Hepatitis C virus infection after liver transplantation is associated with lower levels of activated CD4(+)CD25(+)CD45RO(+)IL-7ralpha(high) T cells.

The expression of interleukin 7 receptor alpha(high) (IL-7Ralpha(high)) discriminates between activated CD25(+)CD45RO(+)CD4(+) T cells [IL-7Ralpha(high) and forkhead box P3-negative (FoxP3(-))] and regulatory T cells (IL-7Ralpha(low) and FoxP3(+)). The IL-7Ralpha(high)CD25(+)CD45RO(+)CD4(+)FoxP3(-) T cell population has been shown to be expanded in the blood and tissues of patients after kidney transplantation and to contain alloreactive T cells (activated T cells). In the present study, we analyzed the distribution of IL-7Ralpha(high)CD25(+)CD45RO(+)CD4(+)FoxP3(-) T cells in the blood of 53 patients after liver transplantation. The IL-7Ralpha(high)CD25(+)CD45RO(+)CD4(+)FoxP3(-) T cell population was significantly expanded (P < 0.0001) in stable transplant recipients versus healthy donors. However, the magnitude of the expansion was significantly higher (P < 0.0001) in liver transplant recipients with no hepatitis C virus (HCV) infection in comparison with those with a preexisting HCV infection. Interestingly, effective suppression of HCV viremia after antiviral therapy was associated with an increase in the IL-7Ralpha(high)CD25(+)CD45RO(+)CD4(+)FoxP3(-) T cell population to levels comparable to those of liver transplant recipients not infected with HCV. The present results indicate that (1) the IL-7Ralpha(high)CD25(+)CD45RO(+)CD4(+)FoxP3(-) T cell population is expanded after liver transplantation, (2) it is a valuable immunological marker for monitoring activated and potential alloreactive CD4 T cells in liver transplantation, and (3) a preexisting HCV infection negatively influences the expansion of this population in liver transplant recipients.

A step-by-step tutorial to use HierFstat to analyse populations hierarchically structured at multiple levels.

The populations of parasites and infectious agents are most of the time structured in complex hierarchy that lies beyond the classical nested design described by Wright's F-statistics (F(IS), F(ST) and F(IT)). In this note we propose a user-friendly step-by-step notice for using recent software (HierFstat) that computes and test fixation indices for any hierarchical structure. We add some tricks and tips for some special data kind (haploid, single locus), some other procedure (bootstrap over loci) and how to handle crossed factors.

Strength of family history in predicting levels of blood pressure, plasma glucose and cholesterol

Rapport de synthèse : L'histoire familiale reflète non seulement la susceptibilité génétique d'un individu à certaines maladies mais également ses comportements et habitudes, notamment partagées au sein d'une famille. L'hypertension artérielle, le diabète et l'hypercholestérolémie sont des facteurs de risque cardio-vasculaire modifiables hautement prévalent. L'association entre l'histoire familiale d'hypertension artérielle ou de diabète et le risque accru de développer de l'hypertension artérielle ou du diabète, respectivement, a été préalablement établie. Par contre, le lien entre l'histoire familiale de facteurs de risque cardio-vasculaire et les traits continus correspondants n'avaient jamais été mis clairement en évidence. De même, la signification d'une histoire familiale inconnue n'avait jusqu'alors pas été décrite. Ce travail, effectué dans le cadre de l'étude Colaus (Cohorte Lausannoise), une cohorte regroupant un échantillon composé de 6102 participants âgés de 35 à 75 ans sélectionnés au hasard dans la population lausannoise, a permis de décrire en détail la relation entre l'histoire familiale des facteurs de risque cardio-vasculaires et les trait correspondants dans la population étudiée. Les différentes analyses statistiques ont permis de mettre en évidence une relation forte entre l'histoire familiale d'hypertension artérielle, de diabète ainsi que de l'hypercholestérolémie et leurs traits dichotomique et continu correspondants. Les anamnèses des frères et soeurs avaient des valeurs prédictives positives plus élevées que les anamnèses parentales. Ceci signifie que les programmes de dépistage ne prenant en compte que l'histoire familiale des frères et soeurs seraient probablement plus efficaces que ceux qui comportent l'évaluation des anamnèses paternelle et maternelle. Plus de 40% des participants ignoraient l'histoire familiale d'hypertension d'au moins un des membres de leur famille. Ceux-ci avaient des valeurs de tension artérielle systolique plus élevées que ceux dont l'histoire familiale était négative, permettant de souligner la valeur prédictive du fait de ne pas connaître l'histoire familiale d'hypertension artérielle. Ces résultats montrent également que, lors d'analyses de la relation entre l'anamnèse familiale de facteurs de risque cardiovasculaires et leurs traits correspondants, les participants donnant des réponses négatives doivent être distingués de ceux qui ne connaissent pas leur anamnèse familiale. Les résultats de cette étude confirment la place centrale qu'occupe l'anamnèse familiale dans l'évaluation du risque cardio-vasculaire auprès de la population générale. L'importance de cet outil prédictif simple et bon marché ne va cesser d'augmenter avec la disponibilité croissante d'information génétique détaillée pour les maladies cardiovasculaires communes.

