Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 20 de 32
Filter
1.
Biomedicines ; 12(5)2024 May 18.
Article in English | MEDLINE | ID: mdl-38791083

ABSTRACT

Eslicarbazepine acetate (ESL) is a third-generation antiepileptic drug indicated as monotherapy for adults with newly diagnosed epilepsy and as adjunctive therapy for the treatment of partial seizures. Our aim was to assess the effectiveness and safety of both acute and repeated ESL administration against reflex audiogenic seizures, as shown by the Genetic Audiogenic Seizures Hamster from Salamanca (GASH/Sal). Animals were subject to the intraperitoneal administration of ESL, applying doses of 100, 150 and 200 mg/kg for the acute study, whereas a daily dose of 100 mg/kg was selected for the subchronic study, which lasted 14 days. In both studies, the anticonvulsant effect of the therapy was evaluated using neuroethological methods. To assess the safety of the treatment, behavioral tests were performed, hematological and biochemical liver profiles were obtained, and body weight was monitored. In addition, the ESL levels in blood were measured after the acute administration of a 200 mg/kg dose. Treatment with ESL caused a reduction in seizure severity. No statistically significant differences were detected between the selected doses or between the acute or repeated administration of the drug. To summarize, the intraperitoneal administration of ESL is safe and shows an anticonvulsant effect in the GASH/Sal.

2.
Int J Mol Sci ; 25(1)2023 Dec 20.
Article in English | MEDLINE | ID: mdl-38203262

ABSTRACT

Vagus nerve stimulation (VNS) is an adjuvant neuromodulation therapy for the treatment of refractory epilepsy. However, the mechanisms behind its effectiveness are not fully understood. Our aim was to develop a VNS protocol for the Genetic Audiogenic Seizure Hamster from Salamanca (GASH/Sal) in order to evaluate the mechanisms of action of the therapy. The rodents were subject to VNS for 14 days using clinical stimulation parameters by implanting a clinically available neurostimulation device or our own prototype for laboratory animals. The neuroethological assessment of seizures and general behavior were performed before surgery, and after 7, 10, and 14 days of VNS. Moreover, potential side effects were examined. Finally, the expression of 23 inflammatory markers in plasma and the left-brain hemisphere was evaluated. VNS significantly reduced seizure severity in GASH/Sal without side effects. No differences were observed between the neurostimulation devices. GASH/Sal treated with VNS showed statistically significant reduced levels of interleukin IL-1ß, monocyte chemoattractant protein MCP-1, matrix metalloproteinases (MMP-2, MMP-3), and tumor necrosis factor TNF-α in the brain. The described experimental design allows for the study of VNS effects and mechanisms of action using an implantable device. This was achieved in a model of convulsive seizures in which VNS is effective and shows an anti-inflammatory effect.


Subject(s)
Epilepsy, Reflex , Vagus Nerve Stimulation , Animals , Cricetinae , Seizures/therapy , Brain , Combined Modality Therapy , Interleukin-1beta
3.
Rev. esp. med. legal ; 48(4): 144-150, Octubre - Diciembre 2022. tab
Article in Spanish | IBECS | ID: ibc-213682

ABSTRACT

Introducción: El principio de autonomía es la base del concepto de consentimiento informado. El consentimiento informado es un derecho del paciente que consiste en que este, previamente a que se efectúe la intervención médica en su cuerpo, debe expresar su conformidad que debe ir precedida de la debida información que le permite decidir según sus intereses. En este trabajo, nuestro objetivo fue conocer la situación de la información médica y del consentimiento informado del paciente en el Servicio de Traumatología y Cirugía Ortopédica del Hospital Universitario de Burgos.Material y métodosSe elaboró y distribuyó un cuestionario anónimo entre 647 pacientes de cirugía ortopédica y traumatología del Hospital Universitario de Burgos. Posteriormente, se realizó un estudio cuantitativo observacional descriptivo de corte transversal. Se estudió la asociación de las variables sociodemográficas con las respuestas a los ítems del cuestionario.ResultadosSolo el 28,9% de los pacientes conoce que la información es un derecho, pero la mayoría (97,3%) manifestaron la necesidad de recibir información sobre riesgos y complicaciones del tratamiento y consideran que la información no aumenta el miedo o ansiedad (63,4%). La mayoría afirmaron que fueron informados sobre la actuación asistencial (98,1%), comprendiendo las explicaciones recibidas (98,0%). El tiempo utilizado fue suficiente (73,7%). En general, la información recibida fue calificada como suficiente (89,8%).ConclusionesLos pacientes, en su mayoría, se sintieron informados y consideraron que el tiempo que el facultativo había tenido para ello era suficiente. (AU)


