RESUMO
Microsatellite analyses show that self-reported ethnicity often correlates poorly with true genetic ancestry. As unknown ancestral differences could potentially have an impact on transplant outcome, we developed an average allele length discrepancy (AALD) score to assess allele length discrepancy between donor/recipient (D/R) using microsatellites analysed routinely in post-transplant chimeric assessment. This was then compared with outcome in a homogeneously treated cohort of pediatric patients undergoing high-resolution sibling or matched unrelated donor transplantation for acute lymphoblastic leukemia (ALL). AALD scores formed a numeric continuum ranging from 0 to 1.4 (median 0.76) for sibling pairs and 0.8-2.17 (median 1.6) for high-resolution matched unrelated donor (HR-MUD) pairs. There was a trend for worse OS with increasing AALD score, which reached statistical significance above a threshold of 1.7 for OS. Patients whose transplants had an AALD score of ⩾1.8 had a risk of non-relapse mortality 4.9 times greater (P=0.025) and relapse risk three times greater (P=0.058) than those scoring <1.8. This approach will now be explored in a Centre International for Blood and Marrow Transplantation Research (CIBMTR) study of 750 D/R pairs across all disease groups; if confirmed, it has the potential to improve donor selection for patients with multiple prospective donors.
Assuntos
Transplante de Células-Tronco Hematopoéticas/métodos , Repetições de Microssatélites , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Condicionamento Pré-Transplante/métodos , Humanos , Análise de Sobrevida , Resultado do TratamentoRESUMO
Hematopoietic stem cell transplantation is becoming an increasingly important approach to treatment of different malignant and non-malignant disorders. There is thus growing demand for diagnostic assays permitting the surveillance of donor/recipient chimerism posttransplant. Current techniques are heterogeneous, rendering uniform evaluation and comparison of diagnostic results between centers difficult. Leading laboratories from 10 European countries have therefore performed a collaborative study supported by a European grant, the EuroChimerism Concerted Action, with the aim to develop a standardized diagnostic methodology for the detection and monitoring of chimerism in patients undergoing allogeneic stem cell transplantation. Following extensive analysis of a large set of microsatellite/short tandem repeat (STR) loci, the EuroChimerism (EUC) panel comprising 13 STR markers was established with the aim to optimally meet the specific requirements of quantitative chimerism analysis. Based on highly stringent selection criteria, the EUC panel provides multiple informative markers in any transplant setting. The standardized STR-PCR tests permit detection of donor- or recipient-derived cells at a sensitivity ranging between 0.8 and 1.6%. Moreover, the EUC assay facilitates accurate and reproducible quantification of donor and recipient hematopoietic cells. Wide use of the European-harmonized protocol for chimerism analysis presented will provide a basis for optimal diagnostic support and timely treatment decisions.
Assuntos
Transplante de Células-Tronco Hematopoéticas/normas , Quimeras de Transplante/genética , Europa (Continente) , Marcadores Genéticos , Testes Genéticos/métodos , Testes Genéticos/normas , Humanos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Transplante HomólogoRESUMO
We present the first detailed study analysing OS in BMT for paediatric ALL following the introduction of high-resolution (HR) HLA matching. A total of 356 consecutive paediatric ALL stem cell transplants performed between 1988 and 2007 were reviewed; 80 of them were performed following the introduction of HR HLA class I and class II matching to the transplant programme in 2002. Comparisons of matched unrelated donor (MUD) transplant outcomes before and after this period were made. Matching at the HR level for HLA-A, -B, -C, -DRB1 and -DQB1 (HR-MUD) correlated with a greater than 25% improvement in 2- and 5-year OS in paediatric ALL patients transplanted with MUDs (P=0.009, P=0.005, respectively). Two-year OS for contemporaneous HLA-matched sibling transplants (80.8%) and HR-MUD transplants (78.8%) was equivalent. At 6%, non-relapse mortality (NRM) in MUD transplants since 2002 was significantly reduced compared with previous epochs. Changes in treatment and epoch-dependent improvements in outcome were reviewed for possible confounders to the influence of HR typing using univariate and multivariate analysis.