Evidence for tuning adipocytes ICER levels for obesity care.

Abnormal adipokine production, along with defective uptake and metabolism of glucose within adipocytes, contributes to insulin resistance and altered glucose homeostasis. Recent research has highlighted one of the mechanisms that accounts for impaired production of adiponectin (ADIPOQ) and adipocyte glucose uptake in obesity. In adipocytes of human obese subjects and mice fed with a high fat diet, the level of the inducible cAMP early repressor (ICER) is diminished. Reduction of ICER elevates the cAMP response element binding protein (CREB) activity, which in turn increases the repressor activating transcription factor 3. In fine, the cascade triggers reduction in the ADIPOQ and GLUT4 levels, which ultimately hampers insulin-mediated glucose uptake. The c-Jun N-terminal kinase (JNK) interacting-protein 1, also called islet brain 1 (IB1), is a target of CREB/ICER that promotes JNK-mediated insulin resistance in adipocytes. A rise in IB1 and c-Jun levels accompanies the drop of ICER in white adipose tissues of obese mice when compared with mice fed with a chow diet. Other than the expression of ADIPOQ and glucose transport, decline in ICER expression might impact insulin signaling. Impairment of ICER is a critical issue that will need major consideration in future therapeutic purposes.

Monitoring multiple angiogenesis-related molecules in the blood of cancer patients shows a correlation between VEGF-A and MMP-9 levels before treatment and divergent changes after surgical vs. conservative therapy.

Anti-angiogenic therapies are currently in cancer clinical trials, but to date there are no established tests for evaluating the angiogenic status of a patient. We measured 11 circulating angiogenesis-associated molecules in cancer patients before and after local treatment. The purpose of our study was to screen for possible relationships among the different molecules and between individual molecules and tumor burden. We measured VEGF-A, PlGF, SCF, MMP-9, EDB+ -fibronectin, sVEGFR-2, sVEGFR-1, salphaVbeta3, sTie-2, IL-8 and CRP in the blood of 22 healthy volunteers, 17 early breast, 17 early colorectal, and 8 advanced sarcoma/melanoma cancer patients. Breast cancer patients had elevated levels of VEGF-A and sTie-2, colorectal cancer patients of VEGF-A, MMP-9, sTie-2, IL-8 and CRP, and melanoma/sarcoma patients of sVEGFR-1. salphaVbeta3 was decreased in colorectal cancer patients. A correlation between VEGF-A and MMP-9 was found. After tumor removal, MMP-9 and salphaVbeta3 significantly decreased in breast and CRP in colorectal cancer, whereas sVEGFR-1 increased in colorectal cancer patients. In sarcoma/melanoma patients treated regionally with TNF and chemotherapy we observed a rise in VEGF-A, SCF, VEGFR-2, MMP-9, Tie-2 and CRP, a correlation between CRP and IL-8, and a decreased in sVEGFR-1 levels. In conclusion, among all factors measured, only VEGF-A and MMP-9 consistently correlated to each other, elevated CRP levels were associated with tumor burden, whereas sVEGF-R1 increased after tumor removal in colorectal cancer. Treatment with chemotherapy and TNF induced changes consistent with an angiogenic switch. These results warrant a prospective study to compare the effect of surgical tumor removal vs. chemotherapy on some of these markers and to evaluate their prognostic/predictive value.