Introduction: The principle of autonomy is the basis of the informed consent concept. Informed consent is a patient´s right consisting in prior to the medical intervention being carried out on his body, he must express his agreement that it must be preceded by the proper information that allows him to decide according to his interests. In this work, our objective was to know the status of medical information and informed consent of the patient in the Traumatology and Orthopedic Surgery Service of the University Hospital of Burgos.Material and methodsAn anonymous questionnaire was prepared and distributed among 647 orthopedic surgery and trauma patients at the University Hospital of Burgos. Subsequently, a descriptive, cross-sectional, observational quantitative study was carried out. The association of sociodemographic variables with the responses to the questionnaire items was studied.ResultsOnly 28.9% of the patients know that information is a right, but the majority (97.3%) expressed the need to receive information on risks and complications of the treatment and consider that the information does not increase fear or anxiety (63.4%). The majority stated that they were informed about the care performance (98.1%), understanding the explanations received (98.0%). The time used was sufficient (73.7%). In general, the information received was rated as sufficient (89.8%).ConclusionsMost of the patients felt informed and considered that the time that the doctor had had for this was sufficient. (AU)


Subject(s)
Humans , Informed Consent , Patient Rights , Access to Information/ethics , 24960 , Epidemiology, Descriptive , Cross-Sectional Studies , Spain
4.
Brain Spine ; 2: 101661, 2022.
Article in English | MEDLINE | ID: mdl-36605386

ABSTRACT

•OGM surgery is much more complex than a simple debate of "from above or from below" (transcranial vs endoscopic).•Lateral Sub-frontal and Superior Interhemispheric seem the most effective, superior and versatile approaches for OGM.•Minimally Invasive Transcranial approaches showed no inferiority in OGM sized <4 â€‹cm.•Endoscopic Endonasal Approaches showed inferior results in surgical and in functional outcomes for OGM.

5.
World Neurosurg ; 135: e339-e349, 2020 Mar.
Article in English | MEDLINE | ID: mdl-31811967

ABSTRACT

OBJECTIVES: Since the introduction of endovascular treatment for cerebral aneurysms, hospitals in which subarachnoid hemorrhage is treated show different availability and/or preferences towards both treatment modalities. The main aim is to evaluate the clinical and angiographic results according to the hospital's treatment preferences applied. METHODS: This study was conducted based on use of the subarachnoid hemorrhage database of the Vascular Pathology Group of the Spanish Neurosurgery Society. Centers were classified into 3 subtypes according to an index in the relationship between endovascular and surgical treatment as: endovascular preference, high endovascular preference, and elevated surgical preference. The clinical results and angiographic results were evaluated among the 3 treatment strategies. RESULTS: From November 2004 to December 2017, 4282 subarachnoid hemorrhage patients were selected for the study: 630 (14.7%) patients from centers with surgical preference, 2766 (64.6%) from centers with endovascular preference, and 886 (20.7%) from centers with high endovascular preference. The surgical preference group obtained the best angiographic results associated with a greater complete exclusion (odds ratio: 1.359; 95% confidence interval: 1.025-1.801; P = 0.033). The surgical preference subgroup obtained the best outcome at discharge (65.45%), followed by the high endovascular preference group (61.5%) and the endovascular preference group (57.8%) (odds ratio: 1.359; 95% confidence interval: 1.025-1.801; P = 0.033). CONCLUSIONS: In Spain, there is significant variability in aneurysm exclusion treatment in aneurysmal subarachnoid hemorrhage. Surgical centers offer better results for both surgical and endovascular patients. A multidisciplinary approach and the maintenance of an elevated quality of surgical competence could be responsible for these results.


