Diacetylene mixed Langmuir monolayers for interfacial polymerization.

Polydiacetylene (PDA) and its derivatives are promising materials for applications in a vast number of fields, from organic electronics to biosensing. PDA is obtained through polymerization of diacetylene (DA) monomers, typically using UV irradiation. DA polymerization is a 1-4 addition reaction with both initiation and growth steps with topochemical control, leading to the "blue" polymer form as primary reaction product in bulk and at interfaces. Herein, the diacetylene monomer 10,12-pentacosadiynoic acid (DA) and the amphiphilic cationic N,N'-dioctadecylthiapentacarbocyanine (OTCC) have been used to build a mixed Langmuir monolayer. The presence of OTCC imposes a monolayer supramolecular structure instead of the typical trilayer of pure DA. Surface pressure, Brewster angle microscopy, and UV-vis reflection spectroscopy measurements, as well as computer simulations, have been used to assess in detail the supramolecular structure of the DA:OTCC Langmuir monolayer. Our experimental results indicate that the DA and OTCC molecules are sequentially arranged, with the two OTCC alkyl chains acting as spacing diacetylene units. Despite this configuration is expected to prevent photopolymerization of DA, the polymerization takes place without phase segregation, thus exclusively leading to the red polydiacetylene form. We propose a simple model for the initial formation of the "blue" or "red" PDA forms as a function of the relative orientation of the DA units. The structural insights and the proposed model concerning the supramolecular structure of the "blue" and "red" forms of the PDA are aimed at the understanding of the relation between the molecular and macroscopical features of PDAs.

UV-Vis reflection spectroscopy under variable angle incidence at the air-liquid interface.

The UV-Vis reflection spectroscopy (UV-Vis-RS) in situ at the air-liquid interface provides information about tilt and aggregation of chromophores in Langmuir monolayers. This information is particularly important given in most cases the chromophore is located at the polar region of the Langmuir monolayer. This region of the Langmuir monolayers has been hardly accessible by other experimental techniques. In spite of its enormous potential, the application of UV-Vis-RS has been limited mainly to reflection measurements under light normal incidence or at lower incidence angles than the Brewster angle. Remarkably, this technique is quite sensitive to the tilt of the chromophores at values of incidence angles close to or larger than the Brewster angle. Therefore, a novel method to obtain the order parameter of the chromophores at the air-liquid interface by using s- and p-polarized radiation at different incidence angles is proposed. This method allowed for the first time the experimental observation of the two components with different polarization properties of a single UV-Vis band at the air-liquid interface. The method of UV-Vis spectroscopy under variable angle incidence is presented as a new tool for obtaining rich detailed information on Langmuir monolayers.

From two-dimensional to three-dimensional at the air/water interface: the self-aggregation of the acridine dye in mixed monolayers.

The formation of well-defined supramolecular structures on the nanoscopic scale is a fundamental step in nanotechnology. The fine control of the layer-by-layer growth of the supramolecular assemblies at interfaces is most desirable. The collapse of a mixed monolayer composed of two surfactants in an equimolar ratio (the organic dye N-10-dodecyl acridine (DAO) and stearic acid (SA)) is analyzed herein. The collapse process of the DAO/SA mixed monolayer has been monitored using surface pressure-molecular area (π-A) and surface potential isotherms, UV-visible reflection spectroscopy, polarization-modulated infrared reflection-absorption spectroscopy (PM-IRRAS), Brewster angle microscopy (BAM), and synchrotron-based in situ X-ray reflectivity (XRR) measurements. The collapse of the DAO/SA mixed monolayer leads to an ordered trilayer. The growth of anisotropic 2D domains of micrometric size is observed during the formation of the trilayer, related to the ordering of the acridine polar headgroups. The trilayer is organized with the first and third monolayers displaying the polar headgroups pointing to the aqueous subphase, whereas the intermediate layer displays the polar headgroups pointing to the air. The trilayer is stabilized by the strong self-aggregation acridine dye group of the DAO molecule. The controlled transition from a monolayer to a trilayer described herein is proposed as a model for further interfacial supramolecular structures of tunable thickness comprising organic dyes.

