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To investigate a potential role of mTOR signaling pathway which interferes with depressive-like behavior induced by calcineurin blockade and to determine the neurobiological mechanisms underlying mood-related disorders.
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Despite using a screening protocol combined with immunosuppression minimization, BK-positive recipients had a greater risk of graft loss and impaired function than recipients free of infection. Future investigations should focus on practices to prevent BK viremia.
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Data were obtained from a comparative bioavailability study of oral TAC formulations (n = 22). TAC whole blood concentrations were measured by LC-MS/MS. Genetic polymorphisms were determined using a direct sequencing method. Nonlinear mixed-effects modelling (NONMEM) was performed to assess the effect of genotypes and demographics on TAC PKs.
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Topical calcineurin inhibitors are widely used to treat inflammatory dermatoses for their steroid-sparing advantage. Herein, we report a patient with chronic lip dermatitis who developed multiple labial melanotic macules after application of tacrolimus 0.1% ointment and pimecrolimus 1% cream. Prior and current reports raise concerns for potential development of pigmented lesions associated with topical calcineurin inhibitor use. These reports highlight the need for careful risk-benefit assessment when prescribing topical calcineurin inhibitors for inflammatory dermatoses, especially when used on sun-exposed sites.
Coinfected patients were younger than monoinfected patients: 45 +/- 6 years vs 55 +/- 9 years (P = .0008). There were no differences in Child score, Model for End-stage Liver Disease score, donor age, graft steatosis, ischemia time, HCV pretransplant viral load or genotype between the groups. Significant rejection episodes were also equally distributed (25% vs 14%; P = .38). Seven coinfected patients and 29 monoinfected patients developed aggressive HCV recurrences (58% vs 49%; P = .75). Median follow-up was 924 days. Global survival at 3 years was 80%. Survivals at 1, 2, and 3 years were 83%, 75%, 62% in the coinfected vs 98%, 89%, 84% in the monoinfected patients, respectively (log-rank test = 0.09).
There was a significantly higher incidence of lymphoceles requiring surgical revisions in the ABO-incompatible group. However, this surgical complication did not affect patient or graft survival. Mean serum creatinine, estimated glomerular filtration rate and proteinuria did not differ between the two groups. Furthermore, ABO-incompatible and ABO-compatible patients had the same incidence of humoral and cellular rejections. Despite a more aggressive induction therapy, no differences in infectious or malignant complications were observed.
The mean time between LT and PTLD was 24.5 months. There were no differences between in Epstein-Barr virus antibody status or tumor lymphocyte subsets. In five of the seven HCV-positive recipients who developed PTLD, PTLD recurred preferentially in the liver allograft, whereas none of the three HCV-negative patients who developed PTLD did so in the liver (71.4 vs. 0%, respectively, P=0.038). In all five patients with graft PTLD, HCV recurred within 12 months followed by PTLD. There were significant differences between groups 1 and 2 in mean lymphocyte infiltrate scores (6.0±2.1 vs. 2.0±0.7, P=0.037), fibrosis stage (2.4±0.5 vs. 0.7±0.5, P=0.029), and frequency of lymphoid follicles in portal areas (33.6±14.8% vs. 1.1±2.3%, P=0.0002).
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Immunosuppression management in kidney transplantation has evolved to include an increasingly diverse choice of medications. Although informed by patient and donor characteristics, choice of immunosuppression regimen varies widely across transplant programs. Using a novel database integrating national transplant registry and pharmacy fill records, immunosuppression use at 6-12 and 12-24 mo after transplant was evaluated for 22 453 patients transplanted in 249 U.S. programs in 2005-2010. Use of triple immunosuppression comprising tacrolimus, mycophenolic acid or azathioprine, and steroids varied widely (0-100% of patients per program), as did use of steroid-sparing regimens (0-77%), sirolimus-based regimens (0-100%) and cyclosporine-based regimens (0-78%). Use of triple therapy was more common in highly sensitized patients, women and recipients with dialysis duration >5 years. Sirolimus use appeared to diminish over the study period. Patient and donor characteristics explained only a limited amount of the observed variation in regimen use, whereas center choice explained 30-46% of the use of non-triple-therapy immunosuppression. The majority of patients who received triple-therapy (79%), cyclosporine-based (87.6%) and sirolimus-based (84.3%) regimens continued them in the second year after transplant. This population-based study of immunosuppression practice demonstrates substantial variation in center practice beyond that explained by differences in patient and donor characteristics.
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This study is a single-institute prospective study that includes 21 adult patients who underwent HSCT and received 24 hours continuous intravenous administration of TAC at the Mie University Hospital between January 2009 and March 2014. After HSCT, the changes in blood TAC concentration/dose (C/D) ratio and TAC dose reduction from initial dose were investigated.
