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1.
Life Sci ; 241: 117141, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31811853

RESUMO

AIMS: Glibenclamide, a diabetes mellitus type 2 medication, has anti-inflammatory and autoimmune properties. This study investigated the effects of glibenclamide on transplant-induced arteriosclerosis as well as the underlying molecular events. METHODS: Male C57Bl/6 (H-2b) and BALB/c (H-2d) mice were used for aorta transplantation. We used hematoxylin and eosin (HE) and Elastic Van Gieson (EVG) staining for histological assessment, and qRT-PCR and ELISA to measure mRNA and protein levels. Mouse peritoneal macrophages were isolated for lipopolysaccharide (LPS) stimulation and glibenclamide treatment followed by ELISA, Western blot, and Transwell assays. RESULTS: Glibenclamide inhibited transplant-induced arteriosclerosis in vivo. Morphologically, glibenclamide reduced inflammatory cell accumulation and collagen deposition in the aortas. At the gene level, glibenclamide suppressed aortic cytokine mRNA levels, including interleukin-1ß (IL-1ß; 10.64 ± 3.19 vs. 23.77 ± 5.72; P < .05), tumor necrosis factor-α (TNF-α; 4.59 ± 0.78 vs. 13.89 ± 5.42; P < .05), and monocyte chemoattractant protein-1 (MCP-1; 202.66 ± 23.44 vs. 1172.73 ± 208.80; P < .01), while IL-1ß, TNF-α, and MCP-1 levels were also reduced in the mouse sera two weeks after glibenclamide treatment (IL-1ß, 39.40 ± 13.56 ng/ml vs. 78.96 ± 9.39 ng/ml; P < .01; TNF-α, 52.60 ± 13.00 ng/ml vs. 159.73 ± 6.76 ng/ml; P < .01; and MCP-1, 56.60 ± 9.07 ng/ml vs. 223.07 ± 36.28 ng/ml; P < .001). Furthermore, glibenclamide inhibited macrophage expression and secretion of inflammatory factors in vitro through suppressing activation of the nuclear factor-κB (NF-κB) pathway and MCP-1 production. CONCLUSION: Glibenclamide protected against aorta transplantation-induced arteriosclerosis by reducing inflammatory factors in vivo and inhibited macrophage migration and MCP-1 production in vitro.


Assuntos
Arteriosclerose/tratamento farmacológico , Movimento Celular/efeitos dos fármacos , Quimiocina CCL2/antagonistas & inibidores , Regulação da Expressão Gênica/efeitos dos fármacos , Glibureto/farmacologia , Macrófagos Peritoneais/efeitos dos fármacos , Transplante de Órgãos/efeitos adversos , Animais , Apoptose/efeitos dos fármacos , Arteriosclerose/etiologia , Arteriosclerose/metabolismo , Arteriosclerose/patologia , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Feminino , Hipoglicemiantes/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL
2.
Int J Cancer ; 146(3): 682-691, 2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30919451

RESUMO

Solid organ transplant recipients (OTRs) have an increased cancer risk but their survival once diagnosed with cancer has seldom been assessed. We therefore investigated cancer-specific survival among OTRs with a wide range of cancer forms nationally in Sweden. The study included 2,143 OTRs with cancer, and 946,089 nontransplanted cancer patients diagnosed 1992-2013. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox regression models adjusted for age, sex and calendar year. Median follow-up was 3.1 (range 0-22) years. Overall, OTRs diagnosed with any cancer had a 35% higher rate of cancer death compared to nontransplanted cancer patients (HR: 1.35, 95% CI: 1.24-1.47). Specifically, higher rates of cancer-specific death were observed among OTRs diagnosed with Hodgkin lymphoma (HR: 15.0, 95% CI: 5.56-40.6), high-grade non-Hodgkin lymphoma (HR: 2.68, 95% CI: 1.90-3.77), malignant melanoma (HR: 2.80, 95% CI: 1.74-4.52) and urothelial (HR: 2.56, 95% CI: 1.65-3.97), breast (HR: 2.12, 95% CI: 1.38-3.25), head/neck (HR: 1.55, 95% CI: 1.02-2.36) and colorectal (HR: 1.42, 95% CI: 1.07-1.88) cancer. The worse outcomes were not explained by differences in distribution of cancer stage or histologic subtypes. For other common cancer forms such as prostate, lung and kidney cancer, the prognosis was similar to that in nontransplanted cancer patients. In conclusion, several but not all types of posttransplantation cancer diagnoses are associated with worse outcomes than in the general population. Reasons for this should be further explored to optimize posttransplantation cancer management.


