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1.
Psychiatry Res ; 281: 112544, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31499341

RESUMO

Even though lithium is widely used as treatment for mood disorders, the exact mechanisms of lithium in the brain remain unknown. A potential mechanism affects the downstream target of the Wnt/ß-catenin signaling pathway, specifically glutamine synthetase (GS). Here, we investigate the effect of lithium on GS-promoter activity in the brain. Over seven days, B6C3H-Glultm(T2A-LacZ) mice that carry LacZ as a reporter gene fused to the GS-promotor received either daily intraperitoneal injections of lithium carbonate (25 mg/kg) or NaCl, or no treatment. Following histochemical staining of ß-galactosidase relative GS-promotor activity was measured by analyzing the intensity of the staining. Furthermore cell counts were conducted. GS-promotor activity was significantly decreased in female compared to male mice. Treatment group differences were only found in male hippocampi, with increased activity after NaCl treatment compared to both the lithium treatment and no treatment. Lithium treatment increased the overall number of cells in the CA1 region in males. Daily injections of NaCl might have been sufficient to induce stress-related GS-promotor activity changes in male mice; however, lithium was able to reverse the effect. Taken together, the current study indicates that lithium acts to prevent stress, rather affecting general GS-promoter activity.

2.
Am J Phys Med Rehabil ; 98(9): 835-838, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30973517

RESUMO

Mechanical insufflation-exsufflation, or "cough assist," is a commonly used method of clearing tracheal and pulmonary secretions in patients with respiratory insufficiency secondary to spinal cord injury. This report presents a novel technique termed the pharyngeal clearance maneuver, which uses a modified application of the mechanical insufflation-exsufflation device to mobilize "secretion burden" at the portion of the trachea above the tracheostomy cuff during cuff deflation. Utilization of this strategy may reduce the risk of aspiration, infection, and respiratory compromise for patients with high cervical spinal cord injury in the acute rehabilitation setting. It is of particular benefit for those whose cuffs are being deflated for the first time and who may have large secretion volumes above the cuff. It can be further used as needed before speaking trials and swallow therapies. We anticipate that the pharyngeal clearance maneuver may be used in other populations with impaired cough and need for invasive ventilator support because of ventilator pump failure (eg, spinal muscular atrophy, congenital myopathies, obesity hypoventilation, amyotrophic lateral sclerosis, muscular dystrophy, and acute inflammatory demyelinating polyneuropathy).

3.
Surg Clin North Am ; 99(1): 49-64, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30471741

RESUMO

Posttransplant malignancy is a leading cause of death after solid organ transplantation (SOT). Recipients of SOT are at significantly higher risk of multiple cancers compared with the general population, most notably nonmelanoma skin cancer and posttransplant lymphoproliferative disorders. Risk factors for posttransplant malignancy include history of malignancy, immunosuppression, oncogenic viral infections, sun exposure, and disease-specific associations. Early detection and treatment of malignancies can improve survival.


Assuntos
Neoplasias/etiologia , Transplante de Órgãos/efeitos adversos , Humanos , Imunossupressão , Fatores de Risco
4.
J Affect Disord ; 242: 1-4, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30153563

RESUMO

BACKGROUND: Identifying correlates of capacity to provide informed consent among individuals with bipolar disorder is essential for patient protection. As part of a clinical trial involving approved, standard treatments, we investigated relationships between clinical characteristics and capacity to provide informed consent in adults with bipolar disorder using the MacArthur Competence Assessment Tool for Clinical Research (MacCAT-CR). After administering the MacCAT-CR, continuing participants in the trial were capable of and provided informed consent. METHODS: Trained, board-certified psychiatrists administered the MacCAT-CR to potential study participants (N = 50) after they provided informed consent, but prior to initiation of study procedures. RESULTS: Higher Schedule for Assessment of Positive Symptoms (SAPS) scores were significantly correlated with worse MacCAT-CR Understanding and Appreciation (p < 0.04) subscale scores; lower Hamilton Depression Rating Scale (HDRS) scores and higher Clinical Global Impression-Severity (CGI-S) scores were significantly correlated with worse Reasoning and Understanding subscale scores (p < 0.03); and patients with comorbid substance use disorders (SUD) had better Appreciation and Reasoning subscale scores (p < 0.05). LIMITATIONS: The MacCAT-CR identifies areas where participants need explanation. However, there is not a predetermined score to indicate understanding of study procedures and therefore input from a trained clinician is needed to determine capacity to provide informed consent. CONCLUSIONS: Our findings suggest that certain measures of illness severity are associated with lower levels of capacity to provide informed consent among adults with bipolar disorder. This study provides important information for clinicians and researchers to consider when obtaining informed consent in this population.