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Treatment with aliskiren decreased the tacrolimus-induced changes in biochemical markers of nephrotoxicity such as blood urea nitrogen and creatinine. Aliskiren also attenuated the effects of tacrolimus on oxidative stress parameters such as malondialdehyde, reduced glutathione and catalase. Histopathological and ultrastructural studies showed that aliskiren attenuated tacrolimus-induced renal damage.
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According to the Japanese renal transplant registry 2005, 834 transplantations were performed using living donors. Among them 112 (13.4%) patients were transplanted from living donors before the initiation of maintenance dialysis. Preemptive kidney transplantation (PreKTx) has been associated with improved allograft and patient survival rates compared to non-PreKTx. This study was designed to summarize our experience with PreKTx.
Intracavernous pressure (ICP) measurement after CN electrical stimulation to assess erectile function and Western blot analysis of expressions of glutathione peroxidase (GPX; antioxidant enzyme), nitrotyrosine (NT; oxidative stress marker), and phosphorylated and total Akt (antiapoptotic factor) in penes.
The object of the study was to model the structural complex of the FK506-binding protein (FKBP) with the CRK peptide imitating the central region of the HIV-1 V3 loop, as well as to define the FKBP stretch giving rise to the binding site for V3 the synthetic copy of which, on the assumption of preserving the spatial peptide structure in the free state, can be considered as a promising applicant for the role of antiviral drug. To this end, the following successive steps were carried out: (i) the NMR-based conformational analysis of CRK was put into practice, and, in the light of the results derived, the best energy CRK structure meeting the requirements of the input NMR data was identified; (ii) molecular docking of the CRK structure with the X-ray FKBP conformation was implemented, and energy refining the simulated structural complex was realized; (iii) the matrix of distances between amino acids of the ligand and receptor was computed to specify the FKBP stretch keeping in touch with CRK followed by analyzing the types of interactions stabilizing the over-molecular ensemble; (iv) 3D structure of this stretch in the unbound status referred to as the FKBP peptide was predicted, and its collation with the X-ray conformation of the identical FKBP site was performed; (v) the potential energy function and its constituents were studied for the structural complex generated by molecular docking of the CRK molecule with the FKBP peptide; and (vi) from all evidence, the virtual FKBP-derived peptide was submitted to be utilized as a prospective structural framework in the anti-HIV-1 drug design. Summing up the results obtained, the following principal conclusion was drawn: a high affinity of the V3 loop peptide to the FKBP is based on the principle of "mirror similarity" that implies the near resemblance of 3D structures for the two individual fragments of the receptor and ligand, which, most likely, accounts for recognizing the immunophilin by V3 and determines the specificity of their efficacious interactions arising from the experimental observations.
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Any published randomised controlled trial (RCT) on intervention for pemphigus vulgaris was included, provided the diagnosis of pemphigus vulgaris was confirmed with appropriate clinical features, histopathology and immunofluorescence studies. Studies which included forms of pemphigus other than pemphigus vulgaris were excluded.
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Low dose of CNI combined with MMF managed to prevent CKD after LT with stable graft function.
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New-onset diabetes after renal transplantation (NODAT) is one of the most frequent metabolic complications after transplantation; it is present in ∼25% of kidney transplant recipients, increasing their cardiovascular risk and inducing graft damage. The medical approach of this entity is still a matter of controversy, so our aim was to review the evidence available and offer a practical approach for diagnosis, treatment, and follow-up.
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Cyclosporine, everolimus, and tacrolimus are the cornerstone of immunosuppressive therapy in renal transplantation. These drugs are characterized by narrow therapeutic windows, highly variable pharmacokinetics (PK), and metabolism by CYP3A enzymes. Recently, the decreased activity allele, CYP3A4*22, was described as a potential predictive marker for CYP3A4 activity. This study investigated the effect of CYP3A4*22, CYP3A5*3, and CYP3A combined genotypes on cyclosporine, everolimus, and tacrolimus PK in renal transplant patients. CYP3A4*22 carriers showed a significant lower clearance for cyclosporine (-15%), and a trend was observed for everolimus (-7%) and tacrolimus (-16%). Patients carrying at least one CYP3A5*1 allele had 1.5-fold higher tacrolimus clearance compared with noncarriers; however, CYP3A5*3 appeared to be nonpredictive for everolimus and cyclosporine. CYP3A combined genotype did not significantly improve prediction of clearance compared with CYP3A5*3 or CYP3A4*22 alone. These data suggest that dose individualization of cyclosporine, everolimus, or tacrolimus therapy based on CYP3A4*22 is not indicated.CPT: Pharmacometrics Systems Pharmacology (2014); 3, e100; doi:10.1038/psp.2013.78; published online 12 February 2014.
