Selectively expanding subsets of T cells in mice by injection of interleukin-2/antibody complexes: implications for transplantation tolerance.

The biological activity of interleukin (IL)-2 and other cytokines in vivo can be augmented by binding to certain anti-cytokine monoclonal antibodies (mAb). Here, we review evidence on how IL-2/anti-IL-2 mAb complexes can be used to cause selective stimulation and expansion of certain T-cell subsets. With some anti-IL-2 mAbs, injection of IL-2/mAb complexes leads to expansion of CD8 T effector cells but not CD4 T regulatory cells (Tregs); these complexes exert less adverse side effects than soluble IL-2 and display powerful antitumor activity. Other IL-2/mAb complexes have minimal effects on CD8 T cells but cause marked expansion of Tregs. Preconditioning mice with these complexes leads to permanent acceptance of MHC-disparate pancreatic islets in the absence of immunosuppression.

The Impact of Cannabis Use on Cognitive Functioning in Patients With Schizophrenia: A Meta-analysis of Existing Findings and New Data in a First-Episode Sample.

Cannabis use is highly prevalent among people with schizophrenia, and coupled with impaired cognition, is thought to heighten the risk of illness onset. However, while heavy cannabis use has been associated with cognitive deficits in long-term users, studies among patients with schizophrenia have been contradictory. This article consists of 2 studies. In Study I, a meta-analysis of 10 studies comprising 572 patients with established schizophrenia (with and without comorbid cannabis use) was conducted. Patients with a history of cannabis use were found to have superior neuropsychological functioning. This finding was largely driven by studies that included patients with a lifetime history of cannabis use rather than current or recent use. In Study II, we examined the neuropsychological performance of 85 patients with first-episode psychosis (FEP) and 43 healthy nonusing controls. Relative to controls, FEP patients with a history of cannabis use (FEP + CANN; n = 59) displayed only selective neuropsychological impairments while those without a history (FEP - CANN; n = 26) displayed generalized deficits. When directly compared, FEP + CANN patients performed better on tests of visual memory, working memory, and executive functioning. Patients with early onset cannabis use had less neuropsychological impairment than patients with later onset use. Together, these findings suggest that patients with schizophrenia or FEP with a history of cannabis use have superior neuropsychological functioning compared with nonusing patients. This association between better cognitive performance and cannabis use in schizophrenia may be driven by a subgroup of "neurocognitively less impaired" patients, who only developed psychosis after a relatively early initiation into cannabis use.

An evolutionary model explaining the Neolithic transition from egalitarianism to leadership and despotism.

The Neolithic was marked by a transition from small and relatively egalitarian groups to much larger groups with increased stratification. But, the dynamics of this remain poorly understood. It is hard to see how despotism can arise without coercion, yet coercion could not easily have occurred in an egalitarian setting. Using a quantitative model of evolution in a patch-structured population, we demonstrate that the interaction between demographic and ecological factors can overcome this conundrum. We model the coevolution of individual preferences for hierarchy alongside the degree of despotism of leaders, and the dispersal preferences of followers. We show that voluntary leadership without coercion can evolve in small groups, when leaders help to solve coordination problems related to resource production. An example is coordinating construction of an irrigation system. Our model predicts that the transition to larger despotic groups will then occur when: (i) surplus resources lead to demographic expansion of groups, removing the viability of an acephalous niche in the same area and so locking individuals into hierarchy; (ii) high dispersal costs limit followers' ability to escape a despot. Empirical evidence suggests that these conditions were probably met, for the first time, during the subsistence intensification of the Neolithic.

