Excess mortality in Glasgow: further evidence of 'political effects' on population health.

OBJECTIVES: The aim of the study was to update previous analyses of 'excess mortality' in Glasgow (Scotland) relative to the similar postindustrial cities of Liverpool and Manchester (England). The excess is defined as mortality after adjustment for socio-economic deprivation; thus, we sought to compare changes over time in both the deprivation profiles of the cities and the levels of deprivation-adjusted mortality in Glasgow relative to the other cities. This is important not only because the original analyses are now increasingly out of date but also because since publication, important (prepandemic) changes to mortality trends have been observed across all parts of the United Kingdom. STUDY DESIGN AND METHODS: Replicating as far as possible the methods of the original study, we developed a three-city deprivation index based on the creation of spatial units in Glasgow that were of similar size to those in Liverpool and Manchester (average population sizes of approximately 1600, 1500 and 1700 respectively) and an area-based measure of 'employment deprivation'. Mortality and matching population data by age, sex and small area were obtained from national agencies for two periods: 2003-2007 (the period covered by the original study) and 2014-2018. The rates of employment deprivation for each city's small areas were calculated for both periods. Indirectly standardised mortality ratios (SMRs) were calculated for Glasgow relative to Liverpool and Manchester, standardised by age and three-city deprivation decile. For context, city-level trends in age-standardised mortality rates by year, sex and city were also calculated. RESULTS: There was evidence of a stalling of improvement in mortality rates in all three cities from the early 2010s. After adjustment for area deprivation, all-cause mortality in Glasgow in 2014-2018 was c.12% higher than in Liverpool and Manchester for all ages (SMR 112.4, 95% CI 111.1-113.6) and c.17% higher for deaths under 65 years (SMR 117.1, 95% CI 114.5-119.7). The excess was higher for males (17% compared with 9% for deaths at all ages; 25% compared with 5% for 0-64 years) and for particular causes of death such as suicide and drug-related and alcohol-related causes. The results were broadly similar to those previously described for 2003-2007, although the excess for premature mortality was notably lower. In part, this was explained by changes in levels of employment deprivation, which had decreased to a greater degree in the English cities: this was particularly true of Manchester (a reduction of -43%, compared with -38% in Liverpool and -31% in Glasgow) where the overall population size had also increased to a much greater extent than in the other cities. CONCLUSIONS: High levels of excess mortality persist in Glasgow. With the political causes recently established - the excess is a 'political effect', not a 'Glasgow effect' - political solutions are required. Thus, previously published recommendations aimed at addressing poverty, inequality and vulnerability in the city are still highly relevant. However, given the evidence of more recent, UK-wide, political effects on mortality - widening mortality inequalities resulting from UK Government 'austerity' measures - additional policies at UK Government level to protect, and restore, the income of the poorest in society are also urgently needed.

Development of Multiwell-Plate Methods Using Pure Cultures of Methanogens To Identify New Inhibitors for Suppressing Ruminant Methane Emissions.

Hydrogenotrophic methanogens typically require strictly anaerobic culturing conditions in glass tubes with overpressures of H2 and CO2 that are both time-consuming and costly. To increase the throughput for screening chemical compound libraries, 96-well microtiter plate methods for the growth of a marine (environmental) methanogen Methanococcus maripaludis strain S2 and the rumen methanogen Methanobrevibacter species AbM4 were developed. A number of key parameters (inoculum size, reducing agents for medium preparation, assay duration, inhibitor solvents, and culture volume) were optimized to achieve robust and reproducible growth in a high-throughput microtiter plate format. The method was validated using published methanogen inhibitors and statistically assessed for sensitivity and reproducibility. The Sigma-Aldrich LOPAC library containing 1,280 pharmacologically active compounds and an in-house natural product library (120 compounds) were screened against M. maripaludis as a proof of utility. This screen identified a number of bioactive compounds, and MIC values were confirmed for some of them against M. maripaludis and M. AbM4. The developed method provides a significant increase in throughput for screening compound libraries and can now be used to screen larger compound libraries to discover novel methanogen-specific inhibitors for the mitigation of ruminant methane emissions.IMPORTANCE Methane emissions from ruminants are a significant contributor to global greenhouse gas emissions, and new technologies are required to control emissions in the agriculture technology (agritech) sector. The discovery of small-molecule inhibitors of methanogens using high-throughput phenotypic (growth) screening against compound libraries (synthetic and natural products) is an attractive avenue. However, phenotypic inhibitor screening is currently hindered by our inability to grow methanogens in a high-throughput format. We have developed, optimized, and validated a high-throughput 96-well microtiter plate assay for growing environmental and rumen methanogens. Using this platform, we identified several new inhibitors of methanogen growth, demonstrating the utility of this approach to fast track the development of methanogen-specific inhibitors for controlling ruminant methane emissions.

