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Biomedical subjects

H F Baker

Publications and source records attributed to H F Baker.

At least 55 records · Page 3Linked to original sources
PubMed1996

What went wrong in BSE? From prion disease to public disaster.

The recent report of 10 cases of a new variant of Creutzfeldt-Jakob disease (CJD) which could be related to bovine spongiform encephalopathy (BSE) has precipitated alarm throughout Europe. The beef trade in the UK has collapsed and the European beef market has been seriously damaged. What went wrong? Much of the difficulty of handling the BSE epidemic arose from the 4-5 year incubation period which made it difficult to ascertain whether measures taken to contain the epidemic had been effective. Public consternation and scientific equivocation arose because these prion diseases are unlike any other group of infectious diseases. Rather than being caused by a conventional micro-organism, the primary pathogenic event consists of the transformation of a normal protein (the prion protein) into an abnormal form, which can transmit disease. Prion disease is endemic in humans and sheep where it is associated with polymorphisms or mutations within the prion protein gene. Although the disease in these cases arises spontaneously, it produces an infectious prion protein. Under certain circumstances, abnormal prion protein contaminates other animals or humans resulting in epidemics of acquired prion disease. This review describes the events of the BSE epidemic and considers the difficulties in assessing the current risk to human health.

Animals↗
PubMed1995

The myth of maternal transmission of spongiform encephalopathy.

It has long been accepted that the pattern of occurrence of scrapie--the form of spongiform encephalopathy associated with sheep--is determined mainly by maternal transmission, and this view has had a profound influence on policy decisions in the control of bovine spongiform encephalopathy and on public concern over the risk to human health form this disease. The occurrence of maternal transmission is, however, not predicted by modern knowledge of the aetiology of spongiform encephalopathy, and even though claims of maternal transmission have been reiterated frequently in the literature, re-examination of the source data reveals that these data are extremely scanty, unreplicated, and probably subject to ascertainment bias. The probability of maternal transmission of spongiform encephalopathy in any species should be viewed with the greatest scepticism.

Animals↗
PubMed1995

A comparison of the behavioural effects of embryonic nigral grafts in the caudate nucleus and in the putamen of marmosets with unilateral 6-OHDA lesions.

The behaviour of marmosets with unilateral 6-hydroxydopamine lesions of the nigrostriatal bundle and grafts of embryonic mesencephalon in either the caudate nucleus or the putamen was compared with that of lesion-alone and unoperated controls. The grafts comprised injections of cell suspensions prepared from marmoset ventral mesencephalon (i.e. allografts) targeted at four sites either entirely within the caudate nucleus or entirely within the putamen. Behavioural tests, including measures of amphetamine-induced rotation, neglect and use of each arm to retrieve food from inside tubes, were given before and after the 6-hydroxydopamine lesion and at regular intervals for 6 months after transplantation surgery. Grafts in the caudate nucleus reduced the ipsilateral rotation induced by amphetamine, whereas grafts in the putamen did not. Despite the absence of an effect on rotation, the putamen grafts were effective in reducing lesion-induced deficits on the task in which the marmosets were required to reach into tubes. In this latter task, the caudate grafts were also effective when the monkeys were given a free choice of which hand to use. However, when constrained to use the hand contralateral to the lesion and graft, the performance of the marmosets with caudate grafts was not significantly improved compared with that of lesion-alone controls. Neither the grafts in the caudate nucleus nor the grafts in the putamen abolished the contralateral somatosensory neglect induced by the lesion, although there was a trend for the marmosets with putamen grafts to contact the label on the contralateral side more quickly than those with caudate grafts or the lesion-alone controls. These results demonstrate that the location of embryonic nigral grafts within the primate striatum influences the profile of functional recovery.

Animals↗
PubMed1995

Conditional learning and memory impairments following neurotoxic lesion of the CA1 field of the hippocampus.

Monkeys with bilateral lesions of the CA1 field of the hippocampus produced by the injection of neurotoxin diagonally along the length of the hippocampus were found to have a severe impairment on the retention of a conditional task learnt prior to surgery and on the new acquisition of several types of this task. They were equally impaired on conditional tasks that required a spatial response or an object choice in response to either visual or spatial cues. They were not impaired on simple visual discrimination tasks, simple spatial discrimination tasks or reversal learning of these tasks. This patterns of impairment resembles that seen in the same species with neurotoxic lesions within the vertical limb of the diagonal band of Broca or transection of the fornix. Monkeys with subtotal lesions of the adjacent medial temporal area were not consistently impaired on any of these tasks. The results suggest that hippocampal lesions produce anterograde and retrograde amnesia for information other than reward association.

