Fatal and nonfatal AIDS and non-AIDS events in HIV-1-positive individuals with high CD4 cell counts according to viral load strata.

BACKGROUND: This study compared the incidence of fatal and nonfatal AIDS and non-AIDS events in HIV-positive individuals with a CD4 cell count more than 350  cells/μl among viral load strata: low (<500  copies/ml), intermediate (500-9999.9  copies/ml) and high (≥ 10000  copies/ml). METHODS: Individuals contributed person-years at risk if their most recent CD4 cell count was more than 350  cells/μl. Follow-up was censored if their CD4 cell count dropped below 350  cells/μl. Poisson regression analysis investigated the relationship between viraemia and the incidence of AIDS and non-AIDS events. RESULTS: Three hundred and fifty-four AIDS events occurred during 51 732  person-years of follow-up (PYFU), crude incidence rate of AIDS across the three strata was 0.53, 0.90 and 2.12 per 100 PYFU, respectively. After adjustment, a higher rate of AIDS was observed in individuals with moderate [incidence rate ratio (IRR) 1.44, 1.02-2.05, P = 0.03] and high viraemia had a higher rate (IRR 3.91, 2.89-5.89, P < 0.0001) compared with low viraemia. Five hundred and seventy-two non-AIDS events occurred during 43 784 PYFU, the crude incidence rates were 1.28, 1.52, and 1.38 per 100 PYFU, respectively. After adjustment, particularly for age, region of Europe and starting combination antiretroviral therapy, there was a 61% (IRR 1.61, 1.21-2.14, P = 0.001) and 66% (IRR 1.66, 1.17-2.32, P = 0.004) higher rate of non-AIDS in individuals with intermediate and high viraemia compared with low viraemia. CONCLUSION: In individuals with a CD4 cell count more than 350  cells/μl, an increased incidence of AIDS and a slightly increased incidence of non-AIDS was found in those with uncontrolled viral replication. The association with AIDS was clear and consistent. However, the association with non-AIDS was only apparent after adjustment and no differences were observed between intermediate and high viraemia.

Infliximab for Crohn's disease in the Swiss IBD Cohort Study: clinical management and appropriateness.

OBJECTIVE: Antitumor necrosis factor a agents have significantly improved the management of Crohn's disease (CD), but not all patients benefit from this therapy. We used data from the Swiss Inflammatory Bowel Disease Cohort Study and predefined appropriateness criteria to examine the appropriateness of use of infliximab (IFX) in CD patients. METHODS: EPACT II (European Panel on the Appropriateness of CD Therapy, 2007; www.epact.ch) appropriateness criteria have been developed using a formal explicit panel process combining evidence from the published literature and expert opinion. Questionnaires relating to EPACT II criteria were used at enrollment and follow-up of all Swiss Inflammatory Bowel Disease Cohort Study patients. A step-by-step analysis of all possible indications for IFX therapy in a given patient allowed identification of the most appropriate indication and final classification in a single appropriateness category (appropriate, uncertain, inappropriate). RESULTS: Eight hundred and twenty-one CD patients were prospectively enrolled between November 2006 and March 2009. IFX was administered to 146 patients (18%) at enrollment and was most frequently used for complex fistulizing disease and for the maintenance of remission induced by biological therapy. IFX therapy was considered appropriate in 44%, uncertain in 44%, and inappropriate in 10% of patients. CONCLUSION: In this cohort, 9 out of 10 indications for IFX therapy were clinically generally acceptable (appropriate or uncertain) according to EPACT II criteria. Uncertain indications resulted mainly from the current more liberal use of IFX in clinical practice as compared with the EPACT II criteria.

Positional scanning-synthetic peptide library-based analysis of self- and pathogen-derived peptide cross-reactivity with tumor-reactive Melan-A-specific CTL.