Subject(s)
Endovascular Procedures , Intracranial Aneurysm/surgery , Neurosurgical Procedures , Subarachnoid Hemorrhage/surgery , Adult , Aged , Databases, Factual , Endovascular Procedures/methods , Female , Humans , Male , Middle Aged , Neurosurgical Procedures/methods , Surgical Instruments , Treatment Outcome
6.
J Med Syst ; 43(3): 69, 2019 Feb 08.
Article in English | MEDLINE | ID: mdl-30737601

ABSTRACT

Transcranial direct current stimulation is one of the non-invasive techniques whose main mechanism of action is based on its modulation of cortical excitability. The objective of this study is to analyze the variables (i.e, demographics, clinicals, stimulation parameters) that could influence into the responses during rehabilitation of the upper extremity in patients with stroke. Our systematic review has been performed by searching full-text articles published from January 2008 to December 2018 in Embase, Medline, PubMed and Cochrane Library databases. Studies with adult patients with ischemic or hemorrhagic stroke at any stage of evolution were included. We compared interventions with any type of transcranial direct current stimulation (anodal, cathodal or bihemispheric, also known as dual) regarding improvement of upper extremity motor function. We included 14 studies with 368 patients, of whom almost 89% have ischemic etiology and more than half are males. Most patients were considered subacute or chronic, while only two studies were selected with patients in the acute phase. Different methods of using transcranial direct current stimulation with several complementary therapies were identified, such as virtual reality, robot therapy, Occupational Therapy, Physiotherapy, Constraint Induced Movement Therapy or Peripheral Nerve Stimulation. In conclusion, there is not significant evidence due to heterogeneity of clinical data and therapies. Clinical studies with greater number of participants and protocols standardized could outline this assessment in future studies.


Subject(s)
Recovery of Function , Stroke Rehabilitation , Transcranial Direct Current Stimulation , Upper Extremity/physiopathology , Female , Humans , Male , Middle Aged
7.
J Med Syst ; 42(3): 50, 2018 Feb 01.
Article in English | MEDLINE | ID: mdl-29392522

ABSTRACT

Until very recently, we considered Virtual Reality as something that was very close, but it was still science fiction. However, today Virtual Reality is being integrated into many different areas of our lives, from videogames to different industrial use cases and, of course, it is starting to be used in medicine. There are two great general classifications for Virtual Reality. Firstly, we find a Virtual Reality in which we visualize a world completely created by computer, three-dimensional and where we can appreciate that the world we are visualizing is not real, at least for the moment as rendered images are improving very fast. Secondly, there is a Virtual Reality that basically consists of a reflection of our reality. This type of Virtual Reality is created using spherical or 360 images and videos, so we lose three-dimensional visualization capacity (until the 3D cameras are more developed), but on the other hand we gain in terms of realism in the images. We could also mention a third classification that merges the previous two, where virtual elements created by computer coexist with 360 images and videos. In this article we will show two systems that we have developed where each of them can be framed within one of the previous classifications, identifying the technologies used for their implementation as well as the advantages of each one. We will also analize how these systems can improve the current methodologies used for medical training. The implications of these developments as tools for teaching, learning and training are discussed.