Plasticity of Membrane Binding by the Central Region of α-Synuclein.

Membrane binding by α-synuclein (αS), an intrinsically disordered protein whose aggregation is associated with Parkinson's disease, is a key step in determining its biological properties under both physiological and pathological conditions. Upon membrane interaction, αS retains a partial level of structural disorder despite acquiring α-helical content. In the membrane-bound state, the equilibrium between the helical-bound and disordered-detached states of the central region of αS (residues 65-97) has been involved in a double-anchor mechanism that promotes the clustering of synaptic vesicles. Herein, we investigated the underlying molecular bases of this equilibrium using enhanced coarse-grained molecular dynamics simulations. The results enabled clarifying the conformational dependencies of the membrane affinity by this protein region that, in addition to playing a role in physiological membrane binding, has key relevance for the aggregation of αS and the mechanisms of the toxicity of the resulting assemblies.

In Silico Study of the Mechanism of Binding of the N-Terminal Region of α Synuclein to Synaptic-Like Membranes.

The membrane binding by α-synuclein (αS), a presynaptic protein whose aggregation is strongly linked with Parkinson's disease, influences its biological behavior under functional and pathological conditions. This interaction requires a conformational transition from a disordered-unbound to a partially helical membrane-bound state of the protein. In the present study, we used enhanced coarse-grained MD simulations to characterize the sequence and conformational determinants of the binding to synaptic-like vesicles by the N-terminal region of αS. This region is the membrane anchor and is of crucial importance for the properties of the physiological monomeric state of αS as well as for its aberrant aggregates. These results identify the key factors that play a role in the binding of αS with synaptic lipid bilayers in both membrane-tethered and membrane-locked conformational states.

Relationship between Toll-like receptor 2 polymorphism and cytomegalovirus disease after liver transplantation.

BACKGROUND: Experimental data suggest that cytomegalovirus (CMV) initiates innate immunity through the activation of Toll-like receptor 2 (TLR2). To assess the clinical relevance of this experimental observation, we assessed the association between the specific single-nucleotide polymorphism that results in the substitution of arginine for glutamine in position 753 of TLR2 (the TLR2 Arg753Gln polymorphism) and CMV replication and disease after liver transplantation. METHODS: Ninety-two liver transplant recipients with chronic hepatitis C were screened for the presence of the TLR2 Arg753Gln polymorphism. CMV load was determined in serially collected blood samples using CMV DNA polymerase chain reaction. Kaplan-Meier estimation and univariable and multivariable stepwise Cox proportional hazard models were used to assess associations. RESULTS: The degree of CMV replication, as measured by CMV load, was significantly higher in patients who were homozygous (mean maximum viral load, 37,059 copies/mL) and heterozygous (mean maximum viral load, 29,718 copies/mL) for this polymorphism, compared with patients without the TLR2 Arg753Gln polymorphism (mean maximum viral load, 3252 copies/mL; P=.003). Kaplan-Meier survival analysis demonstrated an association between being homozygous for the TLR2 Arg753Gln polymorphism and CMV disease (P=.04). A multivariate Cox proportional hazard model demonstrated a trend towards a higher risk of CMV disease among patients who were homozygous for the TLR2 Arg753Gln polymorphism (hazard ratio, 1.91 [95% confidence interval, 0.91-3.40]; P=.08) after adjusting for patient age, CMV serostatus, and allograft rejection. CONCLUSIONS: TLR2 Arg753Gln polymorphism is possibly associated with CMV replication and disease after liver transplantation. This novel clinical observation supports the potential role of TLR2 in the immunologic control of CMV infection in humans.

Association between toll-like receptor polymorphisms and the outcome of liver transplantation for chronic hepatitis C virus.