Assuntos
Neoplasias/mortalidade , Transplante de Órgãos/efeitos adversos , Complicações Pós-Operatórias/mortalidade , Transplantados/estatística & dados numéricos , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Masculino , Pessoa de Meia-Idade , Neoplasias/etiologia , Complicações Pós-Operatórias/etiologia , Sistema de Registros/estatística & dados numéricos , Fatores de Risco , Análise de Sobrevida , Suécia/epidemiologia , Adulto Jovem
5.
J Cancer Res Clin Oncol ; 145(12): 3125-3135, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31587105

RESUMO

PURPOSE: Solid organ (SOT) and allogeneic haematopoietic stem cell (HSCT) transplant recipients have elevated risks of de novo or secondary cancer. We explored risk factors hereof. METHODS: Among SOT and HSCT between January 2004 and December 2014, standardised incidence ratio (SIR) of de novo/secondary cancer compared with the Danish population was determined and risk factors were identified using Poisson regression. RESULTS: During a median of 3.4 (IQR 1.3-6.4) and 2.6 (0.8-5.4) person-years (PY) after SOT and HSCT, a total of 212/1656 (13%) and 75/992 (8%) persons developed cancer; SIR 3.61 (3.0-4.3) and 2.2 (1.6-3.0), resp.). SIR correlated with younger age and was highest for skin and haematological cancers for both types of transplantation. Within the cohort, cancer was associated with older age (adjusted incidence rate ratio > 50 vs ≤ 19 years, among SOT and HSCT: 9.4 (3.4-25.7) and 25.4 (5.1-126.0), resp.) and current elevated C-reactive protein (CRP) (≥ 10 vs < 10 mg/L: 2.5 (1.8-3.4) and 2.3 (1.4-3.9), resp.), but neither with prior cancer nor type of immunosuppressants. CONCLUSION: Rates of de novo or secondary cancers are elevated in both SOT and HSCT compared with the general population and mainly for skin and haematological cancers. Among transplant recipients, older age and current elevated CRP are risk factors.


Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Segunda Neoplasia Primária/etiologia , Neoplasias/etiologia , Transplante de Órgãos/efeitos adversos , Adulto , Estudos de Coortes , Feminino , Humanos , Imunossupressores/efeitos adversos , Incidência , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Transplantados , Adulto Jovem
6.
N Engl J Med ; 381(12): 1136-1147, 2019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31532960

RESUMO

BACKGROUND: Maribavir is a benzimidazole riboside with activity against cytomegalovirus (CMV). The safety and efficacy of maribavir for preemptive treatment of CMV infection in transplant recipients is not known. METHODS: In a phase 2, open-label, maribavir dose-blinded trial, recipients of hematopoietic-cell or solid-organ transplants (≥18 years of age, with CMV reactivation [1000 to 100,000 DNA copies per milliliter]) were randomly assigned to receive maribavir at a dose of 400, 800, or 1200 mg twice daily or the standard dose of valganciclovir for no more than 12 weeks. The primary efficacy end point was the percentage of patients with a response to treatment, defined as confirmed undetectable CMV DNA in plasma, within 3 weeks and 6 weeks after the start of treatment. The primary safety end point was the incidence of adverse events that occurred or worsened during treatment. RESULTS: Of the 161 patients who underwent randomization, 159 received treatment, and 156 had postbaseline data available - 117 in the maribavir group and 39 in the valganciclovir group. The percentage of patients with postbaseline data available who had a response to treatment within 3 weeks was 62% among those who received maribavir and 56% among those who received valganciclovir. Within 6 weeks, 79% and 67% of patients, respectively, had a response (risk ratio, 1.20; 95% confidence interval, 0.95 to 1.51). The percentages of patients with a response to treatment were similar among the maribavir dose groups. Two patients who had a response to treatment had a recurrence of CMV infection within 6 weeks after starting maribavir at a dose of 800 mg twice daily; T409M resistance mutations in CMV UL97 protein kinase developed in both patients. The incidence of serious adverse events that occurred or worsened during treatment was higher in the maribavir group than in the valganciclovir group (52 of 119 patients [44%] vs. 13 of 40 [32%]). A greater percentage of patients in the maribavir group discontinued the trial medication because of an adverse event (27 of 119 [23%] vs. 5 of 40 [12%]). A higher incidence of gastrointestinal adverse events was reported with maribavir, and a higher incidence of neutropenia was reported with valganciclovir. CONCLUSIONS: Maribavir at a dose of at least 400 mg twice daily had efficacy similar to that of valganciclovir for clearing CMV viremia among recipients of hematopoietic-cell or solid-organ transplants. A higher incidence of gastrointestinal adverse events - notably dysgeusia - and a lower incidence of neutropenia were found in the maribavir group. (Funded by ViroPharma/Shire Development; EudraCT number, 2010-024247-32.).