Open to closed system transition traced through the TDIC isotopic signature at the aquifer recharge stage, implications for groundwater 14C dating

14C dating models are limited when considering recent groundwater for which the carbon isotopic signature of the total dissolved inorganic carbon (TDIC) is mainly acquired in the unsaturated zone. Reducing the uncertainties of dating thus implies a better identification of the processes controlling the carbon isotopic composition of the TDIC during groundwater recharge. Geochemical interactions between gas, water and carbonates in the unsaturated zone were investigated for two aquifers (the carbonate-free Fontainebleau sands and carbonate-bearing Astian sands, France) in order to identify the respective roles of CO2 and carbonates on the carbon isotopic signatures of the TDIC; this analysis is usually approached using open or closed system terms. Under fully open system conditions, the seasonality of the 13C values in the soil CO2 can lead to important uncertainties regarding the so-called "initial 14C activity" used in 14C correction models. In a carbonate-bearing unsaturated zone such as in the Astian aquifer, we show that an approach based on fully open or closed system conditions is not appropriate. Although the chemical saturation between water and calcite occurs rapidly within the first metre of the unsaturated zone, the carbon isotopic contents (δ13C) of the CO2 and the TDIC evolve downward, impacted by the dissolution-precipitation of the carbonates. In this study, we propose a numerical approach to describe this evolution. The δ13C and the A 14C (radiocarbon activity) of the TDIC at the base of the carbonate-hearing unsaturated zone depends on (i) the δ13C and the A 14C of the TDIC in the soil determined by the soil CO2, (ii) the water's residence time in the unsaturated zone and (iii) the carbonate precipitation-dissolution fluxes. In this type of situation, the carbonate δ13C-A 14C evolutions indicate the presence of secondary calcite and permit the calculation of its accretion flux, equal to ~ 4.5 ± 0.5 x 10-9 mol grock-1 yr-1. More generally, for other sites under temperate climate and with similar properties to the Astian sands site, this approach allows for a reliable determination of the carbon isotopic composition at the base of the unsaturated zone as the indispensable "input function" data of the carbon cycle into the aquifer.

Diagnostic Performances of 18F-FDG Positron Emission Tomography in Large Vessels Vasculitis: Meta-analysis

Toperform a meta-analysis of FDG-PET performances in the diagnosis of largevessels vasculitis (Giant Cell Arteritis (GCA) associated or not withPolymyalgia Rheumatica(PMR), Takayasu). Materials and methods : The MEDLINE,Cochrane Library, Embase were searched for relevant original articlesdescribing FDG-PET for vasculitis assessment, using MesH terms ("GiantCell Arteritis or Vasculitis" AND "PET"). Criteria for inclusionwere:(1)FDG-PET for diagnosis of vasculitis(2)American College of Rheumatologycriteria as reference standard(3)control group. After data extraction, analyseswere performed using a random-effects model. Results : Of 184 citations(database search and references screening),70 articles were reviewed of which12 eligible studies were extracted (sensitivity range from 32% to 97%). 7studies fulfilled all inclusion criteria. Owing to overlapping population, 1study was excluded. Statistical heterogeneity justified the random-effectsmodel. Pooled 6 studies analysis(116 vasculitis,224 controls) showed a 81%sensitivity (95%CI:70-89%);a 89% specificity (95%CI:77-95%);a 85%PPV(95%CI:63-95%); a 90% NPV(95%CI:79-95%);a 7.1 positive LR(95%CI:3.4-14.9); a0.2 negative LR(95%CI:0.14-0.35) and 90.1 DOR(95%CI: 18.6-437). Conclusion :FDG-PET has good diagnostic performances in the detection of large vesselsvasculitis. Its promising role could be extended to follow up patients undertreatment, but further studies are needed to confirm this possibility.

Effects of the transition time between muscle-tendon stretch and shortening on mechanical efficiency.

