Impact of antiviral preventive strategies on the incidence and outcomes of cytomegalovirus disease in solid organ transplant recipients.

We assessed the impact of antiviral prophylaxis and preemptive therapy on the incidence and outcomes of cytomegalovirus (CMV) disease in a nationwide prospective cohort of solid organ transplant recipients. Risk factors associated with CMV disease and graft failure-free survival were analyzed using Cox regression models. One thousand two hundred thirty-nine patients transplanted from May 2008 until March 2011 were included; 466 (38%) patients received CMV prophylaxis and 522 (42%) patients were managed preemptively. Overall incidence of CMV disease was 6.05% and was linked to CMV serostatus (D+/R- vs. R+, hazard ratio [HR] 5.36 [95% CI 3.14-9.14], pâeuro0/00<âeuro0/000.001). No difference in the incidence of CMV disease was observed in patients receiving antiviral prophylaxis as compared to the preemptive approach (HR 1.16 [95% CI 0.63-2.17], pâeuro0/00=âeuro0/000.63). CMV disease was not associated with a lower graft failure-free survival (HR 1.27 [95% CI 0.64-2.53], pâeuro0/00=âeuro0/000.50). Nevertheless, patients followed by the preemptive approach had an inferior graft failure-free survival after a median of 1.05 years of follow-up (HR 1.63 [95% CI 1.01-2.64], pâeuro0/00=âeuro0/000.044). The incidence of CMV disease in this cohort was low and not influenced by the preventive strategy used. However, patients on CMV prophylaxis were more likely to be free from graft failure.

Impact of enterococcal colonization and infection in solid organ transplantation recipients from the Swiss Transplant Cohort Study.

BACKGROUND: The burden of enterococcal infections has increased over the last decades with vancomycin-resistant enterococci (VRE) being a major health problem. Solid organ transplantation is considered as a risk factor. However, little is known about the relevance of enterococci in solid organ transplantation recipients in areas with a low VRE prevalence. METHODS: We examined the epidemiology of enterococcal events in patients followed in the Swiss Transplant Cohort Study between May 2008 and September 2011 and analyzed risk factors for infection, aminopenicillin resistance, treatment, and outcome. RESULTS: Of the 1234 patients, 255 (20.7%) suffered from 392 enterococcal events (185 [47.2%] infections, 205 [52.3%] colonizations, and 2 events with missing clinical information). Only 2 isolates were VRE. The highest infection rates were found early after liver transplantation (0.24/person-year) consisting in 58.6% of Enterococcus faecium. The highest colonization rates were documented in lung transplant recipients (0.33/person-year), with 46.5% E. faecium. Age, prophylaxis with a betalactam antibiotic, and liver transplantation were significantly associated with infection. Previous antibiotic treatment, intensive care unit stay, and lung transplantation were associated with aminopenicillin resistance. Only 4/205 (2%) colonization events led to an infection. Adequate treatment did not affect microbiological clearance rates. Overall mortality was 8%; no deaths were attributable to enterococcal events. CONCLUSIONS: Enterococcal colonizations and infections are frequent in transplant recipients. Progression from colonization to infection is rare. Therefore, antibiotic treatment should be used restrictively in colonization. No increased mortality because of enterococcal infection was noted.

Cell-mediated immunity to predict cytomegalovirus disease in high-risk solid organ transplant recipients.

Late-onset cytomegalovirus (CMV) disease commonly occurs after discontinuation of antiviral prophylaxis. We determined the utility of testing CD8+ T-cell response against CMV as a predictor of late-onset CMV disease after a standard course of antiviral prophylaxis. Transplant patients at high-risk for CMV disease were enrolled. CD8+ T-cell-mediated immunity (CMI) was tested using the QuantiFERON-CMV assay at baseline, 1, 2 and 3 months posttransplant by measurement of interferon-gamma response to whole blood stimulation with a 21-peptide pool. The primary outcome was the ability of CMI testing to predict CMV disease in the first 6 months posttransplant. There were 108 evaluable patients (D+/R+ n = 39; D-/R+ n = 34; D+/R- n = 35) of whom 18 (16.7%) developed symptomatic CMV disease. At the end of prophylaxis, CMI was detectable in 38/108 (35.2%) patients (cutoff 0.1 IU/mL interferon-gamma). CMV disease occurred in 2/38 (5.3%) patients with a detectable interferon-gamma response versus 16/70 (22.9%) patients with a negative response; p = 0.038. In the subgroup of D+/R- patients, CMV disease occurred in 1/10 (10.0%) patients with a detectable interferon-gamma response (cutoff 0.1 IU/mL) versus 10/25 (40.0%) patients with a negative CMI, p = 0.12. Monitoring of CMI may be useful for predicting late-onset CMV disease.