Assuntos
Cadeias beta de HLA-DQ , Cadeias HLA-DRB1 , Antígenos de Histocompatibilidade Classe I , Teste de Histocompatibilidade , Leucemia-Linfoma Linfoblástico de Células Precursoras , Transplante de Células-Tronco , Doadores não Relacionados , Adolescente , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células Precursoras/mortalidade , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Estudos Retrospectivos , Taxa de Sobrevida , Transplante HomólogoRESUMO
OBJECTIVE: Barth Syndrome (BTHS) is an X-linked multisystem disorder (OMIM 302060) usually diagnosed in infancy and characterized by cardiac problems [dilated cardiomyopathy (DCM) ± endocardial fibroelastosis (EFE) ± left ventricular non-compaction (LVNC)], proximal myopathy, feeding problems, growth retardation, neutropenia, organic aciduria and variable respiratory chain abnormalities. We wished to determine whether BTHS had a significant impact on fetal and perinatal health in a large cohort of family groups originating from a defined region. METHOD: Case note review on 19 families originating from the UK and known to the Barth Syndrome Service of the Bristol Royal Hospital for Children. RESULTS: Details are presented on six kindreds (32%) with genetically and biochemically proven BTHS that demonstrate a wider phenotype including male fetal loss, stillbirth and severe neonatal illness or death. In these families, 9 males were stillborn and 14 died as neonates or infants but there were no losses of females. BTHS was definitively proven in five males with fetal onset of DCM ± hydrops/EFE/LVNC. CONCLUSION: These findings stress the importance of considering BTHS in the differential diagnosis of unexplained male hydrops, DCM, EFE, LVNC or pregnancy loss, as well as in neonates with hypoglycemia, lactic acidosis and idiopathic mitochondrial disease.
Assuntos
Síndrome de Barth/genética , Cardiomiopatia Dilatada/genética , Cromossomos Humanos X/genética , Morte Fetal/genética , Doenças Fetais/genética , Natimorto/genética , Aciltransferases , Síndrome de Barth/epidemiologia , Síndrome de Barth/patologia , Biomarcadores/sangue , Cardiolipinas/sangue , Cardiomiopatia Dilatada/epidemiologia , Cardiomiopatia Dilatada/patologia , Estudos de Coortes , Fibroelastose Endocárdica/epidemiologia , Fibroelastose Endocárdica/genética , Fibroelastose Endocárdica/patologia , Feminino , Morte Fetal/epidemiologia , Doenças Fetais/epidemiologia , Doenças Fetais/patologia , Humanos , Miocárdio Ventricular não Compactado Isolado/epidemiologia , Miocárdio Ventricular não Compactado Isolado/genética , Miocárdio Ventricular não Compactado Isolado/patologia , Lisofosfolipídeos/sangue , Masculino , Linhagem , Análise de Sequência de DNA , Fatores Sexuais , Natimorto/epidemiologia , Fatores de Transcrição/genética , Reino Unido/epidemiologiaRESUMO
OBJECTIVE: Niemann-Pick disease type C (NPC) is a progressive neurovisceral disorder with disrupted intracellular cholesterol metabolism that results in significant alterations to neuronal and axonal structure. Adult patients present with ataxia, gaze palsy, impaired cognition, and neuropsychiatric illness, but the neural substrate has not been well-characterized in vivo. Our aim was to investigate a well-characterized sample of adults with confirmed NPC for gray and white matter abnormalities. METHODS: We utilized a combination of optimized voxel-based morphometry of T1-weighted images and tract-based spatial statistics of diffusion tensor images to examine gray matter volume and white matter structural differences in 6 adult patients with NPC and 18 gender- and age-matched controls. RESULTS: Patients with NPC demonstrated bilateral gray matter reductions in large clusters in bilateral hippocampus, thalamus, superior cerebellum, and insula, in addition to smaller regions of inferoposterior cortex. Patients demonstrated widespread reductions in fractional anisotropy in major white matter tracts. Subsequent analysis of measures of axial and radial diffusivity suggest that these changes are contributed to by both impaired myelination and altered axonal structure. CONCLUSIONS: Findings in gray matter areas are broadly consistent with human and animal studies of selective vulnerability of neuronal populations to the neuropathology of NPC, whereas more widespread white matter changes are consistent with the hypothesis that disrupted myelination and axonal structure predate changes to the neuronal cell body. These findings suggest that volumetric analysis of gray matter and diffusion tensor imaging may be useful modalities for indexing illness stage and monitoring response to emerging treatment.
