RESUMO
Minor histocompatibility antigens (minor H antigens) are genetically polymorphic peptides that have been shown to elicit immune response when mismatched between donor and recipient of haematopoietic stem cell transplantation (HSCT). Depending on the expression profiles, mismatches in these genes may either lead to harmful graft-versus-host (GvH) reaction or desired graft-versus-leukaemia (GvL) effect. We analysed retrospectively the effect of HLA-restricted matching 11 established autosomal minor H antigens on the risk of graft-versus-host disease and relapse in 311 HLA-matched sibling HSCT of a single centre. Increased incidence of chronic GvH disease was shown to be associated with mismatches in the HA-8 and ACC-1. The mRNA expression profiles in a large set of healthy and malignant tissue samples of minor H antigen genes demonstrated in silico that the expression profiles of HA-8 and ACC-1 were surprisingly different: HA-8 gene was expressed in practically all tissues, whereas ACC-1 gene had a restricted profile. The results demonstrated that mismatches in minor H antigens HA-8 and ACC-1 predisposed to chronic graft-versus-host disease (GvHD).
Assuntos
Doença Enxerto-Hospedeiro/genética , Transplante de Células-Tronco Hematopoéticas/métodos , Antígenos de Histocompatibilidade Menor/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Adolescente , Adulto , Idoso , Criança , Feminino , Predisposição Genética para Doença/genética , Genótipo , Doença Enxerto-Hospedeiro/etiologia , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Teste de Histocompatibilidade , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Reação em Cadeia da Polimerase/métodos , Estudos Retrospectivos , Irmãos , Transcriptoma , Transplante Homólogo , Adulto JovemRESUMO
In this 12-month RCT, we examined whether aerobic impact exercise training (3x/week) could facilitate breast cancer survivors' recovery by enhancing their bone structural strength, physical performance and body composition. After the adjuvant chemo- and/ or radiotherapy, 86 patients were randomly assigned into the training or control group. Structural bone traits were assessed with pQCT at the tibia and with DXA at the femoral neck. Agility (figure-8 running), jump force and power (force platform), grip strength and cardiovascular fitness (2-km walk test) were also assessed. Training effects on outcome variables were estimated by two-way factorial ANCOVA using the study group and menopausal status as fixed factors. Bone structural strength was better maintained among the trainees. At the femoral neck, there was a small but significant 2% training effect in the bone mass distribution (p=0.05). At the tibial diaphysis, slight 1% to 2% training effects (p=0.03) in total cross-sectional area and bone structural strength were observed (p=0.03) among the postmenopausal trainees. Also, 3% to 4% training effects were observed in the figure-8 running time (p=0.03) and grip strength (p=0.01). In conclusion, vigorous aerobic impact exercise training has potential to maintain bone structural strength and improve physical performance among breast cancer survivors.
Assuntos
Osso e Ossos/fisiologia , Neoplasias da Mama/reabilitação , Terapia por Exercício/métodos , Aptidão Física/fisiologia , Absorciometria de Fóton , Adulto , Idoso , Densidade Óssea , Osso e Ossos/anatomia & histologia , Feminino , Humanos , Pessoa de Meia-Idade , SobreviventesRESUMO
BACKGROUND: Recent studies implicate that oncoplastic breast cancer surgery provides better aesthetic outcome than conventional resection. Several factors have been associated with poor aesthetic outcome. This study aims to compare patient-reported aesthetic and functional outcome after conventional and oncoplastic resection and to evaluate prognostic factors for poor aesthetic outcome in a population-based setting. METHODS: 637 patients having breast conserving treatment (BCT) due to unilateral primary breast cancer at a single hospital district during 2010 were included. Aesthetic and functional outcome were evaluated using two questionnaires three years after surgery. RESULTS: Questionnaires were returned by 379 (59%) patients; 293 (77%) of these had conventional and 86 (23%) oncoplastic resection. Patients in oncoplastic resection group had larger tumour diameter (p < 0.001), larger resection specimens (p < 0.001), and more often multifocal tumours (p = 0.032), node positive cancer (p = 0.029) and lower quadrant tumour localization (p = 0.007). Aesthetic outcome according to BCTOS questionnaire was good in 284 (75%) patients; 52 (61%) patients in the oncoplastic group and 230 patients (81%) in the conventional resection group, p < 0.001. Larger tumour diameter (p = 0.033), multifocality (p = 0.022), weight of resection specimen (<0.001) and oncoplastic surgery (p < 0.001) were predicting poor aesthetic outcome, when all patients were included. Tumour multifocality (p = 0.013) remained predictor of poor aesthetic outcome in conventional resection group but not in oncoplastic resection group. CONCLUSIONS: Patient satisfaction to aesthetic outcome after BCT is high. Conventional resection provides good aesthetic outcome in appropriately selected patients. Oncoplastic resection enables BCT in patients with larger and multifocal tumours with favourable aesthetic outcome.