High-throughput and sensitive quantitation of plasma catecholamines by ultraperformance liquid chromatography-tandem mass spectrometry using a solid phase microwell extraction plate.

Plasma catecholamines provide a reliable biomarker of sympathetic activity. The low circulating concentrations of catecholamines and analytical interferences require tedious sample preparation and long chromatographic runs to ensure their accurate quantification by HPLC with electrochemical detection. Published or commercially available methods relying on solid phase extraction technology lack sensitivity or require derivatization of catecholamine by hazardous reagents prior to tandem mass spectrometry (MS) analysis. Here, we manufactured a novel 96-well microplate device specifically designed to extract plasma catecholamines prior to their quantification by a new and highly sensitive ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method. Processing time, which included sample purification on activated aluminum oxide and elution, is less than 1 h per 96-well microplate. The UPLC-MS/MS analysis run time is 2.0 min per sample. This UPLC-MS/MS method does not require a derivatization step, reduces the turnaround time by 10-fold compared to conventional methods used for routine application, and allows catecholamine quantification in reduced plasma sample volumes (50-250 μL, e.g., from children and mice).

Impact of genetic polymorphisms in cytomegalovirus glycoprotein B on outcomes in solid organ transplant recipients with cytomegalovirus disease

Le cytomégalovirus (CMV) est le pathogène viral le plus important après transplantation d'organe. Le risque de développer une maladie à CMV chez les patients transplantés dépend d'une combinaison de facteurs de l'hôte et de facteurs viraux. Par exemple, il est bien établi que le status sérologique à CMV du donneur et du receveur est un facteur de risque très important pour développer une maladie à CMV, notamment chez le sous-groupe de patients donneurs positifs / receveurs négatifs (D+/R-). Par contre, il n'est pas complètement élucidé si des polymorphismes viraux spécifiques peuvent influencer l'évolution en la réponse thérapeutique chez des patients avec une infection à CMV. Nous avons évalué le rôle des différents génotypes de la glycoprotéine Β (gB) du CMV sur l'évolution clinique et virologique de la maladie à CMV chez des patients transplantés d'organe sous traitement antiviral.¦Pour ce faire, nous avons étudié 239 patients transplantés d'organe inclus dans une étude multicentrique évaluant deux médicaments antiviraux utilisés comme traitement de la maladie à CMV. Le génotypage de la gB du CMV a été réalisé en utilisant une PCR quantitative en temps réel au début du traitement antiviral. Les polymorphismes de la gB du CMV permettent la discrimination de quatre génotypes distincts (gBl, gB2, gB3 et gB4). Nous avons défini une infection mixte comme la présence simultanée de plus d'un génotype chez un patient avec maladie à CMV.¦La prévalence des différents génotypes de la gB a été 26% pour la gBl, 10% pour la gB2, 10% pour la gB3, et 5% pour la gB4, alors que les infections mixtes étaient présentes dans 49% des cas. Les patients D+/R+ présentaient plus fréquemment une infection mixte que les patients D+/R- (40% vs 12%, ρ <0.001). Les patients avec une infection mixte présentaient une médiane de la charge virale à CMV plus élevée et un temps d'éradication virale plus long comparé à des patients avec une infection par un génotype unique (p=0.005 et p=0.026, respectivement). Dans un modèle multivarié, les infections mixtes étaient un prédicteur important de l'échec de l'éradication de virus au jour 21 du début du traitement antiviral (rapport de côtes entre l'infection mixte vs. infection par un génotype unique = 2.66, intervalle de confiance à 95%= 1.31 à 5.38, p= 0.007). Aucun effet du génotype gB sur le développement d'une récidive clinique ou virologique de l'infection à CMV a été observé.¦Ces résultats indiquent qu'aucun génotype spécifique de la gB ne semble conférer un avantage de virulence au CMV. Cependant, les infections mixtes avec plusieurs génotypes de la gB sont associées à une charge virale plus élevée et à un retard de l'éradication virale suite au traitement antiviral.

