Volumetric and morphological characteristics of the hippocampus are associated with progression to schizophrenia in patients with first-episode psychosis.

BACKGROUND: Abnormalities in the hippocampus have been implicated in the pathophysiology of psychosis. However, it is still unclear whether certain abnormalities are a pre-existing vulnerability factor, a sign of disease progression or a consequence of environmental factors. We hypothesized that first-episode psychosis patients who progress to schizophrenia after one year of follow up will display greater volumetric and morphological changes from the very beginning of the disorder. METHODS: We studied the hippocampus of 41 patients with a first-episode psychosis and 41 matched healthy controls. MRI was performed at the time of the inclusion in the study. After one year, the whole sample was reevaluated and divided in two groups depending on the diagnoses (schizophrenia vs. non-schizophrenia). RESULTS: Patients who progressed to schizophrenia showed a significantly smaller left hippocampus volume than control group and no-schizophrenia group (F=3.54; df=2, 77; P=0.03). We also found significant differences in the morphology of the anterior hippocampus (CA1) of patients with first-episode psychosis who developed schizophrenia compared with patients who did not. CONCLUSIONS: These results are consistent with the assumption of hyperfunctioning dopaminergic cortico-subcortical circuits in schizophrenia, which might be related with an alteration of subcortical structures, such as the hippocampus, along the course of the disease. According with these results, hippocampus abnormalities may serve as a prognostic marker of clinical outcome in patients with a first-episode psychosis.

Reinfection with hookworm after chemotherapy in Papua New Guinea.

Reinfection with hookworm (Necator americanus) following chemotherapy was studied over 2 years in a rural village in Madang Province, Papua New Guinea. The prevalence of hookworm infection had returned to pre-treatment levels after 2 years, and the geometric mean hookworm burden had returned to 58% of the pre-treatment value. The rate of acquisition of adult worms was independent of host age, and was estimated as a geometric mean of 2.9-3.3 worms/host/year (arithmetic mean 7.9-8.9 worms/host/year). There was significant predisposition to hookworm infection; the strength of this predisposition did not vary significantly between age or sex classes.

Isotypic variation in antibody responses in a community in Papua New Guinea to larval and adult antigens during infection, and following reinfection, with the hookworm Necator americanus.

The natural infection of a community with the hookworm Necator americanus induces a vigorous humoral response to both larval and adult parasite antigens. This response occurs in all five human antibody isotypes, and data are presented to show that, at the population level, isotypes respond differently, following chemotherapy and during reinfection, to changes in antigen stimulation. The differential response probably reflects the fact that the parasite, during the course of its life cycle, presents different amounts of antigens at different anatomical locations. It is suggested that IgG and IgM responses against adult excretory-secretory (ES) products most accurately reflect the efficacy of chemotherapy, and the load of resident adult infection, while IgG responses against larval somatic antigens reflect continuous exposure to infection. These hypotheses should now be tested, at the level of the individual, in a longitudinal manner using more closely spaced sampling intervals. This repetitive sampling, and the inclusion of a measure of the exposure of the population to infective stages, will allow more definitive conclusions to be made about the role of the immune response in controlling worm burdens.

Gametocyte sex ratios as indirect measures of outcrossing rates in malaria.

The frequency of recombination between unlike genotypes is central to understanding the generation of genetic diversity in natural populations of malaria. Here we suggest a way of investigating the problem which could complement conventional biochemical approaches to the population genetics of malaria. Sex allocation theory is one of the most successful areas of evolutionary biology. A well-supported prediction is that progressively less female-biased sex ratios are favoured with more outcrossing; equal numbers of males and females being evolutionarily stable in randomly mating outbred populations. We present a simple game theory model to support the idea that outcrossing rates in malaria will be correlated with the sex ratio of gametocytes in the peripheral blood of vertebrate hosts. Blood films from epidemiological surveys and culture-adapted isolates from Madang Province, Papua New Guinea, were used to estimate average gametocyte sex ratio of Plasmodium falciparum in the area. The geometric mean proportion of males in the population was 0.18 (95% confidence limits: 0.15-0.22). From our model, we estimate that, on average, 36% of zygotes are the result of outcrossing. This estimate assumes that most microgametes released following exflagellation are capable of fertilization. If, on average, fewer than about 70% of microgametes are capable of fertilization (as is the case in at least one other species of Plasmodium), the observed sex ratio would be consistent with between zero and 36% of zygotes being the result of outcrossing. These estimates suggest that there is usually a numerically dominant genotype in the gametocyte population in a blood meal, and that a considerable amount of selfing is occurring in P. falciparum populations in the Madang region, even though it is an area of intense year-round transmission.

