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Lamb-Shaffer Syndrome (LSS; OMIM #616803; ORPHA #313892; ORPHA #313884) is an infrequent genetic disorder that affects multiple aspects of human development especially those related to the development of the nervous system. LSS is caused by variants in the SOX5 gene. At the molecular level, SOX5 gene encodes for a transcription factor containing a High Mobility Group (HMG) DNA-Binding domain with relevant functions in brain development in different vertebrate species. Clinical features of Lamb-Shaffer syndrome may include intellectual disability, delayed speech and language development, attention deficits, hyperactivity, autism spectrum disorder, visual problems and seizures. Additionally, patients with the syndrome may present distinct facial dimorphism such as a wide mouth with full lips, small chin, broad nasal bridge, and deep-set eyes. Other physical features that have been reported in some patients include short stature, scoliosis, and joint hypermobility. Here, we report the clinical and molecular characterization of a Spanish LSS cohort of new 20 patients and review all the patients published so far which amount for 111 patients. The most frequent features included developmental delay, intellectual disability, visual problems, poor speech development and facial dysmorphic features. Strikingly, pain insensitivity and hypermetropia seems to be more frequent than previously reported, based on the frequency seen in the Spanish cohort. Eighty-three variants have been reported so far, single nucleotide variants (SNV) and copy number variants represent 47% and 53%, respectively, from the total of variants reported. Similarly to previous reports, the majority of the SNVs variants of the novel patients reported herein fall in the HMG domain of the protein. However, new variants, affecting other functional domains, were also detected. In conclusion, LLS is a rare genetic disorder mostly characterized by a wide range of developmental and neurological symptoms. Early diagnosis would allow to start of care programs, clinical follow up, prospective studies and appropriate genetic counseling, to promote clinical and social improvement to have profound lifelong benefits for patients and their families. Further research is needed to better understand the underlying mechanisms of the syndrome related to SOX5 haploinsufficiency.
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Trastorno del Espectro Autista , Discapacidad Intelectual , Trastornos del Neurodesarrollo , Humanos , Discapacidad Intelectual/genética , Trastorno del Espectro Autista/genética , Estudios Prospectivos , Haploinsuficiencia , Síndrome , Fenotipo , Factores de Transcripción SOXD/genéticaRESUMEN
OBJECTIVE: To assess the value of preoperative 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) scan, combined with clinical variables, in predicting complete cytoreduction in selected patients with advanced ovarian cancer. METHODS: We carried out a multicenter, observational, retrospective study evaluating patients who underwent primary cytoreductive surgery for advanced ovarian cancer in two Spanish centers between January 2017 and January 2022. Inclusion criteria were histological confirmation of invasive epithelial ovarian carcinoma; preoperative International Federation of Gynecology and Obstetrics (FIGO) stage III or IV; upfront cytoreductive surgery; and 18F-FDG PET/CT performed 1 month prior to surgery. A modified 18F-FDG PET/CT peritoneal cancer index score was calculated for all patients. Clinical variables and preoperative 18F-FDG PET/CT findings were analyzed and a multivariate model was constructed. A predictive score based on the odds ratio of the variables was calculated to determine patient selection. RESULTS: A total of 45 patients underwent primary cytoreductive surgery. Complete resection was achieved in 36 (80%) patients. On multivariate analysis, two clinical variables (age ≥58 years and American Society of Anesthesiology score ≥3) and two preoperative 18F-FDG PET/CT scan findings (presence of extra-abdominal lymph node involvement and modified peritoneal cancer index value of 6 or more) were associated with gross residual disease. For this multivariate model predictive of non-complete cytoreduction, the area under the curve was 0.881. A predictive value of ≥5 was the most predictive cut-off for gross residual disease. Complete resection rate was 91.7% in patients with a score of ≤4 and 33.3% in patients with a score of ≥5 points on the predictive score. CONCLUSIONS: In selected patients, a predictive score value ≥5 may be consider as a cut-off point for triaging patients to diagnostic laparoscopy before the primary surgery or neoadjuvant chemotherapy.