The definition of quality of life in solid organ transplantation: A psychological qualitative model

Quality of life has been extensively discussed in acute and chronic illnesses. However a dynamic model grounded in the experience of patients in the course of transplantation has not been to our knowledge developed. In a qualitative longitudinal study, patients awaiting solid organ transplantation participated in semi-structured interviews: Exploring topics pre-selected on previous research literature review. Creative interview was privileged, open to themes patients would like to discuss at the different steps of the transplantation process. A qualitative thematic and reflexive analysis was performed, and a model of the dimensions constitutive of quality of life from the perspective of the patients was elaborated. Quality of life is not a stable construct in a long lasting illness-course, but evolves with illness constraints, treatments and outcomes. Dimensions constitutive of quality of life are defined, each of them containing different sub-categories depending on the organ related illness co-morbidities and the stage of illness-course.

KIR-associated protection from CMV replication requires pre-existing immunity: a prospective study in solid organ transplant recipients.

Previous studies have associated activating Killer cell Immunoglobulin-like Receptor (KIR) genes with protection from cytomegalovirus (CMV) replication after organ transplantation. Whether KIR-associated protection is operating in the context of primary infection, re-activation, or both, remains unknown. Here we correlated KIR genotype and CMV serostatus at the time of transplantation with rates of CMV viremia in 517 heart (n=57), kidney (n=223), liver (n=165) or lung (n=72) allograft recipients reported to the Swiss Transplant Cohort Study. Across the entire cohort we found B haplotypes-which in contrast to A haplotypes may contain multiple activating KIR genes-to be protective in the most immunosuppressed patients (receiving anti-thymocyte globulin induction and intensive maintenance immunosuppression) (hazard ratio after adjustment for covariates 0.46, 95% confidence interval 0.29-0.75, P=0.002). Notably, a significant protection was detected only in recipients who were CMV-seropositive at the time of transplantation (HR 0.45, 95% CI 0.26-0.77, P=0.004), but not in CMV seronegative recipients (HR 0.59, 95% CI 0.22-1.53, P=0.28). These data indicate a prominent role for KIR-and presumably natural killer (NK) cells-in the control of CMV replication in CMV seropositive organ transplant recipients treated with intense immunosuppression.

Pharmacokinetic and pharmacodynamic assessment of valganciclovir in solid organ transplant recipients

