New-onset diabetes mellitus after solid-organ transplant makes for complicated tacrolimus immunosuppression. However, tacrolimus-associated diabetic ketoacidosis has not been reported in bone marrow transplant. We report 24-year-old women, hospitalized with diabetic ketoacidosis, 70 days after undergoing a bone marrow transplant with tacrolimus immunosuppression. Clinicians should be wary about tacrolimus levels and the risk of hyperglycemic states after bone marrow transplant as with other solid-organ transplants.
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Our study showed that the use of statins after transplantation was associated with better survival.
The creatinine level was negatively correlated with IL-10 and positively correlated with TGF-β levels in both the pretransplantation and early post-transplantation period.
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This prospective observational study was conducted on 36 patients with severe AOD and moderate cases not responding to conventional treatment. They were treated with 0.1% tacrolimus eye ointment twice daily for minimum three months in addition to conventional treatment and observed for a period of 6 months. Symptoms and signs after treatment were evaluated. Grades of clinical signs were assessed based on slit lamp clinical photographs; development of possible complications was assessed and analysed by Wilcoxon signed rank test.
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No significant difference was observed in tacrolimus C(12) between the CYP3A5*1/*3 and CYP3A5*3/*3 genotypes. The dose-normalized C(12) of tacrolimus was significantly higher in the CYP3A5*3/*3 genotype than in the CYP3A5*1/*3 genotype. The C(12) ratio of 13-O-demethylate to tacrolimus was significantly lower in the CYP3A5*3/*3 genotype than in the CYP3A5*1/*3 genotype. Tacrolimus C(12) measured by CLIA was 35% higher than that by LC-MS/MS. A higher cross-reactivity was observed in the patients with a tacrolimus C(12) of less than 3 μg/l and CYP3A5*1/*3 genotype.
The histopathologic evaluation carried out to confirm the development of uveitis revealed destruction in the retinae and ciliary bodies of the immunized rats. The mean vitreous levels of TNF-α, IL-1 and IL-6 were significantly higher in the sham group than in the control group (p < 0.05). The levels of these three cytokines showed a significant decrease in the tacrolimus treatment group (p < 0.05). Cytokine levels decreased in the ghrelin treatment group relative to the control group; however, the decrease was not found statistically significant (p > 0.05).
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A novel short-course, bortezomib-based GVHD regimen can abrogate the survival impairment of MMUD RIC HSCT, can enhance early immune reconstitution, and appears to be suitable for prospective randomized evaluation.
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Left ventricular hypertrophy associated with the use of tacrolimus is a rare complication of solid organ transplantation in adult recipients. We present a cardiac transplant recipient who developed severe concentric left ventricular hypertrophy with congestive heart failure related to myocardial hypertrophy on tacrolimus. Hypertrophy improved when the drug was discontinued and replaced with sirolimus.
Tacrolimus is dependent on CYP3A5 enzyme for metabolism. Expression of the CYP3A5 enzyme is controlled by several alleles including CYP3A5*1, CYP3A5*3, CYP3A5*6 and CYP3A5*7. African Americans (AAs) have on average higher tacrolimus dose requirements than Caucasians; however, some have requirements similar to Caucasians. Studies in AAs have primarily evaluated the CYP3A5*3 variant; however, there are other common nonfunctional variants in AAs (CYP3A5*6 and CYP3A5*7) that do not occur in Caucasians. These variants are associated with lower dose requirements and may explain why some AAs are metabolically similar to Caucasians. We created a tacrolimus clearance model in 354 AAs using a development and validation cohort. Time after transplant, steroid and antiviral use, age and CYP3A5*1, *3, *6 and *7 alleles were significant toward clearance. This study is the first to develop an AA-specific genotype-guided tacrolimus dosing model to personalize therapy.