Assuntos
Neoplasias da Mama/cirurgia , Carcinoma Intraductal não Infiltrante/cirurgia , Carcinoma Lobular/cirurgia , Carcinoma Ductal Pancreático/cirurgia , Mamoplastia/métodos , Mastectomia Segmentar/métodos , Satisfação do Paciente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Carcinoma Intraductal não Infiltrante/patologia , Carcinoma Lobular/patologia , Carcinoma Ductal Pancreático/patologia , Estudos de Casos e Controles , Estética , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Inquéritos e Questionários , Carga TumoralRESUMO
The present work aimed to describe the current status of IVIVC/IVIVR development in the pharmaceutical industry, focusing on the use and perception of specific approaches as well as successful and failed case studies. Two questionnaires have been distributed to 13 EFPIA partners of the Oral Biopharmaceutics Tools Initiative and to the Pharmacokinetics Working Party of the European Medicines Agency in order to capture the perspectives and experiences of industry scientists and agency members, respectively. Responses from ten companies and three European Agencies were received between May 21st 2014 and January 19th 2016. The majority of the companies acknowledged the importance of IVIVC/IVIVR throughout the drug development stages and a well-balanced rate of return on investment. However, the IVIVC/IVIVR approach seemed to be underutilized in regulatory submissions. Four of the ten companies stated to have an internal guidance related to IVIVC/IVIVR modelling, whereas three felt that an overall strategy is not necessary. Successful models mainly served to support formulation development and to provide a better mechanistic understanding. There was not yet much experience with safe-space IVIVRs as well as the use of physiologically based modelling in the field of IVIVC. At the same time, the responses from both industry and agencies indicated that there might be a need for a regulatory framework to guide the application of these novel approaches. The relevance of IVIVC/IVIVR for oral IR drug products was recognized by most of the companies. For IR formulations, relationships other than Level A correlation were more common outcomes among the provided case studies, such as multiple Level C correlation or safe-space IVIVR, which could be successfully used for requesting regulatory flexibility. Compared to the responses from industry scientists, there was a trend towards a higher appreciation of the BCS among the regulators, but a less positive attitude towards the utility of non-compendial dissolution methods for establishing a successful IVIVC/IVIVR. The lack of appropriate in vivo data and regulatory uncertainty were considered the major difficulties in IVIVC/IVIVR development. The results of this survey provide unique insights into current IVIVC/IVIVR practices in the pharmaceutical industry. Pursuing an IVIVC/IVIVR should be generally encouraged, considering its high value from both industry and regulators' perspective.