BACKGROUND: Experimental models suggest that immune cells recognize hepatitis C virus (HCV) through toll-like receptor (TLR)-2 and TLR4. We assessed the association between the single nucleotide polymorphism in genes that encode for these receptors and the outcome of liver transplantation for chronic HCV. METHODS: A historical cohort of 92 liver transplant patients with chronic HCV were screened for TLR2 Arg753Gln and TLR4 Asp299Gly and Thr399Ile polymorphisms. The results were correlated with the predefined composite primary outcome of cirrhosis, retransplantation, and death. Statistical analysis was performed using Kaplan-Meier estimation and Cox proportional hazard model. RESULTS: The mean patient age was 49+/-9 years. Sixty percent were male and 84% were white. Twelve (13%) patients had TLR2 Arg753Gln and 32 (35%) had TLR4 Asp299Gly and/or Thr399Ile polymorphism. During the mean follow-up period of 32 months after liver transplantation, the composite primary outcome occurred in 19 (24%) of 80 patients without TLR2 polymorphism, one (14%) of seven patients with heterozygous TLR2 polymorphism, and in all five (100%) patients with homozygous TLR2 polymorphism (P=0.0007). Time-to-event analysis showed a significant association between homozygous TLR2 polymorphism and the primary outcome (P<0.0001). After adjusting for donor age and azathioprine use, homozygous TLR2 mutation (RR 5.20 [1.65-13.9]; P=0.007) remained associated with the primary outcome. TLR4 polymorphisms were not associated with primary outcome. CONCLUSION: Homozygous TLR2 Arg753Gln polymorphism is associated with allograft failure and mortality after liver transplantation for chronic HCV. The potential clinical relevance of this observation should encourage studies to assess its biologic mechanism.

Protein kinase Calpha (PKCalpha) acts upstream of PKCtheta to activate IkappaB kinase and NF-kappaB in T lymphocytes.

NF-kappaB is an ubiquitous transcription factor that is a key in the regulation of the immune response and inflammation. T-cell receptor (TCR) cross-linking leads to NF-kappaB activation, an IkappaB kinase (IKK)-dependent process. However, the upstream kinases that regulate IKK activity following TCR activation remain to be fully characterized. Herein, we demonstrate using genetic analysis, pharmacological inhibition, and RNA interference (RNAi) that the conventional protein kinase C (PKC) isoform PKCalpha, but not PKCbeta1, is required for the activation of the IKK complex following T-cell activation triggered by CD3/CD28 cross-linking. We find that in the presence of Ca(2+) influx, the catalytically active PKCalphaA25E induces IKK activity and NF-kappaB-dependent transcription; which is abrogated following the mutations of two aspartates at positions 246 and 248, which are required for Ca(2+) binding to PKCalpha and cell membrane recruitment. Kinetic studies reveal that an early phase (1 to 5 min) of IKK activation following TCR/CD28 cross-linking is PKCalpha dependent and that a later phase (5 to 25 min) of IKK activation is PKCtheta dependent. Activation of IKK- and NF-kappaB-dependent transcription by PKCalphaA25E is abrogated by the PKCtheta inhibitor rottlerin or the expression of the kinase-inactive form of PKCtheta. Taken together, our results suggest that PKCalpha acts upstream of PKCtheta to activate the IKK complex and NF-kappaB in T lymphocytes following TCR activation.

Pharmacodynamics of oral ganciclovir and valganciclovir in solid organ transplant recipients.

