Transplant vasculopathy has not been systematically investigated in composite tissue allotransplantation (CTA). The impact of multiple acute rejections (ARs) on long-term graft outcomes in reconstructive transplantation remains unknown. This study in a rat hind-limb allotransplantation model systematically analyzes vasculopathy and tissue-specific pathological changes secondary to multiple AR episodes. LEW rats were transplanted with BN rat hind limbs and treated as follows: Group 1 (Iso): isografts. Group 2 (CsA): Cyclosporine (CsA) qd; Group 3 (mult AR): CsA and dexamethasone only when AR was observed. No AR was observed in Groups 1 and 2. Multiple AR were observed in Group 3, and each episode was completely reversed (clinically) with pulsed CsA + dexamethasone treatment. Group 3 animals demonstrated significant vascular lesions along with skin and muscle atrophy, upregulation of profibrotic gene expression and fibrosis when compared to Groups 1 and 2. In addition, allograft bone was sclerotic, weak and prone to malunion and nonunion. Interestingly, vasculopathy was a late finding, whereas muscle atrophy with macrophage infiltration was seen early, after only a few AR episodes. Taken together, multiple AR episodes lead to vasculopathy and tissue-specific pathology in CTA. This is the first evidence of 'composite tissue vasculopathy and degeneration (CTVD)' in CTA. less...

We tested whether reducing macrophage infiltration would improve the survival of allogeneic bone marrow stromal cells (BMSC) transplanted in the contused adult rat thoracic spinal cord. Treatment with cyclosporine, minocycline, or methylprednisolone all resulted in a significant decrease in macrophage infiltration at 3 days postinjury. However, when BMSC were injected at that time point, survival 7 days later was similar between treatment groups and saline-injected controls. In fact, we found that the presence of BMSC resulted in a significant increase in macrophage infiltration into the contusion. less...

OBJECTIVE: To clarify the demographic data, outcomes and complications of renal transplantation in children at Srinagarind (university) Hospital. MATERIAL AND METHOD: The authors reviewed the medical records of children with end-stage renal disease (ESRD) who received renal transplantation at Srinagarind Hospital, Khon Kaen, between August 2001 and July 2008. RESULTS: Eight male and seven female patients were identified Their mean age was 12.8 +/- 3.2 years (range, 5.0-17.6). The major cause of ESRD was a congenital anomaly of the kidneys (53%). All of the children received cadaveric transplantations and none received induction therapy. Triple immunosuppressive drugs comprising cyclosporine, prednisolone and mycophenolate mofetil were administered to 12 patients. Tacrolimus, instead of cyclosporine, was given to three patients who had received a renal transplant since January 2008. The median follow-up time was 15 months (3 to 82 months). The most frequent complication was urinary tract infection (40%). Acute graft loss was found in one patient (6.7%) due to graft infarction. Other complications included herpes viral infection, chronic rejection, acute rejection, severe gingival hyperplasia, myopathy, lymphocele and transitional cell carcinoma of the bladder. Two patients returned to dialysis due to graft infarction and chronic rejection, respectively. The mean serum creatinine at the last follow-up of the remaining cases was 1.2 +/- 0.5 mg/dL (range, 0.6-2.3). All of the patients survived. The 1- and 5-year graft survival rates were 93.3% and 86.7%, respectively. CONCLUSION: The present study demonstrates the potential for successful outcomes of pediatric renal transplantation in this resource-limited area. less...

With the successful testing of the immunosuppressive effects of cyclosporine in transplant patients in 1978, the field of organ transplants began an exponential growth. With that, the field of organ preservation became increasingly important as the need to increase preservation time and improve graft function became paramount. However, for every patient that receives a transplanted organ, there are four more on the waiting list. In addition, a patient dies from the lack of a transplant almost every 1(1/2) hour. To alleviate this donor crisis, there is a need to expand the donor pool to marginal donor organs. The main reason these organs are underutilized is because the current method of static preservation, simple cold storage, is ineffective. This article will provide a general review of the methods of preservation including simple cold storage, hypothermic machine perfusion, normothermic machine perfusion, and oxygen persufflation. In addition, the article will provide a review of how these dynamic preservation methods have improved the recovery and preservation of marginal donor organs including Donation after Cardiac Death and Fatty livers. less...

