Histologic Inflammatory Changes on the Prostatic Gland Due to Immunosuppression for Kidney Transplantation

OBJECTIVE To determine the incidence of type IV prostatitis in patients with kidney transplantation receiving an immunosuppression regimen and to compare it with that of a nonimmunosuppressed control group. METHODS We retrospectively reviewed 216 electronic charts of patients who had undergone surgical treatment for benign prostatic hyperplasia from August 2000 to January 2006. Of the 216 patients, 183 did not receive immunosuppressive therapy and were included in the control group (group 1). The other 33 patients had undergone kidney transplantation and were included in the study group (group 2). The patient data were accessed for age at surgery, International Prostate Symptom Score, prostate volume, preoperative serum prostate-specific antigen level, history of acute urinary retention, and surgical approach (open vs transurethral resection of prostate). Histologic findings from the surgical specimens were also recorded. RESULTS The mean age at surgery, mean serum prostate-specific antigen level, mean prostate volume, and mean International Prostate Symptom Score were not significantly different between both groups. However, histologic evidence of chronic prostatitis was obtained in 145 surgical specimens (78%) from group 1 and in just 3 specimens from group 2 (9%; P < .001). Moreover, nonimmunosuppressed patients had a 38.2 times greater risk of presenting with prostatitis than did the immunosuppressed patients. CONCLUSION Imunnosuppresion therapy in kidney transplantation has a protective factor in the prostatitis incidence. UROLOGY 79: 662-664, 2012. (C) 2012 Elsevier Inc.

Human Adipose-Derived Mesenchymal Stromal Cells Injected Systemically Into GRMD Dogs Without Immunosuppression Are Able to Reach the Host Muscle and Express Human Dystrophin

Duchenne muscular dystrophy (DMD), a lethal X-linked disorder, is the most common and severe form of muscular dystrophies, affecting I in 3,500 male births. Mutations in the DMD gene lead to the absence of muscle dystrophin and a progressive degeneration of skeletal muscle. The possibility to treat DMD through cell therapy has been widely investigated. We have previously shown that human adipose-derived stromal cells (hASCs) injected systemically in SJL mice are able to reach and engraft in the host muscle, express human muscle proteins, and ameliorate the functional performance of injected animals without any immunosuppression. However, before starting clinical trials in humans many questions still need to be addressed in preclinical studies, in particular in larger animal models, when available. The best animal model to address these questions is the golden retriever muscular dystrophy (GRMD) dog that reproduces the full spectrum of human DMD. Affected animals carry a mutation that predicts a premature termination codon in exon 8 and a peptide that is 5% the size of normal dystrophin. These dogs present clinical signs within the first weeks and most of them do not survive beyond age two. Here we show the results of local and intravenous injections of hASCs into GRMD dogs, without immunosuppression. We observed that hASCs injected systemically into the dog cephalic vein are able to reach, engraft, and express human dystrophin in the host GRMD dystrophic muscle up to 6 months after transplantation. Most importantly, we demonstrated that injecting a huge quantity of human mesenchymal cells in a large-animal model, without immunosuppression, is a safe procedure, which may have important applications for future therapy in patients with different forms of muscular dystrophies.

Up-regulation of fas and fasL pro-apoptotic genes expression in type 1 diabetes patients after autologous haematopoietic stem cell transplantation

Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by T cell-mediated destruction of pancreatic beta cells, resulting in insulin deficiency and hyperglycaemia. Recent studies have described that apoptosis impairment during central and peripheral tolerance is involved in T1D pathogenesis. In this study, the apoptosis-related gene expression in T1D patients was evaluated before and after treatment with high-dose immunosuppression followed by autologous haematopoietic stem cell transplantation (HDI-AHSCT). We also correlated gene expression results with clinical response to HDI-AHSCT. We observed a decreased expression of bad, bax and fasL pro-apoptotic genes and an increased expression of a1, bcl-xL and cIAP-2 anti-apoptotic genes in patients' peripheral blood mononuclear cells (PBMCs) compared to controls. After HDI-AHSCT, we found an up-regulation of fas and fasL and a down-regulation of anti-apoptotic bcl-xL genes expression in post-HDI-AHSCT periods compared to pre-transplantation. Additionally, the levels of bad, bax, bok, fasL, bcl-xL and cIAP-1 genes expression were found similar to controls 2 years after HDI-AHSCT. Furthermore, over-expression of pro-apoptotic noxa at 540 days post-HDI-AHSCT correlated positively with insulin-free patients and conversely with glutamic acid decarboxylase autoantibodies (GAD65) autoantibody levels. Taken together, the results suggest that apoptosis-related genes deregulation in patients' PBMCs might be involved in breakdown of immune tolerance and consequently contribute to T1D pathogenesis. Furthermore, HDI-AHSCT modulated the expression of some apoptotic genes towards the levels similar to controls. Possibly, the expression of these apoptotic molecules could be applied as biomarkers of clinical remission of T1D patients treated with HDI-AHSCT therapy.

Prior history of sexually transmitted diseases in women living with AIDS in Sao Paulo, Brazil

Objectives: To describe the epidemiological profile, risk behaviors, and the prior history of sexually transmitted diseases (STDs) in women living with acquired immunodeficiency syndrome (AIDS). Methods: Cross-sectional study, performed at the Centro de Referencia e Treinamento em DST/AIDS of Sao Paulo. The social, demographic, behavioral, and clinical data such as age, schooling, marital status, age at first sexual intercourse, number of sexual partners, parity, use of drugs, time of HIV diagnosis, CD4 count, and viral load determination were abstracted from the medical records of women living with AIDS who had gynecological consultation scheduled in the period from June 2008 to May 2009. Results: Out of 710 women who were scheduled to a gynecological consultation during the period of the study, 598 were included. Previous STD was documented for 364 (60.9%; 95% CI: 56.9%-64.8%) women. The associated factors with previous STDs and their respective risks were: human development index (HDI) <0.50 (ORaj = 5.5; 95% CI: 2.8-11.0); non-white race (ORaj = 5.2; 95% CI: 2.5-11.0); first sexual intercourse at or before 15 years of age (ORaj = 4.4; 95% CI: 2.3-8.3); HIV infection follow-up time of nine years or more (ORaj = 4.2; 95% CI: 2.3-7.8)]; number of sexual partners during the entire life between three and five partners (ORaj = 2.2; 95% CI: 1.1-4.6), and six or more sexual partners (ORaj = 3.9; 95% CI: 1.9-8.0%); being a sex worker (ORaj = 1.9; 95% CI: 1.1-3.1). Conclusions: A high prevalence of a prior history of STDs in the studied population was found. It is essential to find better ways to access HIV infection prevention, so that effective interventions can be more widely implemented. (C) 2012 Elsevier Editora Ltda. All rights reserved.

Centrilobular necrosis as a manifestation of venous outflow block in pediatric malnourished liver transplant recipients - case reports

CLN is a frequent histological finding in biopsies after pediatric: LT, and its pathogenesis has not yet been fully clarified and has different causes. Among the vascular causes, VOB is sometimes difficult to diagnose, especially when technical variants such as split-liver, reduced-liver, or living-related LT are utilized. Three liver-transplanted malnourished children (ages 12, 20, and 28 months) developed altered LFTs and post-operative ascites with right pleural effusion (two cases) and jaundice (one case). Doppler ultrasound examinations were normal and liver biopsies showed CLN interpreted as severe ACR. There were no responses to the medical treatment. Additional investigation with CT angiography suggested obstructed hepatic vein drainage, which was confirmed by interventional radiology and angioplasty of the anastomosis between the hepatic vein and the inferior vena cava, with clinical and histological resolution. It is concluded that in malnourished children undergoing LT with technical variations, in which the occurrence of severe ACR is usually less common because of the severity of the patient condition, the finding of CLN should raise the possibility of VOB, so that excessive immunosuppression and its consequences can be avoided.