Assuntos
Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Infecções por Citomegalovirus/tratamento farmacológico , Citomegalovirus/fisiologia , Ribonucleosídeos/uso terapêutico , Valganciclovir/uso terapêutico , Viremia/tratamento farmacológico , Adulto , Idoso , Aloenxertos , Antivirais/efeitos adversos , Antivirais/farmacologia , Benzimidazóis/efeitos adversos , Benzimidazóis/farmacologia , Citomegalovirus/efeitos dos fármacos , Infecções por Citomegalovirus/virologia , Disgeusia/induzido quimicamente , Feminino , Gastroenteropatias/induzido quimicamente , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Humanos , Análise de Intenção de Tratamento , Masculino , Pessoa de Meia-Idade , Neutropenia/induzido quimicamente , Transplante de Órgãos/efeitos adversos , Ribonucleosídeos/efeitos adversos , Ribonucleosídeos/farmacologia , Valganciclovir/efeitos adversos , Valganciclovir/farmacologia , Ativação Viral/efeitos dos fármacos
7.
Expert Opin Drug Saf ; 18(11): 1017-1030, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31478398

RESUMO

Introduction: Human cytomegalovirus (HCMV) is a major contributor of morbidity and mortality, and its management is essential for the successful outcome of solid organ and hematopoietic stem cell transplantation. Areas covered: This review discusses the safety profiles of currently available and emerging antiviral drugs and the other strategies for HCMV prevention and treatment after transplantation. Expert opinion: Strategies for management of HCMV rely largely on the use of antiviral agents that inhibit viral DNA polymerase (ganciclovir/valganciclovir, foscarnet, and cidofovir/brincidofovir) and viral terminase complex (letermovir), with different types and degrees of adverse effects. An investigational agent, maribavir, exerts its anti-CMV effect through UL97 inhibition, and its safety profile is under clinical evaluation. In choosing the antiviral medication to use, it is important to consider these safety profiles in addition to overall efficacy. In addition to antiviral drugs, reduction of immunosuppression is often generally needed in the management of HCMV infection, but with a potential risk of allograft rejection or graft-versus-host disease. The use of HCMV-specific or non-specific intravenous immunoglobulins remains debated, while adoptive HCMV-specific T cell therapy remains investigational, and associated with unique set of adverse effects.


Assuntos
Antivirais/administração & dosagem , Infecções por Citomegalovirus/prevenção & controle , Infecções Oportunistas/prevenção & controle , Antivirais/efeitos adversos , Infecções por Citomegalovirus/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Imunossupressores/administração & dosagem , Infecções Oportunistas/virologia , Transplante de Órgãos/efeitos adversos , Transplante de Órgãos/métodos
9.
BMC Surg ; 19(1): 111, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31412850

RESUMO

BACKGROUND: Bacteraemia of the donor is not considered to be contraindication of organ procurement. On the other hand, infection of solid organ transplant recipients remains to be a major cause of their morbidity and mortality. When using organs from bacteraemic donors, individual risks need to be assessed and the appropriate antibiotic treatment applied. CASE PRESENTATION: In this case series we report several serious donor-derived infectious complications in four out of five recipients of different organs from one single donor in the early posttransplant period. Donor-transmitted multi-drug resistant strains of Escherichia coli and Klebsiella pneumonia was confirmed by both serologic and molecular testing. CONCLUSIONS: To prevent donor-derived infections, careful microbiological screening followed by targeted antibiotic treatment is essential. Although such complications can never by completely prevented, a high index for potential bacterial infection in organ donors and transplant recipients should be routinely employed.


