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1.
Genes (Basel) ; 11(2)2020 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-32028618

RESUMO

Cutaneous lupus erythematosus (CLE) in humans encompasses multiple subtypes that exhibit a wide array of skin lesions and, in some cases, are associated with the development of systemic lupus erythematosus (SLE). We investigated dogs with exfoliative cutaneous lupus erythematosus (ECLE), a dog-specific form of chronic CLE that is inherited as a monogenic autosomal recessive trait. A genome-wide association study (GWAS) with 14 cases and 29 controls confirmed a previously published result that the causative variant maps to chromosome 18. Autozygosity mapping refined the ECLE locus to a 493 kb critical interval. Filtering of whole genome sequence data from two cases against 654 controls revealed a single private protein-changing variant in this critical interval, UNC93B1:c.1438C>A or p.Pro480Thr. The homozygous mutant genotype was exclusively observed in 23 ECLE affected German Shorthaired Pointers and an ECLE affected Vizsla, but absent from 845 controls. UNC93B1 is a transmembrane protein located in the endoplasmic reticulum and endolysosomes, which is required for correct trafficking of several Toll-like receptors (TLRs). The p.Pro480Thr variant is predicted to affect the C-terminal tail of the UNC93B1 that has recently been shown to restrict TLR7 mediated autoimmunity via an interaction with syndecan binding protein (SDCBP). The functional knowledge on UNC93B1 strongly suggests that p.Pro480Thr is causing ECLE in dogs. These dogs therefore represent an interesting spontaneous model for human lupus erythematosus. Our results warrant further investigations of whether genetic variants affecting the C-terminus of UNC93B1 might be involved in specific subsets of CLE or SLE cases in humans and other species.


Assuntos
Doenças do Cão/genética , Lúpus Eritematoso Cutâneo/genética , Lúpus Eritematoso Cutâneo/veterinária , Proteínas de Membrana Transportadoras/genética , Mutação de Sentido Incorreto , Animais , Doenças do Cão/patologia , Cães , Estudo de Associação Genômica Ampla , Lúpus Eritematoso Cutâneo/patologia , Masculino , Sequenciamento Completo do Genoma
2.
Vet Dermatol ; 24(3): 315-22, e70, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23530522

RESUMO

BACKGROUND: Little information is available on the ciclosporin dose-tapering regimen and clinical response in the treatment of feline hypersensitivity dermatitis. HYPOTHESIS/OBJECTIVES: To test a dose-tapering regimen and assess efficacy and clinical safety for up to 18 weeks. ANIMALS: Eighty-eight client-owned cats with feline hypersensitivity dermatitis. METHODS: Cats that received either a placebo or ciclosporin at 2.5 mg/kg or 7 mg/kg daily for 6 weeks were given 7 mg/kg ciclosporin daily for 4 weeks. Depending on the clinical response, the dose was tapered from daily to every other day over the next 4 weeks and further to twice a week for an additional 4 weeks. RESULTS: After all cats received 7 mg/kg for 4 weeks, the dose could be tapered to every other day for the next 4 weeks in 70% of cats remaining in the study. During the next 4 weeks, 57, 15 and 22% of cats remaining in the study could be treated at twice a week, every other day or daily, respectively. After the first 4 weeks, the mean lesion score and owner-assessed pruritus improved over baseline by 69 and 61%, respectively, and remained stable during the following 8 weeks. Approximately 65% of the cats in the study were reported to have an adverse event (AE), very often mild and resolving spontaneously. The most frequent AEs were gastrointestinal and included primarily vomiting and diarrhoea. Eighty per cent of AEs occurred when cats were on daily treatment. CONCLUSIONS AND CLINICAL IMPORTANCE: Results suggest that the induction dose of 7 mg/kg ciclosporin can be tapered as soon as 4 weeks without deterioration of the clinical response. Establishment of the lowest effective dosing regimen of ciclosporin reduced the frequency of AEs.


Assuntos
Doenças do Gato/tratamento farmacológico , Ciclosporina/administração & dosagem , Ciclosporina/uso terapêutico , Dermatite/veterinária , Hipersensibilidade/veterinária , Animais , Gatos , Dermatite/tratamento farmacológico , Esquema de Medicação , Hipersensibilidade/tratamento farmacológico
3.
Vet Dermatol ; 22(6): 554-64, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21668810