RESUME : Valganciclovir (Valcyte®) is an orally administered ester prodrug of the standard anticytomegalovirus (CMV) drug ganciclovir. This drug enabled an important reduction of the burden of CMV morbidity and mortality in solid organ transplant recipients. Prevention of CMV infection and treatment of CMV disease requires drug administration during many weeks. Oral drug administration is therefore convenient. Valganciclovir has been developed to overcome the poor oral availability of ganciclovir, which limits its concentration exposure after oral administration and thus its efficacy. This prodrug crosses efficiently the intestinal barrier, is then hydrolyzed into ganciclovir, providing exposure similar to intravenous ganciclovir. Valganciclovir is now preferred for the prophylaxis and treatment of CMV infection in solid organ transplant recipients. Nevertheless, adequate dosage adjustment is necessary to optimize its use, avoiding either insufficient or exaggerate exposure related to differences in its pharmacokinetic profile between patients. The main goal of this thesis was to better describe the pharmacokinetic and pharmacodynamic profile of valganciclovir in solid organ transplant recipients, to assess their reproducibility and their predictability, and thus to evaluate the current recommendations for valganciclovir dosage adjustment and the potential contribution of routine therapeutic drug monitoring (TDM) to patients' management. A total of 437 ganciclovir plasma concentration data from 65 transplant patients (41 kidney, 12 lung, 10 heart and 2 liver recipients, 58 under oral valganciclovir prophylaxis, 8 under oral valganciclovir treatment and 2 under intravenous ganciclovir) were measured using a validated chromatographic method (HPLC) developed for this study. The results were analyzed by non-linear mixed effect modeling (NONMEM). A two-compartment model with first-order absorption appropriately described the data. Systemic clearance was markedly influenced by GFR, with further differences between graft types and sex (CL/GFR = 1.7 in kidney, 0.9 in heart and 1.2 in lung and liver recipients) with interpatient variability (CV%) of 26% and interoccasion variability of 12%. Body weight and sex influenced central volume of distribution (V1 = 0.34 l/kg in males and 0.27 l/kg in females) with an interpatient variability of 20%. Residual intrapatient variability was 21 %. No significant drug interaction influenced GCV disposition. VGC prophylactic efficacy and tolerability were good, without detectable dependence on GCV profile. In conclusion, this analysis highlights the importance of thorough adjustment of VGC dosage to renal function and body weight. Considering the good predictability and reproducibility of GCV profile after oral VGC in solid organ transplant recipients, routine TDM does not appear to be clinically indicated. However, GCV plasma measurement may still be helpful in specific clinical situations such as documentation of appropriate exposure in patients with potentially compromised absorption, or lack of response to CMV disease treatment, or under renal replacement therapy. RESUME : Le valganciclovir (Valcyte®) est un promédicament oral du ganciclovir qui est un anti-infectieux de référence contre les infections à cytomegalovirus (CMV). Cet antiviral a permis de réduire les effets délétères de cette infection jusqu'ici responsable d'une importante morbidité et mortalité chez les transplantés d'organe. La prévention et le traitement de l'infection à CMV sont donc nécessaires mais requièrent l'administration d'un agent antiviral sur une longue période. Un médicament administré par voie orale représente donc un avantage évident. Le valganciclovir a été développé dans le but d'améliorer la faible absorption orale du ganciclovir, et donc son efficacité. Cet ester valylique du ganciclovir traverse plus facilement la barrière gastro-intestinale, puis est hydrolysé en ganciclovir dans la circulation sanguine, produisant une exposition comparable à celle d'une perfusion intraveineuse de ganciclovir. De ce fait, le valganciclovir est devenu largement utilisé pour la prophylaxie mais aussi le traitement de l'infection à CMV. Néanmoins une utilisation optimale de ce nouveau médicament nécessite de bonnes connaissances sur son profil pharmacocinétique afin d'établir un schéma de dose adapté pour éviter tant une surexposition qu'une sous-exposition résultant des différences d'élimination entre les patients. Le but de cette thèse a été d'étudier le profil pharmacocinétique et pharmacodynamique du valganciclovir chez les transplantés d'organe ainsi que sa reproductibilité et sa prédictibilité. Il s'agissait d'apprécier de manière critique le schéma actuellement recommandé pour l'adaptation des doses de valganciclovir, mais aussi la contribution éventuelle d'un suivi des concentrations sanguines en routine. Un total de 437 taux sanguins de ganciclovir ont été mesurés, provenant de 65 patients transplantés d'organe (41 rénaux, 12 pulmonaires, 10 cardiaques et 2 hépatiques, 58 sous une prophylaxie orale de valganciclovir, 8 sous un traitement de valganciclovir et 2 sous