The net mechanical efficiency of positive work (eta(pos)) has been shown to increase if it is immediately preceded by negative work. This phenomenon is explained by the storage of elastic energy during the negative phase and its release during the subsequent positive phase. If a transition time (T) takes place, the elastic energy is dissipated into heat. The aim of the present study was to investigate the relationship between eta(pos) and T, and to determine the minimal T required so that eta(pos) reached its minimal value. Seven healthy male subjects were tested during four series of lowering-raising of the body mass. In the first series (S (0)), the negative and positive phases were executed without any transition time. In the three other series, T was varied by a timer (0.12, 0.24 and 0.56 s for series S (1), S (2) and S (3), respectively). These exercises were performed on a force platform sensitive to vertical forces to measure the mechanical work and a gas analyser was used to determine the energy expenditure. The results indicated that eta(pos) was the highest (31.1%) for the series without any transition time (S (0)). The efficiencies observed with transition times (S (1), S (2) and S (3)) were 27.7, 26.0 and 23.8%, respectively, demonstrating that T plays an important role for mechanical efficiency. The investigation of the relationship between eta(pos) and T revealed that the minimal T required so that eta(pos) reached its minimal value is 0.59 s.

Risk factors for survival after lung metastasectomy in colorectal cancer patients: a systematic review and meta-analysis.

BACKGROUND: Resection of lung metastases (LM) from colorectal cancer (CRC) is increasingly performed with a curative intent. It is currently not possible to identify those CRC patients who may benefit the most from this surgical strategy. The aim of this study was to perform a systematic review of risk factors for survival after lung metastasectomy for CRC. METHODS: We performed a meta-analysis of series published between 2000 and 2011, which focused on surgical management of LM from CRC and included more than 40 patients each. Pooled hazard ratios (HR) were calculated by using random effects model for parameters considered as potential prognostic factors. RESULTS: Twenty-five studies including a total of 2925 patients were considered in this analysis. Four parameters were associated with poor survival: (1) a short disease-free interval between primary tumor resection and development of LM (HR 1.59, 95 % confidence interval [CI] 1.27-1.98); (2) multiple LM (HR 2.04, 95 % CI 1.72-2.41); (3) positive hilar and/or mediastinal lymph nodes (HR 1.65, 95 % CI 1.35-2.02); and (4) elevated prethoracotomy carcinoembryonic antigen (HR 1.91, 95 % CI 1.57-2.32). By comparison, a history of resected liver metastases (HR 1.22, 95 % CI 0.91-1.64) did not achieve statistical significance. CONCLUSIONS: Clinical variables associated with prolonged survival after surgery for LM in CRC patients include prolonged disease-free interval between primary tumor and metastatic spread, normal prethoracotomy carcinoembryonic antigen, absence of thoracic node involvement, and a single pulmonary lesion.

Genome-wide association study to identify common variants associated with brachial circumference: a meta-analysis of 14 cohorts.

Brachial circumference (BC), also known as upper arm or mid arm circumference, can be used as an indicator of muscle mass and fat tissue, which are distributed differently in men and women. Analysis of anthropometric measures of peripheral fat distribution such as BC could help in understanding the complex pathophysiology behind overweight and obesity. The purpose of this study is to identify genetic variants associated with BC through a large-scale genome-wide association scan (GWAS) meta-analysis. We used fixed-effects meta-analysis to synthesise summary results across 14 GWAS discovery and 4 replication cohorts comprising overall 22,376 individuals (12,031 women and 10,345 men) of European ancestry. Individual analyses were carried out for men, women, and combined across sexes using linear regression and an additive genetic model: adjusted for age and adjusted for age and BMI. We prioritised signals for follow-up in two-stages. We did not detect any signals reaching genome-wide significance. The FTO rs9939609 SNP showed nominal evidence for association (p<0.05) in the age-adjusted strata for men and across both sexes. In this first GWAS meta-analysis for BC to date, we have not identified any genome-wide significant signals and do not observe robust association of previously established obesity loci with BC. Large-scale collaborations will be necessary to achieve higher power to detect loci underlying BC.

How adult specialists deal with the principles of a successful transition.

