor tumour growth correlated with DETC numbers overlying tumours. Our results suggest that TNF-alpha may be associated with skin tumour regression and may prevent LC accumulation by tumours.

Animals↗

PubMed1998

Regional specificity of brain atrophy in Huntington's disease.

The present study analyzes the relationship between cortical and subcortical brain volumes in patients with Huntington's disease. The brains of seven patients with a clinical diagnosis and positive family history of Huntington's disease and 12 controls were collected at autopsy with consent from relatives. Detailed clinical assessments were available for all study subjects with genotype confirmation for patients with Huntington's disease. Volume analysis of the brain on serial 3-mm coronal slices was performed as previously described. All patients with Huntington's disease exhibited significant brain atrophy resulting from volume reductions in both cortical and subcortical grey matter. Atrophy of the cortex was relatively uniform, although the medial temporal lobe structures were spared. The caudate nucleus and putamen were strikingly reduced in all cases and this atrophy correlated with the severity of cortical atrophy, suggesting an associated disease process. The rate of cortical but not subcortical atrophy correlated with CAG repeat numbers. Loss of frontal white matter correlated with both cortical and striatal atrophy. Age of onset of chorea correlated with the amount of subcortical atrophy, while duration of chorea correlated negatively with atrophy of the white matter. These results suggest a more widespread and global disease process in patients with Huntington's disease.

Adult↗

PubMed1998

The midbrain dopaminergic cell groups in the baboon Papio ursinus.

The present study evaluates the cytoarchitecture of midbrain dopaminergic regions in baboons using similar methodology to that recently applied to compare humans and rats. This information is relevant for the interpretation of nonhuman primate models of Parkinson's disease (PD). The midbrains of four alpha male baboons were serially sectioned into 10 evenly spaced series of 50 microm sections. Series were stained with either cresyl violet or immunohistochemically reacted for tyrosine hydroxylase, substance P, calbindin-D28k, or parvalbumin. The organization of dopaminergic cell groups and the distribution of proteins within these groups were found to be very similar to that previously described in humans [McRitchie et al., J. Comp. Neurol. 364:121-150; 1996]. Dorsal and ventral tiers of the A9 substantia nigra (SN) pars compacta and all divisions of the A8 and A10 cell groups were identified revealing a high degree of homology in the arrangement of chemically distinct midbrain neurons between primates. The major difference between the organization of human and baboon midbrain dopaminergic neurons is the anteroposterior extent of the dense cell clusters within the SN pars compacta. In baboons the dorsomedial cell cluster is absent at posterior levels. The ventral tier cell clusters, which are targeted by PD in humans, are restricted to the posterior and ventral regions of the SN pars compacta of the baboon. In humans these cell clusters are found throughout the rostrocaudal extent of the SN. These ventral cell clusters have been previously shown to have reciprocal connections with sensorimotor regions of the putamen.

Animals↗

PubMed1998

Simplified neuropathological diagnosis of dementia with Lewy bodies.

Pathological criteria have recently been developed to differentiate those cases where Lewy bodies contribute to the dementing process. We applied consensus criteria to 20 cases with a pathological diagnosis of Alzheimer's disease (all demented) and/or Parkinson's disease (three without dementia) and eight controls. In addition, we applied the criteria to the different cortical layers to determine whether the site of the semiquantification affected the diagnosis. In the parietal lobe, few Lewy bodies were observed, and this region could be excluded. Rare Lewy bodies present in the frontal association cortex in a number of Parkinson's disease cases resulted in their classification as limbic or transitional cases with Lewy bodies. Exclusion of this non-limbic association cortex resulted in many of these cases with rare cortical Lewy bodies being re-classified as having brain stem predominant Lewy bodies, thus improving the diagnostic accuracy of the criteria. Most of these cases were non-demented. No other case was re-classified by excluding these cortical regions from the analysis. Few Lewy bodies were present in cortical layers I and II, and these layers could be excluded from the semiquantitative procedure without change to the overall classification of cases. The occasional presence of possible Lewy bodies in cases with Alzheimer's disease and controls incorrectly classified these cases as having brain stem predominant Lewy body disease, although these cases had no brain stem Lewy bodies. These modifications to the consensus criteria for assessing Lewy body disease (i.e. exclude parietal and frontal lobe, cortical layers I and II, and cases without brain stem Lewy bodies), provide significant time and cost savings for neuropathologists and researchers using this criteria to diagnose and study dementia with Lewy bodies.