un traitement intraveineux). Une méthode de chromatographie liquide à haute performance a été développée et validée pour cette étude. Les résultats ont été ensuite analysés par modélisation non linéaire à effets mixtes (NONMEM). Un modèle à deux compartiments avec absorption de premier ordre a permis de décrire les données. La clairance systémique était principalement influencée par le débit de filtration glomérulaire (GFR), avec une différence entre les types de greffe et les sexes (CL/GFR = 1.7 chez les greffés rénaux, 0.9 pour les greffés cardiaques et 1.2 pour le groupe des greffés pulmonaires et hépatiques) avec un variabilité inter-individuelle de 26% (CV%) et une variabilité inter-occasion de 12%. Le poids corporel ainsi que le sexe avaient une influence sur le volume central de distribution (V1 = 0.34 l/kg chez les hommes et 0.27 l/kg chez les femmes) avec une variabilité inter-individuelle de 20%. La variabilité intra-individuelle résiduelle était de 21 %. Aucune interaction médicamenteuse n'a montré d'influence sur le profil du ganciclovir. La prophylaxie avec le valganciclovir s'est révélée efficace et bien tolérée. En conclusion, cette analyse souligne l'importance d'une adaptation de la dose du valganciclovir à la fonction rénale et au poids du patient. Au vu de la bonne reproductibilité et prédictibilité du profil pharmacocinétique du ganciclovir chez les patients transplantés recevant du valganciclovir, un suivi des concentrations sanguines en routine ne semble pas cliniquement indiqué. Néanmoins, la mesure des taux plasmatiques de ganciclovir peut être utile dans certaines situations particulières, comme la vérification d'une exposition appropriée chez des patients susceptibles d'absorption insuffisante, ou ne répondant pas au traitement d'une infection à CMV ou encore sous épuration extra-rénale. RESUME LARGE PUBLIC : Le valganciclovir est un précurseur capable de libérer du ganciclovir, récemment développé pour améliorer la faible absorption orale de ce dernier. Une fois le valganciclovir absorbé, le ganciclovir libéré dans la circulation sanguine devient efficace contre les infections à cytomégalovirus. Ce virus largement répandu est responsable de maladies insidieuses et parfois graves chez les personnes présentant une baisse des défenses immunitaires, comme les greffés d'organe recevant un traitement anti-rejet. Le ganciclovir est administré pendant plusieurs mois consécutifs soit pour prévenir une infection après la transplantation, soit pour traiter une infection déclarée. La facilité d'administration du valganciclovir par voie orale représente un avantage sur une administration du ganciclovir par perfusion, qui nécessite une hospitalisation. Toutefois, la voie orale peut être une source supplémentaire de variabilité chez les patients, avec un impact potentiel sur l'efficacité ou la toxicité du médicament. Le but de cette étude a été - de décrire le devenir de ce médicament dans le corps humain (dont l'étude relève de la discipline de la pharmacocinétique) - de définir les facteurs cliniques pouvant expliquer les différences de concentration sanguine observées entre les patients sous une posologie donnée - d'explorer les relations entre les concentrations du médicament dans le sang et son efficacité ou la survenue d'effets indésirables (dont l'étude relève de la discipline de la pharmacodynamie). Cette étude a nécessité le développement et la validation, d'une méthode d'analyse pour mesurer la concentration sanguine du ganciclovir, puis son application à 437 échantillons provenant de 65 patients transplantés d'organe solide (41 rénaux, 12 pulmonaires, 10 cardiaques et 2 hépatiques) recevant du valganciclovir. Les résultats des mesures effectuées ont été analysés à l'aide d'un outil mathématique afin d'élaborer un modèle du devenir du médicament dans le sang chez chaque patient et à chaque occasion. Cette étude a permis d'évaluer chez des patients recevant le valganciclovir, la vitesse à laquelle l'organisme absorbe, distribue, puis élimine le médicament. La vitesse d'élimination dépendait étroitement de la fonction rénale, du type de greffe et du sexe alors que la distribution dépendait du poids et du sexe du patient. La variabilité non expliquée par ces facteurs cliniques était modérée et vraisemblablement sans conséquence clinique évidente soit sur l'efficacité ou la tolérance, qui se révèlent très satisfaisantes chez les patients de l'étude. Les observations n'ont pas révélé de relation entre les concentrations de médicament et l'efficacité thérapeutique ou la survenue d'effets indésirables, confirmant que les doses relativement faibles utilisées dans notre collectif de patients suffisaient à produire une exposition reproductible à des concentrations adéquates. En conclusion, le profil (et par conséquent l'absorption) du valganciclovir chez les patients transplantés semble bien prédictible après une adaptation de la dose à la fonction rénale et au poids du patient. Un contrôle systématique des concentrations sanguines n'est probablement pas indiqué en routine, mais cette mesure peut présenter un intérêt dans certaines conditions particulières.