Encefalite anti-receptor N-metil-D-aspartato na infância

OBJETIVO: Discutir o diagnóstico diferencial das encefalites além daquelas de etiologia infecciosa, e alertar os pediatras para a possibilidade do diagnóstico de encefalite anti-receptor N-metil-D-aspartato (rNMDA) na população pediátrica, destacando suas principais características clínicas. DESCRIÇÃO: Três pacientes apresentaram-se com uma síndrome neuropsiquiátrica inicial seguida de encefalopatia e transtornos de movimento. As características neuropsiquiátricas iniciais se desenvolveram ao longo de dias ou semanas, com mudanças comportamentais, ansiedade, confusão mental e regressão da fala. Em seguida, os pacientes evoluíram com distúrbios de movimento, caracterizados por coreoatetose ou distonia, acometendo a região orofacial e os membros. Após a exclusão das principais causas de encefalite, foram identificados anticorpos anti-rNMDA no soro e no líquido cefalorraquidiano. Não foram detectadas neoplasias durante a investigação etiológica. Os pacientes foram submetidos a imunossupressão, e dois deles tiveram uma recuperação neurológica completa. Um deles ainda apresenta uma postura distônica leve em um dos membros. COMENTÁRIOS: Os sinais clínicos de encefalite anti-rNMDA em crianças são semelhantes aos anteriormente descritos em adultos. Tumores geralmente não são detectados nessa idade. O diagnóstico de encefalite anti-rNMDA deve ser abordado após a exclusão de outras causas de encefalite na infância, como as de origem infecciosa. Pediatras devem estar atentos a essa condição autoimune passível de tratamento.

Transmission of clear cell tumor in a graft liver from cadaveric donor: Case report

Neoplasms in children after organ transplantation are related to the type and intensity of immunosuppression and the donorrecipient serostatus, especially in relation to the EpsteinBarr virus. The patient was a two-yr-old female child with biliary atresia who underwent a liver transplantation from a female cadaver donor. Two adults received kidney transplants from the same donor. Nine months after transplantation, one of the adult recipients developed an urothelial tumor in the kidney graft. Imaging tests were repeated monthly in the liver-transplanted child and revealed no abnormalities. However, one yr and two months after the transplantation, the patient developed episodes of fever. At that time, imaging and liver biopsy showed a clear cell tumor of urothelial origin in the graft and the disease was limited to the liver. The patient underwent liver retransplantation, and she is currently free of tumor recurrence. Although rare, the occurrence of tumors in the post-transplant period from cadaver donors, without previously diagnosed tumors, is one of the many problems encountered in the complex world of organ transplantation.

Chronic cold stress in mice induces a regulatory phenotype in macrophages: Correlation with increased 11 beta-hydroxysteroid dehydrogenase expression

Susceptibility to infections, autoimmune disorders and tumor progression is strongly influenced by the activity of the endocrine and nervous systems in response to a stressful stimulus. When the adaptive system is switched on and off efficiently, the body is able to recover from the stress imposed. However, when the system is activated repeatedly or the activity is sustained, as during chronic or excessive stress, an allostatic load is generated, which can lead to disease over long periods of time. We investigated the effects of chronic cold stress in BALB/c mice (4 degrees C/4 h daily for 7 days) on functions of macrophages. We found that chronic cold stress induced a regulatory phenotype in macrophages, characterized by diminished phagocytic ability, decreased TNF-alpha and IL-6 and increased IL-10 production. In addition, resting macrophages from mice exposed to cold stress stimulated spleen cells to produce regulatory cytokines, and an immunosuppressive state that impaired stressed mice to control Trypanosoma cruzi proliferation. These regulatory effects correlated with an increase in macrophage expression of 11 beta-hydroxysteroid dehydrogenase, an enzyme that converts inactive glucocorticoid into its active form. As stress is a common aspect of modern life and plays a role in the etiology of many diseases, the results of this study are important for improving knowledge regarding the neuro-immune-endocrine interactions that occur during stress and to highlight the role of macrophages in the immunosuppression induced by chronic stress. (C) 2011 Elsevier Inc. All rights reserved.