Assuntos
Córtex Cerebral/patologia , Fibras Nervosas Mielinizadas/patologia , Doença de Niemann-Pick Tipo C/patologia , Adolescente , Adulto , Estudos Transversais , Imagem de Tensor de Difusão/métodos , Feminino , Humanos , Masculino , Adulto JovemRESUMO
BACKGROUND AND PURPOSE: Microinvasive tumor cells, which are not detected on conventional imaging, contribute to poor prognoses for patients diagnosed with glioblastoma multiforme (GBM, WHO grade IV). Diffusion tensor imaging (DTI) shows promise in being able to detect this infiltration. This study aims to detect a difference in diffusion properties between GBM (infiltrative) and brain metastases (noninfiltrative). MATERIALS AND METHODS: For 49 tumors (30 GBM, 19 metastases), DTI measures (p, q, L, and fractional anisotropy [FA]) were calculated for regions of gross tumor (excluding hemorrhagic and necrotic core), peritumoral edema, peritumoral margin (edema most adjacent to tumor), adjacent normal-appearing white matter (NAWM), and contralateral white matter. Parametric and nonparametric statistical tests were used to determine significance, and receiver operating characteristic (ROC) curve analyses were performed. RESULTS: Mean values of p, L, and FA from regions of signal-intensity abnormality differed from those of normal brain in both tumors. The mean q value did not differ significantly compared with that in normal brain in any region in metastases or in adjacent NAWM of GBM. For GBM compared with metastases, q and FA were significantly lower in gross tumor (P < .001) and q was significantly lower in peritumoral margin (P < .001), which may be due to tumor infiltration. Significant overlap was present, which was reflected in the ROC curve analyses (area under the curve values from 0.732 to 0.804). CONCLUSIONS: DTI may be used to help differentiate between GBM and brain metastases. The results also suggest that DTI has the potential to assist in detecting infiltrative tumor cells in surrounding brain.
Assuntos
Algoritmos , Neoplasias Encefálicas/diagnóstico , Neoplasias Encefálicas/secundário , Imagem de Difusão por Ressonância Magnética/métodos , Glioblastoma/diagnóstico , Glioblastoma/secundário , Interpretação de Imagem Assistida por Computador/métodos , Anisotropia , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Blood samples were collected for quantitative 16S rDNA analysis from the vascular access device (VAD) of patients presenting with fever at participating centres of the UK Children's Cancer and Leukaemia Group. In total, 260 of 301 episodes of fever were evaluable and were classified as probable, possible, unlikely or unclassifiable VAD-associated infection. The sensitivity of the 16S rDNA assay declined concomitantly with delays from time of presentation to sampling. The sensitivity with >0.125 pg of bacterial DNA/microL of whole blood was 80% for the 20 probable VAD-associated infections diagnosed with samples collected on the day of or day following presentation. The specificity rose with increasing amounts of bacterial DNA, from 93% with >0.125 pg, to 98% with 0.25-0.5 pg, and to 100% with >0.5 pg/microL blood. The positive predictive value (for probable or possible) was 88% (95% CI 70-98%) with 0.25 pg/microL, and 100% (95% CI 83-100%) with >0.5 pg/microL. All 18 (6.8%) episodes with >0.5 pg of bacterial DNA/microL blood were associated with positive blood cultures. Identifications derived from the DNA sequence were consistent with the blood culture identifications for 15 of the 17 episodes with a DNA sequence identification. The VAD was removed because of suspected infection in six (2.8%) of 216 episodes with <0.125 pg of bacterial DNA/microL, in one (5%) of 20 episodes with 0.125-0.25 pg/microL, in one (16.7%) of six episodes with 0.25-0.5 pg/microL, and in nine (50%) of 18 episodes with >0.5 pg/microL. A bacterial DNA concentration of >0.5 pg/microL in blood drawn through a central venous catheter at the time of fever presentation had a high positive predictive value for VAD-associated infection and predicted an increased risk of VAD removal because of suspected infection.