A Toll-like receptor-1 variant and its characteristic cellular phenotype is associated with severe malaria in Papua New Guinean children.

Genetic factors are likely to contribute to low severe malaria case fatality rates in Melanesian populations, but association studies can be underpowered and may not provide plausible mechanistic explanations if significant associations are detected. In preparation for a genome-wide association study, 29 candidate single-nucleotide polymorphisms (SNPs) with minor allele frequencies >5% were examined in a case-control study of 504 Papua New Guinean children with severe malaria. In parallel, an immunological substudy was performed on convalescent peripheral blood mononuclear cells (PBMCs) from cases and controls. Following stimulation with a Toll-like receptor (TLR) 1/2 agonist, effector cytokines and chemokines were assayed. The only significant genetic association observed involved a nonsynonymous SNP (TLR1rs4833095) in the TLR1 gene. A recessive (TT) genotype was associated with reduced odds of severe malaria of 0.52 (95% confidence interval (0.29-0.90), P=0.006). Concentrations of pro-inflammatory cytokines interleukin-1ß and tumour necrosis factor α were significantly higher in severe malaria cases compared with healthy controls, but lower in children with the protective recessive (TT) genotype. A genetic variant in TLR1 may contribute to the low severe malaria case fatality rates in this region through a reduced pro-inflammatory cellular phenotype.

Vulnerability to food insecurity in urban slums: experiences from Nairobi, Kenya.

Food and nutrition security is critical for economic development due to the role of nutrition in healthy growth and human capital development. Slum residents, already grossly affected by chronic poverty, are highly vulnerable to different forms of shocks, including those arising from political instability. This study describes the food security situation among slum residents in Nairobi, with specific focus on vulnerability associated with the 2007/2008 postelection crisis in Kenya. The study from which the data is drawn was nested within the Nairobi Urban Health and Demographic Surveillance System (NUHDSS), which follows about 70,000 individuals from close to 30,000 households in two slums in Nairobi, Kenya. The study triangulates data from qualitative and quantitative sources. It uses qualitative data from 10 focus group discussions with community members and 12 key-informant interviews with community opinion leaders conducted in November 2010, and quantitative data involving about 3,000 households randomly sampled from the NUHDSS database in three rounds of data collection between March 2011 and January 2012. Food security was defined using the Household Food Insecurity Access Scale (HFIAS) criteria. The study found high prevalence of food insecurity; 85% of the households were food insecure, with 50% being severely food insecure. Factors associated with food security include level of income, source of livelihood, household size, dependence ratio; illness, perceived insecurity and slum of residence. The qualitative narratives highlighted household vulnerability to food insecurity as commonplace but critical during times of crisis. Respondents indicated that residents in the slums generally eat for bare survival, with little concern for quality. The narratives described heightened vulnerability during the 2007/2008 postelection violence in Kenya in the perception of slum residents. Prices of staple foods like maize flour doubled and simultaneously household purchasing power was eroded due to worsened unemployment situation. The use of negative coping strategies to address food insecurity such as reducing the number of meals, reducing food variety and quality, scavenging, and eating street foods was prevalent. In conclusion, this study describes the deeply intertwined nature of chronic poverty and acute crisis, and the subsequent high levels of food insecurity in urban slum settings. Households are extremely vulnerable to food insecurity; the situation worsening during periods of crisis in the perception of slum residents, engendering frequent use of negative coping strategies. Effective response to addressing vulnerability to household food insecurity among the urban poor should focus on both the underlying vulnerabilities of households due to chronic poverty and added impacts of acute crises.