Population pharmacokinetic analysis and pharmacogenetics of raltegravir in HIV-positive and healthy individuals.

The objectives of this study were to characterize raltegravir (RAL) population pharmacokinetics in HIV-positive (HIV(+)) and healthy individuals, identify influential factors, and search for new candidate genes involved in UDP glucuronosyltransferase (UGT)-mediated glucuronidation. The pharmacokinetic analysis was performed with NONMEM. Genetic association analysis was performed with PLINK using the relative bioavailability as the phenotype. Simulations were performed to compare once- and twice-daily regimens. A 2-compartment model with first-order absorption adequately described the data. Atazanavir, gender, and bilirubin levels influenced RAL relative bioavailability, which was 30% lower in HIV(+) than in healthy individuals. UGT1A9*3 was the only genetic variant possibly influencing RAL pharmacokinetics. The majority of RAL pharmacokinetic variability remains unexplained by genetic and nongenetic factors. Owing to the very large variability, trough drug levels might be very low under the standard dosing regimen, raising the question of a potential relevance of therapeutic drug monitoring of RAL in some situations.

From Support to Control : A Configurational Perspective on Conjugal Quality

The topic of conjugal quality provides an empirical illustration of the relevance of the configurational perspective on families. Based on a longitudinal sample of 1,534 couples living in Switzerland drawn from the study "Social Stratification, Cohesion and Conflict in Contemporary Families", we show that various types of interdependencies with relatives and friends promote distinct conflict management strategies for couples as well as unequal levels of conjugal quality. We find that configurations characterized by supportive and non-interfering relationships with relatives and friends for both partners are associated with higher conjugal quality, while configurations characterized by interference are associated with lower conjugal quality.

Chromosomal rearrangements and genetic structure at different evolutionary levels of the Sorex araneus group.

Robertsonian (Rb) fusions received large theoretical support for their role in speciation, but empirical evidence is often lacking. Here, we address the role of Rb rearrangements on the genetic differentiation of the karyotypically diversified group of shrews, Sorex araneus. We compared genetic structure between 'rearranged' and 'common' chromosomes in pairwise comparisons of five karyotypic taxa of the group. Considering all possible comparisons, we found a significantly greater differentiation at rearranged chromosomes, supporting the role of chromosomal rearrangements in the general genetic diversification of this group. Intertaxa structure and distance were larger across rearranged chromosomes for most of the comparisons, although these differences were not significant. This last result could be explained by the large variance observed among microsatellite-based estimates. The differences observed among the pairs of taxa analysed support the role of both the hybrid karyotypic complexity and the level of evolutionary divergence.

Evolutionary origin and functions of retrogene introns.

Retroposed genes (retrogenes) originate via the reverse transcription of mature messenger RNAs from parental source genes and are therefore usually devoid of introns. Here, we characterize a particular set of mammalian retrogenes that acquired introns upon their emergence and thus represent rare cases of intron gain in mammals. We find that although a few retrogenes evolved introns in their coding or 3' untranslated regions (untranslated region, UTR), most introns originated together with untranslated exons in the 5' flanking regions of the retrogene insertion site. They emerged either de novo or through fusions with 5' UTR exons of host genes into which the retrogenes inserted. Generally, retrogenes with introns display high transcription levels and show broader spatial expression patterns than other retrogenes. Our experimental expression analyses of individual intron-containing retrogenes show that 5' UTR introns may indeed promote higher expression levels, at least in part through encoded regulatory elements. By contrast, 3' UTR introns may lead to downregulation of expression levels via nonsense-mediated decay mechanisms. Notably, the majority of retrogenes with introns in their 5' flanks depend on distant, sometimes bidirectional CpG dinucleotide-enriched promoters for their expression that may be recruited from other genes in the genomic vicinity. We thus propose a scenario where the acquisition of new 5' exon-intron structures was directly linked to the recruitment of distant promoters by these retrogenes, a process potentially facilitated by the presence of proto-splice sites in the genomic vicinity of retrogene insertion sites. Thus, the primary role and selective benefit of new 5' introns (and UTR exons) was probably initially to span the often substantial distances to potent CpG promoters driving retrogene transcription. Later in evolution, these introns then obtained additional regulatory roles in fine tuning retrogene expression levels. Our study provides novel insights regarding mechanisms underlying the origin of new introns, the evolutionary relevance of intron gain, and the origin of new gene promoters.