Assuntos
Bacteriemia/diagnóstico , Sangue/microbiologia , Cateteres de Demora/efeitos adversos , Cateteres de Demora/microbiologia , Leucemia/complicações , Neoplasias/complicações , Adolescente , Bactérias/classificação , Bactérias/isolamento & purificação , Criança , Pré-Escolar , DNA Bacteriano/genética , DNA Ribossômico/genética , Humanos , Lactente , Reação em Cadeia da Polimerase , Valor Preditivo dos Testes , RNA Ribossômico 16S/genética , Sensibilidade e Especificidade , Análise de Sequência de DNA , Reino UnidoRESUMO
We reviewed outcomes after allogeneic hematopoietic cell transplantation (HCT) in 35 children with Chediak-Higashi syndrome (CHS). Twenty-two patients had a history of the life-threatening accelerated phase of CHS before HCT and 11 were in accelerated phase at transplantation. Thirteen patients received their allograft from an human leukocyte antigen (HLA)-matched sibling, 10 from an alternative related donor and 12 from an unrelated donor. Eleven recipients of HLA-matched sibling donor, three recipients of alternative related donor and eight recipients of unrelated donor HCT are alive. With a median follow-up of 6.5 years, the 5-year probability of overall survival is 62%. Mortality was highest in those with accelerated phase disease at transplantation and after alternative related donor HCT. Only four of 11 patients with active disease at transplantation are alive. Seven recipients of alternative related donor HCT had active disease at transplantation and this may have influenced the poor outcome in this group. Although numbers are limited, HCT appears to be effective therapy for correcting and preventing hematologic and immunologic complications of CHS, and an unrelated donor may be a suitable alternative for patients without an HLA-matched sibling. Early referral and transplantation in remission after accelerated phase disease may improve disease-free survival.
Assuntos
Síndrome de Chediak-Higashi/terapia , Transplante de Células-Tronco Hematopoéticas/métodos , Adolescente , Criança , Pré-Escolar , Intervalo Livre de Doença , Feminino , Seguimentos , Doença Enxerto-Hospedeiro , Antígenos HLA/biossíntese , Células-Tronco Hematopoéticas/citologia , Humanos , Masculino , Estudos Retrospectivos , Transplante Homólogo , Resultado do TratamentoRESUMO
OBJECTIVES: To develop standards of care for head injury and thereby identify and prioritize areas of the service needing development; to report the findings from a survey of compliance with such standards in the Eastern region of UK. METHODS: The standards were collaboratively developed through an inclusive and iterative process of regional surveys, multidisciplinary conferences, and working groups, following a method similar to that used by the Society of British Neurological Surgeons. The standards cover seven topics relating to all aspects of service delivery, with standards within each objective. Each standard has been designated a priority level (A, B, or C). The standards were piloted using a self-assessment questionnaire, completed by all 20 hospitals of the Eastern region. RESULTS: Full compliance was 36% and a further 30% of standards were partially met across the region, with some areas of service delivery better than others. Seventy eight per cent of level A standards were either fully or partially met. Results were better in the north of the region compared with the south. CONCLUSION: A survey of compliance with the head injury standards indicate that, with their whole systems approach and subject to further refinement, they are a useful method for identifying deficiencies in service provision and monitoring for quality of care both within organisations and regionally.
Assuntos
Traumatismos Craniocerebrais/terapia , Serviço Hospitalar de Emergência/normas , Hospitalização/estatística & dados numéricos , Atenção à Saúde/normas , Inglaterra , HumanosRESUMO
Stem cell transplantation (SCT) is used to cure or greatly ameliorate a wide variety of genetic diseases, ranging from inherent defects of haemopoietic cell production or function to metabolic diseases mostly affecting solid organs. It ranks as one of the most remarkable therapeutic advances of the past 40 years. Despite rapid technological improvements, however, there are still many short term risks and potential long term toxicities. As a consequence, the rapid emergence of alternative therapies (including new drugs, enzyme and gene therapies), necessitate constant re-evaluation of the risk/benefit ratio for each disease and hence the appropriateness of SCT. This review describes the major aspects of the transplant process, indications for transplantation, outcome statistics, and areas where alternative therapies are becoming available.