Aged↗

PubMed1998

Ultraviolet radiation induced suppression of Mantoux reactions in humans.

The effects of low dose ultraviolet (UV) radiation on delayed type hypersensitivity responses to tuberculin purified protein derivative were investigated in 17 healthy, Mantoux-positive volunteers. Suberythemal and erythemal doses of solar simulated UV from a fluorescent lamp source were delivered to the subjects' lower backs daily for five consecutive days. Mantoux testing with intradermally injected purified protein derivative was then performed at both the irradiated sites and an adjacent, unirradiated site, and the Mantoux induced erythema was quantitated 72 h later with a reflectance erythema meter. In comparison with the unirradiated Mantoux sites, Mantoux induced erythema was significantly reduced at the irradiated test sites. In six subjects, we compared the effects of chronic versus short term UV irradiation on the Mantoux reaction. These volunteers were irradiated on one side of their lower backs with the 5 d UV protocol, and on the other side of their backs for 4 or 5 wk. In all but one subject, the short irradiation protocol induced greater suppression of Mantoux responses than prolonged UV exposure. We conclude that even suberythemal doses of UV significantly reduce delayed type hypersensitivity responses to purified protein derivative, and that an adaptive mechanism appears to counteract the immunosuppressive effects of chronic irradiation.

Adult↗

PubMed1998

Variation in hippocampal neuron number with age and brain volume.

Hippocampal size and neuron number are reduced in a number of conditions, including temporal lobe epilepsy and Alzheimer's disease. Furthermore, a decrease with advancing age has also been suggested. The present study examined the entire hippocampal formation of 12 subjects aged from 46 to 85 years and free from neurological disease. The volume of seven subregions (CA1, CA2-3, CA4, dentate gyrus, subiculum, presubiculum and white matter) was determined and the number of neurons estimated in each of these grey matter subregions using the optical dissector technique. There was a significant relationship between CA1 neuron number and cerebrum volume. Multivariate analysis showed the greater contribution to the variance in CA1 neuron number was made by cerebrum volume (69%) rather than age (2%) or sex (1%). The findings of this study show that, in neurologically normal individuals, brain size is a major determinant of the number of CA1 neurons.

Age Distribution↗

PubMed1998

Sunscreens and vitamin E provide some protection to the skin immune system from solar-simulated UV radiation.

Previous studies have indicated that sunscreens designed to protect from erythema do not adequately prevent immunosuppression. Mice were irradiated with suberythemal doses of solar-simulated ultraviolet radiation (ssUVR) to assess the immunoprotective ability of sunscreens. Whereas C3H/HeJ and BALB/c mice had similar sensitivities to ssUVR-induced inflammation, C3H/HeJ mice were more sensitive to ssUVR-induced immunosuppression. Octyl dimethyl-p-aminobenzoic acid did not protect from immunosuppression and, thus, had an immune protection factor (IPF) of 1. 2-Ethylhexyl-p-methoxycinnamate and microfine titanium dioxide provided limited protection, both having IPF values of 1.127. Immune protection by the sunscreens appeared to be dependent upon absorption of UVA as well as UVB, and was much less than predicted from the sun protection factor. Vitamin E, an inhibitor of lipid peroxidation, also protected the immune system, with an IPF of 1.2, indicating that oxidation of lipids is involved in UVR-induced immunosuppression, and that it should be possible to develop sunscreens which protect the immune system.

Animals↗

PubMed1997

Dendritic epidermal T-cell involvement in induction of CD8+ T cell-mediated immunity against an ultraviolet radiation-induced skin tumor.