The effects on mucociliary clearance of prednisone associated with bronchial section

OBJECTIVE: Infections have been and remain the major cause of morbidity and mortality after lung transplantation. Because mucociliary clearance plays an important role in human defense mechanisms, the influence of drugs on the mucociliary epithelium of patients undergoing lung transplantation must be examined. Prednisone is the most important corticosteroid used after lung transplantation. The aim of this study was to evaluate the effects of bronchial transection and prednisone therapy on mucociliary clearance. METHODS: A total of 120 rats were assigned to 4 groups according to surgical procedure or drug therapy: prednisone therapy (1.25 mg/kg/day); bronchial section and anastomosis + prednisone therapy (1.25 mg/kg/day); bronchial section + saline solution (2 ml/day); and saline solution (2 ml/day). After 7, 15, or 30 days, the animals were sacrificed, and the lungs were removed from the thoracic cavity. The in situ mucociliary transport velocity, ciliary beat frequency and in vitro mucus transportability were evaluated. RESULTS: Animals undergoing bronchial section surgery and anastomosis had a significant decrease in the ciliary beat frequency and mucociliary transport velocity 7 and 15 days after surgery (p<0.001). These parameters were normalized 30 days after the surgical procedure. Prednisone improved mucous transportability in the animals undergoing bronchial section and anastomosis at 15 and 30 days (p<0.05). CONCLUSION: Bronchial section and anastomosis decrease mucociliary clearance in the early postoperative period. Prednisone therapy improves mucus transportability in animals undergoing bronchial section and anastomosis.

Malakoplakia after renal transplantation in the current era of immunosuppressive therapy: case report and literature review

Malakoplakia is a rare chronic granulomatous disease of unknown cause. It is thought to be caused by an acquired bactericidal defect of macrophages. Malakoplakia is associated with chronic infections and immunosuppression. Although it occurs mainly in the urinary tract, it has already been reported in almost every organ system. The isolation of bacteria, especially Escherichia coli, is common in malakoplakia patients. Here, we present a case of primary cutaneous malakoplakia in a kidney transplant recipient who had been taking prednisone, tacrolimus, and mycophenolate. Culture of a lesion grew Burkholderia cepacia complex. Treatment with high doses of trimethoprim-sulfamethoxazole was successful. We also present a systematic review of the literature, identifying 4 previously reported cases of malakoplakia after renal transplantation under similar immunosuppressive therapy, most occurring in the urinary tract or perineum and following benign courses to cure. Data in the literature suggest that malakoplakia has become even rarer since changes were made in the immunosuppressive therapy employed after kidney transplantation.

The Seville Expert Workshop for Progress in Posttransplant Lymphoproliferative Disorders

Posttransplant lymphoproliferative disorders (PTLDs) are associated with significant morbidity and mortality among solid-organ transplant patients, but approaches to diagnosis and management vary considerably. An international multidisciplinary panel evaluated current understanding of risk factors and classification systems and developed recommendations to aid in PTLD prevention. We considered evidence on PTLD risk factors including Epstein- Barr virus serostatus and immunosuppression and identified knowledge gaps for future research. Recommendations address prophylactic and preemptive strategies to minimize PTLD development, including modulation of immunosuppression and antiviral drug regimens. Finally, new classification criteria were outlined that may help facilitate standardized reporting and improve our understanding of PTLD.

De Novo Thrombotic Microangiopathy After Kidney Transplantation: Clinical Features, Treatment, and Long-Term Patient and Graft Survival