RESUMO

This study investigated the efficacy and safety of masitinib, a selective tyrosine kinase inhibitor capable of downregulating mast cell functions, for treatment of canine atopic dermatitis (CAD). Dogs with confirmed CAD received masitinib at 12.5 mg/kg/day (n = 202) or control (n = 104) for 12 weeks. A reduction in CAD Extent and Severity Index (CADESI-02) score of ≥ 50% at week 12 was observed in 61% of masitinib-treated dogs versus 35% of control dogs (P < 0.001), according to the modified intent-to-treat population. For dogs resistant to ciclosporin and/or corticosteroids (60% of the study population), CADESI-02 response rates were 60 versus 31%, respectively (P = 0.004). The mean reduction in pruritus score of severely pruritic dogs was 46 versus 29%, respectively (P = 0.045). Furthermore, 65% of owners with severely pruritic dogs assessed masitinib efficacy as good/excellent versus 35% control (P = 0.05). Overall, 63% of investigators assessed masitinib efficacy as good/excellent versus 35% control (P < 0.001). Premature discontinuations from the modified intent-to-treat population (28.2% masitinib versus 26.0% control) were mainly due to adverse events (13.4 versus 4.8%, respectively) or lack of efficacy (12.4 versus 18.3%, respectively). In total, 13.2% dogs presented with severe adverse events (16.0% masitinib versus 7.7% control). Masitinib showed a risk of reversible protein loss, although regular surveillance of blood albumin and proteinuria allowed for discontinuation of treatment while the dog was still clinically asymptomatic. Masitinib proved to be an effective and mostly well-tolerated treatment of CAD, including severe and refractory cases, with medically manageable adverse effects.


Assuntos
Dermatite Atópica/veterinária , Doenças do Cão/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Animais , Benzamidas , Dermatite Atópica/tratamento farmacológico , Cães , Método Duplo-Cego , Esquema de Medicação/veterinária , Feminino , Masculino , Piperidinas , Estudos Prospectivos , Inibidores de Proteínas Quinases/efeitos adversos , Piridinas , Índice de Gravidade de Doença , Tiazóis/efeitos adversos , Tiazóis/uso terapêutico , Resultado do Tratamento
4.
Blood ; 117(3): 788-97, 2011 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-21030558

RESUMO

In a phase 1/2 two-arm trial, 54 patients with myeloma received autografts followed by ex vivo anti-CD3/anti-CD28 costimulated autologous T cells at day 2 after transplantation. Study patients positive for human leukocyte antigen A2 (arm A, n = 28) also received pneumococcal conjugate vaccine immunizations before and after transplantation and a multipeptide tumor antigen vaccine derived from the human telomerase reverse transcriptase and the antiapoptotic protein survivin. Patients negative for human leukocyte antigen A2 (arm B, n = 26) received the pneumococcal conjugate vaccine only. Patients exhibited robust T-cell recoveries by day 14 with supraphysiologic T-cell counts accompanied by a sustained reduction in regulatory T cells. The median event-free survival (EFS) for all patients is 20 months (95% confidence interval, 14.6-24.7 months); the projected 3-year overall survival is 83%. A subset of patients in arm A (36%) developed immune responses to the tumor antigen vaccine by tetramer assays, but this cohort did not exhibit better EFS. Higher posttransplantation CD4(+) T-cell counts and a lower percentage of FOXP3(+) T cells were associated with improved EFS. Patients exhibited accelerated polyclonal immunoglobulin recovery compared with patients without T-cell transfers. Adoptive transfer of tumor antigen vaccine-primed and costimulated T cells leads to augmented and accelerated cellular and humoral immune reconstitution, including antitumor immunity, after autologous stem cell transplantation for myeloma. This study was registered at www.clinicaltrials.gov as NCT00499577.


Assuntos
Imunoterapia/métodos , Mieloma Múltiplo/terapia , Fragmentos de Peptídeos/imunologia , Vacinação/métodos , Adulto , Idoso , Sequência de Aminoácidos , Antígenos de Neoplasias/imunologia , Terapia Combinada , Exantema/etiologia , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Imunoterapia/efeitos adversos , Imunoterapia Adotiva , Proteínas Inibidoras de Apoptose , Estimativa de Kaplan-Meier , Masculino , Proteínas Associadas aos Microtúbulos/química , Proteínas Associadas aos Microtúbulos/imunologia , Pessoa de Meia-Idade , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/patologia , Náusea/etiologia , Survivina , Linfócitos T/imunologia , Linfócitos T/transplante , Telomerase/química , Telomerase/imunologia , Transplante Autólogo , Resultado do Tratamento , Vacinação/efeitos adversos , Vômito/etiologia
5.
Clin Cancer Res ; 15(13): 4499-507, 2009 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-19509133