Murine epidermis contains 2 distinct cell populations which contribute to the skin immune system, Langerhans cells (LC), and dendritic epidermal T cells (DETC). LCs are important in the induction of immunity against a wide range of antigens; however, the function of DETC is unclear. To investigate the roles of these epidermal cells (EC) in protective antitumor immunity, an in vivo model of an ultraviolet radiation-induced fibrosarcoma, UV-13-1, was used. Mice were immunized with tumor antigen-pulsed EC followed 10 days later by an injection into the ear of 10(5) tumor cells, which did not lead to formation of a detectable tumor, but was intended to simulate the influence of a developing tumor on the ensuing immune response. The mice were then challenged with 2 x 10(6) viable tumor cells in each flank, sufficient to result in growth of a measurable tumor. Protective immunity was induced by DETC, and shown to be long-lasting, with tumors inoculated 160 days after immunization being effectively rejected. The effector cells responsible for protective immunity were CD8+ T cells. Delayed-type hypersensitivity generated by tumor antigen-pulsed EC was dependent on LCs, with no involvement of DETCs. This response, in contrast to that of DETC, required prior culture of EC with GM-CSF, but failed to inhibit tumor growth or incidence. Thus DETC and LC can both activate antitumor immune responses, although only the DETC-dependent response results in protective immunity in the presence of a developing tumor.

Animals↗

PubMed1997

Language-associated cortical regions are proportionally larger in the female brain.

BACKGROUND: Many studies have demonstrated significant sexual dimorphism in verbal ability. However, few studies have examined anatomical differences between the sexes that may underlie such dimorphism. OBJECTIVE: To examine sex differences in the absolute and proportional volumes of the main language-associated regions of the cerebral cortex. DESIGN AND MAIN OUTCOME MEASURES: Control neuropathological case series of consecutive autopsies from a teaching hospital. No significant age-related volume changes were identified in the sample. Two language-associated cortical regions, the superior temporal gyrus (part of the Wernicke area) and its subdivisions (planum temporale, Heschl gyrus, and anterior superior temporal gyrus) and the inferior frontal gyrus (Broca area in the dominant hemisphere), and a non-language-associated region, the frontal pole, were measured using stereological techniques in brains fixed with formaldehyde solution serially sectioned at 3-mm intervals. Volume comparisons between the sexes and between brain hemispheres were performed using 2-way analysis of variance. SETTING: Studies were conducted at the University of Sydney and the Prince of Wales Medical Research Institute, Sydney, Australia. PATIENTS: Ten males and 11 females free from neurologic or neuropathological abnormalities. RESULTS: The volume of the superior temporal cortex, expressed as a proportion of total cerebral volume, was significantly larger in females compared with males (17.8% increase; P = .04). This was accounted for by 1 section of the superior temporal cortex, the planum temporale, which was 29.8% larger in females (P = .04). In addition, the cortical volume fraction of the Broca area in females was 20.4% larger than in males (P = .05). In contrast, no significant differences were found in the proportional volume of the frontal pole or in regional volumes between the left and right hemispheres in either sex group. CONCLUSIONS: Our results suggest that females have proportionally larger Wernicke and Broca language-associated regions compared with males. These anatomical differences may correlate with superior language skills previously demonstrated in females.

Aged↗

PubMed1997

Chronic alcohol consumption does not cause hippocampal neuron loss in humans.

High alcohol consumption for long periods of time causes significant hippocampal neurodegeneration in rodents. A single study using neuronal density measures has reported similar findings in humans. The present study aims to substantiate these findings in human alcoholics using unbiased stereological techniques. Both amnesic (n = 5) and nonamnesic (n = 7) chronic alcoholics were selected and compared with nonalcoholic controls (n = 8) and patients with marked memory loss and hippocampal neurodegeneration caused by Alzheimer's disease (n = 4). Hippocampal volume was significantly reduced in the alcoholics and in patients with Alzheimer's disease. However, in alcoholics the volume reduction occurred exclusively in the white matter, whereas both the gray and white matter were reduced in the patients with Alzheimer's disease. Neuron loss occurred exclusively from the CA1 and subiculum subregions of the hippocampus in Alzheimer's disease. No neuron loss occurred from any subregion of the hippocampus in alcoholics. There were no correlations with age and any of the volume or neuron number measures. Hippocampal volume correlated with brain volume and with the regional gray and white matter volumes within the hippocampus. In addition, hippocampal gray matter volume correlated with the number of CA1 pyramidal neurons. These results do not support the theory that chronic alcohol consumption is neurotoxic to hippocampal pyramidal neurons in humans. Further, the present results suggest that changes observed in rodent models of alcoholism do not parallel those observed in humans, questioning the validity of such models.

Aged↗