A malaria vaccine based on the polymorphic block 2 region of MSP-1 that elicits a broad serotype-spanning immune response.

Polymorphic parasite antigens are known targets of protective immunity to malaria, but this antigenic variation poses challenges to vaccine development. A synthetic MSP-1 Block 2 construct, based on all polymorphic variants found in natural Plasmodium falciparum isolates has been designed, combined with the relatively conserved Block 1 sequence of MSP-1 and expressed in E.coli.

Cellular pathology within the anterior cingulate cortex of patients with late-life depression: a morphometric study.

Previous imaging and morphometric studies have identified volumetric and cellular abnormalities in prefrontal areas in late-life depression. This study aimed to examine cellular morphology using stereological methodology in the supragenual region of the anterior cingulate cortex in late-life depressed patients compared with age-matched controls. Post-mortem tissue was acquired from nine patients with depression and 11 control patients and analyzed using the optical disector and nucleator methods.

Relationship of orthostatic blood pressure to white matter hyperintensities and subcortical volumes in late-life depression.

Background: Structural brain abnormalities are associated with late-life major depression, with numerous studies reporting increased white matter hyperintensities (WMH) and reduced cortical/subcortical grey matter volumes. There is strong evidence linking vascular disease to WMH, but limited evidence on its association with subcortical volumes.

Aims: To investigate the relationship of orthostatic blood pressure changes to WMH and subcortical grey matter volumes in late-life depression.

White matter changes in late-life depression: a diffusion tensor imaging study.

Background: Numerous studies have revealed white matter abnormalities in late-life depression (LLD). The objective was to investigate the integrity of white matter tracts in subjects with LLD compared to similar aged healthy individuals using diffusion tensor imaging (DTI).

Methods: Sixty eight subjects (30 healthy individuals, 38 depressed) underwent DTI on a 3T scanner following clinical and cognitive assessment.

Sertraline or mirtazapine for depression in dementia (HTA-SADD): a randomised, multicentre, double-blind, placebo-controlled trial.

Background: Depression is common in dementia but the evidence base for appropriate drug treatment is sparse and equivocal. We aimed to assess efficacy and safety of two of the most commonly prescribed drugs, sertraline and mirtazapine, compared with placebo.

Methods: We undertook the parallel-group, double-blind, placebo-controlled, Health Technology Assessment Study of the Use of Antidepressants for Depression in Dementia (HTA-SADD) trial in participants from old-age psychiatry services in nine centres in England.

Safety and immunogenicity of multi-antigen AMA1-based vaccines formulated with CoVaccine HT™ and Montanide ISA 51 in rhesus macaques.

Background: Increasing the breadth of the functional antibody response through immunization with Plasmodium falciparum apical membrane antigen 1 (PfAMA1) multi-allele vaccine formulations has been demonstrated in several rodent and rabbit studies. This study assesses the safety and immunogenicity of three PfAMA1 Diversity-Covering (DiCo) vaccine candidates formulated as an equimolar mixture (DiCo mix) in CoVaccine HT™ or Montanide ISA 51, as well as that of a PfAMA1-MSP1₁₉ fusion protein formulated in Montanide ISA 51.

Methods: Vaccine safety in rhesus macaques was monitored by animal behaviour observation and assessment of organ and systemic functions through clinical chemistry and haematology measurements.

Vaccination with Plasmodium knowlesi AMA1 formulated in the novel adjuvant co-vaccine HT™ protects against blood-stage challenge in rhesus macaques.

Plasmodium falciparum apical membrane antigen 1 (PfAMA1) is a leading blood stage vaccine candidate. Plasmodium knowlesi AMA1 (PkAMA1) was produced and purified using similar methodology as for clinical grade PfAMA1 yielding a pure, conformational intact protein. Combined with the adjuvant CoVaccine HT™, PkAMA1 was found to be highly immunogenic in rabbits and the efficacy of the PkAMA1 was subsequently tested in a rhesus macaque blood-stage challenge model.

Cortical thickness and VBM-DARTEL in late-life depression.