Assuntos
Bacteriemia , Farmacorresistência Bacteriana Múltipla , Infecções por Escherichia coli/diagnóstico , Infecções por Escherichia coli/microbiologia , Infecções por Klebsiella/diagnóstico , Infecções por Klebsiella/microbiologia , Transplante de Órgãos/efeitos adversos , Doadores de Tecidos , Adulto , Antibacterianos/uso terapêutico , Escherichia coli/efeitos dos fármacos , Infecções por Escherichia coli/tratamento farmacológico , Feminino , Humanos , Infecções por Klebsiella/tratamento farmacológico , Klebsiella pneumoniae/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Obtenção de Tecidos e Órgãos , Transplantados
10.
BMC Infect Dis ; 19(1): 706, 2019 Aug 09.
Artigo em Inglês | MEDLINE | ID: mdl-31399112

RESUMO

BACKGROUND: HTLV-1 infection is a neglected disease, despite infecting 10-15 million people worldwide and severe illnesses develop in 10% of carriers lifelong. Acknowledging a greater risk for developing HTLV-1 associated illnesses due to immunosuppression, screening is being widely considered in the transplantation setting. Herein, we report the experience with universal HTLV testing of donors and recipients of solid organ transplants in a survey conducted in Spain. METHODS: All hospitals belonging to the Spanish HTLV network were invited to participate in the study. Briefly, HTLV antibody screening was performed retrospectively in all specimens collected from solid organ donors and recipients attended since the year 2008. RESULTS: A total of 5751 individuals were tested for HTLV antibodies at 8 sites. Donors represented 2312 (42.2%), of whom 17 (0.3%) were living kidney donors. The remaining 3439 (59.8%) were recipients. Spaniards represented nearly 80%. Overall, 9 individuals (0.16%) were initially reactive for HTLV antibodies. Six were donors and 3 were recipients. Using confirmatory tests, HTLV-1 could be confirmed in only two donors, one Spaniard and another from Colombia. Both kidneys of the Spaniard were inadvertently transplanted. Subacute myelopathy developed within 1 year in one recipient. The second recipient seroconverted for HTLV-1 but the kidney had to be removed soon due to rejection. Immunosuppression was stopped and 3 years later the patient remains in dialysis but otherwise asymptomatic. CONCLUSION: The rate of HTLV-1 is low but not negligible in donors/recipients of solid organ transplants in Spain. Universal HTLV screening should be recommended in all donor and recipients of solid organ transplantation in Spain. Evidence is overwhelming for very high virus transmission and increased risk along with the rapid development of subacute myelopathy.


Assuntos
Infecções por HTLV-I/epidemiologia , Infecções por HTLV-I/etiologia , Transplante de Órgãos/efeitos adversos , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Espanha/epidemiologia , Doadores de Tecidos/estatística & dados numéricos
11.
Transplant Proc ; 51(6): 1699-1705, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31399160

RESUMO

BACKGROUND: Rejection and infection are 2 major complications affecting the health and survival of patients receiving an allograft organ transplantation. We describe a diagnostic assay that simultaneously monitors for rejection and infection in recipients of kidney transplant by sequencing of cell-free DNA (cfDNA) in plasma. METHODS: By using cfDNA in plasma, we established a noninvasive method that simultaneously monitors rejection and infection in patients with a history of organ transplant. A total of 6200 single-nucleotide polymorphisms were captured by liquid hybridization and sequenced by next-generation sequencing. The donor-derived cfDNA (ddcfDNA) level was calculated based on maximum likelihood estimation, without relying on the donor's genotype. We also analyzed the nonhuman cfDNA to test for infections in the patients' plasma. RESULTS: Artificial ddcfDNA levels quantified by a donor-dependent and donor-independent algorithm were significantly correlated, with the multivariate coefficient of determination, or R2 value, of 0.999. This technique was applied on 30 patients (32 samples) after kidney transplantation, and a significant difference was observed on the ddcfdNA levels between nonrejection and rejection. Furthermore, 1 BK virus infection and 1 cytomegalovirus infection were revealed by this method, and the enrichment efficiency of the viral sequences was 114 and 489 times, respectively, which are consistent with clinical results. CONCLUSION: This method can be used to simultaneously monitor for acute rejection as well as a broad spectrum of infections for patients of allograft organ transplant because it provides comprehensive information for clinicians to optimize immunosuppression therapy.