Subject(s)
Computer Simulation , Education, Medical , General Surgery/education , Virtual Reality , Humans , User-Computer Interface
8.
Pediatr Blood Cancer ; 60(9): E103-5, 2013 Sep.
Article in English | MEDLINE | ID: mdl-23776087

ABSTRACT

Central venous catheter (CVC) removal is indicated when persistent catheter-related bloodstream infection (CRBSI) occurs. This is a retrospective study to analyze the use of linezolid as a salvage therapy for CRBSIs due to coagulase-negative Staphylococci in children diagnosed with acute leukemia. Seven treatment courses of linezolid were administrated to six patients with port-type-CRBSI after non-effective intravenous vancomycin or teicoplanin treatment. Simultaneous lock and systemic therapy with linezolid avoided the removal of port-type-CVC in all cases. Treatment with linezolid was an alternative to catheter removal in these patients. Prospective studies are needed to confirm linezolid effectiveness as a salvage treatment in CRBSI.


Subject(s)
Acetamides/administration & dosage , Anti-Infective Agents/administration & dosage , Central Venous Catheters , Leukemia, Myeloid, Acute/drug therapy , Oxazolidinones/administration & dosage , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Staphylococcal Infections/drug therapy , Staphylococcus , Child , Child, Preschool , Female , Humans , Infant , Leukemia, Myeloid, Acute/microbiology , Leukemia, Myeloid, Acute/pathology , Linezolid , Male , Precursor Cell Lymphoblastic Leukemia-Lymphoma/microbiology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Retrospective Studies , Salvage Therapy , Staphylococcal Infections/microbiology
9.
J Pediatr Hematol Oncol ; 35(5): e194-9, 2013 Jul.
Article in English | MEDLINE | ID: mdl-23652875

ABSTRACT

The use of intensive chemotherapy and central devices has improved patients survival, but it is associated with catheter-related blood-stream infections (CRBSI). An educational program was instituted for preventing CRBSI occurrence in acute leukemia pediatric patients having totally implanted central devices. The Centers of Disease Control and Prevention criteria were used as definition for CRBSI. Data collected were age, sex, diagnosis, chemotherapy, inpatient versus outpatient, microbiological data, risk factors, social risk score, and treatment performed. CRBSI rate decreased from 6.7 to 3.7/1000 catheter-days with preventive measures (P=0.05). A further decrease to 1.5/1000 catheter-days was reached after the intensification of the educational program (P=0.01). Severe neutropenia at the time of catheter insertion was related to CRBSI and to infection recurrence (P<0.05). Most of the episodes occurred during induction chemotherapy. Thirty-six CRBSI episodes occurred in 25 of 73 patients. The most frequent microorganism isolated was Staphylococcus spp. Antibiotherapy was successful in 83.3% of episodes. Six patients needed a central venous access device replacement. Our intervention program was successful to decrease the CRBSI rates and its intensification allowed a further decrease, approaching reported rates in this setting. Severe neutropenia at the time of central venous access device insertion was related to CRBSI occurrence and recurrence.


Subject(s)
Catheter-Related Infections/prevention & control , Catheterization, Central Venous/adverse effects , Central Venous Catheters/adverse effects , Infection Control/methods , Leukemia/drug therapy , Antineoplastic Agents/administration & dosage , Bacteremia/prevention & control , Bacteremia/transmission , Child , Child, Preschool , Cross Infection/prevention & control , Female , Humans , Infant , Infection Control/instrumentation , Infectious Disease Transmission, Professional-to-Patient/prevention & control , Male , Nurses , Physicians , Prospective Studies
11.
Med. clín (Ed. impr.) ; 139(4): 141-149, jul. 2012. tab, ilus
Article in Spanish | IBECS | ID: ibc-101841

