Showing papers by "John Radcliffe Hospital published in 2006"

The second European evidence-based Consensus on the diagnosis and management of Crohn's disease: Definitions and diagnosis

Abstract: Crohn's disease is a lifelong disease arising from an interaction between genetic and environmental factors, but observed predominantly in developed countries of the world. The precise aetiology is unknown and therefore a causal therapy is not yet available. Within Europe there is a distinct North–South gradient, but the incidence appears to have increased in Southern countries in recent years.1 Many patients live with a considerable symptom burden despite medical treatment in the hope that the aetiology of the disease will shortly be revealed and curative therapies emerge. Since it is uncertain that the precise pathogenesis of Crohn's disease will be revealed anytime soon, clinicians have to advise patients on the basis of information available today rather than an unknown future. Despite a multiplicity of randomised trials there will always be many questions that can only be answered by the exercise of judgement and opinion. This leads to differences in practice between clinicians, which may be brought into sharp relief by differences in emphasis between countries. The Consensus endeavours to address these differences. The Consensus is not meant to supersede the guidelines of different countries (such as those from the UK,2 Germany,3 or France), which reach broadly the same conclusions since they are, after all, based on the same evidence. Rather, the aim of the Consensus is to promote a European perspective on the management of Crohn's disease and its dilemmas. Since the development of guidelines is an expensive and time-consuming process, it may help to avoid duplication of effort in the future. A Consensus is also considered important because an increasing number of therapeutic trials are based in Europe, especially in eastern European countries where practice guidelines have yet to be published. This document is based on the European consensus on the diagnosis and management of Crohn's …

Validation and Clinical Utility of a 70-Gene Prognostic Signature for Women With Node-Negative Breast Cancer

Abstract: Background: A 70-gene signature was previously shown to have prognostic value in patients with node-negative breast cancer. Our goal was to validate the signature in an independent group of patients. Methods: Patients (n = 307, with 137 events after a median follow-up of 13.6 years) from fi ve European centers were divided into high- and low-risk groups based on the gene signature classifi cation and on clinical risk classifi cations. Patients were assigned to the gene signature low-risk group if their 5-year distant metastasis – free survival probability as estimated by the gene signature was greater than 90%. Patients were assigned to the clinicopathologic low-risk group if their 10-year survival probability, as estimated by Adjuvant! software, was greater than 88% (for estrogen receptor [ER] – positive patients) or 92% (for ERnegative patients). Hazard ratios (HRs) were estimated to compare time to distant metastases, disease-free survival, and overall survival in high- versus low-risk groups. Results: The 70-gene signature outperformed the clinicopathologic risk assessment in predicting all endpoints. For time to distant metastases, the gene signature yielded HR = 2.32 (95% confi dence interval [CI] = 1.35 to 4.00) without adjustment for clinical risk and hazard ratios ranging from 2.13 to 2.15 after adjustment for various estimates of clinical risk; clinicopathologic risk using Adjuvant! software yielded an unadjusted HR = 1.68 (95% CI = 0.92 to 3.07). For overall survival, the gene signature yielded an unadjusted HR = 2.79 (95% CI = 1.60 to 4.87) and adjusted hazard ratios ranging from 2.63 to 2.89; clinicopathologic risk yielded an unadjusted HR = 1.67 (95% CI = 0.93 to 2.98). For patients in the gene signature high-risk group, 10-year overall survival was 0.69 for patients in both the low – and high – clinical risk groups; for patients in the gene signature low-risk group, the 10-year survival rates were 0.88 and 0.89, respectively. Conclusions: The 70-gene signature adds independent prognostic information to clinicopathologic risk assessment for patients with early breast cancer. [J Natl Cancer Inst 2006;98: 1183 – 92 ]

Quantification of Regulatory T Cells Enables the Identification of High-Risk Breast Cancer Patients and Those at Risk of Late Relapse