Assuntos
Ácidos Nucleicos Livres/sangue , Rejeição de Enxerto/diagnóstico , Transplante de Órgãos/efeitos adversos , Complicações Pós-Operatórias/diagnóstico , Adulto , Algoritmos , Feminino , Rejeição de Enxerto/sangue , Humanos , Hospedeiro Imunocomprometido , /imunologia , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/sangue
12.
BMC Infect Dis ; 19(1): 697, 2019 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-31387529

RESUMO

BACKGROUND: S. pneumoniae is the leading cause of community-acquired pneumonia in the solid organ transplant recipient (SOTR); nevertheless, the prevalence of colonization and of the colonizing/infecting serotypes has not been studied in this population. In this context, the aim of the present study was to describe the rate, characteristics, and clinical impact of S. pneumoniae nasopharyngeal carriage. METHODS: A prospective observational cohort of Solid Organ Transplant recipients (SOTR) was held at the University Hospital Virgen del Rocío, Seville, Spain with the aim to evaluate the S. pneumoniae colonization and the serotype prevalence in SOTR. Two different pharyngeal swabs samples from 500 patients were included in two different seasonal periods winter and spring/summer. Optochin and bile solubility tests were performed for the isolation of thew strains. Antimicrobial susceptibility studies (MICs, mg/l) of levofloxacin, trimethoprim-sulfamethoxazole, penicillin, amoxicillin, cefotaxime, ceftriaxone, erythromycin, azithromycin and vancomycin for each isolate were determined by E-test strips. Capsular typing was done by sequential multiplex PCR reactions. A multivariate logistic regression analysis of factors potentially associated with pneumococcal nasopharyngeal carriage and disease was performed. RESULTS: Twenty-six (5.6%) and fifteen (3.2%) patients were colonized in winter and spring/summer periods, respectively. Colonized SOT recipients compared to non-colonized patients were more frequently men (79.5% vs. 63.1%, P < 0.05) and cohabitated regularly with children (59% vs. 32.2%, P < 0.001). The most prevalent serotype in both studied periods was 35B. Forty-five percent of total isolates were included in the pneumococcal vaccine PPV23. Trimethoprim-sulfamethoxazole and macrolides were the less active antibiotics. Three patients had non-bacteremic pneumococcal pneumonia, and two of them died. CONCLUSIONS: Pneumococcal colonization in SOTR is low with the most colonizing serotypes not included in the pneumococcal vaccines.


Assuntos
Nasofaringe/microbiologia , Transplante de Órgãos/efeitos adversos , Infecções Pneumocócicas/epidemiologia , Streptococcus pneumoniae/isolamento & purificação , Adulto , Antibacterianos , Criança , Feminino , Humanos , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Infecções Pneumocócicas/microbiologia , Vacinas Pneumocócicas , Prevalência , Estudos Prospectivos , Sorogrupo , Espanha/epidemiologia , Streptococcus pneumoniae/efeitos dos fármacos , Streptococcus pneumoniae/patogenicidade , Transplantados/estatística & dados numéricos
13.
World J Gastroenterol ; 25(25): 3123-3135, 2019 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-31333306

RESUMO

The transplanted liver can modulate the recipient immune system to induce tolerance after transplantation. This phenomenon was observed nearly five decades ago. Subsequently, the liver's role in multivisceral transplantation was recognized, as it has a protective role in preventing rejection of simultaneously transplanted solid organs such as kidney and heart. The liver has a unique architecture and is home to many cells involved in immunity and inflammation. After transplantation, these cells migrate from the liver into the recipient. Early studies identified chimerism as an important mechanism by which the liver modulates the human immune system. Recent studies on human T-cell subtypes, cytokine expression, and gene expression in the allograft have expanded our knowledge on the potential mechanisms underlying immunomodulation. In this article, we discuss the privileged state of liver transplantation compared to other solid organ transplantation, the liver allograft's role in multivisceral transplantation, various cells in the liver involved in immune responses, and the potential mechanisms underlying immunomodulation of host alloresponses.