Assuntos
Transtorno Bipolar/psicologia , Consentimento Livre e Esclarecido/psicologia , Competência Mental/psicologia , Adulto , Tomada de Decisões , Feminino , Humanos , Testes de Inteligência , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Resolução de Problemas
5.
Neuropsychopharmacology ; 43(11): 2256-2263, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29946107

RESUMO

The need for treatment response predictive biomarkers is being increasingly recognized in children and adolescents with psychiatric disorders. Structural gray matter abnormalities as a predictor of treatment outcome in pediatric bipolar disorder have not been systematically investigated, especially early in the illness course. With a prospective longitudinal study design, the present study enrolled 52 bipolar adolescents with no history of treatment with mood stabilizers or a therapeutic dose of antipsychotic drugs and 31 healthy controls. Patients were randomly assigned to treatment with quetiapine or lithium after pretreatment data collection. A hierarchical cluster analysis was performed using pretreatment cortical thickness data that identified two discrete patient subgroups. Compared to healthy subjects, patients in subgroup 1 (n = 16) showed widespread greater cortical thickness mainly across heteromodal cortex but also involving some regions of unimodal cortex, while those in subgroup 2 (n = 36) showed regional cortical thinning mainly in superior temporal and superior parietal regions. Patients within subgroup 1 showed a significantly higher response rate to quetiapine than those in subgroup 2 (100% vs 53%). No statistically significant difference was found in lithium response rate between the patient subgroups (63% vs 53%). Pretreatment clinical ratings and neuropsychological data did not differ across subgroups. Our findings suggest the existence of distinct and clinically relevant subgroups of pediatric bipolar patients, as defined by pattern of cortical thickness. These groups appear to differentially respond to antipsychotic treatment-notably with greater cortical thickness relative to controls predicting better treatment response.

7.
Vaccine ; 36(44): 6546-6552, 2018 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-29605515

RESUMO

BACKGROUND: Annual vaccination is the most effective way to prevent and control the health and economic burden caused by seasonal influenza. Healthcare workers (HCWs) play a crucial role in vaccine acceptance and advocacy for their patients. This study explored the drivers of HCWs' vaccine acceptance and advocacy in six European countries. METHODS: Healthcare workers (mainly general practitioners, specialist physicians, and nurses) voluntarily completed a questionnaire in Bulgaria (N = 485), Czech Republic (N = 518), Kosovo (N = 466), Poland (N = 772), Romania (N = 155), and the United Kingdom (N = 80). Twelve-item scales were used to analyse sentiment clusters for influenza vaccination acceptance and engagement with vaccination advocacy. Past vaccination behaviour and patient recommendation were also evaluated. All data were included in a single analysis. RESULTS: For vaccination acceptance, the main cluster (engaged sentiment: 68%) showed strong positive attitudes for influenza vaccination. A second cluster (hesitant sentiment: 32%) showed more neutral attitudes. Cluster membership was predicted by country of origin and age. The odds ratio for past vaccination in the engaged cluster was 39.6 (95% CI 12.21-128.56) although this varied between countries. For vaccination advocacy, the main cluster (confident sentiment: 73%) showed strong positive attitudes towards advocacy; a second cluster (diffident sentiment: 27%) showed neutral attitudes. Cluster membership was predicted by country of origin, age and profession, with specialist physicians being the least likely to belong to the confident sentiment cluster. HCWs characterised by confident advocacy sentiments were also more likely recommend flu vaccination. Again, this association was moderated by country of origin. CONCLUSIONS: These data show that there is room to improve both vaccination acceptance and advocacy rates in European HCWs, which would be expected to lead to higher rates of HCW vaccination. Benefits that could be expected from such an outcome are improved advocacy and better control of morbidity and mortality related to seasonal influenza infection.