Abstract: Purpose To assess the clinical significance of tumor-infiltrating FOXP3-positive regulatory T cells (TR) in breast cancer patients with long-term follow-up. Patients and Methods FOXP3-positive TR were detected by immunohistochemistry with our new, extensively characterized FOXP3 monoclonal antibody, 236A/E7. Numbers of FOXP3-positive lymphocytes in tissue microarray cores from pure ductal carcinoma in situ (DCIS; n = 62), invasive breast cancer (n = 237) or from comparable areas of normal terminal duct lobular breast tissue (n = 10) were determined. A median cutoff of ≥ 15 defined patients with high numbers of TR. Results TR numbers were significantly higher in in situ and invasive breast carcinomas than in normal breast; invasive tumors have significantly higher numbers than DCIS (P = .001). High numbers of FOXP3-positive TR identified patients with DCIS at increased risk of relapse (P = .04) and patients with invasive tumors with both shorter relapse-free (P = .004) and overall survival (P = .007). High...

Memantine for dementia

Abstract: Background Memantine, a low affinity antagonist to glutamate NMDA receptors, may prevent excitatory neurotoxicity in dementia. Objectives To determine efficacy and safety of memantine for people with Alzheimer's disease (AD), vascular (VD) and mixed dementia. Search methods The Specialized Register of the Cochrane Dementia and Cognitive Improvement Group was searched on 8 February 2006. This register contains references from all major healthcare databases and many ongoing trial databases and is updated regularly. In addition, the search engines Copernic and Google were used to identify unpublished trials through inspection of the websites of licensing bodies like the FDA , EMEA and NICE and of companies' websites (Lundbeck, Merz, Forest, Suntori etc) and clinical trials registries. Selection criteria Double-blind, parallel group, placebo-controlled, randomized trials of memantine in people with dementia. Data collection and analysis Data were pooled where possible. Intention-to-treat (ITT) and observed case (OC) analyses are reported. Main results 1. Moderate to severe AD. Two out of three six month studies show a small beneficial effect of memantine. Pooled data indicate a beneficial effect at six months on cognition (2.97 points on the 100 point SIB, 95% CI 1.68 to 4.26, P < 0.00001), activities of daily living (1.27 points on the 54 point ADCS-ADLsev, 95% CI 0.44 to 2.09, P = 0.003) and behaviour (2.76 points on the 144 point NPI, 95% CI 0.88 to 4.63, P=0.004), supported by clinical impression of change (0.28 points on the 7 point CIBIC+, 95% CI 0.15 to 0.41, P < 0.0001). 2. Mild to moderate AD. Pooled data from three unpublished studies indicate a marginal benefical effect at six months on ITT cognition (0.99 points on the 70 point ADAS-Cog, 95% CI 0.21 to 1.78, P = 0.01) which was barely detectable clinically (0.13 CIBIC+ points, 95% CI 0.01 to 0.25, P = 0.03) but no effect on behaviour, activities of daily living or OC analysis of cognition. 3. Mild to moderate vascular dementia. Pooled data from two six month studies indicated a small beneficial effect of memantine on cognition (1.85 ADAS-Cog points, 95% CI 0.88 to 2.83, P = 0.0002), and behaviour (0.84 95% CI 0.06 to 0.91, P = 0.03) but this was not supported by clinical global measures. 4. Patients taking memantine were slightly less likely to develop agitation (134/1739, 7.7% versus 175/1873, 9.3% OR 0.78, 95% CI 0.61 to 0.99, P = 0.04). This effect was slightly larger, but still small, in moderate to severe AD (58/506 [12%] vs 88/499 [18%]; OR = 0.6, 95% CI 0.42 to 0.86, P = 0.005). There is no evidence either way about whether it has an effect on agitation which is already present. 5. Memantine is well tolerated. Authors' conclusions Memantine has a small beneficial effect at six months in moderate to severe AD. In patients with mild to moderate dementia, the small beneficial effect on cognition was not clinically detectable in those with vascular dementia and was detectable in those with AD. Memantine is well tolerated.

PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection.