Assuntos
Aloenxertos/imunologia , Rejeição de Enxerto/imunologia , Tolerância Imunológica , Fígado/imunologia , Transplante de Órgãos/efeitos adversos , Sobrevivência de Enxerto/imunologia , Humanos , Transplante Homólogo/efeitos adversos
14.
BMC Infect Dis ; 19(1): 573, 2019 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-31269923

RESUMO

BACKGROUND: Solid organ transplantation (SOT) is a well-established and life-saving treatment for patients with end-stage organ failure. Organ rejection and infections are among the main complications to SOT and largely determines the clinical outcome. The correct level of immunosuppression is of major importance to prevent these complications. However, it is a consistent observation that in recipients on the same immunosuppressive regimens the clinical outcome varies, and no reliable marker exists to monitor immune function. METHODS: In a prospective, observational study, we plan to enroll 630 adult patients with a planned organ transplantation at Rigshospitalet, University of Copenhagen, Denmark. Prior to and on different time points up to two years after transplantation we will perform a complete immunological profile on the recipients. This profile will consist of classical descriptive immune phenotyping (flow cytometry and circulating biomarkers) and the functional assay TruCulture®. In TruCulture® whole blood is incubated ex vivo with stimulants imitating bacterial, viral and fungal infections, where after a panel of selected cytokines is quantified. Clinical data from electronic health records will be obtained from the PERSIMUNE (Centre of Excellence for Personalized Medicine of Infections Complications in Immune Deficiency at Rigshospitalet, Copenhagen) data repository, a warehouse of data generated as part of routine care including vital signs, biochemistry, microbiology, pathology as well as medication, demographics, diagnoses, hospital contacts, surgical procedures and mortality. DISCUSSION: This will be the first large scale study to determine several aspects of immune function and perform a complete immunological profiling in SOT recipients. It is expected that knowledge generated will provide information to generate prediction models identifying patients at increased risk of infection and/or rejection. If the study is successful, we will subsequently use the generated prediction models to propose personalized immunosuppressive regimens to be tested in future randomized controlled trials. TRIAL REGISTRATION: This study has been approved by the Regional ethical committee (H-17024315), the Danish Data Protection Agency (RH-2016-47, RH-2015-04, I-Suite 03605) and the Danish National board of Health (3-3013-1060/1). The trial is retrospectively registered at clinicaltrials.gov ( NCT03847285 ) the 20th February 2019.


Assuntos
/etiologia , Transplante de Órgãos/efeitos adversos , Transplante de Órgãos/métodos , Adulto , Biomarcadores/sangue , Citocinas/sangue , Humanos , Tolerância Imunológica , Imunossupressão , Imunossupressores/uso terapêutico , Estudos Observacionais como Assunto , Estudos Prospectivos
16.
Mycoses ; 62(9): 730-738, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31192488

RESUMO

Mucormycosis is a rare but important invasive fungal disease that most often affects immunocompromised hosts. The incidence of mucormycosis appears to be increasing worldwide, as risk factors such as the use of immunosuppressive therapies become more common. We report the results of a literature review of 143 mucormycosis cases reported in South America between 1960 and 2018. The number of reported cases has increased by decade, from 6 in the 1960s to 51 in the 2010s. The most common underlying conditions associated with mucormycosis in South America were diabetes mellitus (42.0%) and penetrating trauma/burns (20.0%). Underlying conditions involving immunosuppression, including treatment of haematologic malignancy, solid organ transplant, and corticosteroid use, also accounted for a large proportion of cases (45.5%). Between 1960 and 2018, cases of mucormycosis associated with conditions involving immunosuppression accounted for the highest mortality rate (58.5%), followed by diabetes mellitus (45.0%), and penetrating trauma/burns (37.9%). Overall mortality decreased from 100% to 39.4% during this period, mainly driven by the increasing availability and use of antifungal therapies and surgical intervention. However, these treatments are not yet universally utilised across the region in the treatment of mucormycosis; efforts to improve availability of effective treatments would be likely to improve outcomes.