Detection of metabolite induction in fungal co-cultures on solid media by high-throughput differential ultra-high pressure liquid chromatography-time-of-flight mass spectrometry fingerprinting.

Access to new biological sources is a key element of natural product research. A particularly large number of biologically active molecules have been found to originate from microorganisms. Very recently, the use of fungal co-culture to activate the silent genes involved in metabolite biosynthesis was found to be a successful method for the induction of new compounds. However, the detection and identification of the induced metabolites in the confrontation zone where fungi interact remain very challenging. To tackle this issue, a high-throughput UHPLC-TOF-MS-based metabolomic approach has been developed for the screening of fungal co-cultures in solid media at the petri dish level. The metabolites that were overexpressed because of fungal interactions were highlighted by comparing the LC-MS data obtained from the co-cultures and their corresponding mono-cultures. This comparison was achieved by subjecting automatically generated peak lists to statistical treatments. This strategy has been applied to more than 600 co-culture experiments that mainly involved fungal strains from the Fusarium genera, although experiments were also completed with a selection of several other filamentous fungi. This strategy was found to provide satisfactory repeatability and was used to detect the biomarkers of fungal induction in a large panel of filamentous fungi. This study demonstrates that co-culture results in consistent induction of potentially new metabolites.

Assessment of cytomegalovirus-specific cell-mediated immunity for the prediction of cytomegalovirus disease in high-risk solid-organ transplant recipients: a multicenter cohort study.

BACKGROUND: Cytomegalovirus (CMV) disease remains an important problem in solid-organ transplant recipients, with the greatest risk among donor CMV-seropositive, recipient-seronegative (D(+)/R(-)) patients. CMV-specific cell-mediated immunity may be able to predict which patients will develop CMV disease. METHODS: We prospectively included D(+)/R(-) patients who received antiviral prophylaxis. We used the Quantiferon-CMV assay to measure interferon-γ levels following in vitro stimulation with CMV antigens. The test was performed at the end of prophylaxis and 1 and 2 months later. The primary outcome was the incidence of CMV disease at 12 months after transplant. We calculated positive and negative predictive values of the assay for protection from CMV disease. RESULTS: Overall, 28 of 127 (22%) patients developed CMV disease. Of 124 evaluable patients, 31 (25%) had a positive result, 81 (65.3%) had a negative result, and 12 (9.7%) had an indeterminate result (negative mitogen and CMV antigen) with the Quantiferon-CMV assay. At 12 months, patients with a positive result had a subsequent lower incidence of CMV disease than patients with a negative and an indeterminate result (6.4% vs 22.2% vs 58.3%, respectively; P < .001). Positive and negative predictive values of the assay for protection from CMV disease were 0.90 (95% confidence interval [CI], .74-.98) and 0.27 (95% CI, .18-.37), respectively. CONCLUSIONS: This assay may be useful to predict if patients are at low, intermediate, or high risk for the development of subsequent CMV disease after prophylaxis. CLINICAL TRIALS REGISTRATION: NCT00817908.

L'hypertension chez les transplantés d'organes [Hypertension in solid organ transplants].

Hypertension is highly prevalent in transplantation and affects all type of organs. With the introduction of calcineurin inhibitors as immunosuppressive drugs, acute allograft rejection episodes have been significantly reduced and hence patient and allograft survival rates have dramatically improved. However, cardiovascular complications have become an important cause of morbidity and mortality. Treating cardiovascular risk factors such as diabetes, dyslipidemia and hypertension seems obvious, however in this population, there is little evidence for specific blood pressure targets, or for the best strategy to achieve blood pressure control. The aim of this article is to review the epidemiology and physiopathology of hypertension in transplant recipients as well as its clinical management.

Preemptive treatment approach to cytomegalovirus (CMV) infection in solid organ transplant patients: relationship between compliance with the guidelines and prevention of CMV morbidity.