Renal and neurohormonal responses to increasing levels of lower body negative pressure in men.

BACKGROUND: The stimulation of efferent renal sympathetic nerve activity induces sequential changes in renin secretion, sodium excretion, and renal hemodynamics that are proportional to the magnitude of the stimulation of sympathetic nerves. This study in men investigated the sequence of the changes in proximal and distal renal sodium handling, renal and systemic hemodynamics, as well as the hormonal profile occurring during a sustained activation of the sympathetic nervous system induced by various levels of lower body negative pressure (LBNP). METHODS: Ten healthy subjects were submitted to three levels of LBNP ranging between 0 and -22.5 mm Hg for one hour according to a triple crossover design, with a minimum of five days between each level of LBNP. Systemic and renal hemodynamics, renal water and sodium handling (using the endogenous lithium clearance technique), and the neurohormonal profile were measured before, during, and after LBNP. RESULTS: LBNP (0 to -22.5 mm Hg) induced an important hormonal response characterized by a significant stimulation of the sympathetic nervous system and gradual activations of the vasopressin and the renin-angiotensin systems. LBNP also gradually reduced water excretion and increased urinary osmolality. A significant decrease in sodium excretion was apparent only at -22.5 mm Hg. It was independent of any change in the glomerular filtration rate and was mediated essentially by an increased sodium reabsorption in the proximal tubule (a significant decrease in lithium clearance, P < 0.05). No significant change in renal hemodynamics was found at the tested levels of LBNP. As observed experimentally, there appeared to be a clear sequence of responses to LBNP, the neurohormonal response occurring before the changes in water and sodium excretion, these latter preceding any change in renal hemodynamics. CONCLUSIONS: These data show that the renal sodium retention developing during LBNP, and thus sympathetic nervous stimulation, is due mainly to an increase in sodium reabsorption by the proximal segments of the nephron. Our results in humans also confirm that, depending on its magnitude, LBNP leads to a step-by-step activation of neurohormonal, renal tubular, and renal hemodynamic responses.

Correlations between imatinib pharmacokinetics, pharmacodynamics, adherence, and clinical response in advanced metastatic gastrointestinal stromal tumor (GIST): An emerging role for drug blood level testing?

Imatinib is the standard of care for patients with advanced metastatic gastrointestinal stromal tumors (GIST), and is also approved for adjuvant treatment in patients at substantial risk of relapse. Studies have shown that maximizing benefit from imatinib depends on long-term administration at recommended doses. Pharmacokinetic (PK) and pharmacodynamic factors, adherence, and drug-drug interactions can affect exposure to imatinib and impact clinical outcomes. This article reviews the relevance of these factors to imatinib's clinical activity and response in the context of what has been demonstrated in chronic myelogenous leukemia (CML), and in light of new data correlating imatinib exposure to response in patients with GIST. Because of the wide inter-patient variability in drug exposure with imatinib in both CML and GIST, blood level testing (BLT) may play a role in investigating instances of suboptimal response, unusually severe toxicities, drug-drug interactions, and suspected non-adherence. Published clinical data in CML and in GIST were considered, including data from a PK substudy of the B2222 trial correlating imatinib blood levels with clinical responses in patients with GIST. Imatinib trough plasma levels <1100ng/mL were associated with lower rates of objective response and faster development of progressive disease in patients with GIST. These findings have been supported by other analyses correlating free imatinib (unbound) levels with response. These results suggest a future application for imatinib BLT in predicting and optimizing therapeutic response. Nevertheless, early estimates of threshold imatinib blood levels must be confirmed prospectively in future studies and elaborated for different patient subgroups.