Synthetic combinatorial peptide libraries in positional scanning format (PS-SCL) have recently emerged as a useful tool for the analysis of T cell recognition. This includes identification of potentially cross-reactive sequences of self or pathogen origin that could be relevant for the understanding of TCR repertoire selection and maintenance, as well as of the cross-reactive potential of Ag-specific immune responses. In this study, we have analyzed the recognition of sequences retrieved by using a biometric analysis of the data generated by screening a PS-SCL with a tumor-reactive CTL clone specific for an immunodominant peptide from the melanocyte differentiation and tumor-associated Ag Melan-A. We found that 39% of the retrieved peptides were recognized by the CTL clone used for PS-SCL screening. The proportion of peptides recognized was higher among those with both high predicted affinity for the HLA-A2 molecule and high predicted stimulatory score. Interestingly, up to 94% of the retrieved peptides were cross-recognized by other Melan-A-specific CTL. Cross-recognition was at least partially focused, as some peptides were cross-recognized by the majority of CTL. Importantly, stimulation of PBMC from melanoma patients with the most frequently recognized peptides elicited the expansion of heterogeneous CD8(+) T cell populations, one fraction of which cross-recognized Melan-A. Together, these results underline the high predictive value of PS-SCL for the identification of sequences cross-recognized by Ag-specific T cells.

Multiple causes of the evolution of dispersal in metapopulations

Abstract This work investigates the outcome of the interaction of the multiple causes of selection acting on dispersal in metapopulations. Dispersal, defined here as the ability of individuals to move out of their natal population to reproduce in an other one, has three main causes. First, population variability, as caused by random population extinctions, induces high incentives to disperse through the probability to recolonize an empty population and thus to escape competition for space. This adds to the second cause, kin competition avoidance where individuals in a crowded patch will benefit from the release of competition with relatives caused by dispersal. Dispersal may thus be viewed as an altruistic act. Third, dispersal might evolve as a strategy of avoiding inbred matings which are expected to bear fitness costs due to the presence of a mutation load. The interaction of inbreeding avoidance and kin competition is explored in chapter 2. Conditions conducive to the establishment of a high relatedness within population are expected to induce high dispersal through both kin competition avoidance and inbreeding avoidance. However, the dynamics of inbreeding depression is bound to depend on the level of gene flow as well as on the deleterious mutation parameters. Mutations more prone to settle a high level of inbreeding depression will select for increased dispersal. Chapter 3 investigates the effect of the mating system on the joint dynamics of dispersal and inbreeding depression. Higher inbreeding rates as those found in various mating systems lead to a more efficient purge of the deleterious mutations. However, this decrease in the costs of inbreeding are usually accompanied by a higher within deme relatedness which balances the decreased effect of inbreeding avoidance on the evolution of dispersal. Finally, population turnover, as found in most natural populations has a dual effect on dispersal. Indeed, it increases dispersal by the increased probability of winning a breeding slot in extinct demes it creates but, on the other hand, it counter-selects for dispersal through the slow establishment of unsaturated demic conditions which contribute to lower the local competition for space. Résumé Ce travail se propose d'étudier les effets conjoints des multiples causes de l'évolution de la dispersion en métapopulation. La dispersion, définie ici comme étant la capacité de quitter sa population d'origine pour se reproduire dans une antre population, possède trois principales causes. Premièrement, l'extinction aléatoire de populations sélectionne pour plus de dispersion car elle augmente la Probabilité de recoloniser un patch éteint et donc d'échapper à la compétition locale. La seconde cause, l'évitement de la compétition de parentèle, sélectionne pour plus de dispersion par les bénéfices qu'elle apporte par diminution de la compétition entre individus apparentés. Troisièmement, la dispersion évolue "comme stratégie d'évitement de la dépression de consanguinité présente dans des petites populations isolées. L'interaction entre l'évitement de la consanguinité et de la compétition de parentèle est étudiée dans le chapitre 2. Les conditions conduisant à l'établissement d'un fort apparentement à l'intérieur des populations sont celles qui génèrent le plus de sélection pour la dispersion. Cependant, la dynamique de la dépression de consanguinité est dépendante de la dispersion entre populations ainsi que des paramètres des mutations délétères. Les mutations créant le plus de dépression de consanguinité sont celles qui sélectionneront le plus pour de la dispersion. Le chapitre 3 s'intéresse aux effets du système de reproduction sur la dynamique conjointe du fardeau de mutation et de la dispersion. La purge des mutations délétère étant plus sévère dans des conditions de forte consanguinité, elle diminue les coûts de la consanguinité mais est habituellement accompagné par une augmentation de l'apparentement et donc l'effet peut être neutre sur la dispersion. Finalement, le turnover de populations a un effet dual sur la dispersion. La dispersion est sélectionnée par l'augmentation de la probabilité de gagner une place de reproduction dans des patchs éteints mais elle est également contre sélectionnée par la désaturation des patchs causée par l'extinction et la diminution de la compétition pour l'espace qui intervient dans ce cas.