9.
Emerg Infect Dis ; 22(11)2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27767010

RESUMO

Babesia microti, an intraerythrocytic parasite, is tickborne in nature. In contrast to transmission by blood transfusion, which has been well documented, transmission associated with solid organ transplantation has not been reported. We describe parasitologically confirmed cases of babesiosis diagnosed ≈8 weeks posttransplantation in 2 recipients of renal allografts from an organ donor who was multiply transfused on the day he died from traumatic injuries. The organ donor and recipients had no identified risk factors for tickborne infection. Antibodies against B. microti parasites were not detected by serologic testing of archived pretransplant specimens. However, 1 of the organ donor's blood donors was seropositive when tested postdonation and had risk factors for tick exposure. The organ donor probably served as a conduit of Babesia parasites from the seropositive blood donor to both kidney recipients. Babesiosis should be included in the differential diagnosis of unexplained fever and hemolytic anemia after blood transfusion or organ transplantation.


Assuntos
Babesia microti , Babesiose/parasitologia , Babesiose/transmissão , Transplante de Órgãos/efeitos adversos , Adulto , Idoso , Babesia microti/genética , Babesia microti/imunologia , Babesiose/diagnóstico , Babesiose/tratamento farmacológico , Biomarcadores , Transfusão de Sangue , Eritrócitos/parasitologia , Eritrócitos/patologia , Humanos , Transplante de Rim/efeitos adversos , Masculino , Fatores de Tempo , Doadores de Tecidos , Tomografia Computadorizada por Raios X , Transplante Homólogo
10.
Bipolar Disord ; 18(6): 490-501, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27647671

RESUMO

OBJECTIVES: We tested the hypothesis that, with treatment, functional magnetic resonance imaging (fMRI) regional brain activation in first-episode mania would normalize - i.e., that differences from healthy subjects would diminish over time, and would be associated with clinical remission status, potentially identifying neuroanatomic treatment response markers. METHODS: Forty-two participants with bipolar I disorder were recruited during their first manic episode, pseudo-randomized to open-label lithium or quetiapine, and followed for 8 weeks. fMRI scans were obtained at baseline and then after 1 and 8 weeks of treatment, while participants performed a continuous performance task with emotional distracters. Healthy participants received fMRI scans at these same intervals. Specific region-of-interest (ROI) activations within prefrontal emotional networks were assessed as potential measures of treatment response. RESULTS: ROI data were reduced using exploratory factor analysis, which identified five factors that were organizationally consistent with functional anatomic models of human emotion modulation. Half of the participants with bipolar disorder achieved remission by Week 8 and were contrasted with the other half that did not. Analyses demonstrated that, in the bipolar disorder group in general, treatment led to decreases in activation across brain regions toward healthy subject values. However, differences in activation changes were observed between subjects with bipolar disorder who did or did not achieve remission in subcortical and amygdala factors. CONCLUSIONS: These findings provide evidence for potential neuroanatomic treatment response markers in first-episode bipolar disorder.


Assuntos
Tonsila do Cerebelo , Transtorno Bipolar , Lítio/uso terapêutico , Imagem por Ressonância Magnética/métodos , Fumarato de Quetiapina/uso terapêutico , Adulto , Tonsila do Cerebelo/diagnóstico por imagem , Tonsila do Cerebelo/fisiopatologia , Antimaníacos/uso terapêutico , Transtorno Bipolar/diagnóstico , Transtorno Bipolar/psicologia , Transtorno Bipolar/terapia , Emoções/fisiologia , Cuidado Periódico , Feminino , Humanos , Masculino , Escalas de Graduação Psiquiátrica , Análise e Desempenho de Tarefas , Resultado do Tratamento
11.
Pharmacotherapy ; 35(12): 1109-16, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26616582

RESUMO

Tacrolimus-induced cardiomyopathy (TICM) is a rare but serious adverse effect of tacrolimus, which has been described primarily in pediatric non-renal transplant recipients. We describe a case of TICM in an adult renal transplant recipient that resulted in allograft dysfunction and multiple hospital admissions for heart failure exacerbation. Prompt and complete reversal of TICM occurred after tacrolimus discontinuation. Although tacrolimus-induced cardiomyopathy is reversible, availability of alternative immunosuppressants is limited, particularly in the setting of renal dysfunction. Available studies and patient-specific factors must be considered when determining an alternative maintenance immunosuppression regimen. We chose to use belatacept as alternative immunosuppression in this patient with TICM. Over the next 3 years, the patient remained free of hospital admissions and acute rejection, and demonstrated superior renal allograft function than was observed before her first heart failure admission. We believe that belatacept is an acceptable alternative to tacrolimus therapy for resolution of TICM.