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Nine studies randomized 1907 patients met the inclusion criteria: TAC (n=1); MMF (n=6); both (n=2). Compared to maintenance therapy, late corticosteroid withdrawal was associated with 34% increase in the risk of acute graft rejection (95% CI for OR: 0.47-3.82); 35% and 5% reductions in the risk of graft failure and patient's all-cause mortality (95% CI for OR: 0.26-1.60; 0.23-3.93, respectively); and 4% increase in post-transplant diabetes risk (95% CI for OR: 0.45-2.41). Late corticosteroid withdrawal was associated with substantial reduction in total cholesterol levels (mean difference: 18.1 mg/dL; 95% CI: 7.1-29.0 mg/dL), but did not reduce serum creatinine levels (0.00 mg/dL; 95% CI: 0.17 to 0.17). Stopping corticosteroids was associated with better pediatric growth outcomes.
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The results showed that 18 major proteins were differentially expressed in the cells transfected with or without the HBV whole-X gene. The expression of these genes was further confirmed by reverse transcription-polymerase chain reaction and Western blot analysis.
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The frequencies of cytomegalovirus and bacterial infection in Group A were significantly higher than those in Group B (P<0.001). The short term mortality was 4 (25.0%) in Group A and none in Group B, and the IMK level in all four cases became <100 ng/mL at least one time before death. The rate of CYP3A5*1 allele (expressors) among recipients was significantly higher in Group A than in Group B (63.6% vs. 22.2%, P=0.0147). The rates of CMV infection and bacterial infection, and the IMK levels was significantly higher in recipients with expressors (p=0.0216, p=0.0332, and p=0.0433, respectively).
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Sirolimus is a safe immunosuppressive option in liver transplant recipients suffering from hepatocellular carcinoma. Advagraf showed a lower incidence of side effects than prograf and probably is not as harmful for renal function, offering better compliance and better life quality.
The central issue in organ transplantation remains suppression of allograft rejection. Immunosuppression can be achieved by depleting lymphocytes, diverting lymphocyte traffic, or blocking lymphocyte response pathways. Immunosuppressive drugs include small-molecule drugs, depleting and nondepleting protein drugs (polyclonal and monoclonal antibodies), fusion proteins, intravenous immune globulin, and glucocorticoids. Small-molecule immunosuppressive agents include calcineurin-inhibitors (cyclosporine, tacrolimus), Target-of-Rapamycin Inhibitors (Sirolimus, Everolimus), inhibitors of nucleotide synthesis and azathioprine. The review covers the mode of action of these drugs with a special focus on belatacept, a new promising fusion protein. Different immuo-suppressive strategies mean also different safety profiles. Common side effects include the consequences of diminished immuno- response, i.e. infections and cancer (mainly involving the skin). Toxic side effects of immunosuppressive drugs range in a wide spectrum that involves almost every organ. The major interest of this toxic effects is the cardiovascular tolerance (with large differences from drug to drug), that are discussed seperately. The calcineurin- and mTOR-inhibitors are both metabolized by the CYP450 3A4 enzyme, which is also involved in the metabolism of many other drugs. The review discusses the most important interactions that in- or decreases the through level of these drugs.
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Out of 81 studies, 7 were selected that enrolled 2,170 pediatric patients. The pooled analysis reported that pimecrolimus was no better to vehicle reducing eczema at day-8, day-26 and six weeks (OR 4.95, 95% CI 2.79-8.80), (OR 9.69, 95% CI 4.12-22.83) and (OR 3.83. 95% CI 1.94-7.56), respectively in children. Similarly, pimecrolimus did not show beneficial effects when analyzed for mild or absent pruritus at day 4 (OR 8.29, 95% CI 3.88-17.72 favoring vehicle), day 43 (OR 1.81 95% CI 1.13-2.89 favoring vehicle) and 1 week (OR 2.29, 95%CI 1.45 to 3.60 favoring vehicle) as compared with vehicle. One study comparing pimecrolimus with tacrolimus found no significant difference in achieving mild or absent pruritus (OR 0.94, 95% CI 0.44-1.99). More patients showed an improvement in overall disease in vehicle group at day 8 (OR 3.30, 95% CI 2.03-5.35), day 29 (OR 14.14, 95% CI 6.87-29.13) and day 43 (OR 4.11, 95% CI 2.59-6.52) as compared with pimecrolimus 1% group, as assessed by caregivers. No significant difference was seen between the total AEs in both groups (pimecrolimus vs vehicle/tacrolimus) (OR 1.19, 95% CI 0.85, 1.65).