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Human MSCs acquired from bone marrow were positive for CD73, CD90, and CD105 and negative for CD11b and CD45 by flow cytometry. Ten MSC sheets were created from a total cell number of 1×10(8) MSCs using temperature-responsive culture dishes. These were successfully transplanted over the infarct myocardium of porcine ICM models induced by placing an ameroid constrictor on the left anterior descending coronary artery without any procedural-related complications (MSC group=6: sheet transplantation; sham group=6, oral intake of tacrolimus in both groups). Premature ventricular contractions were rarely detected by Holter electrocardiogram (ECG) in the MSC group in the first week after transplantation. On echocardiography, the cardiac performance of the MSC group was significantly better than that of the sham group at 8 weeks after transplantation. On histological examination 8 weeks after transplantation, left ventricular (LV) remodeling was significantly attenuated compared with the sham group (cardiomyocyte size and interstitial fibrosis were measured). Immunohistochemistry of the von Willebrand factor showed that the vascular density in the infarct border area was significantly greater in the MSC group than the sham group. Expression of angiogenesis-related factors in the infarct border area of the MSC group was significantly greater than that of the sham group, as measured by real-time polymerase chain reaction.
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To analyse NT-proBNP plasma concentration and selected echocardiographic parameters in patients after RTx at various time intervals after the procedure.
Quality of life (QoL) is an outcome criterion of increasing importance after orthotopic liver transplantation (OLT). The background of this development is the dramatic improvement in patient survival rates over the past two decades combined with the question of the quality of this survival. Among 339 OLT performed in Kiel since 1987, 123 recipients (70 males, 53 females) of mean age 56.7 +/- 13.1 years who underwent transplantation between August 1992 and June 2007 were subjected to European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ) C30 plus a liver transplant specific module to analyze QoL. In addition, we included 40 patients listed for OLT in the univariate and multivariate analyses performed using SPSS13.0. A cohort of healthy individuals served as the control group. QoL (global health) among liver recipients was reduced compared with the control group and improved compared with patients on the waiting list. Comparison of the underlying liver diseases showed a comparable QoL between postalcoholic cirrhosis and cholestatic liver diseases. Retransplantation was accompanied by a significant loss of QoL. Cyclosporine-treated recipients displayed a better QoL compared with those treated with tacrolimus. After establishing a system of continuous, systematic QoL assessment, we combined these results with survival outcomes. Further research must focus on advanced statistical methodology that combines these 2 major outcome parameters (QoL and survival). Furthermore, the influence of medical parameters, such of co-morbidity or immunosuppression, needs to be further established with reference to QoL.
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Sixty-five liver transplant patients being administered tacrolimus-based therapy were classified into three subgroups with regard to time posttransplantation. Medication compliance with tacrolimus-based therapy was measured using an electronic medication event monitoring system over a 12-month period: for 6 months tacrolimus was administered twice-daily and for 6 months, once-daily. Dosing, taking, and timing compliance as well as drug holidays were compared intra-individually between twice- and once-daily intake and among the three subgroups. In addition, patient compliance and quality of life were evaluated using questionnaires.
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Reinnervation of a hand transplant ultimately dictates functional recovery but provides a significant regenerative challenge. This article highlights interventions to enhance nerve regeneration through acceleration of axonal regeneration or augmentation of Schwann cell support and discuss their relevance to composite tissue allotransplantation. Surgical techniques that may be performed at the time of transplantation to optimize intrinsic muscle recovery--including appropriate alignment of ulnar nerve motor and sensory components, transfer of the distal anterior interosseous nerve to the recurrent motor branch of the median nerve, and prophylactic release of potential nerve entrapment points--are also presented.
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CD154 surface protein levels were increased 1.44-fold in CD4 T cells from SLE patients as compared with controls in cells evaluated 1 day postactivation ex vivo. This increase correlated clinically with the presence of nephritis and an elevated erythrocyte sedimentation rate. Increased CD154 protein levels also correlated with increased CD154 mRNA levels and with CD154 transcription rates, particularly at later time points following T cell activation. Reporter gene analyses revealed a trend for increased NF-AT, but decreased activator protein 1 and similar NF-kappaB, activity in CD4 T cells from SLE patients as compared with controls. Moreover, NF-AT1 and, in particular, NF-AT2 mRNA levels were notably increased in CD4 T cells from SLE patients as compared with controls.