Assuntos
Doenças Genéticas Inatas/terapia , Doenças Hematológicas/terapia , Transplante de Células-Tronco Hematopoéticas , Doença Enxerto-Hospedeiro/prevenção & controle , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/normas , Humanos , Síndromes de Imunodeficiência/terapia , Erros Inatos do Metabolismo/terapia , Doadores de Tecidos , Condicionamento Pré-Transplante/métodosRESUMO
Donor bone marrow engraftment, which resulted in complete normalization of white cell beta-galactosidase levels in a patient with presymptomatic juvenile onset GM1-gangliosidosis (McKusick 230600), did not improve long-term clinical outcome.
Assuntos
Transplante de Medula Óssea/métodos , Gangliosidose GM1/patologia , Gangliosidose GM1/terapia , beta-Galactosidase/metabolismo , Animais , Células da Medula Óssea/metabolismo , Encéfalo/metabolismo , Criança , Modelos Animais de Doenças , Cães , Feminino , Humanos , Lactente , Imageamento por Ressonância Magnética , Resultado do TratamentoRESUMO
Infective diarrhoea is common among allogeneic stem cell transplant (SCT) recipients, frequently caused by viruses and may be difficult to differentiate from acute graft-versus-host disease (GVHD). Viral pathogens may directly or indirectly impact upon transplant-related mortality. Rotavirus is one of the most common causes of diarrhoea worldwide, but one of the least studied causes of diarrhoea post SCT. In this retrospective study we describe 21 cases of confirmed rotavirus infection in allogeneic SCT recipients. Most of these cases may occur in clusters during the winter and spring period. Symptoms of rotaviral infection were diarrhoea (95%), vomiting (62%), abdominal pain (38%), weight loss and loss of appetite in 38 and 29% of the cases, respectively. Possible extraintestinal manifestations of rotavirus infection were observed. The duration of the symptoms in this series ranged from 4 days to 4 months with median of 15 days. Patients with rotavirus infection were invariably lymphopenic and/or on immunosuppression for GVHD. Of the patients diagnosed with rotavirus, 86% required hospitalisation. In 57% of the cases, other viral pathogens were isolated near to the rotavirus infection period. Rotavirus infection is an important cause of prolonged diarrhoea post SCT, causing significant morbidity and frequently requiring hospitalisation.
Assuntos
Transplante de Medula Óssea/efeitos adversos , Diarreia/virologia , Leucemia/terapia , Infecções por Rotavirus/epidemiologia , Adolescente , Adulto , Criança , Pré-Escolar , Diarreia/epidemiologia , Humanos , Lactente , Depleção Linfocítica , Morbidade , Rotavirus/classificação , Rotavirus/isolamento & purificação , Linfócitos T/imunologia , Transplante Homólogo/efeitos adversosRESUMO
CAMPATH-1H (C-1H) is widely used in vivo and / or in vitro for T cell depletion in hematopoietic SCT. This humanised monoclonal antibody is specific for CD52, a marker coexpressed on the majority of human lymphocytes with CD48 and other glycosylphosphatidyl-inositol (GPI) anchored proteins. We detected CD52 / CD48 dual expression on >99% of CD3(+) lymphocytes from normal individuals and all 15 post-SCT patients whose transplants did not utilise C-1H. By contrast, 23 / 26 patients with transplants involving C-1H (in vivo, in vitro or both) exhibited populations lacking CD52 expression that accounted for 49.7% (4.2-86.2%) of the CD3+ lymphocytes (median and range) in samples evaluated at a median of 2 months post-SCT. Most CD52- cells also lacked CD48 expression. These GPI- T cells were of either donor or mixed donor / recipient origin. They were predominant in the early months after SCT at times of profound lymphopenia and inversely correlated with the recovery of the absolute lymphocyte count (r= - 0.663, P<0.0001). The presence of CD52- cells has been correlated previously with clinical outcome after CAMPATH therapy for both malignant and nonmalignant diseases.