Assuntos
Cardiomiopatias/diagnóstico , Rejeição de Enxerto/prevenção & controle , Imunossupressores/efeitos adversos , Transplante de Rim , Tacrolimo/efeitos adversos , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/diagnóstico por imagem , Diagnóstico Diferencial , Feminino , Humanos , Falência Renal Crônica , Pessoa de Meia-Idade , Ultrassonografia
12.
Transpl Int ; 28(9): 1121-5, 2015 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25864519

RESUMO

De novo thrombotic microangiopathy (TMA) after renal transplant is rare. Cytomegalovirus (CMV)-related post-transplant TMA has only been reported in 6 cases. We report an unusual case of a 75-year-old woman who developed de novo TMA in association with CMV viremia. The recurrence of TMA with CMV viremia, the resolution with treatment for CMV, and the lack of correlation with a calcineurin inhibitor (CNI) in our case support CMV as the cause of the TMA. What is unique is that the use of eculizumab without plasmapheresis led to prompt improvement in renal function. After a failure to identify a genetic cause for TMA and the clear association with CMV, eculizumab was discontinued. This case provides insight into the pathogenesis and novel treatment of de novo TMA, highlights the beneficial effects of complement inhibitors in this disease, and shows that they can be safely discontinued once the inciting etiology is addressed.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Infecções por Citomegalovirus/complicações , Transplante de Rim/efeitos adversos , Microangiopatias Trombóticas/complicações , Idoso , Anticorpos Monoclonais/química , Inibidores de Calcineurina/uso terapêutico , Proteínas do Sistema Complemento , Citomegalovirus , Feminino , Humanos , Imunossupressores/uso terapêutico , Complicações Pós-Operatórias , Recidiva , Microangiopatias Trombóticas/virologia
13.
Am J Nephrol ; 41(1): 37-47, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25634230

RESUMO

BACKGROUND/AIMS: Post-renal transplant recurrent glomerulonephritis (GN) contributes to allograft loss. Rituximab treatment has been used in a multidose strategy with variable efficacy and toxicity. We investigated a novel single-dose approach. METHODS: A single center, retrospective, cohort study was conducted between January 1998 and April 2012 among renal allograft recipients with recurrent GN treated with rituximab (cases) or without (controls). The primary outcome was complete response (CR, urine protein/creatinine ratio (UP/C) <0.3). Secondary outcomes included partial response (PR >50% reduction in UP/C), response relapse, treatment-response by GN type, acute rejection incidence, time to graft loss, and infection incidence. RESULTS: The median dose of rituximab was 200 mg per patient. Of 20 rituximab cases and 13 controls, CR was achieved in eight (40%) versus four (31%), respectively (p = 0.72). Three subjects in each group achieved PR (p = 0.66). Response relapse was similar between the two groups (p = 0.47). Significantly more subjects with recurrent membranous nephropathy (MN) achieved CR with rituximab treatment (p = 0.029). Acute rejection was lower in the rituximab group versus controls (n = 0 vs. 4; p = 0.046). The mean time to graft loss was much later in the rituximab group (35 months, (95% CI 33-37)) versus controls (29 months, (95% CI 24-35)) at 36 months (p = 0.04). There was no infection increase in rituximab-treated subjects (p = 0.16). CONCLUSION: Single-dose rituximab for treatment of recurrent GN was associated with less subsequent rejection and longer time to graft loss without increased infection, but was no more effective than regimens not using rituximab at 36-months except those with recurrent membranous GN.