Abstract: Here, we report on the expression of programmed death (PD)-1 on human virus-specific CD8+ T cells and the effect of manipulating signaling through PD-1 on the survival, proliferation, and cytokine function of these cells. PD-1 expression was found to be low on naive CD8+ T cells and increased on memory CD8+ T cells according to antigen specificity. Memory CD8+ T cells specific for poorly controlled chronic persistent virus (HIV) more frequently expressed PD-1 than memory CD8+ T cells specific for well-controlled persistent virus (cytomegalovirus) or acute (vaccinia) viruses. PD-1 expression was independent of maturational markers on memory CD8+ T cells and was not directly associated with an inability to produce cytokines. Importantly, the level of PD-1 surface expression was the primary determinant of apoptosis sensitivity of virus-specific CD8+ T cells. Manipulation of PD-1 led to changes in the ability of the cells to survive and expand, which, over several days, affected the number of cells expressing cytokines. Therefore, PD-1 is a major regulator of apoptosis that can impact the frequency of antiviral T cells in chronic infections such as HIV, and could be manipulated to improve HIV-specific CD8+ T cell numbers, but possibly not all functions in vivo.

Optimal decision making and the anterior cingulate cortex.

Abstract: Learning the value of options in an uncertain environment is central to optimal decision making. The anterior cingulate cortex (ACC) has been implicated in using reinforcement information to control behavior. Here we demonstrate that the ACC's critical role in reinforcement-guided behavior is neither in detecting nor in correcting errors, but in guiding voluntary choices based on the history of actions and outcomes. ACC lesions did not impair the performance of monkeys (Macaca mulatta) immediately after errors, but made them unable to sustain rewarded responses in a reinforcement-guided choice task and to integrate risk and payoff in a dynamic foraging task. These data suggest that the ACC is essential for learning the value of actions.

European evidence based consensus on the diagnosis and management of Crohn’s disease: current management

Abstract: This second section of the European Crohn's and Colitis Organisation (ECCO) Consensus on the management of Crohn's disease concerns treatment of active disease, maintenance of medically induced remission, and surgery. The first section on definitions and diagnosis includes the aims and methods of the consensus, as well as sections on diagnosis, pathology, and classification of Crohn's disease. The third section on special situations in Crohn's disease includes postoperative recurrence, fistulating disease, paediatrics, pregnancy, psychosomatics, extraintestinal manifestations, and alternative therapy for Crohn's disease.

Immune effector mechanisms in malaria.

Abstract: SUMMARY That humans in endemic areas become immune to malaria offers encouragement to the idea of developing protective vaccines However natural immunity is relatively inefficient, being bought at the cost of substantial childhood mortality, and current vaccines are only partially protective Understanding potential targets and mechanisms of protective immunity is important in the development and evaluation of future vaccines Some of the problems in identifying such targets and mechanisms in humans naturally exposed to malaria may stem from conceptual and methodological issues related to defining who in a population is susceptible, problems in defining immune responsiveness at single time points and issues related to antigenic polymorphism, as well as the failure of many current approaches to examine functional aspects of the immune response Protective immune responses may be directed to the pre erythrocytic parasite, to the free merozoite of the blood stage parasite or to new antigens induced on the infected red cell surface Tackling the methodological issues of defining protection and immune response, together with studies that combine functional assays with new approaches such as allelic exchange and gene knock out offer opportunities for better defining key targets and mechanisms

Randomised controlled trial of a parenting intervention in the voluntary sector for reducing child conduct problems: outcomes and mechanisms of change.