Assuntos
Anticorpos Monoclonais/química , Anticorpos Antineoplásicos/química , Antineoplásicos/farmacologia , Hemoglobinúria Paroxística/metabolismo , Linfócitos T/citologia , Adolescente , Adulto , Alemtuzumab , Anticorpos Monoclonais Humanizados , Antígenos CD/biossíntese , Antígenos CD/química , Antígenos de Neoplasias/biossíntese , Antígenos de Neoplasias/química , Complexo CD3/biossíntese , Antígeno CD48 , Antígeno CD52 , Separação Celular , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Citometria de Fluxo , Glicoproteínas/biossíntese , Glicoproteínas/química , Glicosilfosfatidilinositóis/metabolismo , Humanos , Separação Imunomagnética , Masculino , Pessoa de Meia-Idade , Transplante de Células-Tronco , Linfócitos T/metabolismo , Fatores de Tempo , Quimeras de Transplante , Transplante Homólogo/métodos , Resultado do TratamentoRESUMO
For the past two decades, hematopoietic cell transplantation (HCT) has been used as effective therapy for selected inherited metabolic diseases (IMD). The primary goals of this therapy have been to promote long-term survival with donor-derived engraftment and to optimize quality of life. Careful, multidisciplinary decision-making regarding whether to recommend HCT and how to provide optimal peri- and post-HCT care has proven essential to increase the likelihood of a good outcome. Guidelines for HCT and monitoring have recently been provided in this journal. Here we report data on transplant activity for IMD in Europe and briefly discuss future directions. It is imperative that data collection for these procedures becomes as routine as that for patients undergoing HCT for malignancy and that follow-up is performed in a systematic manner. Large clinical trials have never been performed in this transplant field. Fortunately, accreditation procedures and improvements in information technology can now provide a firm foundation for such trials, which are urgently needed.
Assuntos
Transplante de Células-Tronco Hematopoéticas , Erros Inatos do Metabolismo/terapia , Europa (Continente) , Feminino , Transplante de Células-Tronco Hematopoéticas/estatística & dados numéricos , Transplante de Células-Tronco Hematopoéticas/tendências , Humanos , Masculino , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/epidemiologiaRESUMO
Staphylococcus aureus (S. aureus) is commonly associated with microbial infection of orthopaedic implants. Such infections often lead to osteomyelitis, which may result in failure of the implant due to localised bone destruction. Bacterial adhesion and subsequent colonisation of the device may occur as a consequence of contamination during surgery, or by seeding from a distant site through the blood circulation. Coating of the hydroxyapatite (HA) ceramic component of artificial hip joints with the bisphosphonates clodronate (C) and pamidronate (P) has been proposed as a means to minimise osteolysis and thereby prevent loosening of the implant. However, the effect of the bisphosphonate coating on bacterial adhesion to the HA materials must be determined before this approach can be implemented. In this study coated HA materials were incubated with the S. aureus and the number of adherent bacteria determined using the Modified Vortex Device (MVD) method. The number of bacteria adherent to the P coated HA material was significantly greater than that adherent to uncoated HA (60-fold increase) or to the C coated HA (90-fold increase). Therefore, even though earlier studies suggested that P bound to HA may improve osseointegration, the results presented would suggest that the use of this coating may be limited by the potential increased susceptibility of the coated device to infection.
Assuntos
Aderência Bacteriana , Difosfonatos/metabolismo , Durapatita/metabolismo , Contaminação de Equipamentos/prevenção & controle , Staphylococcus aureus/fisiologia , Ácido Clodrônico/química , Ácido Clodrônico/farmacologia , Materiais Revestidos Biocompatíveis/química , Materiais Revestidos Biocompatíveis/farmacologia , Difosfonatos/química , Difosfonatos/farmacologia , Durapatita/química , Estrutura Molecular , PamidronatoRESUMO
RATIONALE AND OBJECTIVES: Blood oxygen level dependent (BOLD) contrast pharmacological magnetic resonance imaging (phMRI) is an increasingly popular technique that allows the non-invasive investigation of spatial and temporal changes in rat brain function in response to pharmacological stimulation in vivo. Rat brain BOLD contrast phMRI is, at present, established in few neuropharmacological laboratories, and various issues associated with the technique require attention. The present review is primarily aimed at psychopharmacologists with no previous experience of phMRI, who are interested in the practical aspects that phMRI studies entail. RESULTS AND DISCUSSION: Experimental and analytical considerations, including anaesthesia, physiological monitoring, drug dose and delivery, scanning protocols, statistical approaches and the interpretation of phMRI data, are discussed.