RESUMO

PURPOSE: Previously, we showed that adoptive transfer of in vivo vaccine-primed and ex vivo (anti-CD3/anti-CD28) costimulated autologous T cells (ex-T) at day +12 after transplant increased CD4 and CD8 T-cell counts at day +42 and augmented vaccine-specific immune responses in patients with myeloma. Here, we investigated the safety and kinetics of T-cell recovery after infusing ex-T at day +2 after transplant. EXPERIMENTAL DESIGN: In this phase I/II two-arm clinical trial, 50 patients with myeloma received autografts after high-dose melphalan followed by infusions of ex-T at day +2 after transplant. Patients also received pretransplant and posttransplant immunizations using a pneumococcal conjugate vaccine only (arm B; n = 24) or the pneumococcal conjugate vaccine plus an HLA-A2-restricted microltipeptide vaccine for HLA-A2(+) patients (arm A; n = 26). RESULTS: The mean number of T cells infused was 4.26 x 10(10) (range, 1.59-5.0). At day 14 after transplant, the median CD3, CD4, and CD8 counts were 4,198, 1,545, and 2,858 cells/microL, respectively. Interleukin (IL)-6 and IL-15 levels increased early after transplant and IL-15 levels correlated significantly to day 14 T-cell counts. Robust vaccine-specific B- and T-cell responses were generated. T-cell infusions were well tolerated with no effect on hematopoietic recovery. Eight patients (16%) developed a T-cell "engraftment syndrome" characterized by diarrhea and fever that was clinically and histopathologically indistinguishable from grade 1 to 3 acute graft-versus-host disease (GVHD) of the gastrointestinal tract (seven patients) and/or grade 1 to 2 cutaneous GVHD (four patients). CONCLUSIONS: Adoptive T-cell transfers achieve robust T-cell recovery early after transplant and induce moderate-to-severe autologous GVHD in a subset of patients.


Assuntos
Doença Enxerto-Hospedeiro/reabilitação , Imunoterapia Adotiva , Mieloma Múltiplo/terapia , Recuperação de Função Fisiológica/imunologia , Linfócitos T/transplante , Adulto , Idoso , Algoritmos , Células Cultivadas , Feminino , Doença Enxerto-Hospedeiro/imunologia , Antígeno HLA-A2/metabolismo , Humanos , Imunoterapia Adotiva/efeitos adversos , Imunoterapia Adotiva/métodos , Ativação Linfocitária/imunologia , Ativação Linfocitária/fisiologia , Masculino , Melfalan/uso terapêutico , Pessoa de Meia-Idade , Mieloma Múltiplo/imunologia , Agonistas Mieloablativos/uso terapêutico , Síndrome , Transplante Autólogo
6.
BJU Int ; 96(9): 1301-6, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16287449

RESUMO

OBJECTIVES: To assess the long-term outcomes of untreated bladder outlet obstruction (BOO), assuming that, if there is little or no deterioration, a conservative approach to management is justified, as there is little information on the natural history of untreated BOO and lower urinary tract symptoms (LUTS) in men, and studies to date suggest that neither BOO nor LUTS inevitably progress to a stage at which prostatectomy is required. PATIENTS AND METHODS: Men aged >45 years who were investigated in our department between 1972 and 1986, diagnosed with BOO, and who initially opted for no specific treatment were invited for repeat symptomatic and urodynamic evaluation. Identical methods of assessment were used, allowing results to be compared directly. RESULTS: In all, 1068 men were initially diagnosed with BOO; 428 (40%) of these died. Of the 170 men who initially opted for a conservative approach and attended for repeat assessment, 141 (83%) remained untreated, with a mean follow-up of 13.9 years. The only significant urodynamic changes were a reduction in detrusor contractility and an increased prevalence of detrusor overactivity. Most patients reported no change in their symptoms but a significant minority experienced a gradual deterioration. Of the 29 men in whom the conservative approach failed, 22 proceeded to surgery for LUTS, and seven for acute urinary retention. CONCLUSIONS: Patients with untreated BOO do not significantly deteriorate urodynamically in the long term, with only a minority deteriorating symptomatically. These findings justify a conservative approach to men with LUTS associated with BOO.


Assuntos
Obstrução do Colo da Bexiga Urinária/etiologia , Retenção Urinária/etiologia , Urodinâmica/fisiologia , Idoso , Algoritmos , Distribuição de Qui-Quadrado , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estatísticas não Paramétricas , Obstrução do Colo da Bexiga Urinária/fisiopatologia , Obstrução do Colo da Bexiga Urinária/terapia , Retenção Urinária/fisiopatologia , Retenção Urinária/terapia
7.
BJU Int ; 96(9): 1295-300, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16287448

RESUMO

OBJECTIVES: To assess the long-term symptomatic and urodynamic outcomes of men with untreated detrusor underactivity (DUA) as there has been little long-term follow-up information on men with DUA, a cause of lower urinary tract symptoms (LUTS) in a significant minority of men. PATIENTS AND METHODS: Neurologically intact men aged > 18 years who were investigated in our department between 1972 and 1986, diagnosed with DUA, and who initially opted for no specific treatment were invited for a repeat symptomatic and urodynamic evaluation. Identical methods of assessment were used, allowing results to be compared directly. RESULTS: In all, 224 men were initially diagnosed with DUA; 87 (39%) of these died. Of the 69 men who initially opted for a conservative approach and attended for repeat assessment, 58 (84%) remained untreated, with a mean follow-up of 13.6 years. There were no significant changes in symptoms over the follow-up. The only significant urodynamic finding was an increase in the proportion of patients with detrusor overactivity, but with no apparent worsening of chronic retention. Of the 11 men in who failed the conservative approach, eight proceeded to surgery for LUTS, and three for acute urinary retention. CONCLUSIONS: These results provide important information on the natural history of DUA. In men with DUA presenting with LUTS there are few symptomatic and urodynamic changes with time.