Assuntos
Anticorpos Monoclonais Murinos/administração & dosagem , Glomerulonefrite Membranosa/tratamento farmacológico , Fatores Imunológicos/administração & dosagem , Transplante de Rim , Adulto , Anticorpos Monoclonais Murinos/efeitos adversos , Feminino , Taxa de Filtração Glomerular , Glomerulonefrite Membranosa/fisiopatologia , Rejeição de Enxerto/tratamento farmacológico , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Fatores Imunológicos/efeitos adversos , Infecção/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Período Pós-Operatório , Recidiva , Estudos Retrospectivos , Rituximab , Fatores de Tempo , Resultado do Tratamento
14.
Transplantation ; 98(1): 54-65, 2014 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-24978035

RESUMO

BACKGROUND: Descriptions of the sequelae of ABO-incompatible (ABOi) kidney transplantation are limited to single-center reports, which may lack power to detect important effects. METHODS: We examined U.S. Renal Data System registry data to study associations of ABOi live-donor kidney transplantation with clinical complications in a national cohort. Among 14,041 Medicare-insured transplants in 2000 to 2007, 119 non-donor-A2 ABOi transplants were identified. A2-incompatible (n=35) transplants were categorized separately. Infection and hemorrhage events were identified by diagnosis codes on billing claims. Associations of ABO incompatibility with complications were assessed by multivariate Cox regression. RESULTS: Recipients of ABOi transplants experienced significantly (P<0.05) higher incidence of wound infections (12.7% vs. 7.3%), pneumonia (7.6% vs. 3.8%), and urinary tract infections (UTIs) or pyelonephritis (24.5% vs. 15.3%) in the first 90 days compared with ABO-compatible recipients. In adjusted models, ABO incompatibility was associated with twice the risk of pneumonia (adjusted hazard ratio [aHR], 2.22; 95% confidence interval [CI], 1.14-4.33) and 56% higher risk of UTIs or pyelonephritis (aHR, 1.56; 95% CI, 1.05-2.30) in the first 90 posttransplantation days, and 3.5 times the relative risk of wound infections in days 91 to 365 (aHR, 3.55; 95% CI, 1.92-6.57). ABOi recipients, 19% of whom underwent pre- or peritransplant splenectomy, experienced twice the adjusted risk of early hemorrhage (aHR, 1.96; 95% CI, 1.19-3.24). A2-incompatible transplantation was associated only with early risk of UTIs or pyelonephritis. CONCLUSION: ABOi transplantation offers patients with potential live donors an additional transplant option but with higher risks of infectious and hemorrhagic complications. Awareness of these complications may help improve protocols for the management of ABOi transplantation.


Assuntos
Sistema do Grupo Sanguíneo ABO/imunologia , Incompatibilidade de Grupos Sanguíneos/imunologia , Histocompatibilidade , Transplante de Rim/efeitos adversos , Doadores Vivos , Medicare , Hemorragia Pós-Operatória/etiologia , Pielonefrite/etiologia , Infecções Urinárias/etiologia , Adulto , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Modelos de Riscos Proporcionais , Sistema de Registros , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , Estados Unidos
15.
Psychiatry Res ; 223(3): 268-70, 2014 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-25035298

RESUMO

This preliminary study investigated the neurofunctional effects of carbamazepine-extended release (XR) treatment in 11 manic youth with bipolar disorder during performance of a sustained attention task, the Continuous Performance Task - Identical Pairs version (CPT-IP), during functional magnetic resonance imaging (fMRI). All patients underwent baseline fMRI, and 10 patients were scanned again at endpoint. Nine demographically matched healthy youth, who were scanned once, served as controls. Carbamazepine-XR treatment was associated with normalization of activation in right Brodmann area 10 (BA). These results suggest that carbamazepine-XR treatment may correct prefrontal dysfunction in adolescent mania.


Assuntos
Antimaníacos/farmacologia , Atenção , Carbamazepina/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiopatologia , Análise e Desempenho de Tarefas , Adolescente , Atenção/efeitos dos fármacos , Transtorno Bipolar , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/fisiopatologia , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino
16.
J Mol Microbiol Biotechnol ; 24(2): 67-81, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24481069