The population dynamics of acquired immunity to Heligmosomoides polygyrus in the laboratory mouse: strain, diet and exposure.

An experiment was designed to investigate aspects of the population dynamics of acquired immunity to Heligmosomoides polygyrus in laboratory mice. The influence of host strain (CBA or NIH), rate of exposure (5 or 40 L3/mouse/2 weeks) and diet (3 or 16% protein w/w) on the population dynamics of repeated infection and the response to a standard challenge infection were investigated. The time delay between the end of the period of repeated infection and the subsequent challenge (between 1 and 24 weeks) had no effect on worm recovery. The effects of both exposure and diet were significant and similar whether assessed on the basis of the dynamics of repeated infection or response to challenge: low rates of exposure and low dietary protein were both associated with low levels of acquired immunity. Mouse strain was the most important determinant of worm recovery after challenge, but had no significant effect on the degree to which parasite population growth was constrained by acquired immunity during repeated infection. It is suggested that both CBA and NIH mice raise immune responses which act on parasite survival, but that only NIH mice raise responses operative against larval establishment.

Antigenic cross-reactivity between Necator americanus and Ascaris lumbricoides in a community in Papua New Guinea infected predominantly with hookworm.

Sero-epidemiological data are presented in which antigenic cross-reactivity between Necator americanus and Ascaris lumbricoides has been investigated in a community in Papua New Guinea infected predominantly with N. americanus. It is our contention that the antigenic cross-reactivity which undoubtedly exists between these species accounted for (i) a peak in antibody levels against N. americanus in 10-13 years old children (driven by infection with A. lumbricoides), and (ii) the maintenance of apparent antibody levels against A. lumbricoides in older age groups (driven by infection with N. americanus in the absence of overt infection with A. lumbricoides). Cross-reactivity was analysed further, and apparently N. americanus-specific epitopes identified, by immunoblotting. These observations could have considerable bearing on the interpretation of data from sero-epidemiological studies which failed to take account of concurrent infection with these parasites.

Host specificity of and cross-immunity between two strains of Heligmosomoides polygyrus.

The infectivity of wild and laboratory strains of Heligmosomoides polygyrus (Nematospiroides dubius) in laboratory mice and in three species of wild British rodent was compared. Wild strains, of the subspecies H. p. polygyrus, were isolated from wild caught Apodemus sylvaticus. Only very low-level infections of the wild strains became established in laboratory mice. Similar worm burdens of the laboratory strain became established in laboratory mice and A. sylvaticus, although infections in A. sylvaticus were more short lived. Cortisone treatment of hosts increased the establishment and survival of the heterologous worm strain to that of the homologous strain. In contrast, neither strain of parasite established in Clethrionomys glareolus or Microtus agrestis, and cortisone treatment of C. glareolus did not increase establishment. Infection of laboratory mice with the wild-strain parasite induced significant immunity to a challenge infection with the laboratory strain.

Hookworm (Necator americanus) infection and storage iron depletion.

The relationship between iron status and the intensity of infection with hookworm was investigated in a rural population on Karkar Island, Mandang Province, Papua New Guinea. There was a significant negative correlation between plasma ferritin level and hookworm burden, which was strongest in males. In contrast, there was no correlation between plasma ferritin and hookworm egg count, and no consistent correlation between haemoglobin level or haematocrit and either measure of hookworm intensity. The results suggest that the role of hookworm in the aetiology of anaemia may be difficult to assess without the accurate measurement of hookworm burden.

Heligmosomoides polygyrus or Nematospiroides dubius?

The intestinal trichostrongylid nematode of mice, Heligmosomoides polygyrus bakeri, is often referred to as Nematospiroides dubius. Here, Jerzy Behnke, Anne Keymer and John Lewis ask the question: which is correct?

The regulation of gastrointestinal helminth populations.

One quarter of the world's human population suffers infection with helminth parasites. The population dynamics of the ten or so species, which cause disease of clinical significance have been well characterized by epidemiological field survey. The parasites are in general highly aggregated between hosts, and their populations seem to be temporally stable and to recover rapidly from perturbation, including interventions designed to alleviate disease. This paper reviews current understanding of the population regulation of helminth species of medical significance. Both empirical (field and laboratory) and theoretical results are included, and we attempt to interpret the findings in the broader context of the population ecology of free-living species. We begin by considering the evidence for regulation from field data concerning the temporal stability of helminth populations within communities and from the results of perturbation experiments. The detection of regulatory processes is then discussed (with regard to statistical and logistical considerations), and the evidence from both the field and laboratory studies reviewed. Deterministic models are described to investigate the possible consequences of regulation imposed at different points in the parasite life-cycle. The causes and consequences of parasite aggregation are considered, and a stochastic model used to investigate the impact of different combination of regulatory processes and heterogeneity generating mechanisms.