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Gene therapy with hematopoietic stem and progenitor cells is a promising approach to engineering immunity to human immunodeficiency virus (HIV) that may lead to a functional cure for acquired immunodeficiency syndrome (AIDS). In support of this approach, we created lentiviral vectors with an engineered polycistronic platform derived from the endogenous MCM7 gene to express a diverse set of small antiviral RNAs and a drug resistance MGMT(P140K) marker. Multiple strategies for simultaneous expression of up to five RNA transgenes were tested. The placement and orientation of each transgene and its promoter were important determinants for optimal gene expression. Antiviral RNA expression from the MCM7 platform with a U1 promoter was sufficient to provide protection from R5-tropic HIV in macrophages and resulted in reduced hematopoietic toxicity compared with constructs expressing RNA from independent RNA polymerase III promoters. The addition of an HIV entry inhibitor and nucleolar TAR RNA decoy did not enhance antiviral potency over constructs that targeted only viral RNA transcripts. We also demonstrated selective enrichment of gene-modified cells in vivo using a humanized mouse model. The use of these less toxic, potent anti-HIV vectors expressing a drug selection marker is likely to enhance the in vivo efficacy of our stem cell gene therapy approach in treating HIV/AIDS.
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Síndrome de Inmunodeficiencia Adquirida/terapia , Metilasas de Modificación del ADN/genética , Enzimas Reparadoras del ADN/genética , Terapia Genética , VIH/genética , Proteínas Supresoras de Tumor/genética , Síndrome de Inmunodeficiencia Adquirida/genética , Síndrome de Inmunodeficiencia Adquirida/patología , Síndrome de Inmunodeficiencia Adquirida/virología , Animales , Metilasas de Modificación del ADN/metabolismo , Enzimas Reparadoras del ADN/metabolismo , Resistencia a Medicamentos/genética , Vectores Genéticos/uso terapéutico , VIH/inmunología , VIH/patogenicidad , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas/citología , Humanos , Lentivirus/genética , Ratones , Componente 7 del Complejo de Mantenimiento de Minicromosoma/genética , Estabilidad del ARN/genética , ARN Interferente Pequeño/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
We conducted a multicentre, phase II study of interim positron emission tomography (PET) as a guide to risk-adapted therapy in high-risk patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). Patients achieving negative fluorodeoxyglucose (FDG)-PET after three courses of R-MegaCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) received three additional courses, whereas PET-positive patients received two courses of R-IFE (rituximab, ifosfamide, etoposide) followed by BEAM (BCNU, etoposide, cytarabine, melphalan) and autologous stem-cell transplantation. The primary endpoint was progression-free survival (PFS). 71 patients (median age 55 years, range 25-69) were enrolled. With a median follow-up of 42·8 months (range 7·2-58·4), the estimated 4-year PFS and overall survival (OS) were 67% and 78%, respectively, for the global series. Patients in complete remission after interim PET (N = 36) had significantly better 3-year PFS than those with partial response (N = 30) [81% vs. 57%, Hazard ratio (HR) = 2·6, 95% confidence interval (CI) = 1·02-6·65] but not a statistically significant longer OS. A retrospective PET central review was done for 51 patients. According to semiquantitative analysis, 3-year PFS (81% vs. 33%; HR = 6·9, 95% CI = 2·35-20·6) and OS (95% vs. 33%, HR = 19·4, 95% CI = 3·89-97·0) were significantly better for negative than for positive interim PET patients. Early PET assessment is valuable for risk stratification in DLBCL; for this purpose semiquantitative evaluation is a better predictor than visual criteria.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Radioisótopos de Flúor , Fluorodesoxiglucosa F18 , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Tomografía de Emisión de Positrones , Radiofármacos , Adulto , Anciano , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carmustina/administración & dosificación , Terapia Combinada , Ciclofosfamida/administración & dosificación , Citarabina/administración & dosificación , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Etopósido/administración & dosificación , Femenino , Humanos , Ifosfamida/administración & dosificación , Estimación de Kaplan-Meier , Linfoma de Células B Grandes Difuso/diagnóstico por imagen , Linfoma de Células B Grandes Difuso/terapia , Masculino , Melfalán/administración & dosificación , Persona de Mediana Edad , Trasplante de Células Madre de Sangre Periférica , Prednisona/administración & dosificación , Pronóstico , Estudios Prospectivos , Inducción de Remisión , Rituximab , Trasplante Autólogo , Resultado del Tratamiento , Vincristina/administración & dosificaciónRESUMEN