Assuntos
Descoberta de Drogas , Indústria Farmacêutica , Modelos Biológicos , Animais , Humanos , Farmacocinética , Inquéritos e QuestionáriosRESUMO
BACKGROUND AND AIMS: The aim of this study was to analyze feasibility of day surgery in breast cancer patients with breast conserving surgery and sentinel node biopsy. MATERIAL AND METHODS: The study was a randomized controlled trial comparing day surgery with one night hospital stay in breast cancer patients with breast conserving surgery and sentinel node biopsy. A total of 40 patients with ⩽3-cm tumor and clinically N0 were randomized to one night stay group and 38 patients to day surgery group. Within discharge, patients and their relatives were given questionnaires in order to evaluate their experience regarding the duration of hospital stay. RESULTS: Randomized groups were similar regarding patient age and tumor stage. A total of 18 (47%) day surgery group patients were discharged the same day. The most common reason for overnight hospital stay was axillary clearance, 9 (24%). None of the patients in the day surgery group, but 2 patients in the overnight hospital stay group had re-operation due to complications. Perception and preference results were analyzed both according to randomization and actual treatment groups. Patients in both groups had rather similar experiences on the first postoperative day. Also, spouse's or relative's perception after discharge was similar in both groups. CONCLUSION: Day surgery was well received by the patients and their relatives. Day surgery appears as feasible in patients with breast conservation and sentinel node biopsy.
Assuntos
Procedimentos Cirúrgicos Ambulatórios , Neoplasias da Mama/cirurgia , Mastectomia Segmentar/métodos , Biópsia de Linfonodo Sentinela , Adulto , Idoso , Neoplasias da Mama/patologia , Estudos de Viabilidade , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Segurança do Paciente , Satisfação do Paciente , Resultado do TratamentoRESUMO
Linear correlation was demonstrated between serum digoxin and papillary muscle digoxin concentrations in patients undergoing mitral valve surgery. The mean ratio of myocardial tissue to serum digoxin concentrations was 6711. This result supports the use of serum digoxin as a guide for assessing the degree of digitalization under steady-state conditions.
Assuntos
Digoxina/metabolismo , Miocárdio/metabolismo , Adulto , Digoxina/sangue , Humanos , Pessoa de Meia-Idade , Proteínas Musculares/metabolismo , Músculos Papilares/metabolismo , Fósforo/metabolismo , Potássio/sangue , Potássio/metabolismoRESUMO
Two healthy young women had an unexplained persistent elevation of aspartate aminotransferase (ASAT) activity. In both cases electrophoresis of serum ASAT isoenzymes displayed an abnormally moving fraction that comprised the whole serum activity, while liver and muscle revealed the normal cytoplasmic and mitochondrial isoenzymes. In the first case serum ASAT was found to be bound by serum IgG, in the second case the binding protein remained unidentified.
Assuntos
Aspartato Aminotransferases/sangue , Adulto , Proteínas de Transporte/sangue , Reações Falso-Positivas , Feminino , Humanos , Imunoglobulina G/metabolismo , Isoenzimas/sangueRESUMO
A total of 4724 newborns were screened for congenital nasal deformities with two simple tests which were performed by specialized nurses. Altogether 91 (1.9%) pathological cases were found. The parturients' external features and the course of the deliveries showed no differences from those of a control group, nor did the groups differ regarding features of the newborns. On the other hand, in the nasal deformity group, highly significantly (P less than 0.001) more cases of stuffy nose were found already during the first days after birth. In this study, no evidence of birth trauma as the cause of congenital nasal deformities was found. It is proposed that at least the majority of them originated during intrauterine life. The screening method was quite valid: every newborn who failed the screen tests showed some kind of nasal pathology and, on the other hand, those who passed had only minor deviations of the septum.