Tedesco-Silva H, Felipe CR, Park SI, Pinheiro-Machado PG, Garcia R, Slade A, Schmouder R, Medina-Pestana JO. Randomized crossover study to assess the inter- and intrasubject variability of morning mycophenolic acid concentrations from enteric-coated mycophenolate sodium and mycophenolate mofetil in stable renal transplant recipients. Clin Transplant 2009 DOI: 10.1111/j.1399-0012.2009.01169.x. (c) 2009 John Wiley & Sons A/S. Abstract: The delayed release of mycophenolic acid (MPA) from enteric-coated mycophenolate sodium (EC-MPS, myfortic((R))) may have an impact on the variability of MPA trough (C(0 h)) levels. A randomized, two-period crossover study was performed in 24 maintenance renal transplants to evaluate the inter- and intrasubject variability of MPA predose levels from EC-MPS and mycophenolate mofetil (MMF, CellCept((R))), both in combination with cyclosporine. Patients received EC-MPS (720 mg b.i.d.) and MMF (1000 mg b.i.d.) for a period of 21 d each. MPA plasma levels were measured over the final seven consecutive days at -1, 0, 1, 2, and 3 h after the morning MPA dose. Intersubject coefficients of variation (%CV) for MPA troughs were 47.5% (95% CI, 34.1-80.3) and 54.4% (40.0-86.8) for EC-MPS and MMF, respectively; intrasubject %CVs were 62.7% (55.1-72.9) and 42.8% (37.9-49.2). High MPA C(0 h) levels >10 mug/mL were rarely observed with both EC-MPS (1.8%) and MMF (0.6%). Mean MPA area under the curve (AUC)(0-3 h) was comparable between treatments, while MPA C(0 h) was on average 46% higher with EC-MPS. In conclusion, predose MPA trough level monitoring appears of limited value during EC-MPS and MMF therapy given the large intrasubject variability in MPA C(0 h) levels with both treatments. less...

Brill-Zinsser disease, the relapsing form of epidemic typhus, typically occurs in a susceptible host years or decades after the primary infection; however, the mechanisms of reactivation and the cellular reservoir during latency are poorly understood. Herein we describe a murine model for Brill-Zinsser disease, and use PCR and cell culture to show transient rickettsemia in mice treated with dexamethasone >3 months after clinical recovery from the primary infection. Treatment of similarly infected mice with cyclosporine failed to produce recrudescent bacteremia. Therapy with doxycycline for the primary infection prevented recrudescent bacteremia in most of these mice following treatment with dexamethasone. Rickettsia prowazekii (the etiologic agent of epidemic typhus) was detected by PCR, cell culture, and immunostaining methods in murine adipose tissue, but not in liver, spleen, lung, or central nervous system tissues of mice 4 months after recovery from the primary infection. The lungs of dexamethasone-treated mice showed impaired expression of beta-defensin transcripts that may be involved in the pathogenesis of pulmonary lesions. In vitro, R. prowazekii rickettsiae infected and replicated in the murine adipocyte cell line 3T3-L1. Collectively these data suggest a role for adipose tissue as a potential reservoir for dormant infections with R. prowazekii. less...

Sonozaki syndrome-pustulotic arthro-osteitis (PAO) is a relatively rare, chronic illness. This disease belongs to the group of psoriatic arthritis (psoriasis arthropatica, artropatia psoriatica) which in turn belongs to the group of seronegative arthritis. Sonozaki syndrome includes palmoplantar pustulosis, PPP as well as arthro-osteitis. Clinically, symmetrically localised pustulae are observed on feet and hands. Effected joints are painful, swollen with a visible inflammation. Here, we describe a case of a woman aged 55 with a diagnosis of Sonozaki syndrome and hyperthyroidism. At the moment of admission multiple changes in the form of pustulae were observed on hands and soles, filled with pus and blood of the erythemal basis. Oral and genital mucosa were free from changes. The oedema within clavicle and sternum joints was without features of the severe inflammation and tactical tenderness. In additional tests, increased BSR 36/62 was found. Bone scintigraphy-focuses of increased accumulation of MDP-Tc-99 m were found in the sternal projection of the clavicle ends at both sides, and the left-side change is bigger and more strongly saturated and can probably progress to the sternum's manubrium. As a result of the used treatment during hospitalisation, (cyclosporine 3 mg/kg and steroid external therapy upon the skin changes) the improvement of the local changes was observed as well as no progression in the joints' changes. At the moment, the patient is treated in the dermatological and rheumatological out-clinic. Early and correct diagnostics allows for efficient treatment of Sonozaki syndrome and decreases the risk of potential complications, such as the described systemic amyloidosis. less...