Abstract: Background: To test effectiveness of a parenting intervention, delivered in a community-based voluntary-sector organisation, for reducing conduct problems in clinically-referred children. Methods: Randomised controlled trial, follow-up at 6, 18 months, assessors blind to treatment status. Participants )76 children referred for conduct problems, aged 2–9, primarily low-income families, randomised to treatment vs. 6-month wait-list group. Retention was 93% at 6 months, 90% at 18 months. Interventions – Webster-Stratton Incredible Years video-based 14-week group programme, teaches cognitive-behavioural principles for managing behaviour, using a collaborative, practical, problem-solving approach. Primary outcomes – child problem behaviour by parent-report (Eyberg) and home-based direct observation; secondary outcomes – observed positive and negative parenting; parent-reported parenting skill, confidence and depression. Results: Post-treatment improvements were found in child problem behaviour, by parent-report (effect size (ES) .48, p ¼ .05) and direct observation (ES .78, p ¼ .02); child independent play (ES .77, p ¼ .003); observed negative (ES .74, p ¼ .003) and positive (ES .38, p ¼ .04) parenting; parent-reported confidence (ES .40, p ¼ .03) and skill (ES .65, p ¼ .01), using ANCOVA to control for baseline scores. Maternal depression did not change. Consumer satisfaction was high. At 18-month follow-up, although no randomised comparison was possible, changes appeared to maintain, with no significant change toward baseline level on any measure. Change in observed positive parenting appeared to mediate change in child problem behaviour (p < .025). Conclusions: Findings suggest that a group-based cognitive-behavioural parenting programme, delivered by well-trained and supervised staff, can be effective in a community voluntarysector setting, for reducing conduct problems and enhancing parenting skills. Change in parenting skill appears to be a key mechanism for change in child behaviour. Findings have implications for feasibility of translating evidence-based programmes, even for clinically-referred conduct problems, into less specialised community settings, likely to have lower costs and be more accessible for families. Keywords: Parenting, conduct problems, trial (randomised), mediator, voluntary sector. Abbreviations: FNN: Family Nurturing Network.

Regulatory T cells are expanded in blood and disease sites in patients with tuberculosis.

Abstract: Rationale: T-cell responses during tuberculosis (TB) help contain Mycobacterium tuberculosis in vivo but also cause collateral damage to host tissues. Immune regulatory mechanisms may limit this immunopathology, and suppressed cellular immune responses in patients with TB suggest the presence of regulatory activity. CD4+CD25high regulatory T cells mediate suppressed cellular immunity in several chronic infections but have not been described in TB.Objective: To determine whether regulatory T cells are increased in patients with TB and whether they suppress cellular immune responses.Methods: We compared the frequency of circulating regulatory T cells in 27 untreated patients with TB and 23 healthy control subjects using two specific markers: cell-surface CD25 expression and FoxP3 mRNA expression in peripheral blood mononuclear cells.Measurements and Main Results: We detected a threefold increase in the frequency of CD4+CD25high T cells (p < 0.001) and a 2.2-fold increase in FoxP3 expression (p = 0.006) in p...

Inflammation and pre-eclampsia

Abstract: Pre-eclampsia is a common and potentially dangerous disorder of human pregnancy. The maternal syndrome of hypertension, proteinuria and oedema is part of a severe systemic inflammatory response that includes leukocyte and endothelial cell activation. Although the origins of pre-eclampsia remain unclear, a major cause is the failure to develop an adequate blood supply to the placenta, leading to placental oxidative stress. This results in the excess release of placental factors, such as syncytiotrophoblast debris or soluble fms-like tyrosine kinase-1 (sFlt-1), the soluble receptor for vascular endothelial growth factor (VEGF), into the maternal circulation, where they trigger an inflammatory response and endothelial dysfunction. Alternatively, pre-eclampsia can develop in the presence of a normal placenta in women that are susceptible to systemic inflammation, such as with chronic cardiovascular disease or diabetes. While clinical management of pre-eclampsia does not currently include anti-inflammatory agents, current research is focusing on ways to reduce inflammation and oxidative stress.

European evidence based consensus on the diagnosis and management of Crohn's disease: special situations.