ABSTRACT

Fundamento y objetivo: La leucemia linfoblástica aguda (LLA) es el cáncer más frecuente en la edad pediátrica, con tasas de curación del 80-85%. En la LLA de fenotipo T (LLA-T, 15% de casos) los factores pronósticos no están bien definidos. Nuestro objetivo es analizar la supervivencia y los factores pronósticos clínicos en una serie de pacientes con LLA-T. Pacientes y método: Se analizaron los niños con LLA-T (1-18 años) tratados según los protocolos SHOP/LLA-89/LLA-94/LLA-99/LLA-2005 (desde febrero de 1989 hasta noviembre de 2009) en 37 instituciones. Resultados: Se incluyeron 218 pacientes con LLA-T sobre un total de 1.652 LLA pediátricas. De ellos, 164 (75%) eran varones. La edad mediana fue de 7,8 años (extremos 1,3-18,6). La mediana de leucocitos fue 78,2×109/l (extremos 0,8-930). Quince niños (6,8%) tuvieron infiltración del sistema nervioso central (SNC). En cuanto a la respuesta al tratamiento de inducción, 150 (75%) pacientes tenían menos de 5% de blastos en médula ósea del día +14 y 199 alcanzaron la remisión completa. La supervivencia global (SG) media (DE) a 60 meses para los protocolos SHOP/LLA-89, LLA-94 y LLA-99 fue del 48 (8), 49 (6) y 70 (6) %, respectivamente, y la SG a 48 meses para el protocolo SHOP/LLA-05 (protocolo en curso) del 74 (8) %. La mediana de seguimiento fue de 206, 152, 74 y 17 meses, respectivamente. El análisis de factores pronósticos no mostró diferencias significativas en cuanto a sexo ni edad. Resultaron significativos la cifra de leucocitos mayor o igual a 200×109/l (p=0,024), la infiltración del SNC al diagnóstico (p<0,006), la respuesta al tratamiento (médula ósea día +14) (p=0,005) y la remisión completa al final de la inducción (p=0,0000). Conclusiones: Los resultados obtenidos en la LLA-T con los protocolos SHOP/LLA-89 y SHOP/LLA-94 fueron inferiores a otros protocolos contemporáneos, pero la supervivencia mejoró en los 2 últimos protocolos. En concordancia con otras series de LLA-T, la respuesta al tratamiento fue el principal factor pronóstico (AU)


Background and objectives: Acute lymphoblastic leukemia (ALL) is the most frequent cancer in childhood, with cure rates of 80-85%. In T-cell ALL (15% of ALL), prognostic factors are ill defined. We aimed to describe the event-free survival (EFS) and analyze clinical prognostic factors in a series of pediatric T-ALL of 4 consecutive clinical trials. Patients and methods: Children with T-ALL aged 1-18 years treated in 37 institutions in Spain were enrolled in 4 consecutive trials from February-1989 to November-2009. Results: A total of 218 T-ALL patients out of 1,652 pediatric ALL were evaluable during the study period (SHOP/ALL-89: 35, ALL-94: 63, ALL-99: 62, ALL-2005: 58). There were 164 boys (75%). Median age (years) was 7.8 range (1.3-18.6). Median leukocytes (109/L) was 78.2, range 0.8-930. Fifteen (6.8%) children had central nervous system (CNS) involvement at diagnosis. Regarding response to induction treatment, 150 (75%) patients had less than 5% blasts on day-14 bone marrow and 199 achieved complete remission at the end of induction. Overall survival (OS) at 60 months for SHOP/ALL-89, ALL-94, ALL-99 was 48 (8), 49 (6), 70 (6) %, respectively, and at 48 months for SHOP/ALL-2005 (ongoing protocol) was 74 (8) %. Median follow-up (months) was 206, 152, 74 and 17 respectively. Analysis of prognostic factors revealed no statistical differences regarding sex or age. Leukocyte count over 200×109/l (P=.024), CNS infiltration at diagnosis (P<.006) and treatment response had prognostic significance (end-induction complete remission) (P=.0000), day 14-bone marrow (P=.005). Conclusions:Results for the SHOP/ALL-89 and ALL-94 protocols were inferior to other contemporary protocols but there has been an improvement in survival in the 2 last trials. In line with other T-ALL series, response to treatment had the strongest prognostic impact (AU)