Animals↗
PubMed1994

Behavioral assessment of the effects of embryonic nigral grafts in marmosets with unilateral 6-OHDA lesions of the nigrostriatal pathway.

Grafts of embryonic nigral tissue were made into the striatum of marmosets (Callithrix jacchus) which had previously received a unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal bundle. The grafts comprised injections of cell suspensions prepared from embryonic (74 day) marmoset ventral mesencephalic tissue targeted at multiple striatal sites in the caudate nucleus, the putamen, and the nucleus accumbens on the same side as the initial lesion. A series of behavioral tests was used to assess the monkeys prior to surgery, following the 6-OHDA lesion, and at regular intervals for 6 months after transplantation surgery. Lesioned and grafted (n = 6) or lesion alone (n = 4) monkeys were matched as far as possible with respect to their scores prior to transplantation so that explicit graft-derived recovery could be distinguished from any spontaneous recovery that might occur. Sham-lesioned or unoperated monkeys served as further controls (n = 5). The grafts were functionally effective as measured by a reduction, and in some cases a reversal, of spontaneous, amphetamine- and apomorphine-induced rotation. The reversal of amphetamine-induced rotation correlated with the number of dopaminergic neurons in the grafts visualized by tyrosine hydroxylase immunohistochemistry. Successful use of the hands was restored by the grafts on tasks in which the monkeys reached into tubes to retrieve food. However, functional recovery was not seen on some other behavioral tests. In particular, grafts did not influence ipsilateral biases induced by the lesion, including the position of the head with respect to the rest of the body, hand preference while reaching for food at a conveyor belt, and neglect of contralateral stimuli either at the conveyor belt or of adhesive labels placed around the feet. Indeed, the graft group was impaired compared with the lesion group in the accuracy of reaches at the conveyor belt. Overall, these results indicate that embryonic nigral grafts can yield a partial recovery from the symptoms induced by unilateral nigrostriatal lesions in a primate model of hemiparkinsonism.

Animals↗
PubMed1994

Induction of beta (A4)-amyloid in primates by injection of Alzheimer's disease brain homogenate. Comparison with transmission of spongiform encephalopathy.

Amyloid plaques, associated with argyrophilic dystrophic neurites, and cerebral amyloid angiopathy (CAA), but no neurofibrillary tangles, were found in the brains of three middle-aged marmoset monkeys that had been injected intracerebrally (ic) 6-7 yr earlier with brain tissue from a patient with early-onset Alzheimer's disease. Such changes were not found in the brains of three age-matched control marmosets. Immunochemically the amyloid plaques and CAA stained with antibody to beta (A4)-protein. The plaques and CAA displayed dichroic birefringence when stained with Congo red and viewed under polarized light. beta (A4)-amyloid plaques and CAA were also found in the brain of one of two marmosets injected ic 6 yr previously with brain tissue from a patient with prion disease with concomitant beta (A4)-amyloid plaques and CAA. An occasional beta (A4)-amyloid plaque was found in the brains of two of four marmosets injected ic > 4.5 yr previously with brain tissue from three elderly patients, two of whom had suspected (but untransmitted) CJD. No beta (A4)-amyloid plaques or CAA were found in six marmosets who were older than the injected animals, in four marmosets that had not developed spongiform encephalopathy (SE) having been injected several years previously with human brain tissue from three younger patients with suspected or atypical prion disease, or in 10 younger marmosets who had undergone various neurosurgical procedures. Seventeen marmosets injected in the same way with brain tissue from patients or animals with SE developed SE 17-49 mo after injection. These results suggest that beta (A4)-amyloidosis is a transmissible process comparable to the transmissibility of SE.

Adult↗
PubMed1994

Restoration of cognitive abilities by cholinergic grafts in cortex of monkeys with lesions of the basal nucleus of Meynert.