Abstract: This third section of the European Crohn's and Colitis Organisation (ECCO) Consensus on the management of Crohn's disease concerns postoperative recurrence, fistulating disease, paediatrics, pregnancy, psychosomatics, extraintestinal manifestations, and alternative therapy. The first section on definitions and diagnosis reports on the aims and methods of the consensus, as well as sections on diagnosis, pathology, and classification of Crohn's disease. The second section on current management addresses treatment of active disease, maintenance of medically induced remission, and surgery of Crohn's disease.

Connection Patterns Distinguish 3 Regions of Human Parietal Cortex

Abstract: Three regions of the macaque inferior parietal lobule and adjacent lateral intraparietal sulcus (IPS) are distinguished by the relative strengths of their connections with the superior colliculus, parahippocampal gyrus, and ventral premotor cortex. It was hypothesized that connectivity information could therefore be used to identify similar areas in the human parietal cortex using diffusionweighted imaging and probabilistic tractography. Unusually, the subcortical routes of the 3 projections have been reported in the macaque, so it was possible to compare not only the terminations of connections but also their course. The medial IPS had the highest probability of connection with the superior colliculus. The projection pathway resembled that connecting parietal cortex and superior colliculus in the macaque. The posterior angular gyrus and the adjacent superior occipital gyrus had a high probability of connection with the parahippocampal gyrus. The projection pathway resembled the macaque inferior longitudinal fascicle, which connects these areas. The ventral premotor cortex had a high probability of connection with the supramarginal gyrus and anterior IPS. The connection was mediated by the third branch of the superior longitudinal fascicle, which interconnects similar regions in the macaque. Human parietal areas have anatomical connections resembling those of functionally related macaque parietal areas.

Quantum dot semiconductor nanocrystals for immunophenotyping by polychromatic flow cytometry

Abstract: Immune responses arise from a wide variety of cells expressing unique combinations of multiple cell-surface proteins. Detailed characterization is hampered, however, by limitations in available probes and instrumentation. Here, we use the unique spectral properties of semiconductor nanocrystals (quantum dots) to extend the capabilities of polychromatic flow cytometry to resolve 17 fluorescence emissions. We show the need for this power by analyzing, in detail, the phenotype of multiple antigen-specific T-cell populations, revealing variations within complex phenotypic patterns that would otherwise remain obscure. For example, T cells specific for distinct epitopes from one pathogen, and even those specific for the same epitope, can have markedly different phenotypes. The technology we describe, encompassing the detection of eight quantum dots in conjunction with conventional fluorophores, should expand the horizons of flow cytometry, as well as our ability to characterize the intricacies of both adaptive and innate cellular immune responses.

Expression of elevated levels of pro-inflammatory cytokines in SARS-CoV-infected ACE2+ cells in SARS patients: relation to the acute lung injury and pathogenesis of SARS.

Abstract: The authors have previously shown that acute lung injury (ALI) produces a wide spectrum of pathological processes in patients who die of severe acute respiratory syndrome (SARS) and that the SARS coronavirus (SARS-CoV) nucleoprotein is detectable in the lungs, and other organs and tissues, in these patients. In the present study, immunohistochemistry (IHC) and in situ hybridization (ISH) assays were used to analyse the expression of angiotensin-converting enzyme 2 (ACE2), SARS-CoV spike (S) protein, and some pro-inflammatory cytokines (PICs) including MCP-1, TGF-beta1, TNF-alpha, IL-1beta, and IL-6 in autopsy tissues from four patients who died of SARS. SARS-CoV S protein and its RNA were only detected in ACE2+ cells in the lungs and other organs, indicating that ACE2-expressing cells are the primary targets for SARS-CoV infection in vivo in humans. High levels of PICs were expressed in the SARS-CoV-infected ACE2+ cells, but not in the uninfected cells. These results suggest that cells infected by SARS-CoV produce elevated levels of PICs which may cause immuno-mediated damage to the lungs and other organs, resulting in ALI and, subsequently, multi-organ dysfunction. Therefore application of PIC antagonists may reduce the severity and mortality of SARS.