Introduction. Posttransplant thrombotic microangiopathy (TMA)/hemolytic uremic syndrome (HUS) can occur as a recurrent or de novo disease. Methods. A retrospective single-center observational study was applied in order to examine the incidence and outcomes of de novo TMA/HUS among transplantations performed between 2000 and 2010. Recurrent HUS or antibody-mediated rejections were excluded. Results. Seventeen (1.1%) among 1549 kidney transplant recipients fulfilled criteria for de novo TMA. The mean follow-up was 572 days (range, 69-1769). Maintenance immunosuppression was prednisone, tacrolimus (TAC), and mycophenolic acid in 14 (82%) patients. Mean age at onset was 40 +/- 15 years, and serum creatinine was 6.1 +/- 4.1 mg/dL. TMA occurred at a median of 25 days (range, 1-1755) after transplantation. Nine (53%) patients developed TMA within 1 month of transplantation and only 12% after 1 year. Clinical features were anemia (hemoglobin < 10 g/dL) in 9 (53%) patients, thrombocytopenia in 7 (41%), and increased lactate dehydrogenase in 12 (70%). Decreased haptoglobin was observed in 64% and schistocytes in 35%. Calcineurin inhibitor (CM) withdrawal or reduction was the first step in the management of 10/15 (66%) patients, and 6 (35%) received fresh frozen plasma (FFP) and/or plasmapheresis. TAC was successfully reintroduced in six patients after a median of 17 days. Eight (47%) patients needed dialytic support after TMA diagnosis and 75% remained on dialysis. At 4 years of follow-up, death-censored graft survival was worse for TMA group (43.0% versus 85.6%, log-rank = 0.001; hazard ratio = 3.74) and there was no difference in patient survival (53.1% versus 82.2%, log-rank = 0.24). Conclusion. De novo TMA after kidney transplantation is a rare but severe condition with poor graft outcomes. This syndrome may not be fully manifested, and clinical suspicion is essential for early diagnosis and treatment, based mainly in CM withdrawal and FFP infusions and/or plasmapheresis.

Preserving the B-Cell Compartment Favors Operational Tolerance in Human Renal Transplantation

Transplanted individuals in operational tolerance (OT) maintain long-term stable graft function after completely stopping immunosuppression. Understanding the mechanisms involved in OT can provide valuable information about pathways to human transplantation tolerance. Here we report that operationally tolerant individuals display quantitative and functional preservation of the B-c ell compartment in renal transplantation. OT exhibited normal numbers of circulating total B cells, naive, memory and regulatory B cells (Bregs) as well as preserved B-cell receptor repertoire, similar to healthy individuals. In addition, OT also displayed conserved capacity to activate the cluster of differentiation 40 (CD40)/signal transducer and activator of transcription 3 (STAT3) signaling pathway in Bregs, in contrast, with chronic rejection. Rather than expansion or higher activation, we show that the preservation of the B-cell compartment favors OT. Online address: http://www.molmed.org doi: 10.2119/molmed.2011.00281

Treatment with probiotics in experimental oral colonization by Candida albicans in murine model (DBA/2)

The aim of this study is to evaluate the oral colonization by Candida albicans in experimental murine immunosuppressed DBA/2 and treatment with probiotic bacteria. To achieve these objectives, 152 DBA/2-immunosuppressed mice were orally inoculated with a suspension of C. albicans containing 10(8) viable yeast cells, the animals were treated with nystatin or with the probiotics (Lactobacillus acidophilus and Lactobacillus rhamnosus). Evaluations were performed by Candida count from oral mucosa swabbing. The oral mucosa colonization by C. albicans started at day 1 after inoculation, remained maximal from day 3 until day 7, and then decreased significantly. Probiotics reduced the C. albicans colonization significantly on the oral mucosa in comparison with the untreated animal group. In the group treated with L. rhamnosus, the reduction in yeast colonization was significantly higher compared with that of the group receiving nystatin. Immunosuppressed animal model DBA/2 is a relevant model for experimental Candida oral colonization, and the treatment with probiotics in this model may be an effective alternative to prevent it. Oral Diseases (2012) 18, 260-264

Risks, Benefits, and Therapeutic Potential of Hematopoietic Stem Cell Transplantation for Autoimmune Diabetes

Type 1 diabetes mellitus is a chronic disease that results from the autoimmune response against pancreatic insulin producing beta cells. Apart of several insulin regimens, since the decade of 80s various immunomodulatory regimens were tested aiming at blocking some steps of the autoimmune process against beta cell mass and at promoting beta cell preservation. In the last years, some independent research groups tried to cure type 1 diabetes with an "immunologic reset" provided by autologous hematopoietic stem cell transplantation in newly diagnosed patients, and the majority of patients became free form insulin with increasing levels of C-peptide along the time. In this review, we discuss the biology of hematopoietic stem cells and the possible advantages and disadvantages related to the high dose immunosuppression followed by autologous hematopoietic stem cell transplantation.