Background: Numerous studies have revealed structural brain changes in late life depression, mainly in white matter or whole lobes with few focussing just on grey matter (GM). The objective was to investigate GM changes in older depressed and similar aged healthy subjects using two different methods, cortical thickness in frontal lobe structures and voxel-based morphometry (VBM).

Methods: Sixty eight subjects participated (30 healthy comparison subjects, 38 depressed) and underwent 3T T1 MR imaging as well as clinical and cognitive assessments.

Towards an in vitro model of Plasmodium hypnozoites suitable for drug discovery.

Background: Amongst the Plasmodium species in humans, only P. vivax and P. ovale produce latent hepatic stages called hypnozoites, which are responsible for malaria episodes long after a mosquito bite.

Immunization with different PfAMA1 alleles in sequence induces clonal imprint humoral responses that are similar to responses induced by the same alleles as a vaccine cocktail in rabbits.

Background: Antibodies to key Plasmodium falciparum surface antigens have been shown to be important effectors that mediate clinical immunity to malaria. The cross-strain fraction of anti-malarial antibodies may however be required to achieve strain-transcending immunity. Such antibody responses against Plasmodium falciparum apical membrane antigen 1 (PfAMA1), a vaccine target molecule that is expressed in both liver and blood stages of the parasite, can be elicited through immunization with a mixture of allelic variants of the parasite molecule.

Malaria infection by sporozoite challenge induces high functional antibody titres against blood stage antigens after a DNA prime, poxvirus boost vaccination strategy in Rhesus macaques.

Background: A DNA prime, poxvirus (COPAK) boost vaccination regime with four antigens, i.e. a combination of two Plasmodium knowlesi sporozoite (csp/ssp2) and two blood stage (ama1/msp142) genes, leads to self-limited parasitaemia in 60% of rhesus monkeys and survival from an otherwise lethal infection with P.

Neuropathological correlates of late-life depression in older people.

Background: Depression is common in old age and is associated with risk of dementia, but its neuropathological correlates in the community are unknown.

Aims: To investigate for the first time in a population-representative sample of people with no dementia the association between depression observed during life and neurofibrillary tangles, diffuse and neuritic plaques, Lewy bodies, brain atrophy and cerebrovascular disease found in the brain at post-mortem.

Method: Out of 456 donations to a population-based study, 153 brains were selected where donors had no dementia measured in life.

Examination of glucose transporter-1, transforming growth factor-β and neuroglobin immunoreactivity in the orbitofrontal cortex in late-life depression.

Aims:   This study immunohistochemically examined the orbitofrontal cortex for three possible candidates in hypoxic/ischemic signaling: the cytokine transforming growth factor-β, the glucose transporter-1 and the neuron-specific oxygen-binding protein neuroglobin.

Methods:   Post-mortem tissue from 20 depressed and 20 non-depressed individuals was obtained and the expression of the three proteins was analyzed using image analysis software.

Results:   No significant changes were found in transforming growth factor-β or neuroglobin in the orbitofrontal cortex between depressed and non-depressed individuals.

A study of orthostatic hypotension, heart rate variability and baroreflex sensitivity in late-life depression.

Background: To determine if subjects with late-life depression have significant cardiovascular autonomic abnormalities (orthostatic blood pressure drop, heart rate variability and baroreflex sensitivity).

Methods: A case-control study, in secondary care facilities, of forty two older (> 60 years) individuals with lifetime history of major depression and 31 age and sex matched comparison subjects. Autonomic function was assessed by measuring postural blood pressure, heart rate variability and baroreflex sensitivity using non-invasive beat-to-beat blood pressure and continuous ECG monitoring (Task Force® Monitor, CNSystems, Graz, Austria).

Generation of humoral immune responses to multi-allele PfAMA1 vaccines; effect of adjuvant and number of component alleles on the breadth of response.

There is increasing interest in multi-allele vaccines to overcome strain-specificity against polymorphic vaccine targets such as Apical Membrane Antigen 1 (AMA1). These have been shown to induce broad inhibitory antibodies in vitro and formed the basis for the design of three Diversity-Covering (DiCo) proteins with similar immunological effects. The antibodies produced are to epitopes that are shared between vaccine alleles and theoretically, increasing the number of component AMA1 alleles is expected to broaden the antibody response.