Microarrays Reveal that Each of the Ten Dominant Lineages of Staphylococcus aureus Has a Unique Combination of Surface-Associated and Regulatory Genes

Abstract: Staphylococcus aureus is a persistent resident of the human nose in 20% of the population and intermittently carried by another 60% (16). Most carriers harbor a single strain (2). S. aureus is a common cause of minor skin and wound infections, but only rarely causes severe community-acquired invasive infections such as bacteremia, endocarditis, and osteomyelitis. In contrast, S. aureus is the most common cause of hospital-acquired infection, which often occurs in association with breaches of the skin and mucous membranes in the immunocompromised host (14). Hundreds of S. aureus virulence factors and putative virulence genes have been described, including those involved in adherence to human tissue, evasion of the immune response, toxin secretion, and regulation of virulence gene expression (29). Specific toxins have also been described that play a pivotal role in toxin-mediated disease such as toxic shock syndrome (toxic shock syndrome toxin-1, encoded by tst; enterotoxins B and C, encoded by seb, sec) (5), scalded skin syndrome (exfoliative toxins A and B, encoded by eta, etb) (19), food poisoning (enterotoxin A, encoded by sea) (5), and more recently hemolytic pneumonia and skin and soft tissue infection (Panton Valentine leukocidin [PVL], encoded by the lukS-PV and lukF-PV genes) (20). Many of these genes are variably present as a result of being carried on mobile genetic elements (MGE) (22). However, critical to the development of targeted or preventive strategies is the elucidation of which if any of these genes are important in invasive infection. An important isolate collection associated with community-acquired invasive disease or carriage by healthy donors in the Oxford, United Kingdom, region (7) has been examined using multilocus sequence typing (MLST) (6), in which fragments of seven housekeeping genes were amplified and sequenced. Unique alleles at the seven loci were given an allelic number, and the allelic profile (string of seven integers) was used to define sequence type (ST) for each isolate. Isolates with an identical profile were considered to be clonal, and those with at least five of seven matching genes were considered to belong to the same clonal cluster (CC). Isolates clustered into 10 major CCs, none of which were associated with invasive disease (7). This argued against the presence of virulent genotypes but did not exclude the possibility that one or more variable genes were overrepresented in the invasive-isolate group. This possibility was examined during a study that defined the presence or absence of 33 putative virulence genes in this isolate collection using PCR (27). Seven genes were found to be present more commonly in invasive isolates, including eta and those encoding fibronectin binding protein A (fnbA), collagen binding protein (cna), serine-aspartate repeat containing protein E (sdrE), staphylococcal enterotoxin J (sej), gamma-hemolysin (hlg), and intracellular adhesin (ica). This suggested there were differences between isolates that did not correlate with lineage. It also suggested that some isolates are potentially more virulent than others. Each S. aureus isolate is thought to carry hundreds of variable genes including many putative virulence determinants. The first S. aureus comparative-genomics studies using a microarray (covering 92% of the genes found in the S. aureus COL genome) estimated that 22% of the S. aureus genome was variable (8). Many of the variable genes are known or putative virulence and resistance genes carried on MGE, and these elements are likely to transfer horizontally among staphylococci (see reference 22 for a review). The accumulation of such MGE may result in the emergence of “superbugs” that are increasingly resistant and virulent (22). The whole-genome sequencing of seven isolates of S. aureus (1, 10, 12, 18; www.genome.ou.edu/staph.html) has allowed us to design, print, and validate a multistrain PCR product S. aureus microarray carrying PCR products for every gene identified from these projects, probably the most comprehensive microarray of its kind (33). Here we describe the use of the seven-strain S. aureus microarray to investigate the Oxford collection of community-acquired S. aureus isolates. The aims were to identify which regions of the S. aureus genome vary, investigate gene distribution in a typical S. aureus population, and perform a comprehensive search for differences between invasive and carriage isolates.

