Selective recognition of malaria antigens by human serum antibodies is not genetically determined but demonstrates some features of clonal imprinting

Malaria infection induces the production of serum antibodiesto a variety of malaria antigens but the prevalence of antibodiesto any particular antigen ins typically mucb less than 100%.It has been assumed that non-responsiveness to defined antigensin malaria immune subjects is due to HLA mediated restricutionof the Immune response. In this study we have investigated therole of HLA and non-HLA genes in the antibody response to twomerozoite surface antigens (MSP1 and MSP2) and a sexual stageantigen (Pfs260/230) opf P{lasmodium falcpartum, and concludethat host genotype is not a major determinant of responsiveness.Although antibody levels vary in accordance with seasonal variationsin malaria transmission in semi-immune children, antibiody levelsremain stable in clncall immine adults.     

The Heritability of Depression Symptoms in Elderly Danish Twins: Occasion-Specific Versus General Effects

Depression symptomatology was assessed up to four times at 2-year intervals on a sample of 2100 Danish twins initially aged 70 years and older. Data were analyzed using the biometric growth model approach proposed by Neale and McArdle (2000). Results show that occasion-specific depression is moderately and equally heritable in men and women (occasion-specific estimates of heritability ranged from 22% to 37%). Estimates of phenotypic variance, genetic variance, and heritability did not vary systematically across waves. In the best-fitting growth model, depression symptomatology was accounted for by two factors: (1) a level (i.e., average) effect that was highly heritable (estimate of 69% in women and 64% in men) and reflected overall vulnerability, and (2) a residual effect that was nonheritable and reflected occasion-specific circumstances that could either exacerbate or moderate inherited vulnerability. Attempts to identify specific genetic contributions to depression might profitably focus on average levels across multiple assessments, while attempts to identify specific environmental effects might profitably focus on deviations about this average.     

Membrane properties of rat locus coeruleus neurones

Intracellular recordings were made from neurones in the locus coeruleus contained within a slice cut from rat pons and maintained in vitro. Most neurones fired action potentials spontaneously at frequencies of between 1 and 5 Hz; this did not arise from spontaneous synaptic input but appeared to result from endogenous properties of the membrane conductances. Under voltage clamp at potentials near threshold for action potential generation (? 55 mV) there was a persistent inward calcium current. This current became less with membrane hyperpolarization and was abolished at about ?70 mV. Two potassium currents were observed. The first had properties similar to that generally described as the “fast” potassium current (I_K,A); it flowed transiently (for about 200 ms) when the membrane potential passed from about ?65 to ?45 mV, and was blocked by 4-aminopyridine. The second was a calcium-activated potassium current (I_K,Ca); it flowed for several seconds following a burst of calcium action potentials. Spontaneous and evoked action potentials had both tetrodotoxin-sensitive and tetrodotoxin-resistant components. The latter was apparently due to calcium entry. The potential changes occurring during the spontaneous firing of locus coeruleus neurones could be reconstructed qualitatively from the ionic conductances observed. The membrane properties of the locus coeruleus neurones were remarkably uniform; however, about 5% of cells impaled within the region of the locus coeruleus were electrophysiologically distinct. These atypical cells had short duration action potentials, did not fire spontaneously and had large spontaneous depolarizing synaptic potentials.     

A novel method for making "tissue" microarrays from small numbers of suspension cells.

Tissue microarrays (TMAs) are a highly efficient method for large-scale protein expression studies. To date most TMAs have been constructed using paraffin-embedded specimens. The authors developed a method that allows construction of TMAs from small numbers of cells in suspension. Spun pellets of 1x10 to 1x10 cells are directly processed and embedded in paraffin in an Eppendorf tube. Cylindrical cores of 0.6 mm are taken from these tubes and embedded in a recipient paraffin block to create a TMA. This relatively simple but versatile method enables very small numbers of cells in suspension to be analyzed using the TMA technology and allows for the study of hematolymphoid and related disorders of the blood and bone marrow for which solid tissue samples cannot be readily obtained. With the increasing trend toward obtaining small samples for screening and diagnostic purposes, this method provides a means to manipulate small volume samples for high-throughput immunohistochemical analysis. This method is also amenable for use for cultured cells.     

Serological, chemical, and structural analyses of the Escherichia coli cross-reactive capsular polysaccharides K13, K20, and K23.