RESUMO

Purines of exogenous and endogenous sources are degraded to uric acid in human beings. Concentrations >6.8 mg uric acid/dl serum cause hyperuricemia and its symptoms. Pharmaceuticals and the reduction of the intake of purine-rich food are used to control uric acid levels. A novel approach to the latter proposition is the enzymatic reduction of the purine content of food by purine-degrading enzymes. Here we describe the production of recombinant guanine deaminase by the yeast Arxula adeninivorans LS3 and its application in food. In media supplemented with nitrogen sources hypoxanthine or adenine, guanine deaminase (AGDA) gene expression is induced and intracellular accumulation of guanine deaminase (Agdap) protein occurs. The characteristics of the guanine deaminase isolated from wild-type strain LS3 and a transgenic strain expressing the AGDA gene under control of the strong constitutive TEF1 promoter were determined and compared. Both enzymes were dimeric and had temperature optima of 55°C with high substrate specificity for guanine and localisation in both the cytoplasm and vacuole of yeast. The enzyme was demonstrated to reduce levels of guanine in food. A mixture of guanine deaminase and other purine degradation enzymes will allow the reduction of purines in purine-rich foods.


Assuntos
Microbiologia de Alimentos , Guanina Desaminase/metabolismo , Purinas/análise , Saccharomycetales/enzimologia , Estabilidade Enzimática , Análise de Alimentos , Guanina Desaminase/química , Guanina Desaminase/genética , Multimerização Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Saccharomycetales/genética , Especificidade por Substrato , Temperatura Ambiente
17.
J Mol Microbiol Biotechnol ; 23(6): 418-30, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-24022585

RESUMO

Hyperuricemia and its symptoms are becoming increasingly common worldwide. Elevated serum uric acid levels are caused by increased uric acid synthesis from food constituents and reduced renal excretion. Treatment in most cases involves reducing alcohol intake and consumption of meat and fish or treatment with pharmaceuticals. Another approach could be to reduce uric acid level in food, either during production or consumption. This work reports the production of recombinant urate oxidase by Arxula adeninivorans and its application to reduce uric acid in a food product. The A. adeninivorans urate oxidase amino acid sequence was found to be similar to urate oxidases from other fungi (61-65% identity). In media supplemented with adenine, hypoxanthine or uric acid, induction of the urate oxidase (AUOX) gene and intracellular accumulation of urate oxidase (Auoxp) was observed. The enzyme characteristics were analyzed from isolates of the wild-type strain A. adeninivorans LS3, as well as from those of transgenic strains expressing the AUOX gene under control of the strong constitutive TEF1 promoter or the inducible AYNI1 promoter. The enzyme showed high substrate specificity for uric acid, a broad temperature and pH range, high thermostability and the ability to reduce uric acid content in food.


Assuntos
Manipulação de Alimentos/métodos , Saccharomycetales/enzimologia , Urato Oxidase/metabolismo , Ácido Úrico/metabolismo , Adenina/metabolismo , DNA Fúngico/química , DNA Fúngico/genética , Estabilidade Enzimática , Perfilação da Expressão Gênica , Concentração de Íons de Hidrogênio , Hipoxantina/metabolismo , Dados de Sequência Molecular , Proteínas Recombinantes/química , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Saccharomycetales/genética , Análise de Sequência de DNA , Homologia de Sequência de Aminoácidos , Especificidade por Substrato , Temperatura Ambiente , Urato Oxidase/química , Urato Oxidase/genética
18.
Hum Immunol ; 74(11): 1478-85, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23876679

RESUMO

Recent studies strongly suggest an increasing role for immune responses against self-antigens (Ags) which are not encoded by the major histocompatibility complex in the immunopathogenesis of allograft rejection. Although, improved surgical techniques coupled with improved methods to detect and avoid sensitization against donor human leukocyte antigen (HLA) have improved the immediate and short term function of transplanted organs. However, acute and chronic rejection still remains a vexing problem for the long term function of the transplanted organ. Immediately following organ transplantation, several factors both immune and non immune mechanisms lead to the development of local inflammatory milieu which sets the stage for allograft rejection. Traditionally, development of antibodies (Abs) against mismatched donor HLA have been implicated in the development of Ab mediated rejection. However, recent studies from our laboratory and others have demonstrated that development of humoral and cellular immune responses against non-HLA self-Ags may contribute in the pathogenesis of allograft rejection. There are reports demonstrating that immune responses to self-Ags especially Abs to the self-Ags as well as cellular immune responses especially through IL17 has significant pro-fibrotic properties leading to chronic allograft failure. This review summarizes recent studies demonstrating the role for immune responses to self-Ags in allograft immunity leading to rejection as well as present recent evidence suggesting there is interplay between allo- and autoimmunity leading to allograft dysfunction.


