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K J Jeffery

Publications and source records attributed to K J Jeffery.

At least 19 recordsLinked to original sources
PubMed2001

Immigration and the ephemerality of a natural population bottleneck: evidence from molecular markers.

Population bottlenecks are often invoked to explain low levels of genetic variation in natural populations, yet few studies have documented the direct genetic consequences of known bottlenecks in the wild. Empirical studies of natural population bottlenecks are therefore needed, because key assumptions of theoretical and laboratory studies of bottlenecks may not hold in the wild. Here we present microsatellite data from a severe bottleneck (95% mortality) in an insular population of song sparrows (Melospiza melodia). The major findings of our study are as follows: (i) The bottleneck reduced heterozygosity and allelic diversity nearly to neutral expectations, despite non-random survival of birds with respect to inbreeding and wing length. (ii) All measures of genetic diversity regained pre-bottleneck levels within two to three years of the crash. This rapid recovery was due to low levels of immigration. (iii) The rapid recovery occurred despite a coincident, strong increase in average inbreeding. These results show that immigration at levels that are hard to measure in most field studies can lead to qualitatively very different genetic outcomes from those expected from mutations only. We suggest that future theoretical and empirical work on bottlenecks and metapopulations should address the impact of immigration.

Animals↗
PubMed2000

The influence of HLA class I alleles and heterozygosity on the outcome of human T cell lymphotropic virus type I infection.

The inflammatory disease human T cell lymphotropic virus type I (HTLV-I)-associated myelopathy (HAM/TSP) occurs in only 1-2% of HTLV-I-infected individuals and is associated with a high provirus load of HTLV-I. We hypothesize that a person's risk of developing HAM/TSP depends upon the efficiency of their immune response to the virus, which differs between individuals because of polymorphism in genes that influence this response. Previously we showed that the possession of HLA-A*02 was associated with a lower risk of HAM/TSP, and with a lower provirus load in healthy carriers of HTLV-I. However, HLA-A*02 did not account for all the observed difference in the risk of HAM/TSP. Here we present evidence, in the same study population in Japan, that HLA-Cw*08 was also associated with disease protection (probability value, two-tailed test = 0.002) and with a lower proviral load in healthy carriers. Possession of the A*02 and/or Cw*08 genes prevented 36% of potential HAM/TSP cases. In contrast, HLA-B*5401 was associated with a higher susceptibility to HAM/TSP (probability value, two-tailed test = 0.0003) and with a higher provirus load in HAM/TSP patients. At a given provirus load, B*5401 appeared to increase the risk of disease. The fraction of HAM/TSP cases attributable to B*5401 was 17%. Furthermore, individuals who were heterozygous at all three HLA class I loci have a lower HTLV-I provirus load than those who were homozygous at one or more loci. These results are consistent with the proposal that a strong class I-restricted CTL response to HTLV-I reduces the proviral load and hence the risk of disease.

Alleles↗
PubMed2000

Do infectious diseases drive MHC diversity?

The primary function of the major histocompatibility complex (MHC) is to allow the immune system to identify infectious pathogens and eliminate them. Infectious diseases are now thought to be the main selection force that drives and maintains the extraordinary diversity of the MHC.

Alleles↗
PubMed1999

Genetic control and dynamics of the cellular immune response to the human T-cell leukaemia virus, HTLV-I.

About 1% of people infected with the human T-cell leukaemia virus, type 1 (HTLV-I) develop a disabling chronic inflammatory disease of the central nervous system known as HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Patients with HAM/TSP have a vigorous immune response to HTLV-I, and it has been widely suggested that this immune response, particularly the HTLV-I-specific cytotoxic T-lymphocyte (CTL) response, causes the tissue damage that is seen in HAM/TSP. In this paper we summarize recent evidence that a strong CTL response to HTLV-I does in fact protect against HAM/TSP by reducing the proviral load of HTLV-I. We conclude that HTLV-I is persistently replicating at a high level, despite the relative constancy of its genome sequence. These results imply that antiretroviral drugs could reduce the risk of HAM/TSP by reducing the viral load, and that an effective anti-HTLV-I vaccine should elicit a strong CTL response to the virus. The dynamic nature of the infection also has implications for the epidemiology and the evolution of HTLV-I.