Maximising response to postal questionnaires – A systematic review of randomised trials in health research

Abstract: Postal self-completion questionnaires offer one of the least expensive modes of collecting patient based outcomes in health care research. The purpose of this review is to assess the efficacy of methods of increasing response to postal questionnaires in health care studies on patient populations. The following databases were searched: Medline, Embase, CENTRAL, CDSR, PsycINFO, NRR and ZETOC. Reference lists of relevant reviews and relevant journals were hand searched. Inclusion criteria were randomised trials of strategies to improve questionnaire response in health care research on patient populations. Response rate was defined as the percentage of questionnaires returned after all follow-up efforts. Study quality was assessed by two independent reviewers. The Mantel-Haenszel method was used to calculate the pooled odds ratios. Thirteen studies reporting fifteen trials were included. Implementation of reminder letters and telephone contact had the most significant effect on response rates (odds ratio 3.7, 95% confidence interval 2.30 to 5.97 p = <0.00001). Shorter questionnaires also improved response rates to a lesser degree (odds ratio 1.4, 95% confidence interval 1.19 to 1.54). No evidence was found that incentives, re-ordering of questions or including an information brochure with the questionnaire confer any additional advantage. Implementing repeat mailing strategies and/or telephone reminders may improve response to postal questionnaires in health care research. Making the questionnaire shorter may also improve response rates. There is a lack of evidence to suggest that incentives are useful. In the context of health care research all strategies to improve response to postal questionnaires require further evaluation.

Imaging of acute stroke

Abstract: Summary Thrombolytic therapy has led to a higher proportion of patients presenting to hospital early, and this, with parallel developments in imaging technology, has greatly improved the understanding of acute stroke pathophysiology. Additionally, MRI, including diffusion-weighted imaging (DWI) and gradient echo, or T2*, imaging is important in understanding basic structural information—such as distinguishing acute ischaemia from haemorrhage. It has also greatly increased sensitivity in the diagnosis of acute cerebral ischaemia. The pathophysiology of the ischaemic penumbra can now be assessed with CT or MRI-based perfusion imaging techniques, which are widely available and clinically applicable. Pathophysiological information from CT or MRI increasingly helps clinical trial design, may allow targeted therapy in individual patients, and may extend the time scale for reperfusion therapy.

Vacuolar and plasma membrane stripping and autophagic elimination of Toxoplasma gondii in primed effector macrophages

Abstract: Apicomplexan protozoan pathogens avoid destruction and establish a replicative niche within host cells by forming a nonfusogenic parasitophorous vacuole (PV). Here we present evidence for lysosome-mediated degradation of Toxoplasma gondii after invasion of macrophages activated in vivo. Pathogen elimination was dependent on the interferon γ inducible-p47 GTPase, IGTP, required PI3K activity, and was preceded by PV membrane indentation, vesiculation, disruption, and, surprisingly, stripping of the parasite plasma membrane. Denuded parasites were enveloped in autophagosome-like vacuoles, which ultimately fused with lysosomes. These observations outline a series of mechanisms used by effector cells to redirect the fate of a classically nonfusogenic intracellular pathogen toward a path of immune elimination.

5-Methyltetrahydrofolate Rapidly Improves Endothelial Function and Decreases Superoxide Production in Human Vessels Effects on Vascular Tetrahydrobiopterin Availability and Endothelial Nitric Oxide Synthase Coupling

Abstract: Background— The circulating form of folic acid, 5-methyltetrahydrofolate (5-MTHF), may have beneficial effects on endothelial function; however, its mechanisms of action remain uncertain. Decreased...

Rapid modulation of GABA concentration in human sensorimotor cortex during motor learning.

Abstract: Movement representations within the human primary motor and somatosensory cortices can be altered by motor learning. Decreases in local GABA concentration and its release may facilitate this plasti...