Assuntos
Doenças da Bexiga Urinária/etiologia , Urodinâmica/fisiologia , Adulto , Idoso , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Ressecção Transuretral da Próstata/métodos , Doenças da Bexiga Urinária/fisiopatologia , Transtornos Urinários/etiologia , Transtornos Urinários/fisiopatologia
8.
J Urol ; 174(5): 1887-91, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16217330

RESUMO

PURPOSE: Despite long-term symptomatic and uroflowmetry studies following transurethral prostate resection (TURP) there are sparse pressure flow data. Consequently there is minimal information to account for the long-term symptomatic failure and flow rate decrease seen with time following early improvements after surgery. MATERIALS AND METHODS: Men older than 45 years who were investigated at our department between 1972 and 1986, diagnosed with bladder outlet obstruction and elected surgical intervention were invited for repeat symptomatic and urodynamic assessment. Identical methods were used, allowing direct comparison of results. RESULTS: A total of 1,068 men were initially diagnosed with bladder outlet obstruction, of whom 428 (40%) died in the interim. Of the men who were followed 217 underwent TURP with a mean followup since surgery of 13.0 years. A significant, sustained decrease in the majority of symptoms and improvements of urodynamic parameters was seen. Long-term symptomatic failure and decreased flow rate were principally associated with detrusor under activity (DUA) rather than obstruction. Presentation predictive factors for the future development of DUA were decreased detrusor contractility and a lesser degree of obstruction. CONCLUSIONS: This unique long-term study provides valuable information on surgically treated bladder outlet obstruction. The association of long-term failure following surgery with DUA emphasizes the importance of pressure flow studies before repeat surgery. However, our faith in the long-term efficacy of TURP is justified.


Assuntos
Hiperplasia Prostática/complicações , Ressecção Transuretral da Próstata/métodos , Obstrução do Colo da Bexiga Urinária/diagnóstico , Obstrução do Colo da Bexiga Urinária/cirurgia , Retenção Urinária/diagnóstico , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Probabilidade , Hiperplasia Prostática/diagnóstico , Estudos Retrospectivos , Medição de Risco , Índice de Gravidade de Doença , Estatísticas não Paramétricas , Taxa de Sobrevida , Fatores de Tempo , Ressecção Transuretral da Próstata/efeitos adversos , Resultado do Tratamento , Obstrução do Colo da Bexiga Urinária/etiologia , Obstrução do Colo da Bexiga Urinária/mortalidade , Retenção Urinária/epidemiologia , Urodinâmica/fisiologia
9.
Eur J Cancer Care (Engl) ; 12(1): 91-7, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12641561

RESUMO

The objective of this study was to examine the feasibility, implementation, acceptability and impact of an evidence-based specialist breast care nurse (SBN) model of care in Australia. Primary data were collected from four diverse Australian breast cancer treatment centres over a 12-month period. The design was a multicentre demonstration project. Information about the provision of care and patient needs was collected through prospective logs. Structured interviews were conducted with women who received the SBN intervention (N = 167) and with a control group of women treated prior to the intervention period (N = 133). Health professionals (N = 47) were interviewed about their experience of the SBN. Almost all women had contact with an SBN at five scheduled consultations and 67% of women in the intervention group requested at least one additional consultation with the SBN. Women in the intervention group were more likely to receive hospital fact sheets and to be told about and participate in clinical trials. Ninety-eight per cent of women reported that the availability of an SBN would affect their choice of hospital, with 48% indicating that they would recommend only a hospital with a SBN available. Health professionals reported that SBNs improved continuity of care, information and support for the women, and resulted in more appropriate referrals and use of the time of other members of the team. In conclusion, the SBN model is feasible and acceptable within diverse Australian treatment centres; there is evidence that some aspects of care were improved by the SBN.


Assuntos
Neoplasias da Mama/enfermagem , Papel do Profissional de Enfermagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Medicina Baseada em Evidências/métodos , Estudos de Viabilidade , Humanos , Masculino , Pessoa de Meia-Idade , New South Wales , Qualidade da Assistência à Saúde
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