Subject(s)
Humans , Male , Female , Infant , Child, Preschool , Child , Adolescent , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Leukemic Infiltration/pathology , Induction Chemotherapy/methods , Clinical Protocols , Survival Rate , Prognosis , Disease Progression , Age and Sex Distribution , Treatment Outcome
12.
Med Clin (Barc) ; 139(4): 141-9, 2012 Jul 07.
Article in Spanish | MEDLINE | ID: mdl-22459573

ABSTRACT

BACKGROUND AND OBJECTIVES: Acute lymphoblastic leukemia (ALL) is the most frequent cancer in childhood, with cure rates of 80-85%. In T-cell ALL (15% of ALL), prognostic factors are ill defined. We aimed to describe the event-free survival (EFS) and analyze clinical prognostic factors in a series of pediatric T-ALL of 4 consecutive clinical trials. PATIENTS AND METHODS: Children with T-ALL aged 1-18 years treated in 37 institutions in Spain were enrolled in 4 consecutive trials from February-1989 to November-2009. RESULTS: A total of 218 T-ALL patients out of 1,652 pediatric ALL were evaluable during the study period (SHOP/ALL-89: 35, ALL-94: 63, ALL-99: 62, ALL-2005: 58). There were 164 boys (75%). Median age (years) was 7.8 range (1.3-18.6). Median leukocytes (10(9)/L) was 78.2, range 0.8-930. Fifteen (6.8%) children had central nervous system (CNS) involvement at diagnosis. Regarding response to induction treatment, 150 (75%) patients had less than 5% blasts on day-14 bone marrow and 199 achieved complete remission at the end of induction. Overall survival (OS) at 60 months for SHOP/ALL-89, ALL-94, ALL-99 was 48 (8), 49 (6), 70 (6) %, respectively, and at 48 months for SHOP/ALL-2005 (ongoing protocol) was 74 (8) %. Median follow-up (months) was 206, 152, 74 and 17 respectively. Analysis of prognostic factors revealed no statistical differences regarding sex or age. Leukocyte count over 200×10(9)/l (P=.024), CNS infiltration at diagnosis (P<.006) and treatment response had prognostic significance (end-induction complete remission) (P=.0000), day 14-bone marrow (P=.005). CONCLUSIONS: Results for the SHOP/ALL-89 and ALL-94 protocols were inferior to other contemporary protocols but there has been an improvement in survival in the 2 last trials. In line with other T-ALL series, response to treatment had the strongest prognostic impact.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Adolescent , Antineoplastic Agents/administration & dosage , Child , Child, Preschool , Consolidation Chemotherapy , Female , Follow-Up Studies , Humans , Induction Chemotherapy , Infant , Maintenance Chemotherapy , Male , Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/mortality , Retrospective Studies , Spain , Survival Analysis , Treatment Outcome
14.
Br J Haematol ; 154(5): 600-11, 2011 Sep.
Article in English | MEDLINE | ID: mdl-21707583

ABSTRACT

Philadelphia-chromosome acute lymphoblastic leukaemia (Ph+ ALL) is a subgroup of ALL with very high risk of treatment failure. We report here the results of the Sociedad Española de Hematología y Oncología Pediátricas (SEHOP/SHOP) in paediatric Ph+ ALL treated with intermediate-dose imatinib concurrent with intensive chemotherapy. The toxicities and outcome of these patients were compared with historical controls not receiving imatinib. Patients with Ph+ ALL aged 1-18years were enrolled in three consecutive ALL/SHOP trials (SHOP-94/SHOP-99/SHOP-2005). In the SHOP-2005 trial, imatinib (260mg/m(2) per day) was given on day-15 of induction. Allogeneic haematopoietic stem-cell transplantation (HSCT) from a matched related or unrelated donor was scheduled in first complete remission (CR1). Forty-three patients were evaluable (22 boys, median age 6·8years, range, 1·2-15). Sixteen received imatinib whereas 27 received similar chemotherapy without imatinib. Seventeen of 27 and 15 of 16 patients in the non-imatinib and imatinib cohort, respectively, underwent HSCT in CR1. With a median follow-up of 109 and 39months for the non-imatinib and imatinib cohorts, the 3-year event-free survival (EFS) was 29·6% and 78·7%, respectively (P=0·01). These results show that, compared to historical controls, intermediate dose of imatinib given concomitantly with chemotherapy and followed by allogeneic HSCT markedly improved early EFS in paediatric Ph+ ALL.