Prevalence of mutations in common tumour types in Northern England and comparable utility of national and international Trial Finders.

PURPOSE: Tumour genomic profiling is of increasing importance in early phase trials to match patients to targeted therapeutics. Mutations vary by demographic group; however, regional differences are not characterised. This was investigated by comparing mutation prevalence for common cancers presenting to Newcastle Experimental Cancer Medicine Centre (ECMC) to The Cancer Genome Atlas (TCGA) and utility of trial matching modalities. METHODS: Detailed clinicogenomic data were obtained for patients presenting September 2017-December 2020. Prevalence of mutations in lung, colorectal, breast and prostate cancer was compared to TCGA GDC Data Portal. Experimental Cancer (EC) Trial Finder utility in matching trials was compared to a Molecular Tumour Board (MTB) and commercial sequencing reports. RESULTS: Of 311 patients with advanced cancer, this consisted of lung (n = 131, 42.1%), colorectal (n = 44, 14.1%), breast (n = 36, 11.6%) and prostate (n = 18, 5.6%). More than one mutation was identified in the majority (n = 260, 84%). Significant prevalence differences compared to TCGA were identified, including a high prevalence of EGFR in lung (P = 0.001); RB1 in breast (P = 0.0002); and multiple mutations in prostate cancer. EC Trial Finder demonstrated significantly different utility than sequencing reports in identifying trials (P = 0.007). CONCLUSIONS: Regional differences in mutations may exist with advanced stage accounting for prevalence of specific mutations. A national Trial Finder shows utility in finding targeted trials whilst commercial sequencing reports may over-report 'actionable' mutations. Understanding local prevalence and trial availability could increase enrolment onto matched early phase trials.

Distinct distribution of killer-cell immunoglobulin-like receptor genes in the Mugil and Ilaita areas of Papua New Guinea.

The frequency of the killer-cell immunoglobulin-like receptor (KIR) genes and transmembrane alleles of KIR2DL4 were studied in coastal (Mugil community) and inland (Ilaita community) communities in Papua New Guinea. Linkage disequilibria between KIR genes and between alleles of KIR2DL4 and the KIR genes were similar to those found in other populations suggesting conservation of the usual gene order in Papua New Guinean haplotypes. Significant differences in the frequency of KIR genes were found between the two populations despite being separated by only 300 km. Examples of individuals who lacked the KIR2DL4 gene and others whose KIR2DL4 allele appeared to have 11 adenines in the polyadenine tract in exon 6 were identified. A relatively low frequency of the KIR A haplotype was found in both populations and particularly in the inland community. The KIR gene frequencies were consistent with the inland Ilaita community being closely related to Australian Aborigines and southern Indians, whereas the KIR gene frequencies of the coastal Mugil community appeared to have been influenced either by recent or ancient admixture from populations with a higher frequency of the KIR A haplotype.

Signal transduction in host cells by a glycosylphosphatidylinositol toxin of malaria parasites.

In this study, we have identified a dominant glycolipid toxin of Plasmodium falciparum. It is a glycosylphosphatidylinositol (GPI). The parasite GPI moiety, free or associated with protein, induces tumor necrosis factor and interleukin 1 production by macrophages and regulates glucose metabolism in adipocytes. Deacylation with specific phospholipases abolishes cytokine induction, as do inhibitors of protein kinase C. When administered to mice in vivo the parasite GPI induces cytokine release, a transient pyrexia, and hypoglycemia. When administered with sensitizing agents it can elicit a profound and lethal cachexia. Thus, the GPI of Plasmodium is a potent glycolipid toxin that may be responsible for a novel pathogenic process, exerting pleiotropic effects on a variety of host cells by substituting for the endogenous GPI-based second messenger/signal transduction pathways. Antibody to the GPI inhibits these toxic activities, suggesting a rational basis for the development of an antiglycolipid vaccine against malaria.