Human T-lymphotropic virus 1↗
PubMed1999

HLA alleles determine human T-lymphotropic virus-I (HTLV-I) proviral load and the risk of HTLV-I-associated myelopathy.

The risk of disease associated with persistent virus infections such as HIV-I, hepatitis B and C, and human T-lymphotropic virus-I (HTLV-I) is strongly determined by the virus load. However, it is not known whether a persistent class I HLA-restricted antiviral cytotoxic T lymphocyte (CTL) response reduces viral load and is therefore beneficial or causes tissue damage and contributes to disease pathogenesis. HTLV-I-associated myelopathy (HAM/TSP) patients have a high virus load compared with asymptomatic HTLV-I carriers. We hypothesized that HLA alleles control HTLV-I provirus load and thus influence susceptibility to HAM/TSP. Here we show that, after infection with HTLV-I, the class I allele HLA-A*02 halves the odds of HAM/TSP (P < 0.0001), preventing 28% of potential cases of HAM/TSP. Furthermore, HLA-A*02(+) healthy HTLV-I carriers have a proviral load one-third that (P = 0.014) of HLA-A*02(-) HTLV-I carriers. An association of HLA-DRB1*0101 with disease susceptibility also was identified, which doubled the odds of HAM/TSP in the absence of the protective effect of HLA-A*02. These data have implications for other persistent virus infections in which virus load is associated with prognosis and imply that an efficient antiviral CTL response can reduce virus load and so prevent disease in persistent virus infections.

Alleles↗
PubMed1999

Learned interaction of visual and idiothetic cues in the control of place field orientation.

In a symmetrical environment (like a square box) hippocampal place cells use a mixture of visual and idiothetic (movement) information to tell them which way the environment is oriented. The present experiment tested the hypothesis that if the visual landmarks were mobile, place cells would learn to disregard these and rely on idiothetic cues instead. Place cells were recorded in a square box surrounded by circular black curtains. A cue card hung on the curtain behind one of the walls to break the fourfold symmetry. The relative influence of this card on the location of place fields was assessed each day by confining the rat on a rotating platter underneath an opaque cover, and then rotating the card and the platter by different amounts, to see whether subsequently recorded place fields had rotated with the card or with the rat. For some rats, these trials had been preceded by trials in which the card had been visibly moved from trial to trial, so that the rats had seen that it was mobile. Other rats received no prior visual information that the card was mobile. In the rats that had previously seen the card move, place fields initially rotated with the card but by the end of five sessions usually rotated with the rat instead. For rats that had never seen the card move, place fields always followed the card. Thus, the cells were able to "learn" that their preferred directional input, the card, was unreliable. A third group of rats, who were covered only for 30 s while the card was moved, showed mixed behaviour, suggesting a degradation of the idiothetic trace with time.

Animals↗
PubMed1998

Place cells, navigational accuracy, and the human hippocampus.

The hippocampal formation in both rats and humans is involved in spatial navigation. In the rat, cells coding for places, directions, and speed of movement have been recorded from the hippocampus proper and/or the neighbouring subicular complex. Place fields of a group of the hippocampal pyramidal cells cover the surface of an environment but do not appear to do so in any systematic fashion. That is, there is no topographical relation between the anatomical location of the cells within the hippocampus and the place fields of these cells in an environment. Recent work shows that place cells are responding to the summation of two or more Gaussian curves, each of which is fixed at a given distance to two or more walls in the environment. The walls themselves are probably identified by their allocentric direction relative to the rat and this information may be provided by the head direction cells. The right human hippocampus retains its role in spatial mapping as demonstrated by its activation during accurate navigation in imagined and virtual reality environments. In addition, it may have taken on wider memory functions, perhaps by the incorporation of a linear time tag which allows for the storage of the times of visits to particular locations. This extended system would serve as the basis for a spatio-temporal event or episodic memory system.