The Escherichia coli K13, K20, and K23 capsular polysaccharide antigens are serologically related. All of these polysaccharides contain ribose and 2-keto-3-deoxyoctonate in equimolar quantities. The K13 and K20 polysaccharides are partially O-acetylated. A comparison of these polysaccharides after O-deacetylation, by nuclear magnetic resonance and permethylation analysis, showed that these polysaccharides contained the disaccharide repeat unit leads to)-beta-ribofuranosyl-(1 leads to 7)-beta-2-keto-3-deoxyoctonate. They differed in the presence and location of an acetyl moiety. The K13 polysaccharide was O-acetylated at C-4 of the 2-keto-3-deoxyoctonate. The K20 antigen was O-acetylated at C-5 of the ribose moiety. The K23 polymer was nonacetylated. The cross-reactivity of these antigens was demonstrated by tandem-crossed immunoelectrophoresis. Antibodies to K23 could be completely absorbed from OK K23 serum by K13, K20, and K23 antigenic extracts. The K13 and K20 antibodies could be completely absorbed from their respective antisera only by homologous antigenic extracts. Monoclonal antibodies were prepared against a protein conjugate of the K13 polysaccharide. Analyses of the reactions of these antibodies with the three polysaccharides suggest that the K13 polysaccharide has at least three antigenic sites, one of which is common to the K13, K20, and K23 polysaccharides.     

Apoptosis induced in macrophages and T blasts by the mycotoxin sporidesmin and protection by Zn2+ salts.

Incubation of 48 h concanavalin A stimulated spleen cells (T blasts) and murine peritoneal macrophages with the mycotoxin sporidesmin results in DNA fragmentation characteristic of apoptosis. Morphological changes, particularly condensed chromatin, observed following incubation of these cells with sporidesmin and the immunotoxin gliotoxin and related epipolythiodioxopiperazines (ETP) also show changes characteristic of apoptosis. The presence of Zn2+ salts in the culture medium at concentrations non toxic to the cells over the time period studied protects against DNA damage and morphological change. Interaction between Zn2+ and the reduced form of a simple ETP compound assessed by spectral changes demonstrated the formation of a weak complex between the two molecules. Complex formation between zinc and thiol however was insufficient to prevent oxidative damage to plasmid DNA in vitro by inhibiting auto-oxidation of the reduced ETP compound because of the looseness of the interaction. Cd2+, which appears to form a tighter complex with the dithiol does inhibit cleavage of plasmid DNA. These results establish that the toxicity of sporidesmin may be due in part to its ability to induce apoptosis or programmed cell death in sensitive cells. In addition the immunotoxin gliotoxin and related compounds have now been shown to induce the same characteristic morphological changes in cells of haemopoietic origin. The inhibition of apoptosis induced by ETP compounds by Zn2+ appears to be due to direct inhibition of apoptosis rather than Zn2+ acting as an antioxidant. These results demonstrate the inhibition of apoptosis induced by ETP compounds by Zn2+ and suggest an alternate explanation for the known prophylactic effect of Zn2+ on sporidesmin induced tissue damage.     

Naturally acquired human antibodies which recognize the first epidermal growth factor-like module in the Plasmodium falciparum merozoite surface protein 1 do not inhibit parasite growth in vitro.

Merozoite surface protein 1, one of the major surface proteins of the invasive blood stage of the malaria parasite, is a prime candidate for the development of a vaccine against the human disease. Previously, monoclonal antibodies which both inhibited the growth of Plasmodium falciparum in vitro and bound to the first of two epidermal growth factor-like modules located near the carboxy terminus of the protein had been identified. In this study, we have used affinity chromatography on a recombinant fusion protein corresponding to the first epidermal growth factor-like module in P. falciparum merozoite surface protein 1 to prepare antibody induced by natural infection. The antibody was purified from the total immunoglobulin G fraction of adult West African donors, shown to passively confer immunity against falciparum malaria. Such affinity-purified antibodies were shown to recognize the native protein by a number of separate criteria and to block the binding of an inhibitory monoclonal antibody, but they failed to inhibit parasite invasion in an in vitro growth assay. These results indicate that antibody alone is not sufficient to interfere with erythrocyte invasion.     

The Application of Creatine Supplementation in Medical Rehabilitation

Numerous health conditions affecting the musculoskeletal, cardiopulmonary, and nervous systems can result in physical dysfunction, impaired performance, muscle weakness, and disuse-induced atrophy. Due to its well-documented anabolic potential, creatine monohydrate has been investigated as a supplemental agent to mitigate the loss of muscle mass and function in a variety of acute and chronic conditions. A review of the literature was conducted to assess the current state of knowledge regarding the effects of creatine supplementation on rehabilitation from immobilization and injury, neurodegenerative diseases, cardiopulmonary disease, and other muscular disorders. Several of the findings are encouraging, showcasing creatine’s potential efficacy as a supplemental agent via preservation of muscle mass, strength, and physical function; however, the results are not consistent. For multiple diseases, only a few creatine studies with small sample sizes have been published, making it difficult to draw definitive conclusions. Rationale for discordant findings is further complicated by differences in disease pathologies, intervention protocols, creatine dosing and duration, and patient population. While creatine supplementation demonstrates promise as a therapeutic aid, more research is needed to fill gaps in knowledge within medical rehabilitation.     

Use of past care markers in risk-adjustment: accounting for systematic differences across providers

The European Journal of Health Economics - Risk-adjustment models are used to predict the cost of care for patients based on their observable characteristics, and to derive efficient and equitable...