Assuntos
Cavidade Nasal/anormalidades , Nariz/anormalidades , Traumatismos do Nascimento/complicações , Traumatismos do Nascimento/diagnóstico , Feminino , Humanos , Recém-Nascido , Masculino , Mucosa Nasal/metabolismo , Septo Nasal/anormalidadesRESUMO
Serum IgE levels and nasal/aural secretion eosinophils and basophils cells were studied in 84 patients with ear discharge despite previous radical operation, in 83 patients with postoperatively dry ears, and in 30 normal persons. Serum IgE values suggesting atopy (greater than 100 U/ml, PRIST) were more frequent (p less than 0.05) among patients with draining ears than among persons with healthy ears. Normal IgE concentrations showed reversed frequency distribution. Nasal secretion eosinophils and/or basophilic cells were also found more frequently (p less than 0.05) among patients with discharging ears than in other groups. Analogously, those with both serum IgE of greater than 100 U/ml and 'positive' nasal cytology more often had infected than dry (p less than 0.01) or normal (p less than 0.05) ears. Aural secretions showed eosinophils and/or basophilic cells in 14 (17%) patients; 11 of them had such cells in their nasal secretions too. It would seem that atopy is probably one cause of persistent therapy-resistant otitis media and it must be taken into account when considering the treatment of a chronic ear.
Assuntos
Otite Média/imunologia , Basófilos/análise , Doença Crônica , Orelha Média/imunologia , Orelha Média/metabolismo , Eosinófilos/análise , Humanos , Hipersensibilidade Imediata , Imunoglobulina E/análise , Contagem de Leucócitos , Processo Mastoide/cirurgia , Mucosa Nasal/imunologia , Mucosa Nasal/metabolismo , Otite Média/cirurgiaRESUMO
Suitable bacteriological techniques revealed anaerobic bacteria in 38 (33%) of 114 chronically discharging middle ears. The genus Bacteroides was cultured from 25 ears. Aerobic bacteriology showed the predominance of staphylococci, facultative enteric gramnegative rods, diphtheroid bacilli and Pseudomonas species. Anaerobic bacterial cultures were always mixed with aerobic bacteria. 12 ears were culture-negative, and 9 of the 108 Gram-stained smers revealed no bacteria. No significant difference in bacteriology was noted between ears with or without local antimicrobial treatment, or between profusely draining or only moist ears. The ears with postoperative recurrent infection or with clinical suspicion of cholesteatoma grew anaerobes significantly more often, and were seldom sterile. Because anaerobic bacteria are frequently associated with chronic otitis media, their characteristics with regard to susceptibility to antimicrobials and to air must be remembered in the choice of therapy.
Assuntos
Otite Média/microbiologia , Bactérias/isolamento & purificação , Técnicas Bacteriológicas , Colesteatoma/microbiologia , Doença Crônica , Humanos , Infecção da Ferida Cirúrgica/microbiologia , Membrana Timpânica/lesõesRESUMO
A laryngocele is an air-filled swelling of the upper pouch (the sacculus) of the laryngeal ventricle of Morgagni, which may herniate through the thyro-hyoid membrane to form a mass which is palpable subcutaneously in the neck. The condition is rare, but is found at times in individuals with laryngeal malignancy and in individuals who have been pre-disposed to it by increased internal laryngeal pressure. When the condition is discovered it is always an indication for a thorough examination of the larynx, with follow-up, bearing in mind the possibility of malignancy.
Assuntos
Doenças da Laringe/diagnóstico , Ar , Humanos , Doenças da Laringe/cirurgia , Masculino , Pessoa de Meia-IdadeRESUMO
Late hearing results in 627 ears (574 patients) operated on radically for chronic otitis media are presented. Clinically, the ears were followed-up annually for 5-14 years. The results are correlated with the severity of histopathological changes in the tympanic cavity and in the mastoid air-cell system and also with the management of the tympanic mucosa and ossicular chain at operation. The mean post-operative air-bone gap was significantly better in ears with mild histopathological changes than in ears with severe histopathological changes in the middle ear (17.0 db./33.1 db.; p less than 0.001) or mastoid (29.0 db./34.2 db.; p less than 0.01) at operation. The difference in hearing results in favour of the former group was more significant in ears in which the tympanic mucosa had been saved at operation (p less than 0.01/p less than 0.001) than in ears in which the mucosa had been removed (p less than 0.05).