The HIV-1 coreceptor CCR5 is a validated target for HIV/AIDS therapy. The apparent elimination of HIV-1 in a patient treated with an allogeneic stem cell transplant homozygous for a naturally occurring CCR5 deletion mutation (CCR5(Δ32/Δ32)) supports the concept that a single dose of HIV-resistant hematopoietic stem cells can provide disease protection. Given the low frequency of naturally occurring CCR5(Δ32/Δ32) donors, we reasoned that engineered autologous CD34(+) hematopoietic stem/progenitor cells (HSPCs) could be used for AIDS therapy. We evaluated disruption of CCR5 gene expression in HSPCs isolated from granulocyte colony-stimulating factor (CSF)-mobilized adult blood using a recombinant adenoviral vector encoding a CCR5-specific pair of zinc finger nucleases (CCR5-ZFN). Our results demonstrate that CCR5-ZFN RNA and protein expression from the adenoviral vector is enhanced by pretreatment of HSPC with protein kinase C (PKC) activators resulting in >25% CCR5 gene disruption and that activation of the mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway is responsible for this activity. Importantly, using an optimized dose of PKC activator and adenoviral vector we could generate CCR5-modified HSPCs which engraft in a humanized mouse model (albeit at a reduced level) and support multilineage differentiation in vitro and in vivo. Together, these data establish the basis for improved approaches exploiting adenoviral vector delivery in the modification of HSPCs.
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Endonucleasas/genética , Genómica/métodos , Células Madre Hematopoyéticas/citología , Receptores CCR5/genética , Dedos de Zinc/genética , Síndrome de Inmunodeficiencia Adquirida/terapia , Adenoviridae/genética , Animales , Antígenos CD34/genética , Antígenos CD34/metabolismo , Apoptosis , Diferenciación Celular , Supervivencia Celular , Células Cultivadas , Modelos Animales de Enfermedad , Endonucleasas/metabolismo , Quinasas MAP Reguladas por Señal Extracelular/genética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Eliminación de Gen , Marcación de Gen , Vectores Genéticos , Factor Estimulante de Colonias de Granulocitos/genética , Factor Estimulante de Colonias de Granulocitos/metabolismo , VIH-1 , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas/metabolismo , Humanos , Ratones , Receptores CCR5/metabolismoRESUMEN
UNLABELLED: The role of (18)F-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) in the diagnosis and follow-up of infectious diseases has expanded recently. The aim of this report is to communicate our experience regarding its role in the diagnosis and management of occult bacterial infections in children. We present three pediatric patients with occult bacterial infections and negative conventional studies in whom (18)F-FDG PET/CT had a significant effect on clinical management. One patient had streptococcal endocarditis and prolonged fever. (18)F-FDG PET/CT identified pneumonia and osteomyelitis, and was also used to monitor therapeutic response. Other patient had a cerebrospinal shunt fluid infection. (18)F-FDG PET/CT was used to determine the exact localization of infection and establish the best surgical approach. The last patient had fever of unknown origin. (18)F-FDG PET/CT identified splenic abscesses, which were surgically treated. CONCLUSION: (18)F-FDG PET/CT should be considered as a useful diagnostic tool in children with suspected bacterial infections, if conventional diagnostic imaging techniques have failed to yield positive results.
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Infecciones Bacterianas/diagnóstico por imagen , Fiebre de Origen Desconocido/etiología , Fluorodesoxiglucosa F18 , Tomografía de Emisión de Positrones/métodos , Radiofármacos , Tomografía Computarizada por Rayos X/métodos , Adolescente , Infecciones Bacterianas/complicaciones , Niño , Femenino , Humanos , MasculinoRESUMEN
Predictive models of tumor response based on heterogeneity metrics in medical images, such as textural features, are highly suggestive. However, the demonstrated sensitivity of these features to noise does affect the model being developed. An in-depth analysis of the noise influence on the extraction of texture features was performed based on the assumption that an improvement in information quality can also enhance the predictive model. A heuristic approach was used that recognizes from the beginning that the noise has its own texture and it was analysed how it affects the quantitative signal data. A simple procedure to obtain noise image estimation is shown; one which makes it possible to extract the noise-texture features at each observation. The distance measured between the textural features in signal and estimated noise images allows us to determine the features affected in each observation by the noise and, for example, to exclude some of them from the model. A demonstration was carried out using synthetic images applying realistic noise models found in medical images. Drawn conclusions were applied to a public cohort of clinical images obtained using FDG-PET to show how the predictive model could be improved. A gain in the area under the receiver operating characteristic curve between 10 and 20% when noise texture information is used was shown. An improvement between 20 and 30% can be appreciated in the estimated model quality.