Assuntos
Aloenxertos/patologia , Autoantígenos/imunologia , Rejeição de Enxerto/imunologia , Transplante de Órgãos , Complicações Pós-Operatórias/imunologia , Animais , Autoimunidade , Microambiente Celular , Fibrose , Rejeição de Enxerto/etiologia , Antígenos HLA/imunologia , Humanos , Imunidade Celular , Imunidade Humoral , Interleucina-17/imunologia
19.
PLoS One ; 8(1): e53745, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23341990

RESUMO

BACKGROUND: Ipilimumab, a cytotoxic T-lymphocyte antigen-4 (CTLA-4) blocking antibody, has been approved for the treatment of metastatic melanoma and induces adverse events (AE) in up to 64% of patients. Treatment algorithms for the management of common ipilimumab-induced AEs have lead to a reduction of morbidity, e.g. due to bowel perforations. However, the spectrum of less common AEs is expanding as ipilimumab is increasingly applied. Stringent recognition and management of AEs will reduce drug-induced morbidity and costs, and thus, positively impact the cost-benefit ratio of the drug. To facilitate timely identification and adequate management data on rare AEs were analyzed at 19 skin cancer centers. METHODS AND FINDINGS: Patient files (n = 752) were screened for rare ipilimumab-associated AEs. A total of 120 AEs, some of which were life-threatening or even fatal, were reported and summarized by organ system describing the most instructive cases in detail. Previously unreported AEs like drug rash with eosinophilia and systemic symptoms (DRESS), granulomatous inflammation of the central nervous system, and aseptic meningitis, were documented. Obstacles included patients delay in reporting symptoms and the differentiation of steroid-induced from ipilimumab-induced AEs under steroid treatment. Importantly, response rate was high in this patient population with tumor regression in 30.9% and a tumor control rate of 61.8% in stage IV melanoma patients despite the fact that some patients received only two of four recommended ipilimumab infusions. This suggests that ipilimumab-induced antitumor responses can have an early onset and that severe autoimmune reactions may reflect overtreatment. CONCLUSION: The wide spectrum of ipilimumab-induced AEs demands doctor and patient awareness to reduce morbidity and treatment costs and true ipilimumab success is dictated by both objective tumor responses and controlling severe side effects.


Assuntos
Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/imunologia , Antígeno CTLA-4/imunologia , Melanoma/tratamento farmacológico , Melanoma/patologia , Neoplasias Cutâneas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/efeitos adversos , Antineoplásicos/imunologia , Antineoplásicos/uso terapêutico , Sistema Endócrino/efeitos dos fármacos , Feminino , Trato Gastrointestinal/efeitos dos fármacos , Humanos , Ipilimumab , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Sistema Nervoso/efeitos dos fármacos , Pâncreas/efeitos dos fármacos , Sistema Respiratório/efeitos dos fármacos , Estudos Retrospectivos , Pele/efeitos dos fármacos
20.
Transpl Int ; 26(7): 662-72, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23279211

RESUMO

Currently available immunosuppressive agents can be classified into three categories: induction agents, maintenance therapy, and treatment for rejection. This review article will focus on induction immunosuppression. There are three antibodies which are used for induction therapy: the lymphocyte-depleting agents - anti-thymocyte globulin and alemtuzumab, and basiliximab which is nondepleting. Historically, immunosuppressant selection was solely based on efficacy for prevention of rejection. In the current era of transplantation, it is now common practice in the transplant community to select induction therapy on the basis of risk-benefit considerations for each patient. This article will focus on the efficacy of available induction agents and the selection of induction agent based on donor and recipient risk factors.


Assuntos
Imunossupressores/uso terapêutico , Transplante de Rim , Alemtuzumab , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Soro Antilinfocitário/uso terapêutico , Basiliximab , Função Retardada do Enxerto/etiologia , Humanos , Imunossupressores/efeitos adversos , Doadores Vivos , Proteínas Recombinantes de Fusão/uso terapêutico
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