Assuntos
Audição , Otite Média/cirurgia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Doença Crônica , Orelha Média/patologia , Feminino , Seguimentos , Humanos , Masculino , Processo Mastoide/patologia , Pessoa de Meia-Idade , Otite Média/patologia , Otite Média/fisiopatologia , Período Pós-Operatório , TimpanoplastiaRESUMO
This study consisted of the evaluation of the plain X-ray findings of films taken at early follow-up (mean 1.5 months after surgery) and at late follow-up (4-14 years after the early films) of 211 ears which had been operated on radically and obliterated. Residual cells which were detected on the basis of the early films were associated with a more frequent occurrence of post-operative infection and were thus hallmarks of a poorer prognosis. Changes in the bone surrounding the surgical cavity and the radiological quality of the walls of the surgical cavity, the presence of new bone formation in the cavity and other radiological features did not yield useful information about post-operative complications. New bone formation was associated with a smaller amount of post-operative cavitation. Post-operative X-ray examination of the obliterated ear is a prognostically useful examination, but it does not significantly contribute further to the information available by clinical and otomicroscopic examination in regards to the complications of infection and cholesteatoma.
Assuntos
Otopatias/diagnóstico por imagem , Processo Mastoide/diagnóstico por imagem , Otite Média/cirurgia , Adulto , Colesteatoma/diagnóstico por imagem , Doença Crônica , Otopatias/cirurgia , Feminino , Seguimentos , Humanos , Masculino , Processo Mastoide/cirurgia , Osteogênese , Complicações Pós-Operatórias/diagnóstico por imagem , RadiografiaRESUMO
The frequency of post-operative cholesteatomas, epidermizations and retraction pockets in a series of 343 chronically infected ears (315 patients) without cholesteatoma at primary surgery was evaluated. The ears were operated on radically, exclusively by the Palva method, with removal of the bridge in 248 ears and preservation of it in 95 ears. Musculo-periosteal obliteration and seclusion of the aditus were performed in every case with a Palva flap and with a temporalis muscle-fascia graft. The primary operations took place over the period 1964-1972, and all the ears without cholesteatoma at primary surgery were included; they were followed up annually. The evaluation of this material was carried out in 1976-1979 and the follow-up time was on an average of 8.5 years (5-15 years). Cholesteatoma was found in six (6/343; 1.7 per cent), epidermization of the tympanum in four (4/343; 1.2 per cent), and retraction pockets without cholesteatoma in six (6/343; 1.7 per cent) of the ears. Preservation or removal of the bridge at operation did not cause any significant difference in the frequency of the post-operative complications mentioned (p greater than 0.05). Most of the complications were discovered after the first postoperative year.
Assuntos
Colesteatoma/etiologia , Otopatias/etiologia , Orelha Média/cirurgia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Doença Crônica , Meato Acústico Externo/cirurgia , Feminino , Humanos , Masculino , Métodos , Pessoa de Meia-Idade , Otite Média/cirurgia , Complicações Pós-Operatórias , Fatores de TempoRESUMO
The over-all distribution of the pre-operative bacteria of 806 ears and the post-operative bacteria of 109 post-operatively moist or discharging ears correlated very well, the only clear difference being the detection of diphtheroid bacilli more often post-operatively than pre-operatively. When comparing the pre- and post-operative bacteriology of 109 post-operatively infected chronic ears which had undergone radical surgery and obliteration with Palva flaps (and which were drawn from a group of 806 ears originally operated on and followed yearly for 5-14 years) it was noticed that Pseudomonas aeruginosa and Proteus sp were cultured more often post-operatively than pre-operatively in the same ears. Statistically, other bacteria were not found to be significantly present in the same ears.