Estimating the cost-effectiveness of modern screening mammography programmes

Context: The debate about the balance of risks and benefits of mammography screening has prompted a comprehensive review by an independent panel in the UK. However, the panel's remit did not cover the important economic dimension of breast cancer screening. Methods: The life histories of two cohort studies of 50-year-old women, who would be eligible within the National Health Service (NHS) breast screening programme (NHSBSP), were simulated over 35 years, using a life table approach. One cohort participant was offered screening at age 50 and triennially thereafter until age 70, assuming 75% attendance, while the other received no screening. Based on the findings from the panel's report, the cost-effectiveness of the NHSBSP was assessed for various scenarios of screening effect on breast cancer incidence (base case scenario: screening advances diagnosis by 5 years; 10% incidence reduction after screening stops).

PD-1 is a regulator of NY-ESO-1-specific CD8+ T cell expansion in melanoma patients.

The programmed death 1 (PD-1) receptor is a negative regulator of activated T cells and is up-regulated on exhausted virus-specific CD8(+) T cells in chronically infected mice and humans. Programmed death ligand 1 (PD-L1) is expressed by multiple tumors, and its interaction with PD-1 resulted in tumor escape in experimental models. To investigate the role of PD-1 in impairing spontaneous tumor Ag-specific CD8(+) T cells in melanoma patients, we have examined the effect of PD-1 expression on ex vivo detectable CD8(+) T cells specific to the tumor Ag NY-ESO-1. In contrast to EBV, influenza, or Melan-A/MART-1-specific CD8(+) T cells, NY-ESO-1-specific CD8(+) T cells up-regulated PD-1 expression. PD-1 up-regulation on spontaneous NY-ESO-1-specific CD8(+) T cells occurs along with T cell activation and is not directly associated with an inability to produce cytokines. Importantly, blockade of the PD-1/PD-L1 pathway in combination with prolonged Ag stimulation with PD-L1(+) APCs or melanoma cells augmented the number of cytokine-producing, proliferating, and total NY-ESO-1-specific CD8(+) T cells. Collectively, our findings support the role of PD-1 as a regulator of NY-ESO-1-specific CD8(+) T cell expansion in the context of chronic Ag stimulation. They further support the use of PD-1/PD-L1 pathway blockade in cancer patients to partially restore NY-ESO-1-specific CD8(+) T cell numbers and functions, increasing the likelihood of tumor regression.

Guard cell-specific calcium sensitivity of high density and activity SV/TPC1 channels.

The slow vacuolar (SV) channel, a Ca2+-regulated vacuolar cation conductance channel, in Arabidopsis thaliana is encoded by the single-copy gene AtTPC1. Although loss-of-function tpc1 mutants were reported to exhibit a stoma phenotype, knowledge about the underlying guard cell-specific features of SV/TPC1 channels is still lacking. Here we demonstrate that TPC1 transcripts and SV current density in guard cells were much more pronounced than in mesophyll cells. Furthermore, the SV channel in motor cells exhibited a higher cytosolic Ca2+ sensitivity than in mesophyll cells. These distinct features of the guard cell SV channel therefore probably account for the published stomatal phenotype of tpc1-2.

Absolute height-specific thresholds to identify elevated blood pressure in children.