Cytomegalovirus (CMV) remains a major cause of morbidity in solid organ transplant patients. In order to reduce CMV morbidity, we designed a program of routine virological monitoring that included throat and urine CMV shell vial culture, along with peripheral blood leukocyte (PBL) shell vial quantitative culture for 12 weeks post-transplantation, as well as 8 weeks after treatment for acute rejection. The program also included preemptive ganciclovir treatment for those patients with the highest risk of developing CMV disease, i.e., with either high-level viremia (>10 infectious units [IU]/106 PBL) or low-level viremia (<10 IU/106 PBL) and either D+/R- CMV serostatus or treatment for graft rejection. During 1995-96, 90 solid organ transplant recipients (39 kidneys, 28 livers, and 23 hearts) were followed up. A total of 60 CMV infection episodes occurred in 45 patients. Seventeen episodes were symptomatic. Of 26 episodes managed according to the program, only 4 presented with CMV disease and none died. No patient treated preemptively for asymptomatic infection developed disease. In contrast, among 21 episodes managed in non-compliance with the program (i.e., the monitoring was not performed or preemptive treatment was not initiated despite a high risk of developing CMV disease), 12 episodes turned into symptomatic infection (P=0.0048 compared to patients treated preemptively), and 2 deaths possibly related to CMV were recorded. This difference could not be explained by an increased proportion of D+/R- patients or an increased incidence of rejection among patients with episodes treated in non-compliance with the program. Our data identify compliance with guidelines as an important factor in effectively reducing CMV morbidity through preemptive treatment, and suggest that the complexity of the preemptive approach may represent an important obstacle to the successful prevention of CMV morbidity by this approach in the regular healthcare setting.

Novel 2-[(benzylamino)methyl]pyrrolidine-3,4-diol derivatives as alpha-mannosidase inhibitors and with antitumor activities against hematological and solid malignancies.

Novel alpha-mannosidase inhibitors of the type (2R,3R,4S)-2-({[(1R)-2-hydroxy-1-arylethyl]amino}methyl)pyrrolidine-3,4-diol have been prepared and assayed for their anticancer activities. Compound 30 with the aryl group=4-trifluoromethylbiphenyl inhibits the proliferation of primary cells and cell lines of different origins, irrespective of Bcl-2 expression levels, inducing a G2/Mcell cycle arrest and by modification of genes involved in cell cycle progression and survival.

IL1B and DEFB1 Polymorphisms Increase Susceptibility to Invasive Mold Infection After Solid-Organ Transplantation.

BACKGROUND: Single-nucleotide polymorphisms (SNPs) in immune genes have been associated with susceptibility to invasive mold infection (IMI) among hematopoietic stem cell but not solid-organ transplant (SOT) recipients. METHODS: Twenty-four SNPs from systematically selected genes were genotyped among 1101 SOT recipients (715 kidney transplant recipients, 190 liver transplant recipients, 102 lung transplant recipients, 79 heart transplant recipients, and 15 recipients of other transplants) from the Swiss Transplant Cohort Study. Association between SNPs and the end point were assessed by log-rank test and Cox regression models. Cytokine production upon Aspergillus stimulation was measured by enzyme-linked immunosorbent assay in peripheral blood mononuclear cells (PBMCs) from healthy volunteers and correlated with relevant genotypes. RESULTS: Mold colonization (n = 45) and proven/probable IMI (n = 26) were associated with polymorphisms in the genes encoding interleukin 1β (IL1B; rs16944; recessive mode, P = .001 for colonization and P = .00005 for IMI, by the log-rank test), interleukin 1 receptor antagonist (IL1RN; rs419598; P = .01 and P = .02, respectively), and β-defensin 1 (DEFB1; rs1800972; P = .001 and P = .0002, respectively). The associations with IL1B and DEFB1 remained significant in a multivariate regression model (P = .002 for IL1B rs16944; P = .01 for DEFB1 rs1800972). The presence of 2 copies of the rare allele of rs16944 or rs419598 was associated with reduced Aspergillus-induced interleukin 1β and tumor necrosis factor α secretion by PBMCs. CONCLUSIONS: Functional polymorphisms in IL1B and DEFB1 influence susceptibility to mold infection in SOT recipients. This observation may contribute to individual risk stratification.