Subject(s)
Hematopoietic Stem Cell Transplantation/methods , Piperazines/administration & dosage , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Pyrimidines/administration & dosage , Adolescent , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Benzamides , Child , Child, Preschool , Disease-Free Survival , Female , Follow-Up Studies , Humans , Imatinib Mesylate , Infant , Male , Philadelphia Chromosome , Piperazines/toxicity , Precursor Cell Lymphoblastic Leukemia-Lymphoma/mortality , Pyrimidines/toxicity , Spain , Tissue Donors , Transplantation, Homologous , Treatment Outcome
16.
Blood ; 117(14): 3759-69, 2011 Apr 07.
Article in English | MEDLINE | ID: mdl-21273304

ABSTRACT

Fanconi anemia is characterized by congenital abnormalities, bone marrow failure, and cancer predisposition. To investigate the origin, functional role, and clinical impact of FANCA mutations, we determined a FANCA mutational spectrum with 130 pathogenic alleles. Some of these mutations were further characterized for their distribution in populations, mode of emergence, or functional consequences at cellular and clinical level. The world most frequent FANCA mutation is not the result of a mutational "hot-spot" but results from worldwide dissemination of an ancestral Indo-European mutation. We provide molecular evidence that total absence of FANCA in humans does not reduce embryonic viability, as the observed frequency of mutation carriers in the Gypsy population equals the expected by Hardy-Weinberg equilibrium. We also prove that long distance Alu-Alu recombination can cause Fanconi anemia by originating large interstitial deletions involving FANCA and 2 adjacent genes. Finally, we show that all missense mutations studied lead to an altered FANCA protein that is unable to relocate to the nucleus and activate the FA/BRCA pathway. This may explain the observed lack of correlation between type of FANCA mutation and cellular phenotype or clinical severity in terms of age of onset of hematologic disease or number of malformations.


Subject(s)
Fanconi Anemia Complementation Group A Protein/genetics , Fanconi Anemia Complementation Group A Protein/physiology , Fanconi Anemia/genetics , Fanconi Anemia/pathology , Mutation , Adolescent , Age of Onset , Base Sequence , Cell Culture Techniques , Cells, Cultured , Child , Child, Preschool , Chromosome Aberrations , Comparative Genomic Hybridization , DNA Mutational Analysis , Fanconi Anemia/diagnosis , Fanconi Anemia/epidemiology , Fanconi Anemia Complementation Group A Protein/metabolism , Gene Frequency , Humans , Infant , Models, Biological , Molecular Sequence Data , Mutation/physiology , Phenotype , Spain/epidemiology
17.
J Med Genet ; 48(4): 242-50, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21217111

ABSTRACT

BACKGROUND: Fanconi anaemia (FA) is a rare syndrome characterized by bone marrow failure, malformations and cancer predisposition. Chromosome fragility induced by DNA interstrand crosslink (ICL)-inducing agents such as diepoxybutane (DEB) or mitomycin C (MMC) is the 'gold standard' test for the diagnosis of FA. OBJECTIVE: To study the variability, the diagnostic implications and the clinical impact of chromosome fragility in FA. METHODS: Data are presented from 198 DEB-induced chromosome fragility tests in patients with and without FA where information on genetic subtype, cell sensitivity to MMC and clinical data were available. RESULTS: This large series allowed quantification of the variability and the level of overlap in ICL sensitivity among patients with FA and the normal population. A new chromosome fragility index is proposed that provides a cut-off diagnostic level to unambiguously distinguish patients with FA, including mosaics, from non-FA individuals. Spontaneous chromosome fragility and its correlation with DEB-induced fragility was also analysed, indicating that although both variables are correlated, 54% of patients with FA do not have spontaneous fragility. The data reveal a correlation between malformations and sensitivity to ICL-inducing agents. This correlation was also statistically significant when the analysis was restricted to patients from the FA-A complementation group. Finally, chromosome fragility does not correlate with the age of onset of haematological disease. CONCLUSIONS: This study proposes a new chromosome fragility index and suggests that genome instability during embryo development may be related to malformations in FA, while DEB-induced chromosome breaks in T cells have no prognostic value for the haematological disease.