Variability of voriconazole plasma levels measured by new high-performance liquid chromatography and bioassay methods.

Voriconazole (VRC) is a broad-spectrum antifungal triazole with nonlinear pharmacokinetics. The utility of measurement of voriconazole blood levels for optimizing therapy is a matter of debate. Available high-performance liquid chromatography (HPLC) and bioassay methods are technically complex, time-consuming, or have a narrow analytical range. Objectives of the present study were to develop new, simple analytical methods and to assess variability of voriconazole blood levels in patients with invasive mycoses. Acetonitrile precipitation, reverse-phase separation, and UV detection were used for HPLC. A voriconazole-hypersusceptible Candida albicans mutant lacking multidrug efflux transporters (cdr1Delta/cdr1Delta, cdr2Delta/cdr2Delta, flu1Delta/flu1Delta, and mdr1Delta/mdr1Delta) and calcineurin subunit A (cnaDelta/cnaDelta) was used for bioassay. Mean intra-/interrun accuracies over the VRC concentration range from 0.25 to 16 mg/liter were 93.7% +/- 5.0%/96.5% +/- 2.4% (HPLC) and 94.9% +/- 6.1%/94.7% +/- 3.3% (bioassay). Mean intra-/interrun coefficients of variation were 5.2% +/- 1.5%/5.4% +/- 0.9% and 6.5% +/- 2.5%/4.0% +/- 1.6% for HPLC and bioassay, respectively. The coefficient of concordance between HPLC and bioassay was 0.96. Sequential measurements in 10 patients with invasive mycoses showed important inter- and intraindividual variations of estimated voriconazole area under the concentration-time curve (AUC): median, 43.9 mg x h/liter (range, 12.9 to 71.1) on the first and 27.4 mg x h/liter (range, 2.9 to 93.1) on the last day of therapy. During therapy, AUC decreased in five patients, increased in three, and remained unchanged in two. A toxic encephalopathy probably related to the increase of the VRC AUC (from 71.1 to 93.1 mg x h/liter) was observed. The VRC AUC decreased (from 12.9 to 2.9 mg x h/liter) in a patient with persistent signs of invasive aspergillosis. These preliminary observations suggest that voriconazole over- or underexposure resulting from variability of blood levels might have clinical implications. Simple HPLC and bioassay methods offer new tools for monitoring voriconazole therapy.

Significance of serum adiponectin levels in patients with chronic liver disease.

Adiponectin, which plays a pivotal role in metabolic liver diseases, is reduced in concentration in patients with NASH (non-alcoholic steatohepatitis). The aim of the present study was to determine adiponectin concentrations in patients with different forms and stages of chronic liver diseases. Serum adiponectin concentrations were measured in 232 fasting patients with chronic liver disease: 64 with NAFLD (non-alcoholic fatty liver disease), 123 with other chronic liver disease (e.g. viral hepatitis, n=71; autoimmune disease, n=18; alcohol-induced liver disease, n=3; or elevated liver enzymes of unknown origin, n=31) and 45 with cirrhosis. Circulating adiponectin levels were significantly lower in patients with NAFLD in comparison with patients with other chronic liver disease (4.8+/-3.5 compared with 10.4+/-6.3 microg/ml respectively; P<0.0001). Circulating adiponectin levels were significantly higher in patients with cirrhosis in comparison with patients without cirrhosis (18.6+/-14.5 compared with 8.4+/-6.1 microg/ml respectively; P<0.0001). Adiponectin concentrations correlated negatively with body weight (P<0.001), serum triacylglycerols (triglycerides) (P<0.001) and, in women, with BMI (body mass index) (P<0.001). Adiponectin concentrations correlated positively with serum bile acids (P<0.001), serum hyaluronic acid (P<0.001) and elastography values (P<0.001). Adiponectin levels were decreased in patients with NAFLD. In conclusion, adiponectin levels correlate positively with surrogate markers of hepatic fibrosis (transient elastography, fasting serum bile acids and hyaluronate) and are significantly elevated in cases of cirrhosis.