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Fluorodesoxiglucosa F18 , Tomografía de Emisión de Positrones , Humanos , Curva ROCRESUMEN
INTRODUCTION AND OBJECTIVES: Since different PET/CT (Positron Emission Tomography/Computed Tomography) scanners give different qualitative readings, a program for clinical trial qualification (CTQ) is mandatory to guarantee a reliable and reproducible use of PET/CT in prospective multi-centre clinical trials. Within this work we will show the results carried out in performing CTQ in Spain. MATERIALS AND METHODS: We set up, under the auspices of Grupo Español de Linfomas/Trasplante Autólogo de Médula Osea (GELTAMO), a CTQ program consisting of the acquisition and analysis of 18F uniformity and image quality phantoms for the reduction of inter-scanner variability (ISV). The ISV was estimated on background activity concentration (BAC) and sphere to background ratio (SBR) and defined as their 95% confidence level. RESULTS: Twenty-six out of 27 (96%) scanners fulfilled the CTQ requirements. The CTQ was fulfilled at the first round in 27% of the cases, while in 38%, 15% and 20%, two, three or more than three iterations, were required, respectively. The mean CTQ time was (1.8 ± 1.4) months (range: 0.3-4.6). The ISV in BAC and SBR were 20.3% and 67.7%. CONCLUSIONS: The CTQ proven to be a reliable tool to reduce ISV. This enabled to set-up clinical trials in which PET/CT was used to evaluate different clinical endpoints.
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Diffuse large B-cell lymphoma (DLBCL) accounts for approximately 30% of non-Hodgkin lymphoma (NHL) cases in adult series. DLBCL is characterized by marked clinical and biological heterogeneity, encompassing up to 16 distinct clinicopathological entities. While current treatments are effective in 60% to 70% of patients, those who are resistant to treatment continue to die from this disease. An expert panel performed a systematic review of all data on the diagnosis, prognosis, and treatment of DLBCL published in PubMed, EMBASE and MEDLINE up to December 2017. Recommendations were classified in accordance with the Grading of Recommendations Assessment Development and Evaluation (GRADE) framework, and the proposed recommendations incorporated into practical algorithms. Initial discussions between experts began in March 2016, and a final consensus was reached in November 2017. The final document was reviewed by all authors in February 2018 and by the Scientific Committee of the Spanish Lymphoma Group GELTAMO.
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Atherosclerosis is an inflammatory disease, but the response of the endogenous anti-inflammatory system during this process has not been evaluated previously. Cortisol is the end product of this anti-inflammatory system, but is also able to activate cellular processes that induce atherogenesis; however, it is unknown whether atherogenesis occurs when circulating concentrations of endogenous cortisol are increased or when they are decreased. We have evaluated the counter-regulatory responses of cortisol and interleukin-1beta (IL-1beta) during the short- and long-term responses to vascular injury in rabbits fed a 2% cholesterol diet. In the short-term group (n=18), serum cortisol and IL-1beta concentrations were measured after 10, 20 and 30 days. Rabbits developed hypercholesterolemia and hypercortisolemia, with only modest increases in IL-1beta. Although inflammation was low-grade, atherogenesis took place, with subintimal lipid accumulation evident on day 30. In the second group (n=18), we evaluated variables after 40, 60 and 90 days. This group developed hypercholesterolemia, but serum cortisol concentrations were inappropriately normal, while IL-1beta concentrations were elevated 8.6-fold; advanced atherosclerotic plaques were evident on days 60 and 90. These results show that atherogenesis occurs when high endogenous cortisol levels are suppressing inflammation, and are consistent with a promotion of early atherogenesis by high cortisol concentrations.