BACKGROUND: A randomized, double-blind study was conducted to evaluate the pharmacokinetics of ganciclovir following oral administration of ganciclovir or valganciclovir for prophylaxis of cytomegalovirus (CMV) disease in solid organ transplant recipients (n = 240/372). METHODS: The correlations between individual exposure to ganciclovir during prophylaxis, with CMV viremia incidence during and after treatment, CMV disease up to 12 months posttransplant, and hematological toxicity were assessed. RESULTS: Mean daily areas under the curve (AUCs) of ganciclovir from valganciclovir and oral ganciclovir were 46.3 +/- 15.2 and 28.0 +/- 10.9 microg.h/ml (mean +/- SD), respectively. Viremia was suppressed during prophylaxis when exposure to ganciclovir was 40-50 microg.h/ml, AUCs typical of those achieved in valganciclovir-treated patients. The development of viremia 1 month after ending prophylaxis was also reduced with higher ganciclovir AUC (median predicted incidence, 20% and 10% at AUCs of 33 and 50 microg h/ml, respectively). The development of CMV disease within 1 year of transplant was 17.6% and independent of prophylactic exposure to ganciclovir. There was only a weak tendency to increased neutropenia and leukopenia with higher ganciclovir exposure. CONCLUSIONS: The greater systemic exposure to ganciclovir delivered by valganciclovir was associated with delayed development of viremia. There was only a weak association between AUC and hematological toxicity.

Pharmacokinetic profile of ganciclovir after its oral administration and from its prodrug, valganciclovir, in solid organ transplant recipients.

BACKGROUND: Valganciclovir (Valcyte) has recently been approved for the prevention of cytomegalovirus (CMV) disease in high-risk (CMV donor positive [D+]/recipient negative [R-]) solid organ transplant (SOT) recipients. Large-scale studies describing the pharmacokinetics of valganciclovir in SOT recipients are lacking. A recent randomised, double-blind study of valganciclovir in 364 D+/R- (intent-to-treat population) SOT recipients provided valuable data on which a population pharmacokinetic analysis was performed. METHODS: The pharmacokinetics of ganciclovir from oral ganciclovir (Cymevene, 1000 mg three times daily) and from valganciclovir (900 mg once daily) were described with plasma levels from 240 patients (1181 datapoints describing 449 pharmacokinetic profiles) using nonlinear mixed-effects modelling (NONMEM) software. A two-compartment pharmacokinetic model with separate absorption/metabolism and absorption parameters for valganciclovir and ganciclovir, respectively, was developed. RESULTS: Exposure to ganciclovir from valganciclovir averaged 1.65-fold greater than that from oral ganciclovir (95% CI 1.58, 1.81); respective daily area under the plasma concentration-time curve values were 46.3 +/- 15.2 microg . h/mL and 28.0 +/- 10.9 microg . h/mL. The relative systemic exposure of ganciclovir was approximately 8-fold higher from valganciclovir than oral ganciclovir. Exposure to ganciclovir from valganciclovir was similar among liver, heart and kidney transplant recipients (46.0 +/- 16.1, 40.2 +/- 11.8 and 48.2 +/- 14.6 microg . h/ mL, respectively). Adherence to the prescribed dosing regimens, which were reduced for renal impairment, gave consistent exposure to ganciclovir. CONCLUSION: Oral valganciclovir produces exposures of ganciclovir exceeding those attained with oral ganciclovir, but in line with those reported after standard intravenous administration of ganciclovir. This indicates that oral valganciclovir is suitable in circumstances requiring prophylactic use of ganciclovir and allows for more convenient management of patients at risk of CMV disease.

UV-Vis Reflection-Absorption Spectroscopy at air-liquid interfaces.

UV-Visible Reflection-Absorption Spectroscopy (UVRAS) technique is reviewed with a general perspective on fundamental and applications. UVRAS is formally identical to IR Reflection-Absorption Spectroscopy (IRRAS), and therefore, the methodology developed for this IR technique can be applied in the UV-visible region. UVRAS can be applied to air-solid, air-liquid or liquid-liquid interfaces. This review focuses on the use of UVRAS for studying Langmuir monolayers. We introduce the theoretical framework for a successful understanding of the UVRAS data, and we illustrate the usage of this data treatment to a previous study from our group comprising an amphiphilic porphyrin. For ultrathin films with a thickness of few nm, UVRAS produces positive or negative bands when p-polarized radiation is used, depending on the incidence angle and the orientation of dipole absorption. UVRAS technique provides highly valuable information on tilt of chromophores at the air-liquid interface, and moreover allows the determination of optical parameters. We propose UVRAS as a powerful technique to investigate the in situ optical properties of Langmuir monolayers.