Assuntos
Mapeamento Encefálico , Encéfalo/irrigação sanguínea , Imageamento por Ressonância Magnética/métodos , Anestesia , Animais , Encéfalo/efeitos dos fármacos , Circulação Cerebrovascular , Interpretação Estatística de Dados , Esquema de Medicação , Humanos , Processamento de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/instrumentação , Monitorização Fisiológica , Oxigênio/sangue , RatosRESUMO
Autosomal recessive osteopetrosis (OP) is a rare, lethal disorder in which osteoclasts are absent or nonfunctional, resulting in a bone marrow cavity insufficient to support hematopoiesis. Because osteoclasts are derived from hematopoietic precursors, allogeneic hematopoietic cell transplantation can cure the bony manifestations of the disorder. However, high rates of graft failure have been observed in this population. It is not possible to harvest bone marrow from these patients for reinfusion should graft failure be observed. We report that 8 of 10 patients with OP had high numbers of circulating CD34(+) cells (3% +/- 0.9%). This increased proportion of peripheral CD34(+) cells made it possible to harvest 2 x 10(6) CD34(+) cells per kilogram with a total volume of blood ranging from 8.3 to 83.7 mL (1.3-11.6 mL/kg). In addition, colony-forming assays documented significantly more colony-forming unit-granulocyte-macrophage and burst-forming unit-erythroid in the blood of osteopetrotic patients compared with controls; the numbers of colony-forming units approximated those found in control marrow. We conclude that OP patients with high levels of circulating CD34(+) are candidates for peripheral blood autologous harvest by limited exchange transfusion. These cells are then available for reinfusion should graft failure be observed in patients for whom retransplantation is impractical.
Assuntos
Antígenos CD34/sangue , Osteopetrose/fisiopatologia , Transplante de Células-Tronco de Sangue Periférico , Células-Tronco , Criança , Pré-Escolar , Ensaio de Unidades Formadoras de Colônias , Feminino , Humanos , Lactente , Recém-Nascido , Contagem de Leucócitos , Masculino , Osteopetrose/terapia , Transplante Autólogo , Transplante HomólogoRESUMO
Several reports have pointed to the unevenness in the UK of services for rehabilitation after head injury. A study was conducted in the Eastern Region of England to define the key stages in recovery and rehabilitation, by an iterative process of questionnaire, interview and consensus conference. Findings were translated into a draft set of maps showing current availability of services which were revised after feedback. Working groups then developed a set of definitions and classification codes for each stage of rehabilitation which were likewise disseminated for feedback. The maps were then redrafted to correspond with the definitions together with a flowchart of potential head injury rehabilitation services. The definitions were piloted at a regional neurosurgery unit and a rehabilitation hospital. Core services for neurorehabilitation region-wide were found to be variable and uncoordinated with fragmented and inequitable allocation of resources. The definitions and mapping system that emerged from this study should facilitate the design of care pathways for patients and identify gaps in the services.
Assuntos
Traumatismos Craniocerebrais/reabilitação , Recursos em Saúde/provisão & distribuição , Inglaterra , Geografia , Pesquisas sobre Atenção à Saúde , Humanos , Projetos Piloto , Centros de Reabilitação/provisão & distribuiçãoRESUMO
In order to determine molecules involved in the differentiation and proliferation of human CD8(+) cells, two ex vivo expansion models were established: coculture of freshly purified human CD8(+) cells with irradiated autologous feeders (AF) or stimulation with anti-CD3. Two different proliferation kinetics of CD8(+) cells and expression patterns of CD57 were observed between these conditions. Differential display reverse transcriptase-polymerase chain reaction was applied to investigate the differential expression of mRNA species between CD8(+) CD57(+) and CD8(+) CD57(-) populations. A differentially expressed RNA species called alpha nascent polypeptide associated complex (alpha NAC) was found at a higher level in CD8(+) CD57(-) cells than in CD8(+) CD57(+) cells. In the presence of AF, the expression of alpha NAC was reduced on culturing whilst proliferation increased. Similarly, in cultures stimulated with anti-CD3, alpha NAC reverted to its inactive form and differentiation and proliferation increased. Using a phosphorothioate-modified oligodeoxynucleotide antisense directed specifically against alpha NAC mRNA, protein expression was inhibited and increased CD8(+) cell proliferation and CD25 expression were observed irrespective of the culture conditions. This suggests that alpha NAC protein is antiproliferative molecule. This is the first description of the function of the alpha NAC protein in human CD8(+) T cells.