Robert Koch redux: malaria immunology in Papua New Guinea.

Over a century ago, the malaria expedition of the brilliant microbiologist Robert Koch to the Dutch East Indies (Indonesia) and German New Guinea (now Papua New Guinea, or PNG), resulted in profound observations that are still central to our current understanding of the epidemiology and acquisition of immunity to the malaria parasite Plasmodium. The tradition of malaria research in PNG pioneered by Koch continues to this day, with a number of recent studies still continuing to elucidate his original concepts and hypotheses. These include age and exposure-related acquisition of immunity, species-specific and cross-species immunity, correlates of protective immunity and determining the prospects for anti-malaria vaccines.

CD1d-restricted immunoglobulin G formation to GPI-anchored antigens mediated by NKT cells.

Immunoglobulin G (IgG) responses require major histocompatibility complex (MHC)-restricted recognition of peptide fragments by conventional CD4(+) helper T cells. Immunoglobulin G responses to glycosylphosphatidylinositol (GPI)- anchored protein antigens, however, were found to be regulated in part through CD1d-restricted recognition of the GPI moiety by thymus-dependent, interleukin-4-producing CD4(+), natural killer cell antigen 1.1 [(NK1.1)+] helper T cells. The CD1-NKT cell pathway regulated immunogobulin G responses to the GPI-anchored surface antigens of Plasmodium and Trypanosoma and may be a general mechanism for rapid, MHC-unrestricted antibody responses to diverse pathogens.

Inhibition of development of exoerythrocytic forms of malaria parasites by gamma-interferon.

A specific DNA probe was used to study the effect of recombinant rat, mouse, and human gamma-interferon (gamma-IFN) on the course of sporozoite-induced malaria infections. In mice and rats infected with sporozoites of Plasmodium berghei, mouse and rat gamma-IFN's strongly inhibited the development of the exoerythrocytic forms in the liver liver cells of the hosts, but not the development of the erythrocytic stages. The degree of inhibition of the exoerythrocytic forms was proportional to the dose of gamma-IFN administered, but was independent of the number of sporozoites used for challenge. A 30 percent reduction in the development of exoerythrocytic forms in rat liver was achieved when 150 units (about 15 nanograms of protein) of rat gamma-IFN were injected a few hours before sporozoite challenge; the reduction was 90 percent or more with higher doses of gamma-IFN. The effect was less pronounced if the gamma-IFN was administered 18 hours before or a few hours after challenge. Human gamma-IFN also diminished the parasitemia in chimpanzees infected with sporozoites of the human malaria parasite Plasmodium vivax. The target of gamma-IFN activity may be the infected hepatocytes themselves, as shown by in vitro experiments in which small doses of the human lymphokine inhibited the development of exoerythrocytic forms of Plasmodium berghei in a human hepatoma cell line. These results suggest that immunologically induced interferon may be involved in controlling malaria infection under natural conditions.

A rhoptry antigen of Plasmodium falciparum contains conserved and variable epitopes recognized by inhibitory monoclonal antibodies.

Four monoclonal antibodies produced against Plasmodium falciparum recognize an antigen in merozoites that is localized in rhoptries, as judged by a punctate, double dot fluorescence pattern. All four antibodies bound to the same affinity purified antigen in a two site immunoradiometric assay. Immunoprecipitation of antigen by monoclonal antibody followed by sodium dodecyl sulphate-polyacrylamide gel electrophoresis yielded protein bands of 80, 66 and 42 kDa. Western blotting gave bands of 80 and 66 kDa only with three of the antibodies: the fourth did not blot. Based on protease inhibitor data the 66 kDa band is considered to be a cleavage product of the 80 kDa band, but the 42 kDa band does not appear to derive from the latter and may be a coprecipitation product. This group of antigens labels with both [35S]methionine and [3H]histidine. Two of the monoclonal antibodies inhibited merozoite invasion of erythrocytes. One of these inhibitors recognizes a variable epitope, whereas the second recognizes a highly conserved epitope present in all 106 primary isolates of P. falciparum tested from Brazil, Thailand and Papua New Guinea.