CCR5 mediates Fas- and caspase-8 dependent apoptosis of both uninfected and HIV infected primary human CD4 T cells.

DESIGN: HIV Env interaction with the corresponding chemokine receptor dictates the molecular mechanism of death of both HIV-infected and uninfected primary CD4 T cells. CXCR4/T tropic HIV virus (X4) triggers CD4 T cell death through a caspase independent mechanism, whereas CCR5/M tropic HIV virus (R5) HIV triggers a caspase dependent death. In the present study, we have investigated the pathway whereby R5 Env-CR5 interactions lead to a caspase dependent cell death. METHODS: CD4 T cells were infected with X4 or R5 HIV strains, or were mock infected. After infection, cells were treated with caspase inhibitors or decoys of death receptor signaling pathways and cell viability was analyzed. The role of R5 HIV Env in induction of cell death of uninfected T cells was analyzed by co-culturing uninfected CD4 T cells with R5 Env expressing cells in the absence or presence of various inhibitors of death receptor signaling. RESULTS: Infection of CD4 T cells with R5, but not with X4 HIV strains results in the activation of caspase-8 and cell death that is reversed by a decoy of the Fas receptor. Isolated activation of CCR5 by membrane-bound, or soluble R5 Env causes a Fas- and caspase-8 dependent death also of uninfected CD4 T cells. Additional studies demonstrate that isolated CCR5 activation by R5 Env leads to both de novo expression of FasL and induction of susceptibility to Fas-mediated apoptosis in resting primary CD4 T cells. CONCLUSIONS: These results ascribe to CCR5 a novel role in activating the Fas pathway and caspase-8 as well as triggering FasL production when activated by R5 Env, ultimately causing CD4 T cell death.

Definitions of cytomegalovirus infection and disease in transplant recipients.

Cytomegalovirus (CMV) infection and disease are important causes of morbidity and mortality among transplant recipients. For the purpose of developing consistent reporting of CMV in clinical trials, definitions of CMV infection and disease were developed and published. This study seeks to update the definitions of CMV on the basis of recent developments in diagnostic techniques, as well as to add to these definitions the concept of indirect effects caused by CMV.

The pathogenesis of hepatitis C virus is influenced by cytomegalovirus.

We investigated the effect of beta-herpesviruses on allograft failure and mortality, hepatitis C virus (HCV) replication, and liver histologic characteristics among 92 HCV-infected liver transplant recipients. Reactivation of cytomegalovirus (CMV) but not of human herpesvirus 6 (HHV-6) was independently associated with allograft failure and mortality (risk ratio, 3.71; 95% confidence interval, 1.64-8.39); allograft failure and mortality was observed in 48% of patients with CMV disease, 35% of patients with subclinical CMV infection, and 17% of patients without CMV infection (P=.0275). CMV reactivation was highly predictive of mortality (P<.001), regardless of whether it remained subclinical or evolved into CMV disease. Patients with CMV disease had a higher fibrosis stage (P=.05) and had a trend toward a higher hepatitis activity index (P=.10) and HCV load (P=.10) at 16 weeks after liver transplantation. The pathogenesis of HCV is influenced by its interaction with CMV but not with HHV-6.

Safety and efficacy of nebulized zanamivir in hospitalized patients with serious influenza.

