Social Spaces: Place Cells Represent the Locations of Others.

How does the brain represent the location of others? Recordings in rats and bats show that, along with representing self-location in an environment, some hippocampal neurons are modulated by the position of another individual.

The use of prophylaxis against HIV after sexual exposure in pregnancy to reduce the risk of vertical transmission.

We present a case demonstrating the use of HIV prophylaxis post-sexual exposure in pregnancy. This has not been presented before but has certainly been discussed.

Chickenpox in adults - clinical management.

Acute varicella zoster virus (VZV) infection, or chickenpox, is still perceived by many as a mild infection of childhood. However, chickenpox is increasingly common in adults and adolescents who together with immunosuppressed individuals are at a higher risk of severe infection. Antiviral therapy is available which both ameliorates symptoms and decreases the severity of chickenpox if administered early in the course of the infection. Passive immunisation with varicella zoster immunoglobulin (VZIG) may prevent or attenuate infection following exposure to varicella of an immunocompromised or pregnant individual or a neonate. Active immunisation is available and is universal in many developed countries. This review reflects current best practice in management of chickenpox in adults by specialist physicians in the UK. The accompanying flowchart has been formulated to guide emergency physicians and general practitioners through the decision-making process regarding treatment and admission for specialist care.

The fuzzy-boundary arena--a method for constraining an animal's range in spatial experiments without using walls.

A method is described for confining an animal within an experimenter-defined area without the use of physical boundaries. The area of exploration is constrained by the presence of an aversive noise, triggered whenever the animal steps across a computer-controlled boundary. The radius of the invisible boundary is constantly reset so that the boundary becomes "fuzzy" and the animal cannot use it as a spatial localizing cue. The effectiveness of this technique is demonstrated both with behavioural data confirming reliable confinement, and also recordings of hippocampal place cells made from rats exploring the arena. The place cell data reveal that indeed, the cells did not appear to be controlled by the fuzzy boundary, in contrast with the strong control normally exerted by fixed boundaries. This technique is thus promising for studies of spatial behaviour in which the strong influence of walls needs to be removed in order to allow the study of more subtle processes such as landmark use and path integration.

No association between hepatitis B or C viruses and vulval lichen planus in a UK population.

The aim of the study was to investigate the prevalence of hepatitis C (HCV) antibodies, hepatitis B surface antigen (HBsAg) carriage and liver disease in 100 females with genital lichen planus (LP) in Oxfordshire. Sera were screened for HCV antibodies (AxSYM HCV 3.0 Abbott), HBV surface antigen (AxSYM HBsAg V2 Abbott), mitochrondrial and anti-smooth muscle antibodies. Liver function tests were undertaken. All sera were negative for HCV antibody and HBsAg. Transiently abnormal liver function tests (2) and liver specific antibodies (2) were detected in four patients with no underlying liver disease. We found no association between HBV or HCV and genital LP in this population.

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.

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.

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.

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.

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.

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.

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.

Learning of landmark stability and instability by hippocampal place cells.

Place cells in the rat hippocampus fire whenever the animal is in a particular location. In a symmetrical environment, their receptive fields (place fields) are oriented by visual cues, and if these are unavailable they are oriented by movement-generated (idiothetic) cues. The present study tested the hypothesis that the cells would learn not to 'trust' a visual cue if the rat experienced it to be unstable (Knierim et al., 1995. Place cells, head direction cells and the learning of landmark stability. J. Neurosci. 15, 1648-1659). In an otherwise symmetrical environment, a visual cue was moved with respect to the idiothetic cues, either in sight or out-of-sight of the rat. When the visual cue was moved out-of-sight of the rat, place fields were initially oriented by this cue in preference to the idiothetic cues. However, if the cue was seen by the rat to be mobile, place fields ceased following the visual cue and became oriented by the idiothetic cues instead. If the cue was not seen to be mobile until the rat had had several days of experience in the environment, then the fields continued to be oriented by the (now visibly mobile) visual cue. It thus appears that the orienting influence of a visual cue on place fields can be either strengthened or weakened relative to the idiothetic cues, depending on the experience of the rat.

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.

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.

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.

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.