OBJECTIVES: To evaluate whether adult specialists comply with the basic principles for a successful transition of adolescents with chronic disorders, and to determine whether the characteristics of the adult specialists have an influence on applying these principles. METHODS: Out of 299 adult specialists in four French-speaking Swiss cantons, 209 (70%) answered a paper-and-pencil mailed questionnaire between May and July 2007. Only those having received the transfer of at least one adolescent in the previous 2 years (N=102) were included in the analysis. We analyzed four dependent variables: discussing common concerns of adolescent patients, seeing the patient alone, having a transition protocol, and having a previous contact with the pediatric specialist. A logistic regression was performed for each dependent variable controlling for the physicians' characteristics (number of transfers, age, gender, workplace, and perceived experience). RESULTS: Fifty-four percent of the physicians did not spend time alone with their patients, and sensitive issues such as sexuality or substance use were not widely discussed with their young patients. Most respondents (59%) did not have an established protocol, and 54% did not have any contact with the pediatric specialist. In the multivariate analyses, the adult specialists' characteristics had little impact. CONCLUSIONS: For many adolescents with chronic disorders the transition from pediatric to adult healthcare seems to be limited to a simple transfer, often lacking adequate communication between physicians. Applying simple but basic principles such as a good coordination between providers would probably improve the quality of healthcare of adolescents with chronic illness.

Administrative Transition Planning Notebook, November 15, 2006

Seven Years ofInnovation, Technological Advances, Enhanced Service & Fluid Commerce in the Iowa Alcoholic Beverages Division.

Meta-analysis of estrogen response in MCF-7 distinguishes early target genes involved in signaling and cell proliferation from later target genes involved in cell cycle and DNA repair.

ABSTRACT: BACKGROUND: Many studies have been published outlining the global effects of 17 beta-estradiol (E2) on gene expression in human epithelial breast cancer derived MCF-7 cells. These studies show large variation in results, reporting between ~100 and ~1500 genes regulated by E2, with poor overlap. RESULTS: We performed a meta-analysis of these expression studies, using the Rank product method to obtain a more accurate and stable list of the differentially expressed genes, and of pathways regulated by E2. We analyzed 9 time-series data sets, concentrating on response at 3-4 hrs (early) and at 24 hrs (late). We found >1000 statistically significant probe sets after correction for multiple testing at 3-4 hrs, and >2000 significant probe sets at 24 hrs. Differentially expressed genes were examined by pathway analysis. This revealed 15 early response pathways, mostly related to cell signaling and proliferation, and 20 late response pathways, mostly related to breast cancer, cell division, DNA repair and recombination. CONCLUSIONS: Our results show that meta-analysis identified more differentially expressed genes than the individual studies, and that these genes act together in networks. These results provide new insight into E2 regulated mechanisms, especially in the context of breast cancer.

Active smoking and the risk of type 2 diabetes : a systematic review and meta-analysis