The immunohistochemical examination of GABAergic interneuron markers in the dorsolateral prefrontal cortex of patients with late-life depression.

Background: The "vascular depression" hypothesis has sought to explain differences in etiology between early and late life depression, and has been reinforced by recent imaging and morphometric studies. Gamma-aminobutyric acid (GABA) is thought to play a major role in the neurobiology of depression. However, it is unclear whether there is an effect on GABA neuronal subpopulations in an elderly depressed cohort.

Sleep in dementia and caregiving--assessment and treatment implications: a review.

Background: The increasing prevalence of dementia will precipitate a significant burden in terms of the costs of caring for people with dementia over the next 30 years; sleep disturbances in dementia are an important factor contributing to this burden.

Methods: We reviewed sleep disturbances in people with dementia and their carers and describe the various diagnostic, assessment and treatment strategies available to physicians in the management of this clinically significant problem.

Results: Sleep disturbances in people with dementia and their carers (i) are highly prevalent; (ii) impact significantly on quality of life of both people with dementia and their carers; (iii) increase the rate of cognitive decline; and (iv) accelerate the breakdown of community-based care.

Morphometric analysis of neuronal and glial cell pathology in the caudate nucleus in late-life depression.

Objective: To assess glial and neuronal density and neuronal volume in two areas of the caudate nucleus in late-life major depression.

Design: A postmortem study using the disector and nucleator methods to estimate neuronal density and volume and glial density of cells from human brain tissue from the anterior portion (dorsolateral and ventromedial aspects) of the caudate nucleus.

Setting: Brain tissues were obtained from the Newcastle Brain Tissue Resource at Newcastle University, UK.

Allelic diversity and naturally acquired allele-specific antibody responses to Plasmodium falciparum apical membrane antigen 1 in Kenya.

Although Plasmodium falciparum apical membrane antigen 1 (AMA1) is a leading malaria vaccine candidate, extensive allelic diversity may compromise its vaccine potential. We have previously shown that naturally acquired antibodies to AMA1 were associated with protection from clinical malaria in this Kenyan population. To assess the impact of allelic diversity on naturally acquired immunity, we first sequenced the ectodomain-encoding region of P.

Deep-coverage rhesus red blood cell proteome: a first comparison with the human and mouse red blood cell.

Background: Macaques are the closest evolutionary relatives of humans routinely used in basic and applied biomedical research. Their genetic, physiological, immunological and metabolic similarity to humans, second only to that of the great apes, makes them invaluable models of human disease. These similarities also mean that macaques are often the only experimental models available for evaluating increasingly specific drugs in development, and as a proof-of-concept bridge can help reduce the numbers of compounds that fail in clinical pharmaceutical research.

Cognitive style and depressive symptoms in elderly people - extending the empirical evidence for the cognitive vulnerability-stress hypothesis.

Introduction: Depression is common in older people and its identification and treatment has been highlighted as one of the major challenges in an ageing world. Poor physical and cognitive health, bereavement, and prior depression are important risk factors for depression in elderly people. Attributional or cognitive style has been identified as a risk factor for depression in children, adolescents and younger adults but its relevance for depression and mood in elderly people has not been investigated in the context of other risk factors.

Electrophysiological changes in late life depression and their relation to structural brain changes.

Background: Late life depression is often accompanied by slowed information processing during neuropsychological testing, and this has been related to underlying cerebrovascular disease. We investigated whether changes in electrophysiological markers of information processing might share the same pathological correlates.

Methods: Differences in power spectra frequency, contingent negative variation (CNV), post-imperative negative variation (PINV), and auditory P300a amplitude and latency in 19 patients with DSM-IV major depression aged ≥ 60 years were compared with 25 recordings in age-matched healthy controls.

A morphometric examination of neuronal and glial cell pathology in the orbitofrontal cortex in late-life depression.

Background: The orbitofrontal cortex has been implicated as a key component in depression by several imaging studies. This study aims to examine morphometrically glial cell and neuronal density and neuronal volume in the orbitofrontal cortex of late-life major depression patients.

Methods: Post mortem tissue from 13 patients with major depression and 11 matched controls was obtained and analyzed using the optical disector and nucleator methods.