OBJECTIVE: : Identification of children with elevated blood pressure (BP) is difficult because of the multiple sex, age, and height-specific thresholds to define elevated BP. We propose a simple set of absolute height-specific BP thresholds and evaluate their performance to identify children with elevated BP in two different populations. METHODS: : Using the 95th sex, age, and relative-height BP US thresholds to define elevated BP in children (standard criteria), we derived a set of (non sex- and non age-specific) absolute height-specific BP thresholds for 11 height categories by 10 cm increments. Using data from large school-based surveys conducted in Switzerland (N = 5207; 2621 boys, 2586 girls; age range: 10.1-14.9 years) and in the Seychelles (N = 25 759; 13 048 boys, 12 711 girls; age range: 4.4-18.8 years), we evaluated the performance of these height-specific thresholds to identify children with elevated BP. We also derived sex-specific absolute height-specific BP thresholds and compared their performance. RESULTS: : In the Swiss and the Seychelles surveys, the prevalence of elevated BP (standard criteria) was 11.4 and 9.1%, respectively. The height-specific thresholds to identify elevated BP had a sensitivity of 80 and 84%, a specificity of 99 and 99%, a positive predictive value of 92 and 91%, and a negative predictive value of 97 and 98%, respectively. Performance of sex-specific absolute height-specific BP thresholds was similar. CONCLUSION: : A simple table of height-specific BP thresholds allowed identifying children with elevated BP with high sensitivity and excellent specificity.

Causal mechanisms underlying host specificity in bat ectoparasites.

In parasites, host specificity may result either from restricted dispersal capacity or from fixed coevolutionary host-parasite adaptations. Knowledge of those proximal mechanisms leading to particular host specificity is fundamental to understand host-parasite interactions and potential coevolution of parasites and hosts. The relative importance of these two mechanisms was quantified through infection and cross-infection experiments using mites and bats as a model. Monospecific pools of parasitic mites (Spinturnix myoti and S. andegavinus) were subjected either to individual bats belonging to their traditional, native bat host species, or to another substitute host species within the same bat genus (Myotis). The two parasite species reacted differently to these treatments. S. myoti exhibited a clear preference for, and had a higher fitness on, its native host, Myotis myotis. In contrast, S. andegavinus showed no host choice, although its fitness was higher on its native host M. daubentoni. The causal mechanisms mediating host specificity can apparently differ within closely related host-parasite systems.

Consensus paper: the role of the cerebellum in perceptual processes.

Various lines of evidence accumulated over the past 30 years indicate that the cerebellum, long recognized as essential for motor control, also has considerable influence on perceptual processes. In this paper, we bring together experts from psychology and neuroscience, with the aim of providing a succinct but comprehensive overview of key findings related to the involvement of the cerebellum in sensory perception. The contributions cover such topics as anatomical and functional connectivity, evolutionary and comparative perspectives, visual and auditory processing, biological motion perception, nociception, self-motion, timing, predictive processing, and perceptual sequencing. While no single explanation has yet emerged concerning the role of the cerebellum in perceptual processes, this consensus paper summarizes the impressive empirical evidence on this problem and highlights diversities as well as commonalities between existing hypotheses. In addition to work with healthy individuals and patients with cerebellar disorders, it is also apparent that several neurological conditions in which perceptual disturbances occur, including autism and schizophrenia, are associated with cerebellar pathology. A better understanding of the involvement of the cerebellum in perceptual processes will thus likely be important for identifying and treating perceptual deficits that may at present go unnoticed and untreated. This paper provides a useful framework for further debate and empirical investigations into the influence of the cerebellum on sensory perception.

Fab antibodies capable of blocking T cells by competitive binding have the identical specificity but a higher affinity to the MHC-peptide-complex than the T cell receptor.