Three groups of marmosets were trained to perform a series of visual discrimination tasks in a Wisconsin General Test Apparatus. Two groups then received bilateral lesions of the basal nucleus of Meynert using the excitotoxin N-methyl-D-aspartate and were found to be severely impaired on relearning a visual discrimination first learnt prior to surgery. One lesioned group then received grafts of acetylcholine-rich tissue dissected from the basal forebrain of fetal marmosets. Three months later the marmosets with lesion alone remained impaired on a number of retention and reversal tasks whereas the transplanted animals were no longer significantly impaired. Histological examination of the brains indicated that all lesioned animals had sustained substantial loss of the cholinergic neurons of the basal nucleus of Meynert (assessed by nerve growth factor receptor immunoreactivity) and that the lesion-alone animals showed marked loss of the cholinergic marker acetylcholinesterase in the dorsolateral frontal and parietal cortex. All transplanted animals had surviving graft tissue (visualized by Cresyl Violet staining, dense acetylcholinesterase staining and the presence of a limited number of nerve growth factor receptor-immunoreactive neurons) in the neocortex and 5/6 transplanted animals showed near complete restitution of acetylcholinesterase staining in frontal and parietal cortex. Examination of individual animal data showed that the animal without this restitution performed very poorly. The performance of the remaining transplanted animals was significantly better than that of the animals with lesion alone. There was a significant positive correlation between the degree of acetylcholinesterase staining and good performance on tasks sensitive to frontal lobe damage. These results demonstrate that acetylcholine-rich tissue transplanted into the neocortex of primates with damage to the cholinergic projections to the neocortex can produce substantial restitution of function provided that an appropriate level of interaction between graft and host tissue is achieved.

Acetylcholine↗
PubMed1993

Cognitive inflexibility after archicortical and paleocortical prefrontal lesions in marmosets.

The behaviour and cognitive abilities of marmosets with bilateral ablations of either the archicortex on the mediodorsal surface or the paleocortex on the ventrolateral surface of the frontal lobes were assessed in terms of the types of information being handled, the mode of action (inhibitory versus productive mechanisms), and the level of functioning of these frontal areas. Although there was a tendency for the ventrolateral ablation to produce a greater impairment on object than on spatial discrimination in comparison to the mediodorsal ablation, the differences between the two groups was not marked in this respect. The effect of ablations of either of these areas was more marked on tasks which required the inhibition of prepotent responses than on tasks where novel or arbitrary responses were appropriate. The major effect of both lesions was the production of perseverative behaviour which occurred at the level of motor output in the first few days after surgery but was then observed at the level of choice behaviour and attentional set in formal cognitive tests. Impairments were also seen on postoperative retention of tasks learnt prior to surgery. It is suggested that all these impairments arise from an inability to use or modify stored information.

Animals↗
PubMed1993

Experimental induction of beta-amyloid plaques and cerebral angiopathy in primates.

Moderate numbers of amyloid plaques with associated argyrophilic dystrophic neurites and cerebral amyloid angiopathy (CAA) but no neurofibrillary tangles (NFTs) were found in the brains of 3 middle-aged common marmosets (Callithrix jacchus) inoculated intracerebrally (i.c.) 6-7 years earlier with brain tissue from a patient with early onset Alzheimer's disease. The plaques and vascular amyloid stained positively with antibodies to beta (A4)-protein. The brains of 3 age-matched control marmosets from the same colony did not show these neuropathological features. beta-amyloid plaques and CAA (but no spongiform encephalopathy) were also found in the brain of a marmoset inoculated with brain tissue from a patient with prion disease with concomitant beta-amyloid plaques and CAA. An occasional beta-amyloid plaque was found in the brains of two marmosets inoculated with brain tissue from elderly patients. No beta-amyloid plaques nor CAA were found in 6 other marmosets who were older than the inoculated marmosets, 10 further marmosets who were slightly younger but who had been inoculated several years previously with brain tissue which did not contain beta-amyloid, and 10 younger marmosets who had been subjected to various neurosurgical procedures. These results suggest that beta-amyloidosis is a transmissible process.

Alzheimer Disease↗
PubMed1993

Behavioral effects of cholinergic grafts.