Influenza is an important cause of hospitalization due to lower respiratory tract involvement for which there is no specific antiviral treatment with proven efficacy. We conducted a double-blind, randomized, placebo-controlled trial to assess the tolerability and efficacy of nebulized zanamivir (16 mg four times a day) in combination with rimantadine compared to rimantadine with nebulized saline for treating influenza in adults hospitalized with influenza. Twenty patients tolerated the inhaled zanamivir (ZNV) plus rimantadine without decline in peak expiratory flow rates compared to the 21 who received inhaled saline. The study was terminated early because the approval of ZNV made further enrollment untenable. No significant differences were observed in the proportion of patients shedding virus by treatment day 3 (57% ZNV plus rimantadine, 67% placebo plus rimantadine), or in the durations of hospitalization and supplemental oxygen use. More ZNV plus rimantadine recipients exhibited no or mild cough on day 3 of treatment (94 vs 55%, P=0.01). Two rimantadine-resistant viruses emerged during rimantadine monotherapy; no ZNV resistance was observed. Nebulized ZNV appears to be well tolerated in this hospitalized population but further studies are needed to assess its efficacy.

Risk factors for cytomegalovirus viremia and disease developing after prophylaxis in high-risk solid-organ transplant recipients.

BACKGROUND: Cytomegalovirus (CMV) D+/R- solid-organ transplant (SOT) recipients carry increased risk of developing CMV disease; however, other risk factors in these patients have not been delineated. METHODS: We examined 20 demographic and clinical variables for their association with the development of CMV disease, as defined by an independent endpoint committee (IEC) and also by the investigator (investigator treated [IT]), or CMV viremia within 12 months of transplant in D+/R- transplant recipients who received prophylaxis with valganciclovir or oral ganciclovir for 100 days. RESULTS: Recipients with low creatinine clearance (Ccr,<40 mL/min) at screening had a significantly increased hazard of developing IEC-defined CMV disease (hazards ratio [HR]=4.28, confidence interval [CI] 1.69, 10.83). Females were twice as likely (HR=2.19, CI .21, 3.99) to develop IEC-defined CMV disease than males. These variables were associated with an increased risk of IEC-defined CMV disease in time-dependent models. Recipients with blood group A were also more likely to develop IEC-defined CMV disease than those with group O (HR=2.36 CI 1.24, 4.51) in the logistic regression model only. Prophylactic drug, organ type, recipient age, rejection episodes, and maintenance immunosuppression regimen were not associated with IEC-defined CMV disease. Female sex was the only variable associated with the development of CMV viremia (odds ratio [OR]=1.65; CI 1.03, 2.65) and IT CMV disease (OR=1.78; CI 1.08, 2.93). CONCLUSIONS: Low Ccr at screening and blood type A are risk factors for IEC-defined CMV disease, and female sex was a risk factor for IEC- and IT-defined CMV disease and viremia in high-risk SOT recipients. These variables should perhaps be considered when optimizing treatment.

The clinical use of various blood compartments for cytomegalovirus (CMV) DNA quantitation in transplant recipients with CMV disease.

BACKGROUND: The quantitation of cytomegalovirus (CMV) DNA is a cornerstone in the management of CMV disease in transplant recipients. However, a consensus as to what is the optimal blood compartment for the detection and quantitation of CMV DNA in peripheral blood is nonexistent. METHODS: With an automated quantitative assay, we have simultaneously quantified the CMV DNA load in whole blood (WB), plasma (PL), peripheral blood leukocytes (PBL), and peripheral blood mononuclear cells (PBMC) in 319 samples from 17 transplant recipients with 19 episodes of CMV disease that were treated with 2 weeks of intravenous ganciclovir. RESULTS: Higher levels of CMV DNA were observed in WB than PL (PL minus WB mean difference, 0.67 log; 95% confidence interval, -1.02 to -0.32; P=0.0009). This observation was most evident before treatment with intravenous ganciclovir (pretreatment geometric mean CMV DNA was 45,412 copies per ml of WB vs. 14,995 copies per ml of PL). In contrast, the CMV DNA levels between PBL and PBMC were highly comparable throughout the course of CMV disease and its treatment. Intravenous ganciclovir exerted a uniform effect on the four blood compartments with no statistically significant difference in the degree and rate of CMV DNA decline between WB and PL and between PBL and PBMC. CONCLUSIONS: Although our study demonstrates the adequacy of all blood compartments for CMV DNA quantification, the higher sensitivity of WB and its yield of higher CMV DNA render it an optimal sample for monitoring CMV DNA load during CMV disease in immunocompromised patients.