Rapport de synthèse : Introduction : plusieurs études observationnelles suggèrent qu'il existe une association entre le tabagisme actif et l'incidence du diabète de type 2. Toutefois de telles études n'ont jamais été synthétisées de façon systématique. Objectif : conduire une revue systématique avec meta-analyse des études évaluant l'association entre le tabagisme actif et l'incidence du diabète de type 2. Méthode : nous avons effectué une recherche dans les bases de donnée électroniques MEDLINE et EMBASE de 1966 à mai 2007, et l'avons complétée par une recherche manuelle des bibliographies des articles clés retenus ainsi que par la recherche d'abstracts de congrès scientifiques et le contact d'experts. Pour être inclues dans notre revue, les études devaient avoir un design de type cohorte, reporter un risque de glycémies jeun élevée, d'intolérance au glucose ou de diabète de type 2 en relation avec le statut tabagique des participants lors du recrutement et devaient exclure les sujets avec un diabète au début de l'étude. Deux auteurs ont sélectionné de façon indépendante les études et ont extrait les données. Les risques relatifs de diabète étaient ensuite compilés, utilisant un modèle de type « random effect ». Résultats : la recherche a aboutit à 25 études de cohorte prospectives (N=1'165'374 participants) et a reporté en tout 45'844 cas de diabète de type 2 pendant une durée de suivi s'étendant sur 5 à 30 années. Sur les 25 études, 24 reportaient un risque augmenté de diabète chez les fumeurs par comparaison aux non fumeurs. Le risque relatif (RR) commun de toutes les études était de 1.44 (intervalle de confiance (IC) à 95% : 1.31-1.58). Le risque de diabète était plus élevé chez les fumeurs de plus de 20 cigarettes par jour (RR : 1.61, IC 95% : 1.43-1.80) en comparaison aux fumeurs ayant une consommation inférieure (RR : 1.29, IC 95% : 1.13-1.48) et le risque était moindre pour les anciens fumeurs (RR :1.23; IC 95% : 1.14-1.33) comparé aux fumeurs actifs. Ces éléments parlent en faveur d'un effet dose-réponse et donc d'une relation de causalité, sans pour autant la prouver. Conclusion : notre étude révèle que le tabagisme actif est associé avec un risque augmenté de 44% de diabète de type 2. Des recherches futures sont nécessaires pour évaluer si cette association est causale et pour clarifier les mécanismes d'action. Dans l'intervalle, les professionnels de santé devraient mentionner l'éviction du diabète comme une raison supplémentaire d'arrêter de fumer ou de ne pas commencer à fumer.

K-T transition in Deccan Traps of central India marks major marine Seaway across India

Deccan intertrappean sediments in central India are generally considered as terrestrial deposits of Maastrichtian age, but the Cretaceous-Tertiary (K-T) position is still unknown. Here we report the discovery of the K-T transition, a marine incursion and environmental changes preserved within the intertrappean sediments at Jhilmili, Chhindwara District, Madhya Pradesh. Integrative biostratigraphic, sedimentologic, mineralogic and chemostratigraphic analyses reveal the basal Danian in the intertrappean sediments between lower and upper trap basalts that regionally correspond to C29r and the C29R/C29N transition, respectively. Intertrappean deposition occurred in predominantly terrestrial semi-humid to and environments. But a short aquatic interval of fresh water ponds and lakes followed by shallow coastal marine conditions with brackish marine ostracods and early Danian zone P1a planktic foraminifera mark this interval very close to the K-T boundary. This marine incursion marks the existence of a nearby seaway, probably extending inland from the west through the Narmada and Tapti rift valleys. The Jhilmili results thus identify the K-T boundary near the end of the main phase of Deccan eruptions and indicate that a major seaway extended at least 800 km across India. (C) 2009 Elsevier B.V. All rights reserved.

Soluble MHC-peptide complexes containing long rigid linkers abolish CTL-mediated cytotoxicity.

Soluble MHC-peptide (pMHC) complexes induce intracellular calcium mobilization, diverse phosphorylation events, and death of CD8+ CTL, given that they are at least dimeric and co-engage CD8. By testing dimeric, tetrameric, and octameric pMHC complexes containing spacers of different lengths, we show that their ability to activate CTL decreases as the distance between their subunit MHC complexes increases. Remarkably, pMHC complexes containing long rigid polyproline spacers (&gt; or =80 A) inhibit target cell killing by cloned S14 CTL in a dose- and valence-dependent manner. Long octameric pMHC complexes abolished target cell lysis, even very strong lysis, at nanomolar concentrations. By contrast, an altered peptide ligand antagonist was only weakly inhibitory and only at high concentrations. Long D(b)-gp33 complexes strongly and specifically inhibited the D(b)-restricted lymphocytic choriomeningitis virus CTL response in vitro and in vivo. We show that complications related to transfer of peptide from soluble to cell-associated MHC molecules can be circumvented by using covalent pMHC complexes. Long pMHC complexes efficiently inhibited CTL target cell conjugate formation by interfering with TCR-mediated activation of LFA-1. Such reagents provide a new and powerful means to inhibit Ag-specific CTL responses and hence should be useful to blunt autoimmune disorders such as diabetes type I.