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Aorta Torácica/patología , Aterosclerosis/etiología , Hidrocortisona/sangre , Hipercolesterolemia/complicaciones , Interleucina-1beta/sangre , Animales , Aterosclerosis/sangre , Aterosclerosis/patología , Colesterol/sangre , Colesterol en la Dieta , Ritmo Circadiano , Modelos Animales de Enfermedad , Células Espumosas/patología , Hipercolesterolemia/sangre , Hipercolesterolemia/inducido químicamente , Hipercolesterolemia/patología , Inflamación/sangre , Inflamación/etiología , Conejos , Factores de TiempoRESUMEN
Positron emission tomography (PET) images are characterised by low signal-to-noise ratio and blurred edges when compared with other image modalities. It is therefore advisable to use noise reduction methods for qualitative and quantitative analyses. Given the importance of the maximum and mean uptake values, it is necessary to avoid signal loss, which could modify the clinical significance. This paper proposes a method of non-linear image denoising for PET. It is based on spatially adaptive wavelet-shrinkage and uses context modelling, which explicitly considers the correlation between neighbouring pixels. This context modelling is able to maintain the uptake values and preserve the edges in significant regions. The algorithm is proposed as an alternative to the usual filtering that is performed after reconstruction.
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Algoritmos , Aumento de la Imagen/métodos , Interpretación de Imagen Asistida por Computador/métodos , Fantasmas de Imagen , Tomografía de Emisión de Positrones/métodos , Relación Señal-Ruido , HumanosRESUMEN
The synchronous diagnosis of a thyroid metastasis and of the primary colon adenocarcinoma that produces it is very rare, with only 5 cases reported to date, all of them treated with thyroid surgery showing a mean survival of 7 months. An ¹8F-FDG PET/CT in an asymptomatic 74-year-old woman with a thyroid cytology suggestive of malignancy but uncertain about the origin of the tumor revealed an stage IV colon adenocarcinoma with KRAS mutation and multiple metastasis (thyroid, lung, and liver). A prompt therapeutic planning with chemotherapy allowed 21 months of survival.
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Adenocarcinoma/patología , Neoplasias del Colon/patología , Fluorodesoxiglucosa F18 , Mutación , Tomografía Computarizada por Tomografía de Emisión de Positrones , Proteínas Proto-Oncogénicas p21(ras)/genética , Neoplasias de la Tiroides/secundario , Anciano , Femenino , Humanos , Neoplasias de la Tiroides/diagnóstico por imagen , Neoplasias de la Tiroides/genéticaRESUMEN
INTRODUCTION: Abdominal fat and its increment over time in particular has become a cardiovascular risk factor in uraemic patients. OBJECTIVES: To analyse changes in abdominal fat in haemodialysis patients over one year and study their possible correlation with the variation in adipocytokine serum levels. As a secondary objective, we tried to validate the data obtained by bioelectrical impedance analysis (BIA) with data obtained by dual X-ray absorptiometry (DXA). MATERIAL AND METHODS: A prospective one-year study was performed in 18 patients on haemodialysis (HD). In each patient, body composition by BIA and DXA was estimated at baseline and after one year. Several adipocytokine and biochemical parameters were determined. RESULTS: A significant increase in phase angle [4.8° (4.1-5.6) vs. 5.2° (4.4-5.8), P<.05], BIA intracellular water [48.3% (43.1-52.3) vs. 50.3% (45.7-53.4), P<.05] and the ratio between the percentage of android/gynecoid (A/G) distribution of fat measured by DXA [1.00 (0.80-1.26) vs. 1.02 (0.91-1.30), P<.05] was observed. A statistically significant relationship between leptin and adiponectin concentrations and the percentage of fat mass measured by BIA, as well as the abdominal fat percentage estimated by DXA, was found (P<.01). CONCLUSION: HD patients exhibit a gain in fat mass over time, especially in the abdomen, evidenced by an increased A/G ratio. These findings might explain the increased cardiovascular risk in these patients.