Structural analysis of the glycosyl-phosphatidylinositol membrane anchor of the merozoite surface proteins-1 and -2 of Plasmodium falciparum.

Plasmodium falciparum accumulates the two merozoite surface proteins-1 and -2 during schizogony. Both proteins are proposed to be anchored in membranes by glycosyl-phosphatidylinositol membrane anchors. In this report the identity of these GPI-anchors is confirmed by labelling with tritiated precursors and additionally by specific enzymatic and chemical treatments. Detailed structural analysis of the core-glycans showed that the GPI-anchors of both proteins possess an extra alpha 1-2 linked mannose at the conserved trimannosyl-core-glycan. MSP-1 and MSP-2 labelled with tritiated myristic acid possess primarily radioactive myristic acid at inositol rings in both GPI-anchors. Additionally the hydrophobic fragments released from [3H]myristic acid labelled GPI-anchors were identified as diacyl-glycerols, carrying preferentially [3H]palmitic acid in an ester-linkage.

The 140/130/105 kilodalton protein complex in the rhoptries of Plasmodium falciparum consists of discrete polypeptides.

Four monoclonal antibodies (MAbs) recognise an antigen localised in the rhoptries of Plasmodium falciparum merozoites using both indirect immunofluorescence assay and immunoelectron microscopy with immunogold labeling. All MAbs immunoprecipitated bands at 140, 130 and 105 kDa from [35S]methionine-labeled parasites; however, one MAb immunoblotted only the 130 kDa protein and another MAb immunoblotted the 105 kDa protein. The affinity purified antigen complex consisted of proteins of 140, 130, 105 and 98 kDa. The individual proteins were subjected to peptide mapping with Staphylococcus aureus V8 protease; the 98 kDa protein was a degradation product of the 105 kDa protein and the 140, 130, and 105 kDa proteins were found to be unrelated. The antigen complex was synthesised at the mid trophozoite stage and was considered to be soluble as judged by release from mature schizonts by freeze/thaw lysis. One of the MAbs inhibited parasite growth and/or merozoite invasion of erythrocytes, in vitro, to a small but significant extent.

Technetium-99m-nitroimadazole uptake in a swine model of demand ischemia.

UNLABELLED: Nitroheterocycles are electron affinic, lipophilic compounds that are retained in hypoxic tissue. This study was designed to test the hypothesis that 99mTc-5-oxa-amine-oxime nitroimadazole (BMS-194796) is retained in ischemic myocardial tissue in a swine model of demand ischemia and that the retained tracer can be imaged in vivo. METHODS: Eighteen domestic swine were anesthetized, intubated and instrumented, including placement of a stenois (80% narrowing) mounted on a catheter into the left anterior descending (LAD) coronary artery. Twelve experiments had complete sets of data for analysis. Each animal was paced at about 200 bpm for 4 min, and 28 mCi of 99mTc BMS-194796 were injected during the last minute of pacing. Dynamic planar imaging was started after pacing and completed at 2.5 hr. In the last 8 experiments, SPECT imaging was performed after planar imaging and completed 3.5 hr after injection. Hemodynamic measurements were made continuously. Blood flow by microspheres and myocardial lactate extraction were measured at control, during pacing and after 2 hr of recovery. The animals were then killed; the risk region was delineated and the hearts were removed, sliced, imaged and stained with triphenyl tetrazolium chloride. RESULTS: Nine of the 12 animals became ischemic (net lactate production) during pacing; 3 did not. None of the 3 nonischemic experiments showed focal uptake on ex vivo or in vivo imaging. All 9 of the ischemic experiments showed focal BMS uptake in the risk region on ex vivo imaged slices; 6 of 9 had uptake in the risk region on in vivo imaging; and 4 of these 6 had small scattered areas of subendocardial necrosis in the risk region on triphenyl tetrazolium chloride staining. Four animals had small infarcts in the distribution of proximal LAD branch vessels occluded by the stenosis catheter. All animals with branch vessel infarcts had positive in vivo images. Overall, 8 of 9 ischemic experiments had positive in vivo images. CONCLUSION: These data support the conclusion that focal myocardial retention of BMS-194796 can be visualized on in vivo imaging in closed chest large animal model after intravenous injection.