A randomized, prospective, double-blinded evaluation of selective bowel decontamination in liver transplantation.

BACKGROUND: Bacterial infection is a frequent, morbid, and mortal complication of liver transplantation. Selective bowel decontamination (SBD) has been reported to reduce the rate of bacterial infection after liver transplantation in uncontrolled trials, but benefits of this intervention have been less clear in controlled studies. METHODS: Eighty candidates for liver transplantation were randomly assigned in a double-blinded fashion to an SBD regimen consisting of gentamicin 80 mg+polymyxin E 100 mg+nystatin 2 million units (37 patients) or to nystatin alone (43 patients). Both treatments were administered orally in 10 ml (increasing to 20 ml, according to predefined criteria), four times daily, through day 21 after transplantation. Anal fecal swab cultures were performed on days 0, 4, 7, and 21. Rates of infection, death, and charges for medical care were assessed from day 0 through day 60. RESULTS: More than 85% of patients in both treatment groups began study treatment more than 3 days before transplantation. Rates of infection (32.4 vs. 27.9%), death (5.4 vs. 4.7%), or charges for medical care (median $194,000 vs. $163,000) were not reduced in patients assigned to SBD. On days 0, 4, 7, and 21, growth of aerobic gram-negative flora in fecal cultures of patients assigned to SBD was significantly less than that of patients taking nystatin alone; growth of aerobic gram-positive flora, anaerobes, and yeast was not significantly different. CONCLUSION: Routine use of SBD in patients undergoing liver transplantation is not associated with significant benefit.

Kaposi's Sarcoma and Transplantation.

Kaposi's sarcoma is a tumour of multicentric origin, composed of endothelium-lined vascular spaces and spindle-shaped cells. The incidence of Kaposi's sarcoma in transplant recipients is 400--500 times greater than that in the general population, and is rising within the transplant population, currently comprising more than 5% of all de novo neoplasms in this group. The exact pathogenesis is still unknown but DNA sequences from human herpesvirus 8 (HHV-8) are present in the different clinical variants of Kaposi's sarcoma. Risk factors associated with development of these tumours posttransplantation include the geographical origin of the patient, HSV-8 infection before and after transplantation, and the immunosuppressive regimen used, but the importance of each factor remains to be determined. Apart from conventional treatment with surgical excision, radiotherapy or chemotherapy, cessation, reduction or modification of immunosuppressive therapy has been shown to be effective in a significant number of patients. This article reviews recent advances in our understanding of Kaposi's sarcoma after transplantation.

Valganciclovir for the prevention and treatment of cytomegalovirus disease in immunocompromised hosts.

Valganciclovir (Valcyte, Roche), a prodrug of the deoxyguanosine analog ganciclovir (Cytovene, Roche), is indicated for induction and maintenance treatment of cytomegalovirus retinitis in patients with AIDS and for prevention of cytomegalovirus disease in selected high-risk solid organ transplant recipients. After oral administration, valganciclovir is rapidly absorbed and converted to ganciclovir by intestinal and hepatic esterases. Valganciclovir is a highly recognized substrate of the intestinal peptide transporter PEPT1, which underlies the tenfold higher bioavailability of ganciclovir after valganciclovir compared to oral ganciclovir administration. At oral dose of 900 mg, valganciclovir provides a systemic ganciclovir exposure that is comparable to intravenous ganciclovir, at the standard dose of 5 mg/kg of body weight. Subsequent phosphorylation of ganciclovir, which occurs preferentially within cytomegalovirus-infected cells, results in the active metabolite, ganciclovir triphosphate, which is responsible for suppressing viral DNA synthesis by competitively inhibiting the incorporation of the natural substrate deoxyguanosine into viral DNA and thereby, terminating cytomegalovirus replication.