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Grasa Abdominal , Adipoquinas/sangre , Composición Corporal , Enfermedades Cardiovasculares/etiología , Fallo Renal Crónico/sangre , Fallo Renal Crónico/complicaciones , Diálisis Renal , Anciano , Femenino , Humanos , Fallo Renal Crónico/terapia , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Factores de RiesgoRESUMEN
Two hundred and ten nuclear medicine physicians, radiologists, and hematologists from 26 countries attended the 6th International Workshop on Positron Emission Tomography (PET) in Lymphoma and Myeloma held in Menton, France, in September 2016. The meeting was under the auspices of the European Lymphoma Institute (ELI), the European Association of Nuclear Medicine (EANM) the Lymphoma Study Association (LYSA), the Italian Foundation on Lymphoma (FIL) and the Carnot Institute for Lymphoma (CALYM). Forty scientific posters were presented. For the first time, specialists in the field of multiple myeloma (MM) were involved in the expert session. The aim was to establish from the experience of Italian and French studies new guidelines of FDG-PET/CT reporting for myeloma staging and restaging. The meeting dedicated an entire session to MM imaging followed by a session on the role of PET in Peripheral T cell Lymphoma. An entire session addressed the issues of Deauville scale particularly for end treatment assessment and the challenging consequences of immunomodulatory treatments on PET reporting. A specific session presented the potential role of baseline metabolic tumor measurement to predict outcome and identify different risk categories and the main results obtained in different lymphoma entities were described. Whether it could replace clinical staging has been extensively discussed. The more recent results obtained in the H10 trial have been presented and compared to the published data in early stage Hodgkin lymphoma. Finally, the ongoing studies using PET for guiding therapeutic strategies have been reported by the various lymphoma cooperative groups that participated to the meeting.
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PURPOSE: Sm-153 EDTMP is an effective treatment of painful bone metastases from different neoplasms. However, there are few studies describing clinical experience with this therapeutic modality. The aim of this clinical study was to evaluate the efficacy of Sm-153 EDTMP in a group of patients with skeletal metastases and poor pain control with conventional therapies. MATERIALS AND METHODS: Sixty-four patients with painful bone metastases treated with Sm-153 EDTMP were retrospectively evaluated. Nine patients were treated twice. The most common primaries were breast in 28 cases (44%) and prostate in 27 (41%). Treatment efficacy was assessed by a visual analog scale, analgesic consumption, and performance status before and after treatment. Response was graded as complete, moderate, or minor. Toxicity evaluation included analytic parameters (blood counts, renal function) and clinical follow up. RESULTS: Efficacy and toxicity were evaluated separately for each dose (total doses: 73), and complete follow up was only possible in 62 of 73 administrations. The response rate was 85% (21% complete, 40% moderate, and 24% minor). Onset of improvement took place a median of 7 days after Sm-153 EDTMP administration, and pain relief persisted for a mean of 3 months. No relevant toxicity was found in the early phase. Myelotoxicity appeared in 29% of the administrations and was mild in most cases (there was one case of grade 4 leukopenia). CONCLUSIONS: Sm-153 EDTMP is a good therapeutic option for patients with painful bone metastases. It is an effective treatment of pain relief without major secondary effects.
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Neoplasias Óseas/radioterapia , Neoplasias Óseas/secundario , Compuestos Organometálicos/uso terapéutico , Compuestos Organofosforados/uso terapéutico , Dolor/prevención & control , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Óseas/complicaciones , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dolor/etiología , Pronóstico , Radiofármacos/uso terapéutico , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
En el contexto de: los avances tecnológicos de los últimos 20 años, sumados al crecimiento demográfico, los cambios macroeconómicos a escala global, el aumento del papel protagónico de la mujer en el ámbito profesional, las realidades asistenciales de los nóveles médicos egresados, la labor asistencial de los docentes universitarios, los recursos necesarios para la educación en salud y las herramientas heterogéneas de las cuales disponen los ámbitos de formación en salud del país proponemos repensar ¿qué perfil docente en el ámbito de la salud necesitan nuestras casas de estudios universitarios? ¿cuáles son las competencias necesarias a adquirir y desarrollar por nuestros exigidos docentes universitarios actuales? Realizamos una revisión del significado en cuanto a competencias docentes, y aportes de diversos autores en este contexto. Proponemos la reflexión de este importante aspecto, explicitando finalmente ejes de acción y objetivos para un programa de formación docente continua en el ámbito de la salud.