Major effects of delayed graft function and cold ischaemia time on renal allograft survival

Abstract: Background. There is mounting evidence fromexperimental and clinical studies that the quality oforgans from cadaver donors may be influenced byevents occurring around the time of brain death, andthat these may affect transplant outcome. The aim ofthis study is to investigate the influence of donorfactors on renal allograft outcome in a homogeneouscohort of 518 patients transplanted in a single centreover a 9 year period.Methods. Endpoints of the study were delayed graftfunction (DGF), acute rejection (AR), 1 year graftsurvival and long-term survival of those grafts thatreached 1 year. Multivariate analysis was performed todetermine factors that may have influenced the graftoutcome indicators.Results: DGF was the major predictor of graft failureoverall with cold ischaemia time (CIT) as an importantindependent factor. The level of histocompatibility didnot influence graft survival. DGF was the majorfactor affecting 1 year graft survival (P<0.0005) witheffects persisting beyond 1 year. DGF was significantlyinfluenced by CIT, donor age, female kidney into malerecipient and donor creatinine (P<0.05). Other donorfactors and factors associated with donor managementwere not risk factors for DGF, rejection episodesor graft survival. The risk factors for a number ofAR episodes were HLA–DR mismatch and DGF(P<0.005). When grafts surviving for 1 year wereconsidered, only CIT, recipient age and creatinine at1 year (P<0.05) were found to affect graft survivalsignificantly.Conclusions. The results of this analysis of well-matched transplant recipients show that CIT andDGF are the most important predictors of poorshort and long-term graft survival. Therefore, inorder to improve the long-term survival of renalallografts efforts should focus on limiting CIT andthe damage that occurs during this period and onimproving our understanding of DGF.Keywords: cold ischaemia time; delayed graftfunction; donor factors; outcome;renal transplantation

Molecular and Pharmacological Determinants of the Therapeutic Response to Artemether-Lumefantrine in Multidrug-Resistant Plasmodium falciparum Malaria

Abstract: The emergence of drug resistance in Plasmodium falciparum has significantly undermined malaria-control programs in countries where it is endemic [1]. To ensure high cure rates and to combat this threat, the World Health Organization (WHO) has recommended the use of artemisinin combination therapy (ACT), although debate regarding the most suitable combination and how ACTs should be deployed and funded still continues. Artemisinins ensure rapid reduction of the initial infecting biomass, with the residual parasites being removed by a more slowly eliminated component usually included in combination therapy. The rationale supporting the use of ACT is improvement of anti-malarial efficacy, facilitation of adherence to a full treatment course, and minimization of selection of drug-resistant parasites. Artemether-lumefantrine (AL) is currently the only combination therapy widely available that is manufactured to Good Manufacturing Practice standards in a fixed-dose preparation (each tablet contains 20 mg of artemether and 120 mg of lumefantrine). The fixed-dose regimen ensures that malaria parasites always encounter artemether and metabolites in the presence of lumefantrine and provides protection against the emergence of resistance to both components, but absorption of the lipophilic lumefantrine is erratic, and the drug needs to be administered twice per day [2]. Therapeutic levels are more reliably achieved by coadministration with a fatty meal and by extending the treatment course from 4 to 6 doses [3-5]. The WHO now advocates the higher, 6-dose regimen for the treatment of P. falciparum malaria in all areas, irrespective of the levels of host immunity or prevalence of multidrug resistance. On the western border of Thailand, P. falciparum has become resistant to chloroquine, sulfadoxine-pyrimethamine, mefloquine, and halofantrine [6], although there have been no convincing reports of clinical resistance to the artemisinin derivatives. In studies conducted to determine the molecular basis of mefloquine resistance, we have highlighted a central role of amplification of pfmdr1 [7]. In vitro cross-resistance has been observed between lumefantrine, mefloquine, and halofantrine, and subsequent molecular studies have suggested a common mechanism of resistance [8]. We hypothesized that pfmdr1 polymorphisms would also contribute to treatment failure following AL treatment. To investigate the relative contributions of host, pharmacokinetic, and parasitological factors in determining therapeutic outcome following treatment with AL, we analyzed the cumulative AL experience at the Shoklo Malaria Research Unit (SMRU; Mae Sod, Tak Province, Thailand) between 1995 and 2002.