Animals↗
PubMed1997

Robotic and neuronal simulation of the hippocampus and rat navigation.

The properties of hippocampal place cells are reviewed, with particular attention to the nature of the internal and external signals that support their firing. A neuronal simulation of the firing of place cells in open-field environments of varying shape is presented. This simulation is coupled with an existing model of how place-cell firing can be used to drive navigation, and is tested by implementation as a miniature mobile robot. The sensors on the robot provide visual, odometric and short-range proximity data, which are combined to estimate the distance of the walls of the enclosure from the robot and the robot's current heading direction. These inputs drive the hippocampal simulation, in which the robot's location is represented as the firing of place cells. If a goal location is encountered, learning occurs in connections from the concurrently active place cells to a set of 'goal cells', which guide subsequent navigation, allowing the robot to return to an unmarked location. The system shows good agreement with actual place-cell firing, and makes predictions regarding the firing of cells in the subiculum, the effect of blocking long-term synaptic changes, and the locus of search of rats after deformation of their environment.

Animals↗
PubMed1997

Diagnosis of viral infections of the central nervous system: clinical interpretation of PCR results.

BACKGROUND: Standard laboratory techniques, such as viral culture and serology, provide only circumstantial or retrospective evidence of viral infections of the central nervous system (CNS). We assessed the diagnostic accuracy of PCR of cerebrospinal fluid (CSF) in the diagnosis of viral infections of the CNS. METHODS: We examined all the CSF samples that were received at our diagnostic virology laboratory between May, 1994, and May, 1996, by nested PCR for viruses associated with CNS infections in the UK. We collected clinical and laboratory data for 410 patients from Oxford city hospitals (the Oxford cohort) whose CSF was examined between May, 1994, and May, 1995. These patients were classified according to the likelihood of a viral infection of the CNS. We used stratified logistic regression analysis to identify the clinical factors independently associated with a positive PCR result. We calculated likelihood ratios to estimate the clinical usefulness of PCR amplification of CSF. FINDINGS: We tested 2233 consecutive CSF samples from 2162 patients. A positive PCR result was obtained in 143 patients, including 22 from the Oxford cohort. Logistic regression analysis of the Oxford cohort showed that fever, a virus-specific rash, and a CSF white-cell count of 5/microL or more were independent predictors of a positive PCR result. The likelihood ratio for a definite diagnosis of viral infection of the CNS in a patient with a positive PCR result, relative to a negative PCR result, was 88.2 (95% CI 20.6-378). The likelihood ratio for a possible diagnosis of viral infection of the CNS in a patient with a negative PCR result, relative to a positive PCR result, was 0.10 (0.03-0.39). INTERPRETATION: A patient with a positive PCR result was 88 times as likely to have a definite diagnosis of viral infection of the CNS as a patient with a negative PCR result. A negative PCR result can be used with moderate confidence to rule out a diagnosis of viral infection of the CNS. We believe that PCR will become the first-line diagnostic test for viral meningitis and encephalitis.

Adolescent↗
PubMed1997

LTP and spatial learning--where to next?

Hebb suggested, in 1949, that memories could be stored by forming associative connections between neurons if the criterion for increasing the connection strength between them be that they were active simultaneously. Much attention has been devoted towards trying to determine a) if there is a physiological substrate of such a rule, and b) if so, whether the phenomenon participates in real-life memory formation. The discovery of the electrically induced increase in synaptic strength known as long-term potentiation (LTP), in the early 1970s, demonstrated that a neural version of the Hebb rule could be observed under laboratory conditions in the hippocampus, a structure important for some types of learning. However, a quarter of a century later, the evidence linking LTP to learning and memory is still contradictory. The purpose of the present article is to review and assess the types of approach that have been taken in trying to determine whether hippocampal synaptic plasticity participates in memory formation.