Subject(s)
Chromosome Fragility , Fanconi Anemia/genetics , Cross-Linking Reagents/pharmacology , Epoxy Compounds/pharmacology , Fanconi Anemia/diagnosis , Humans , Mitomycin/pharmacology , Mosaicism , Phenotype
18.
Br J Haematol ; 149(6): 874-8, 2010 Jun.
Article in English | MEDLINE | ID: mdl-20346006

ABSTRACT

Pandemic influenza A (2009-H1N1) usually results in mild clinical illness, but in some individuals it can be life-threatening. There are no reports of this disease among paediatric patients with acute lymphoblastic leukaemia (ALL). We report ten consecutive patients with ALL and pandemic influenza treated in a single institution. Median age was 7 years (range: 3-12). All were treated with oseltamivir. There were no deaths. Two patients under intensive chemotherapy developed pneumonia and one required ventilatory support. ALL patients under maintenance treatment had mild disease. In conclusion, in our series only patients under intensive treatment developed a moderate to severe disease.


Subject(s)
Influenza A Virus, H1N1 Subtype , Influenza, Human/complications , Precursor Cell Lymphoblastic Leukemia-Lymphoma/complications , Antiviral Agents/therapeutic use , Child , Child, Preschool , Female , Humans , Influenza, Human/drug therapy , Male , Oseltamivir/therapeutic use , Prognosis , Prospective Studies
20.
Leuk Lymphoma ; 51(1): 114-24, 2010 Jan.
Article in English | MEDLINE | ID: mdl-20001230

ABSTRACT

We studied a series of 68 subjects diagnosed with childhood acute myeloid leukemia (AML) using conventional cytogenetics and fluorescence in situ hybridization (FISH), polymerase chain reaction (PCR) to analyze mutations in FLT3 and NPM1 genes, and/or array comparative genomic hybridization (CGH). Cytogenetic/FISH abnormalities were observed in 71% of subjects, FLT3-ITD mutations in 15%, and NPM1 mutations in 13%. The array CGH alterations (average 3.6 per case) were observed in 96% of the tested subjects. The most frequent alterations were gains of 8q24.3 and 11p15.5-p15.4 in 16% of the samples. Six genes (AKT1, RUNX1, LTB, SDC1, RUNX1T1, and JAK2) from the imbalanced regions have been reported to be involved in AML, whereas other 30 cancer genes, not previously reported in an AML context, were identified as imbalanced. They probably correspond to non passenger alterations that cooperate with the recurrent translocations. The clinical data and genetic changes were tested to find out the possible association with prognosis. Genomic instability (four or more genomic imbalances) was correlated with poor patient outcome (p = 0.029).


Subject(s)
Gene Dosage , Leukemia, Myeloid, Acute/genetics , Mutation , Adolescent , Bone Marrow Cells/cytology , Child , Child, Preschool , Cytogenetics , Female , Humans , In Situ Hybridization, Fluorescence , Infant , Infant, Newborn , Karyotyping , Leukemia, Myeloid, Acute/diagnosis , Leukemia, Myeloid, Acute/therapy , Male , Nucleophosmin , Polymerase Chain Reaction , Prognosis , Translocation, Genetic
SELECTION OF CITATIONS
SEARCH DETAIL
...