Myocardial uptake of a (99m)Tc-nitroheterocycle in a swine model of occlusion and reperfusion.

UNLABELLED: The purpose of this study was to evaluate the window for scan positivity of the radiolabeled nitroheterocycle (99m)Tc-BRU-59-21 in the peri-ischemic period using a swine model of occlusion and reperfusion. METHODS: A balloon catheter was placed in the left anterior descending coronary artery in each of 19 domestic swine. Blood flow and hemodynamic measurements were made at baseline, during occlusion, and at 15 and 180 min after reperfusion. A dose of approximately 925 MBq (99m)Tc-BRU-59-21 was injected before a brief (6 min) period of coronary occlusion at the following times: 15 min (n = 2), 5 min (n = 2), and 2.2 min (n = 5). In 5 experiments the dose was injected 15 min after reperfusion. Animals underwent SPECT imaging 3 h later. Animals were then killed, and hearts were removed, sliced, stained with triphenyl tetrazolium chloride, and imaged on the detector. RESULTS: The risk region became ischemic during occlusion on the basis of severe reduction in blood flow and lactate production, but necrosis occurred in only 3 experiments. Focal tracer uptake was seen in the risk region in animals injected 5 and 2.2 min before occlusion but not in animals injected 15 min before occlusion and 15 min after reperfusion. CONCLUSION: The window for scan positivity for (99m)Tc-BRU-59-21 injected in the peri-ischemic period is short using this model of balloon occlusion and reperfusion in swine.

In vivo uptake of radiolabeled antibody to proliferating smooth muscle cells in a swine model of coronary stent restenosis.

UNLABELLED: Z2D3 is a monoclonal chimeric antibody fragment that is directed against a protein expressed on the surface of proliferating smooth muscle cells. The purpose of this study was to investigate the uptake of 111In-labeled Z2D3 F(ab')2 in a swine model of coronary neointimal proliferation after overexpansion coronary stenting. METHODS: Twenty-two domestic swine underwent overexpansion coronary stenting of 2 vessels. Fifteen swine survived 2-4 wk, at which time they received an injection of 111In Z2D3 F(ab')2 and underwent planar imaging. After the swine were killed, the hearts were excised and imaged on the detector. The cross-sectional area of each stented vessel was measured with digital morphometry. RESULTS: Pathology could be correlated with imaging for 24 vessels. The cross-sectional area of stenosis comprising neointimal proliferation ranged from 8% to 95%, with a mean +/- SD of 41% +/- 21%. The maximal stenosis ranged from 13% to 95%, with a mean of 51% +/- 20%. Seventeen of 24 vessels (71%) showed focal uptake on in vivo imaging, and 7 of 24 (29%) did not. Twenty of 24 (83%) showed uptake on ex vivo imaging. Of 11 stented vessels with maximal vessel stenosis less than 50%, 7 (64%) showed uptake both in vivo and ex vivo, and of 13 stented vessels with maximal vessel stenosis greater than 50%, 10 (77%) showed uptake both in vivo and ex vivo. CONCLUSION: Uptake of a radiolabeled antibody directed against a component of proliferating neointimal tissue can be visualized in the coronary arteries on in vivo imaging using a scintillation gamma camera.

A specific S-antigen of Plasmodium falciparum is expressed in a proportion of primary isolates in Brazil, Thailand and Papua New Guinea.

The expression by Plasmodium falciparum of a specific S-antigen has been examined in primary isolates in different regions of the world using a monoclonal antibody that recognizes an epitope within a known repeated amino acid sequence. The epitope was expressed by a small proportion of primary isolates in each of Brazil, Thailand and Papua New Guinea, demonstrating that this S-antigen gene is widespread. The data are consistent with the possibility that the occurrence of P. falciparum strains expressing a particular S-antigen is periodic, related to the duration of immunity against that antigen in a given human population.