Assuntos
Bactérias/isolamento & purificação , Otite Média/microbiologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Doença Crônica , Orelha Média/microbiologia , Orelha Média/cirurgia , Feminino , Seguimentos , Fungos/isolamento & purificação , Humanos , Masculino , Pessoa de Meia-Idade , Otite Média/cirurgia , Complicações Pós-Operatórias/microbiologia , Período Pós-OperatórioRESUMO
Hearing results are presented for 164 ears with chronic otitis media which were operated on radically and obliterated with a musculo-periosteal flap (Palva flap), and in which tympanoplasty was performed. The ears were followed-up annually for 5-13 years (mean 6.8 years). Results are compared with the method of ossiculoplasty and with the condition of the stapes superstructure at operation. Ossiculoplasty using autogenous cortical bone columellas resulted in a somewhat greater improvement in the post-operative air-bone gap than ossiculoplasty with auto- or homo-graft ossicles, when compared with the pre-operative gap. Similarly, the post-operative gap improved more in ears with an intact stapes superstructure than in ears in which the stapes superstructure was absent. The use of an autogenous cortical bone columella can be recommended in cases in which the patient's own ossicles are affected by disease and cannot be used.
Assuntos
Audição , Otite Média/cirurgia , Timpanoplastia/métodos , Adolescente , Adulto , Idoso , Transplante Ósseo , Criança , Ossículos da Orelha/transplante , Feminino , Seguimentos , Testes Auditivos , Humanos , Masculino , Pessoa de Meia-Idade , Cirurgia do EstriboRESUMO
OrBiTo is a new European project within the IMI programme in the area of oral biopharmaceutics tools that includes world leading scientists from nine European universities, one regulatory agency, one non-profit research organization, four SMEs together with scientists from twelve pharmaceutical companies. The OrBiTo project will address key gaps in our knowledge of gastrointestinal (GI) drug absorption and deliver a framework for rational application of predictive biopharmaceutics tools for oral drug delivery. This will be achieved through novel prospective investigations to define new methodologies as well as refinement of existing tools. Extensive validation of novel and existing biopharmaceutics tools will be performed using active pharmaceutical ingredient (API), formulations and supporting datasets from industry partners. A combination of high quality in vitro or in silico characterizations of API and formulations will be integrated into physiologically based in silico biopharmaceutics models capturing the full complexity of GI drug absorption. This approach gives an unparalleled opportunity to initiate a transformational change in industrial research and development to achieve model-based pharmaceutical product development in accordance with the Quality by Design concept. Benefits include an accelerated and more efficient drug candidate selection, formulation development process, particularly for challenging projects such as low solubility molecules (BCS II and IV), enhanced and modified-release formulations, as well as allowing optimization of clinical product performance for patient benefit. In addition, the tools emerging from OrBiTo are expected to significantly reduce demand for animal experiments in the future as well as reducing the number of human bioequivalence studies required to bridge formulations after manufacturing or composition changes.
Assuntos
Biofarmácia/métodos , Trato Gastrointestinal/metabolismo , Absorção Intestinal , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/metabolismo , Farmacocinética , Administração Oral , Animais , Química Farmacêutica , Simulação por Computador , Formas de Dosagem , Humanos , Modelos Biológicos , Permeabilidade , Preparações Farmacêuticas/química , Desenvolvimento de Programas , SolubilidadeRESUMO
Currently, the EMEA, FDA, and WHO as regulatory authorities accept rapidly dissolving (>85% dissolved in 30 min) biopharmaceutics classification system (BCS) I drug products for biowaiver candidates. In the draft EMEA guideline the requirement has been set tighter, that is, the drug product should be very rapidly dissolving (>85% dissolved in 15 min) to be eligible for a biowaiver. Pharmacokinetic modeling of 32 BCS I drugs was performed to demonstrate that very rapid dissolution is not necessary to guarantee bioequivalence for them. Rapid dissolution and similar dissolution profiles are sufficient criteria for all BCS I drugs.