Animals↗
PubMed1997

Directional control of hippocampal place fields.

Pyramidal cells in the rat hippocampus fire whenever the animal is in a particular place, suggesting that the hippocampus maintains a representation of the environment. Receptive fields of place cells (place fields) are largely determined by the distance of the rat from environmental walls. Because these walls are sometimes distinguishable only by their orientation with respect to the outside room, it has been hypothesised that a polarising directional input enables the cells to locate their fields off-centre in an otherwise symmetrical environment. We tested this hypothesis by gaining control of the rat's internal directional sense, independently of other cues, to see whether manipulating this sense could, by itself, produce a corresponding alteration in place field orientation. Place cells were recorded while rats foraged in a rectangular box, in the absence or presence of external room cues. With room cues masked, slow rotation of the rat and the box together caused the fields to rotate accordingly. Rotating the recording box alone by 180 degrees rarely caused corresponding field rotation, while rotating the rat alone 180 degrees outside the environment and then replacing it in the recording box almost always resulted in a corresponding rotation of the fields. This shows that place field orientation can be controlled by controlling the internal direction-sense of the rat, and it opens the door to psycho-physical exploration of the sensory basis of the direction sense. When room cues were present, distal visual cues predominated over internal cues in establishing place field orientation.

Animals↗
PubMed1997

Aseptic meningitis and encephalitis: the role of PCR in the diagnostic laboratory.

In this study we have devised a simple and robust PCR strategy to detect a wide range of viruses, bacteria, and parasites, all of which are capable of causing aseptic meningitis and encephalitis. The techniques developed have been used in a routine diagnostic virology laboratory to test prospectively 2,233 cerebrospinal fluid specimens. A virus was detected in 147 specimens of cerebrospinal fluid from 143 patients. Four sets of primers were sufficient to detect the virus in 135 (94%) of the PCR-positive patients. We conclude that with appropriate primers, PCR can be systematically and economically applied to test for a range of organisms in a routine diagnostic laboratory. In our opinion, PCR will soon become the "gold standard" test for viral infections of the central nervous system.

Algorithms↗
PubMed1997

Modifiable neuronal connections: an overview for psychiatrists.

Synaptic plasticity is currently the target of much neurobiological research, because it is thought to play an important role in brain function (particularly memory formation). However, it has attracted little attention from psychiatrists to date despite accumulating evidence that links it to various clinical syndromes, including amnesia and possibly psychosis. The purpose of this article is to present an overview of the two major arms of synaptic plasticity research-theoretical (the field of neural network modeling) and neurobiological (long-term potentiation). Artificial neural networks are a class of theoretical model that has been developed with the aim of understanding how information could, in principle, be represented by large numbers of interconnected and relatively simple units. Over the past few decades, several theoretical accounts of information-processing mechanisms have been developed, and these are briefly reviewed. The principle common to representation formation in nearly all neural networks is that of "associability"-the idea that streams of information are combined by forming, strengthening, or pruning connections between them to form new representations that can later be retrieved. Associability also lies at the heart of psychological theories of information storage in the brain. Research into associability has directed the attention of many experimenters toward the possible biological correlates of such mechanisms. Of particular interest is the recent discovery that some neurons appear to possess connections of modifiable strength. The implications of this finding for psychiatry are discussed in relation to representational disorders such as delusions and amnesia.

Amnesia↗
PubMed1995

Medial septal control of theta-correlated unit firing in the entorhinal cortex of awake rats.

The present study investigated whether the medial septal nucleus controls theta-correlated unit activity in the entorhinal cortex (EC), as it does in the hippocampus. Single neurones were recorded from the medial EC of rats as they ran on a linear track or chased food pellets on a small platform. The most prominent pattern of cell activity observed was burst firing occurring near the peaks of the ongoing dentate gyrus theta rhythm. This rhythmic unit activity was abolished by microinjections of lignocaine into the medial septal nucleus, but was resistant to cholinergic blockade.