Antigen-induced (Dumonde Glynn) arthritis in the sheep: a large joint animal model of arthritis.

OBJECTIVE: To determine if the Dumonde Glynn model of arthritis can be established in sheep since a larger model would facilitate injection and the measurement of joints. METHODS: Three groups of sheep were immunised with ovalbumin in Freund's adjuvant. Arthritis was induced in group 1 (n = 10, by the injection of 5 mg ovalbumin in 0.5 ml to the right hock joint. Control groups received saline (n = 10) or no treatment (n = 6). RESULTS: Following joint injection the mean AP diameter increased so that there was a 32% difference between the right and left joints at 24 hr (p < 0.001) declining gradually to 12% (p < 0.01) 19 days after the induction of arthritis. The level of haptoglobin in group 1 prior to the induction of arthritis was 0.04 +/- 0.01. Haemoglobin binding capacity (mg/ml) peaked on day 3 at 0.33 +/- 0.13 (p < 0.01), and was 0.110 +/- 0.05 thirteen days after joint injection. Features observed included proliferation of the joint lining, fibrin deposition and early erosion of cartilage. Synovial membrane showed an infiltrate of inflammatory cells identified as monocytes/macrophages and lymphocytes. Synovial histology scores were 1.8 +/- 0.2 for the left joint and 9.3 +/- 0.73 for the arthritic right joint. CONCLUSION: We conclude that this is a model of mono-arthritis particularly useful when a larger joint is required for intra-articular injection or repeated joint measurements such as in a clinical trial.

Influence of exercise on clearance of oxidant stress products and loosely bound iron.

The significance of free radical chemistry within the exercise and post-exercise milieu is not yet well understood. It is yet to be determined whether adequate biochemical defense mechanisms exist to protect the organism from oxygen-centered radicals generated by exercise. Rats trained at 70% VO2peak for 6 wk were compared with controls after an exhaustive run. Post-exhaustion urinary malondialdehyde, gastrocnemius loosely bound iron, and susceptibility to oxidant stress were assessed. Exhaustive exercise resulted in a significant (P < 0.05) increase in urinary malondialdehyde, tissue loosely bound iron, and susceptibility to oxidative stress in both control and trained rats. The untrained group's tissue iron and susceptibility to oxidative stress were both significantly greater than trained rats. Electrical stimulation of perfused hindquarters of untrained and trained rats resulted in a significant increase of malondialdehyde into the perfusate. Trained rats cleared the malondialdehyde from the perfusate more rapidly than did the untrained.

Signal transduction in host cells mediated by glycosylphosphatidylinositols of the parasitic protozoa, or why do the parasitic protozoa have so many GPI molecules?

Considerable circumstantial evidence indicates that glycosylphosphatidylinositol (GPI) molecules of mammalian origin are able to mediate signal transduction in lymphoid cells. For example, perturbation of GPI-anchored surface proteins, but not transmembrane forms of these molecules, can lead to the activation of T lymphocytes. GPIs appear also to be precursors of pharmacologically active phosphoinositol-glycans which mediate responses to hormones such as insulin, nerve growth factor and IL-2. Nonetheless, the biochemical mechanisms of signal transduction by GPIs remain obscure. We have shown that structurally defined GPIs of protozoal parasite origin are able to mediate signal transduction in host macrophages and lymphocytes, by substituting for the putative endogenous GPI-based signalling mechanisms of the host. Signalling by parasite GPIs appears to involve the activation of protein tyrosine kinase and protein kinase C. Evidence from other sources indicates that structurally variant GPIs may provide anergic signals to down-regulate host cell function. These phenomena may represent mechanisms by which eukaryotic parasites regulate host cell function, and can explain a variety of pathological and immunological features of protozoal infections. Furthermore, protozoal GPIs may prove to be an informative model system for the analysis of GPI-mediated signal transduction in lymphocytes and macrophages.