Immunogenetic correlates of susceptibility to infection with Heligmosomoides polygyrus in outbred mice.

Outbred MF1 mice were characterized with respect to their susceptibility to infection with Heligmosomoides polygyrus (Nematoda) on the basis of faecal egg counts after 8 weeks of repeated infection (50 larvae/week). Selective breeding for resistance and susceptibility was carried out over 3 generations. The H-2 type of a sample of the mice was determined, and antigen recognition assessed on the basis of Western blots against adult and larval H. polygyrus homogenate. The selective breeding programme yielded very strong evidence for the heritability of susceptibility to infection. The results were consistent with a model of single gene control with resistance dominant over susceptibility. The presence of the H-2k haplotype was significantly associated with susceptibility, as was the recognition of a 17 kDa antigen in blots against both larval and adult worm homogenate. The proportion of mice phenotypically susceptible to infection, the proportion bearing the H-2k haplotype, and the proportion recognizing the 17 kDa antigen, were all approximately 0.25.

Epidemiology and immunology of Necator americanus infection in a community in Papua New Guinea: humoral responses to excretory-secretory and cuticular collagen antigens.

Baseline data from an immuno-epidemiological study of hookworm infection in a rural village in Madang Province, Papua New Guinea are reported. Necator americanus was found to be the commonest helminth infection, with a prevalence of near 100% and intensity of 40 worms per host in adults. Enterobius vermicularis, Ascaris lumbricoides and Trichuris trichiura were also present, at prevalences of 53, 10 and 3% respectively; Ancylostoma duodenale was absent. The frequency distribution of N. americanus was highly over-dispersed, and was well described by a negative binomial distribution with aggregation parameter, k, of 0.370. Intensity of infection was significantly related to host age, but did not differ between the sexes. Haemoglobin levels and haematocrit values were indicative of anaemia in the community, but were unrelated to hookworm infection. Levels of antibodies (IgG, IgA and IgM combined) against adult Necator cuticular collagen and excretory-secretory (ES) products were determined. Serum concentrations of the two types of antibody were significantly correlated with each other. Significant positive correlations were found between anti-ES antibody levels and hookworm egg production, and between anti-collagen antibody levels and host age. It is suggested that the level of anti-collagen antibodies may reflect cumulative exposure to infection, whereas levels of anti-ES antibodies may be more dependent on current worm burden. No evidence was found to suggest that either antibody response is important in regulating parasite population growth. Similarly, the presence of a positive correlation between eosinophil concentration and infection intensity in adults indicates that eosinophilia reflects, rather than determines, the host's worm burden.

The ecology of host--parasite interactions.

In their attempts to explain observed patterns in population dynamics and community structure, ecologists have, until recently, been preoccupied with the effects of predation and competition. An increasing number of new studies, however, highlight the role of parasites (broadly defined to include viruses, bacteria, protozoans, helminths and arthropods) in determining both the abundance and distribution of animal species. This review outlines theoretical advances that have been made in this area and presents field and laboratory evidence for the importance of parasites in community ecology.

The influence of protein deficiency on immunity to Heligmosomoides polygyrus (Nematoda) in mice.

The influence of dietary protein on the efficiency with which mice could be immunized against infection with the nematode Heligomosomoides polygyrus was investigated. Immunization with irradiated larvae did not protect outbred mice fed synthetic diets containing 2% or 4% protein against a challenge infection, while animals fed a diet containing 8% protein were significantly resistant. In further experiments with high-responder NIH mice, protein malnutrition was again found to cause a significant depression in immunity. Immunization primed all mice for an intense production of antibody against larval worms in a challenge infection, and although a slightly higher titre of antibody was detected in the plasma of mice fed a 16% compared with a 2% protein diet it seemed unlikely that this was sufficient to account for the reduced resistance of the malnourished mice. The development of eosinophilia in the blood of immunized mice was significantly delayed in malnourished animals following challenge, and it is suggested that a reduction in the number of granulocytes attacking larval worms contributed to the low level of resistance observed in these animals. Protein malnutrition thus markedly suppresses the effectiveness of immunization of mice against an intestinal nematode, and it is suggested that this result may be of general significance with regard to the potential for widespread immunization of people against infections of this type.