Experimental work in animals and, to a more limited extent, in humans, has demonstrated that the cholinergic system is involved in mechanisms which control learning and memory. Since there is cholinergic loss in a variety of dementing illnesses, any treatment designed to alleviate the mental symptoms of these diseases must address the issue of cholinergic dysfunction even if other treatments are also required to overcome other neurotransmitter imbalances. Work in rodents has demonstrated that cholinergic-rich fetal neural tissue transplants can, under certain circumstances, alleviate the behavioral effects of cholinergic lesions or of cholinergic decline associated with aging. More complex cognitive testing can be achieved using primates and, in this case, the common marmoset is a suitable species to use because its rapid and reliable reproductive rate aids the provision of appropriate transplant tissue. Marmosets with transection of the fornix are deprived of a cholinergic input into the dentate gyrus, posterior hippocampus and entorhinal cortex and are specifically impaired on learning tasks which require remembering a rule of responding (non-evaluative memory). Transplantation of cholinergic-rich fetal septal tissue into the hippocampus of such animals completely restores their ability to learn this type of task, whereas transplantation of cholinergic-poor fetal hippocampal tissue into the same area produces no such improvements. These results demonstrate that where a learning impairment is produced by a relatively simple procedure which has a major effect on one neurotransmitter, that function can be restored by transplantation of tissue containing that neurotransmitter even where the impairment consists of a very "high level" cognitive dysfunction.

Acetylcholine↗
PubMed1993

Experimental transmission of BSE and scrapie to the common marmoset.

Two young male common marmosets (Callithrix jacchus) were injected intracerebrally and intraperitoneally with a crude brain homogenate prepared from a cow with bovine spongiform encephalopathy (BSE). Two other marmosets were similarly injected with brain homogenate from a sheep with natural scrapie. The two animals injected with scrapie material developed neurological signs 38 and 42 months after injection and the two animals injected with BSE material developed neurological signs after 46 and 47 months. Post mortem examination of the brains revealed spongiform encephalopathy especially in the basal nuclei and diencephalon of all the animals and, in addition, involvement of the cerebral cortex of the marmosets injected with scrapie material. The experiment extends the host range of experimental BSE to include a primate species.

Animals↗
PubMed1993

Stimulus-bound perseveration after frontal ablations in marmosets.

Marmosets with bilateral ablations of either the lateral or ventral surface of the frontal lobes were found to perseverate on object but not spatial serial reversal. They also perseverated on reversal of a visuospatial task where different stimuli required different spatial responses. No differences were found between the two lesion groups. Since the control animals showed mild perseveration on spatial but not object serial reversal it is argued that frontal ablations do not lead to perseveration of a natural tendency but rather that object and visuospatial perseveration are forms of stimulus-bound behaviour which do not occur when the animal is performing a spatial task in which stimulus position is irrelevant. Perseveration was reduced by pretreatment with a dopamine-blocking drug (haloperidol). It is suggested that information from temporal lobe mechanisms, involved in long-term memory, and from frontal lobe mechanisms, which exert shorter acting influences on behaviour, compete within the basal ganglia to determine stimulus choice. The ascending dopaminergic pathway may modulate the balance between these competing factors.

Animals↗
PubMed1993

Genetics of human prion disease.

Prion diseases are fatal neurodegenerative disorders in which an abnormal isoform of prion protein (PrPSc) accumulates in brain. Prion disease is either inherited as an autosomal dominant disorder with very high penetrance, sporadic, where no epidemiological association with other human or animal prion diseases can be demonstrated or acquired, where disease results from contamination with PrPSc from another case of prion disease. No human case of prion disease is known to have been acquired from an animal but about 50 cases have been acquired from contaminated growth hormone or gonadotrophin prepared from human pituitaries, from human meningeal transplants or other neuro-surgical procedures. Several thousand cases of the prion disease, kuru, occurred in Papua New Guinea, mainly during the first half of this century. This epidemic probably started with a sporadic case of Creutzfeldt-Jakob disease but was transmitted through funerary practices which are though to have involved endo-cannibalism. Inherited cases of prion disease are associated with mutations in the PrP gene. There are at least five point mutations and a further five mutations involving five to nine extra repeats of the five octapeptide repeat sequence in the PrP gene, all of which may lead to one of the forms of human prion disease i.e. Creutzfeldt-Jakob disease, Gerstmann-Sträussler syndrome and atypical prion dementia. In addition there is a common polymorphism at codon 129 of the PrP gene. This may affect age at onset and duration of illness in inherited and sporadic cases.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