Animals↗
PubMed1995

Paradoxical enhancement of long-term potentiation in poor-learning rats at low test stimulus intensities.

Much empirical evidence and numerous theoretical models point to modification of synaptic efficacy as a mechanism for memory formation. To evaluate theoretical models, it is necessary to obtain quantitative experimental data relating learning to experimentally induced synaptic efficacy changes (such as long-term potentiation, LTP). An important problem in this type of experiment is how to quantify the LTP induced by a given stimulation protocol. Of relevance is the informally well-known observation that LTP magnitude appears to vary as a function of the intensity of the stimulus used to evoke baseline responses. The present study found that using a measure of LTP that circumvents this variation, a strong negative correlation of learning with potentiation emerges. Spatial learning ability was compared with the magnitude of subsequent LTP induction as follows: rats underwent a day of spatial training in a watermaze followed by 5 days of bilateral perforant path tetanisation. Baseline electrophysiological responses were evoked over a range of stimulus intensities (input/output [IO] curves) before and after tetanisation. Although LTP was observed across the whole of the IO curve, it showed a smooth decline with increasing current. The animals were then grouped according to their watermaze performance and IO curves compared between good and poor learners. After tetanisation, there was a negative within-animal correlation between learning and evoked potential size with weak test stimuli and a positive correlation with strong stimuli. The decline of LTP across the IO curve differed between good and poor spatial learners; the poor learners showed higher percentage potentiation with test stimuli close to zero intensity, but a faster decrease in LTP across the curves. The findings are therefore: (1) the measured amount of LTP declined systematically with increasing stimulus strength, and (2) the parameters of the decline correlated with spatial learning ability. These results raise two important issues. First, because measured LTP varied systematically across the IO curve, it appears that for quantitative analyses the widely used method of LTP measurement using a single test stimulus intensity risks missing significant features of the data. It is suggested that a measure be used that incorporates data from a range of stimulus intensities. Second, when such a measure is used there is a striking negative correlation of spatial learning ability with LTP. These apparently paradoxical results are discussed.

Animals↗
PubMed1995

Two cases of infected atherosclerotic aneurysms and a comparison with infective endocarditis.

Two cases of infected atherosclerotic aneurysms thought to have arisen following haematogenous seeding of atheromatous lesions are described. Although infective endocarditis also arises by the haematogenous route, there are striking contrasts in both the range and therefore likely source of organisms, together with a perceived difference in the rate of blood-culture positivity. This case report provides a focus for discussion of these observations.

Aged↗
PubMed1993

Cumulative long-term potentiation in the rat dentate gyrus correlates with, but does not modify, performance in the water maze.

The electrically induced increase in hippocampal synaptic strength known as long-term potentiation (LTP) is thought to involve some of the same mechanisms as those mediating information storage during spatial learning. Physiological saturation of synaptic weights might therefore be expected to occlude spatial learning. In support of this, Castro et al. (Castro CA, Silbert LH, McNaughton BL, Barnes CA, 1989, Nature 342:545-548) reported that repeated induction of LTP to asymptotic levels, over a 14-day period, blocked the ability of rats to learn the position of a hidden platform in a water maze shortly afterwards. The authors have attempted to replicate this finding in two experiments. In Experiment 1, rats were given either 400 Hz stimulation as 50 trains/day over a 5-day period, to induce LTP, or were given the same number of stimulus pulses at 1 Hz. Two hours after the last stimulation session they underwent eight spatial learning trials, occurring at 2-hour intervals. In Experiment 2, the procedure of Castro et al. was followed exactly, with LTP induced by 10 trains of 400 Hz stimulation daily for 14 days. Spatial learning trials began 10 minutes after the last stimulation session and consisted of 12 trials with alternating 30-second and 2-minute intervals. In neither experiment was a significant impairment of spatial learning observed. However, there was a strong positive correlation, in both experiments, between the final level of LTP and subsequent performance in the water maze.

Animals↗