In the context of: the technological advances of the last 20 years, added to the demographic growth, the macroeconomic changes on a global scale, the increase in the leading role of women in the professional field, the healthcare realities of graduated medical professionals, the work health care of university teachers, the necessary resources for health education and the heterogeneous tools available to the health training areas of the country, we propose to rethink which teaching profile in the field of health do our universities need? What are the necessary skills to acquire and develop for our current demanding university teachers? We carry out a review of the meaning in terms of teaching competences, and contributions from various authors in this context. We propose the reflection of this important aspect, finally explaining lines of action and objectives for a continuous teacher training program in the field of health.
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Educación Médica , Formación del Profesorado , UniversidadesRESUMEN
Hematopoietic stem cell gene therapy for HIV/AIDS is a promising alternative to lifelong antiretroviral therapy. One of the limitations of this approach is the number and quality of stem cells available for transplant following in vitro manipulations associated with stem cell isolation and genetic modification. The development of methods to increase the number of autologous, gene-modified stem cells available for transplantation would overcome this barrier. Hematopoietic stem and progenitor cells (HSPC) from adult growth factor-mobilized peripheral blood were cultured in the presence of an aryl hydrocarbon receptor antagonist (AhRA) previously shown to expand HSPC from umbilical cord blood. Qualitative and quantitative assessment of the hematopoietic potential of minimally cultured (MC-HSPC) or expanded HSPC (Exp-HSPC) was performed using an immunodeficient mouse model of transplantation. Our results demonstrate robust, multilineage engraftment of both MC-HSPC and Exp-HSPC although estimates of expansion based on stem cell phenotype were not supported by a corresponding increase in in vivo engrafting units. Bone marrow of animals transplanted with either MC-HSPC or Exp-HSPC contained secondary engrafting cells verifying the presence of primitive stem cells in both populations. However, the frequency of in vivo engrafting units among the more primitive CD34+/CD90+ HSPC population was significantly lower in Exp-HSPC compared with MC-HSPC. Exp-HSPC also produced fewer lymphoid progeny and more myeloid progeny than MC-HSPC. These results reveal that in vitro culture of adult HSPC in AhRA maintains but does not increase the number of in vivo engrafting cells and that HSPC expanded in vitro contain defects in lymphopoiesis as assessed in this model system. Further investigation is required before implementation of this approach in the clinical setting.
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Células Madre Hematopoyéticas/citología , Receptores de Hidrocarburo de Aril/antagonistas & inhibidores , Animales , Antígenos CD34/metabolismo , Compuestos Azo/farmacología , Linaje de la Célula , Células Cultivadas , Sangre Fetal/citología , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas/efectos de los fármacos , Células Madre Hematopoyéticas/metabolismo , Humanos , Antígenos Comunes de Leucocito/metabolismo , Ratones , Ratones Endogámicos NOD , Modelos Animales , Fenotipo , Pirazoles/farmacología , Receptores de Hidrocarburo de Aril/metabolismo , Antígenos Thy-1/metabolismo , Trasplante HeterólogoRESUMEN
Genetic modification of adult human hematopoietic stem and progenitor cells (HSPCs) with lentiviral vectors leads to long-term gene expression in the progeny of the HSPCs and has been used to successfully treat several monogenic diseases. In some cases, the gene-modified cells have a selective growth advantage over nonmodified cells and eventually are the dominant engrafted population. However, in disease indications for which the gene-modified cells do not have a selective advantage, optimizing transduction of HSPC is paramount to successful stem cell-based gene therapy. We demonstrate here that transduction of adult CD34+ HSPCs with lentiviral vectors in the presence of rapamycin, a widely used mTORC1 inhibitor, results in an approximately threefold increase in stable gene marking with minimal effects on HSPC growth and differentiation. Using this approach, we have demonstrated that we can enhance the frequency of gene-modified HSPCs that give rise to clonogenic progeny in vitro without excessive increases in the number of vector copies per cell or changes in integration pattern. The genetic marking of HSPCs and expression of transgenes is durable, and transplantation of gene-modified HSPCs into immunodeficient mice results in high levels of gene marking of the lymphoid and myeloid progeny in vivo. The prior safe clinical history of rapamycin in other applications supports the use of this compound to generate gene-modified autologous HSPCs for our HIV gene therapy clinical trials.