Previous studies have suggested that inflammatory bowel disease is particulary frequent and severe in familial Mediterranean fever (FMF) families. An 8-month-old boy was admitted to our hospital with chronic bloody diarrhea, failure to thrive and high-grade fever. He was diagnosed as Crohn's disease (CD) based on clinical, laboratory and histological findings and, corticosteroid therapy was started. The patient did not respond to intensive medical therapy including intravenous corticosteroid, mesalazine, azathioprine, intravenous cyclosporine and enteral feeding. MEFV gene mutation analysis revealed homozygous M694V mutation. In addition to azathioprine and cyclosporine therapy, with the diagnosis of FMF, colchicine therapy was started and partial remission was observed within 2 weeks. To the best of our knowledge, this is the first report of association of CD and FMF in an infant. In cases of CD resistant to medical therapy, possibility of underlying FMF should be considered, especially in countries where FMF is prevalent. less...

Rituximab (RTX) has been successfully used as a rescue therapy in children with steroid-dependent nephrotic syndrome (SDNS). However, little is known regarding maintenance therapy after a successful response to RTX in such patients. The efficacy and safety of a single RTX infusion (375 mg/m(2)) were assessed in ten patients who had persistent SDNS associated with minimal-change disease (MCD) despite the long-term use of cyclosporine (CsA). The mean follow-up after RTX infusion was 17 months. Applying RTX resulted in a significant reduction in the mean prednisolone (PSL) dose from 0.39 +/-0.18 to 0.15 +/- 0.14 mg/kg per day. The mean 12-month relapse rates significantly decreased from 4.1 +/- 1.7 to 0.6 +/- 0.6. All but one patient who had continued CsA as maintenance therapy after a single RTX infusion were able to withdraw from PSL without any relapses during the study period, whereas the remaining five patients who discontinued CsA experienced relapses after CD19 cells re-emerged, leading to the reintroduction of CsA or an additional RTX infusion. Infusion reactions occurred in five of ten patients. These data indicate that a single RTX infusion may improve response to CsA in patients with persistent SDNS due to the phenomenon of secondary resistance to CsA. less...

Data are scarce concerning the calcineurin inhibitor dose reduction required following introduction of everolimus in maintenance heart transplant recipients to maintain stable renal function. In a 48-week, multicenter, single-arm pilot study in heart transplant patients >12 months post-transplant, everolimus was started at 1.5 mg/day (subsequently adjusted to target C(0) 5-10 ng/ml). Mycophenolate mofetil or azathioprine was discontinued on the same day and cyclosporine (CsA) dose was reduced by 25%, with a further 25% reduction each time calculated glomerular filtration rate (cGFR) decreased to <75% of baseline. Of 36 patients enrolled, 25 were receiving everolimus at week 48. From baseline to week 48, there was a mean decrease of 44.5%, 50.9% and 44.6% in CsA dose, C(0) and C(2), respectively. Mean cGFR was 68.9 +/- 14.5 ml/min at baseline and 61.6 +/- 11.5 ml/min at week 48 (P = 0.018). The prespecified criterion for stable renal function was met, i.e. a mean decrease <or=25% of cGFR from baseline. Two patients experienced biopsy-proven acute rejection Grade 3A (5.6%). Between baseline and week 48, there were significant increases in total cholesterol, LDL cholesterol and triglycerides, and small but significant elevations in liver enzymes. This 1-year pilot study suggests that CsA dose reduction of ca. 40% after initiation of everolimus was associated with a decrease in cGFR, however, based on the prespecified criteria stable renal function was attained. less...