In transplant rejection, graft versus host or autoimmune diseases T cells are mediating the pathophysiological processes. Compared to unspecific pharmacological immune suppression specific inhibition of those T cells, that are involved in the disease, would be an alternative and attractive approach. T cells are activated after their T cell receptor (TCR) recognizes an antigenic peptide displayed by the Major Histocompatibility Complex (MHC). Molecules that interact with MHC-peptide-complexes in a specific fashion should block T cells with identical specificity. Using the model of the SSX2 (103-111)/HLA-A*0201 complex we investigated a panel of MHC-peptide-specific Fab antibodies for their capacity blocking specific T cell clones. Like TCRs all Fab antibodies reacted with the MHC complex only when the SSX2 (103-111) peptide was displayed. By introducing single amino acid mutations in the HLA-A*0201 heavy chain we identified the K66 residue as the most critical binding similar to that of TCRs. However, some Fab antibodies did not inhibit the reactivity of a specific T cell clone against peptide pulsed, artificial targets, nor cells displaying the peptide after endogenous processing. Measurements of binding kinetics revealed that only those Fab antibodies were capable of blocking T cells that interacted with an affinity in the nanomolar range. Fab antibodies binding like TCRs with affinities on the lower micromolar range did not inhibit T cell reactivity. These results indicate that molecules that block T cells by competitive binding with the TCR must have the same specificity but higher affinity for the MHC-peptide-complex than the TCR.

Dissecting TCR-MHC/peptide complex interactions with A2/peptide multimers incorporating tumor antigen peptide variants: crucial role of interaction kinetics on functional outcomes.

Soluble peptide/MHC-class-I (pMHC) multimers have recently emerged as unique reagents for the study of specific interactions between the pMHC complex and the TCR. Here, we assessed the relative binding efficiency of a panel of multimers incorporating single-alanine-substituted variants of the tumor-antigen-derived peptide MAGE-A10(254-262) to specific CTL clones displaying different functional avidity. For each individual clone, the efficiency of binding of multimers incorporating MAGE-A10 peptide variants was, in most cases, in good although not linear correlation with the avidity of recognition of the corresponding variant. In addition, we observed two types of discrepancies between efficiency of recognition and multimer binding. First, for some peptide variants, efficient multimer binding was detected in the absence of measurable effector functions. Some of these peptide variants displayed antagonist activity. Second, when comparing different clones we found clear discrepancies between the dose of peptide required to obtain half-maximal lysis in CTL assays and the binding efficiency of the corresponding multimers. These discrepancies, however, were resolved when the differential stability of the TCR/pMHC complexes was determined. For individual clones, decreased recognition correlated with increased TCR/pMHC off-rate. TCR/pMHC complexes formed by antagonist ligands displayed off-rates faster than those of TCR/pMHC complexes formed with weak agonists. In addition, when comparing different clones, the efficiency of multimer staining correlated better with relative multimer off-rates than with half-maximal lysis values. Altogether, the data presented here reconcile and extend our previous results on the impact of the kinetics of interaction of TCR with pMHC complexes on multimer binding and underline the crucial role of TCR/pMHC off-rates for the functional outcome of such interactions.

Measurement with an automated oscillometric wrist device with position sensor leads to lower values than measurements obtained with an automated oscillometric arm device from the same manufacturer in elderly persons.

OBJECTIVE: Home blood pressure (BP) monitoring is recommended by several clinical guidelines and has been shown to be feasible in elderly persons. Wrist manometers have recently been proposed for such home BP measurement, but their accuracy has not been previously assessed in elderly patients. METHODS: Forty-eight participants (33 women and 15 men, mean age 81.3±8.0 years) had their BP measured with a wrist device with position sensor and an arm device in random order in a sitting position. RESULTS: Average BP measurements were consistently lower with the wrist than arm device for systolic BP (120.1±2.2 vs. 130.5±2.2 mmHg, P<0.001, means±SD) and diastolic BP (66.0±1.3 vs. 69.7±1.3 mmHg, P<0.001). Moreover, a 10 mmHg or greater difference between the arm and wrist device was observed in 54.2 and 18.8% of systolic and diastolic measures, respectively. CONCLUSION: Compared with the arm device, the wrist device with position sensor systematically underestimated systolic as well as diastolic BP. The magnitude of the difference is clinically significant and questions the use of the wrist device to monitor BP in elderly persons. This study points to the need to validate BP measuring devices in all age groups, including in elderly persons.