Asunto(s)
Terapia Genética/métodos , Células Madre Hematopoyéticas/efectos de los fármacos , Sirolimus/farmacología , Transducción Genética/métodos , Animales , Técnicas de Cultivo de Célula/métodos , Citometría de Flujo , Vectores Genéticos , Factor Estimulante de Colonias de Granulocitos/farmacología , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Técnicas In Vitro , Lentivirus , Ratones , Ratones Endogámicos NOD , Reacción en Cadena de la PolimerasaAsunto(s)
Angina de Pecho/metabolismo , AMP Cíclico/metabolismo , Monocitos/metabolismo , Anciano , Angina de Pecho/patología , Aterosclerosis/etiología , Aterosclerosis/metabolismo , Aterosclerosis/fisiopatología , Estudios de Casos y Controles , Colesterol/sangre , Femenino , Humanos , Interleucina-6/sangre , Masculino , Persona de Mediana Edad , Monocitos/patologíaRESUMEN
Introducción: La grasa abdominal y, sobre todo, su ganancia a lo largo del tiempo, se ha consolidado como un factor de riesgo cardiovascular en pacientes urémicos. Objetivos: Analizar los cambios en la grasa abdominal en los pacientes de hemodiálisis (HD) a lo largo de un año y estudiar sus posibles relaciones con los cambios en los niveles circulantes de adipocitocinas. Como objetivo secundario intentamos validar los datos obtenidos por bioimpedancia eléctrica (BIA) con los obtenidos por absorciometría dual de rayos X (DXA). Material y métodos: Se realizó un estudio prospectivo de un año de duración en 18 pacientes en HD. En cada paciente se cuantificó, basalmente y al cabo de un año, la composición corporal por BIA y DXA y se determinaron varios parámetros bioquímicos incluyendo adipocitocinas. Resultados: Se evidenció un aumento significativo del ángulo de fase [4,8° (4,1-5,6) frente a 5,2° (4,4-5,8); p<0,05], del agua intracelular por BIA [48,3% (43,1-52,3) frente a 50,3% (45,7-53,4); p<0,05] y del cociente entre el porcentaje de grasa de distribución androide/ginecoide (A/G) medido por DXA [1,00 (0,80-1,26) frente a 1,02 (0,91; 1,30); p<0,05]. Se encontró una relación estadísticamente significativa entre las concentraciones de leptina y adiponectina tanto con el porcentaje de masa grasa medida por BIA como con la grasa abdominal estimada mediante DXA (p<0,01). Conclusión: Los pacientes en HD experimentan una ganancia de grasa con el tiempo, especialmente en localización abdominal, evidenciada por un aumento del cociente A/G, lo que podría explicar el aumento del riesgo cardiovascular que presentan (AU)
Introduction: Abdominal fat and its increment over time in particular has become a cardiovascular risk factor in uraemic patients. Objectives: To analyse changes in abdominal fat in haemodialysis patients over one year and study their possible correlation with the variation in adipocytokine serum levels. As a secondary objective, we tried to validate the data obtained by bioelectrical impedance analysis (BIA) with data obtained by dual X-ray absorptiometry (DXA). Material and methods: A prospective one-year study was performed in 18 patients on haemodialysis (HD). In each patient, body composition by BIA and DXA was estimated at baseline and after one year. Several adipocytokine and biochemical parameters were determined. Results: A significant increase in phase angle [4.8° (4.1-5.6) vs. 5.2° (4.4-5.8), P<.05], BIA intracellular water [48.3% (43.1-52.3) vs. 50.3% (45.7-53.4), P<.05] and the ratio between the percentage of android/gynecoid (A/G) distribution of fat measured by DXA [1.00 (0.80-1.26) vs. 1.02 (0.91-1.30), P<.05] was observed. A statistically significant relationship between leptin and adiponectin concentrations and the percentage of fat mass measured by BIA, as well as the abdominal fat percentage estimated by DXA, was found (P<.01). Conclusion: HD patients exhibit a gain in fat mass over time, especially in the abdomen, evidenced by an increased A/G ratio. These findings might explain the increased cardiovascular risk in these patients (AU)