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Beta-adrenergic augmentation of Ca(2+) sparks and cardiac contractility has been functionally linked to phosphorylation-dependent dissociation of FK506 binding protein 12.6 (FKBP12.6) regulatory proteins from ryanodine receptors subtype 2 (RYR2). We used FKBP12.6 null mice to test the extent to which the dissociation of FKBP12.6 affects Ca(2+) sparks and mediates the inotropic action of isoproterenol (ISO), and to investigate the underlying mechanisms of cyclic ADP-ribose (cADPR) regulation of Ca(2+) sparks.
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Pyoderma gangrenosum (PG) is an uncommon neutrophilic dermatosis that can have a chronic course often leading to ulceration and extreme tenderness. Treatment is often directed toward reducing the inflammatory process to prevent progression of the ulcer and minimize pain. The mainstay of therapy is systemic corticosteroids. Other immunosuppressants have been utilized in cases of PG resistant to corticosteroids, including cyclosporine and tacrolimus. A patient with severe and recalcitrant PG was prescribed systemic corticosteroids and cyclosporine but continued to have progression of her disease warranting admission to the hospital. Her hospital course was complicated requiring hospitalization for one month. Although her health was deteriorating, her PG improved in the hospital setting with corticosteroids without concomitant cyclosporine. The patient admitted to non-compliance with her medication in the outpatient setting, attributing her behavior mainly to depression. Pyoderma gangrenosum can be recalcitrant to any form of therapy and medication non-adherence must be considered a potential cause.
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Organ transplant recipients have a high incidence of cancer associated with persistent viral infections, such as human herpes virus 8. This virus is associated with Kaposi's sarcoma, and a change in the dose or type of immunosuppression regimen should be the first step in its treatment. A multidisciplinary approach with nephrologists, dermatologists and oncologists is necessary for the management of this disease. We report a clinical case with atypical presentation and discuss the treatment options.
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Our results demonstrate that a steroid-free immunosuppressive regimen consisting of alemtuzumab, sirolimus, and tacrolimus is feasible for simultaneous islet and kidney transplantation. The question of whether this induction regimen is superior to more standard induction deserves large studies.
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The most common cutaneous adverse event in our cohort was papulopustular rash, followed by eczema and xerosis. Patients were managed with symptom target therapy, and suspension of the EGFR inhibitor was rarely required. As the use of EGFR inhibitors increases, it is important to promptly identify and treat adverse events. Further studies are necessary to develop targeted therapeutic and preventative measures.
Prion diseases or transmissible spongiform encephalopathies (TSEs) are infectious and fatal neurodegenerative disorders in humans and animals. Pathological features of TSEs include the conversion of cellular prion protein (PrP(C)) into an altered disease-associated conformation generally designated PrP(Sc), abnormal deposition of PrP(Sc) aggregates, and spongiform degeneration of the brain. The molecular steps leading to PrP(C) aggregation are unknown. Here, we have utilized an inducible oligomerization strategy to test if, in the absence of any infectious prion particles, the encounter between PrP(C) molecules may trigger its aggregation in neuronal cells. A chimeric PrP(C) composed of one (Fv1) or two (Fv2) modified FK506-binding protein (Fv) fused with PrP(C) were created, and transfected in N2a cells. Similar to PrP(C), Fv1-PrP and Fv2-PrP were glycosylated, displayed normal localization, and anti-apoptotic function. When cells were treated with the dimeric Fv ligand AP20187, to induce dimerization (Fv1) or oligomerization (Fv2) of PrP(C), both dimerization and oligomerization of PrP(C) resulted in the de novo production, release and deposition of extracellular PrP aggregates. Aggregates were insoluble in non-ionic detergents and partially resistant to proteinase K. These findings demonstrate that homologous interactions between PrP(C) molecules may constitute a minimal and sufficient molecular event leading to PrP(C) aggregation and extracellular deposition.
This study suggests that pimecrolimus 1% cream is an effective and well-tolerated treatment for steroid-induced rosacea.