Assuntos
Infecções Fúngicas Invasivas/epidemiologia , Mucormicose/sangue , Mucormicose/epidemiologia , Antifúngicos/uso terapêutico , Complicações do Diabetes , Neoplasias Hematológicas/complicações , Humanos , Hospedeiro Imunocomprometido , Imunossupressão/efeitos adversos , Infecções Fúngicas Invasivas/tratamento farmacológico , Mucormicose/tratamento farmacológico , Transplante de Órgãos/efeitos adversos , América do Sul/epidemiologia
17.
Eur J Pharmacol ; 857: 172458, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31202799

RESUMO

Adaptive immunity has gained importance in transplant immunology for years, based on models in which T-cells orchestrate the immune responses during rejection. Most recently, researches revealed that innate immune cells, including mast cells (MCs) also play a pivotal role in allograft rejection. MC mediated immunoregulatory responses influence the innate and adaptive immune responses. Their capability to produce an array of both pro-inflammatory and anti-inflammatory mediators, expressing a wide range of costimulatory molecules in addition to acting as antigen-presenting cells (APCs), make them effective immune cells far beyond their classical role as primary orchestrator cells of allergy. Activated regulatory Tcells (Treg) cells contribute to MC recruitment into grafts by releasing interleukin (IL)-9. Tregs are capable of stabilizing MCs and suppressing IgE mediated degranulation through interaction of Treg expressing OX40 with MCs expressing OX40L. MCs in turn release transforming growth factor (TGF)-ß and IL-10 which possess suppressive properties. Thus, these cells can suppress the proliferation of T-cells and support the generation of Tregs. MCs in addition to orchestrating immune responses in grafts by cell-to-cell interactions with variety of immune cells, cause histologic changes, mainly fibrosis by releasing mediators such as histamine, fibroblast growth factor-2 (FGF-2), TGF-ß, chymase, and cathepsin G. The role of MCs in transplant rejection remains controversial. The accumulation of MCs in rejected grafts suggests that they play a role in preventing graft tolerance, and contribute to the progression of chronic rejection of allografts. However, high expression of MC-related gene products in tolerant grafts and their known interaction with Tregs on the other hand, support the notion that they are an integral component in achieving peripheral tolerance.


Assuntos
Mastócitos/imunologia , Transplante de Órgãos , Imunidade Adaptativa , Animais , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/imunologia , Humanos , Transplante de Órgãos/efeitos adversos , Doenças Vasculares/etiologia , Doenças Vasculares/imunologia
18.
Acta Oncol ; 58(7): 1041-1047, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31035840

RESUMO

Background: Fluorine-18-fluorodeoxyglucose positron emission tomography (PET) has an established and central role in diagnosis, staging and response evaluation of lymphoproliferative diseases. It has shown a high sensitivity and specificity at diagnosis in posttransplant lymphoproliferative disorders (PTLDs). However, little is known about the performance of interim and end of treatment (EOT) PET in PTLD patients with regards to response assessment, relapse prediction and outcome. Methods: We performed a single-center retrospective study in which we analyzed consecutive patients diagnosed with CD20-positive PTLD after solid organ transplantation between 2008 and 2017, who all received risk-stratified sequential treatment according to the PTLD-1 phase II trial. Interim and EOT PET studies were scored according to the Deauville criteria. Results: Forty-one patients were included with median follow-up of 41.5 months (range 1-108). Positive and negative predictive values for disease recurrence were 13% and 85% for interim and 33% and 87% for EOT PET, respectively. There was no significant difference in overall survival, progression-free survival nor time to progression between negative versus positive patients on interim and EOT scans. Conclusions: Negative interim and/or negative end of treatment PET identify PTLD patients with low risk of disease recurrence.


Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Recidiva Local de Neoplasia/diagnóstico , Transplante de Órgãos/efeitos adversos , Tomografia por Emissão de Pósitrons , Adulto , Idoso , Antígenos CD20/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Feminino , Fluordesoxiglucose F18/administração & dosagem , Seguimentos , Humanos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Linfoma Difuso de Grandes Células B/etiologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Valor Preditivo dos Testes , Prednisona/uso terapêutico , Prognóstico , Intervalo Livre de Progressão , Compostos Radiofarmacêuticos/administração & dosagem , Estudos Retrospectivos , Rituximab/uso terapêutico , Vincristina/uso terapêutico , Adulto Jovem
19.
Transplant Rev (Orlando) ; 33(3): 173-181, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31060880

RESUMO

Intestinal transplantation (ITX) constitutes a salvage treatment for irreversible intestinal failure and failure of parenteral nutrition. Chronic rejection (CR) remains the key obstacle for long-term intestinal graft survival but the pathomechanisms are incompletely understood. This study systematically reviews experimental models addressing CR after ITX in order to summarize current knowledge on CR pathogenesis and identify promising experimental strategies. A systematic literature search was conducted in line with the PRISMA guidelines, and 68 out of 677 articles qualified for the final analysis. The average methodological quality of the studies was suboptimal with 7 out of 11 points as assessed by a modified Oxford Centre for Evidence-Based Medicine score. Histology of the chronically rejected graft was almost universally integrated as outcome parameter but we found significant heterogeneity in utilized transplant techniques, organ preservation, immunosuppression and time points of CR-assessment. Several studies identified cellular and humoral immunologic mechanisms in chronic intestinal rejection. Yet, neither preventive nor therapeutic strategies against CR have been successfully introduced into human intestinal transplantation highlighting the persistent need for optimized experimental models. In this review, we aim to improve the translational value of forthcoming investigations on CR by discussing the experimental status quo and potential innovative approaches.


Assuntos
Rejeição de Enxerto/etiologia , Rejeição de Enxerto/terapia , Intestinos/transplante , Transplante de Órgãos/efeitos adversos , Animais , Modelos Animais de Doenças , Rejeição de Enxerto/diagnóstico
20.
Am J Med ; 132(8): 977-983.e1, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31077652

RESUMO

BACKGROUND: Cryptococcal epidemiology is changing in the modern antiretroviral era, and immune status informs outcomes. We describe the differences in clinical presentation and mortality of cryptococcosis by immune status in the antiretroviral therapy era. METHODS: We conducted a single-center retrospective cohort study of patients diagnosed with cryptococcosis from 2002 through 2017. Data included demographics, clinical features, diagnostics, and mortality. RESULTS: We identified 304 patients with Cryptococcus neoformans infections: 105 (35%) were people living with human immunodeficiency virus (HIV), 41 (13%) had a history of transplantation, and 158 (52%) were non-HIV nontransplant (NHNT). Age analysis showed that people living with HIV were younger (40 years) than transplant (53 years) and NHNT (61 years) (P < .001). Fevers and headache were more common in people living with HIV (70% and 57%) than in transplant (49% and 29%) and NHNT (49% and 38%) (P = .003 and P = .001), respectively. Meningitis was more common in people living with HIV (68%) than in transplant recipients (32%) or NHNT (39%, P < .001). Disseminated cryptococcosis was more common in people living with HIV (97%) as compared with transplant (66%) or NHNT (73%) (P < .001). Time to diagnosis from hospitalization was longer for transplant (median 2 days, interquartile range [IQR] ± 9 days) and NHNT patients (median 2 days, IQR ± 7 days) as compared with people living with HIV (median 1 day, IQR ± 2 days) (P = .003). NHNT patients had a higher risk of 90-day mortality (hazard ratio 3.3; 95% confidence interval, 1.9-5.8) as compared with people living with HIV. CONCLUSIONS: The majority of cryptococcosis occurs in NHNT patients. NHNT patients had more localized pulmonary cryptococcosis and significantly higher 90-day mortality. Cryptococcosis in NHNT patients appears to be a distinct entity that needs further study and requires a higher level of clinical suspicion than it currently receives.


Assuntos
Criptococose/mortalidade , Adulto , Estudos de Coortes , Criptococose/etiologia , Cryptococcus neoformans/efeitos dos fármacos , Cryptococcus neoformans/patogenicidade , Feminino , Infecções por HIV/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Transplante de Órgãos/efeitos adversos , Transplante de Órgãos/métodos , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Fatores de Risco , Estatísticas não Paramétricas
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