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BACKGROUND: Data on perioperative chemotherapy in resectable pancreatic ductal adenocarcinoma (rPDAC) are limited. NEONAX examined perioperative or adjuvant chemotherapy with gemcitabine plus nab-paclitaxel in rPDAC (National Comprehensive Cancer Network criteria). PATIENTS AND METHODS: NEONAX is a prospective, randomized phase II trial with two independent experimental arms. One hundred twenty-seven rPDAC patients in 22 German centers were randomized 1 : 1 to perioperative (two pre-operative and four post-operative cycles, arm A) or adjuvant (six cycles, arm B) gemcitabine (1000 mg/m2) and nab-paclitaxel (125 mg/m2) on days 1, 8 and 15 of a 28-day cycle. RESULTS: The primary endpoint was disease-free survival (DFS) at 18 months in the modified intention-to-treat (ITT) population [R0/R1-resected patients who started neoadjuvant chemotherapy (CTX) (A) or adjuvant CTX (B)]. The pre-defined DFS rate of 55% at 18 months was not reached in both arms [A: 33.3% (95% confidence interval [CI] 18.5% to 48.1%), B: 41.4% (95% CI 20.7% to 62.0%)]. Ninety percent of patients in arm A completed neoadjuvant treatment, and 42% of patients in arm B started adjuvant chemotherapy. R0 resection rate was 88% (arm A) and 67% (arm B), respectively. Median overall survival (mOS) (ITT population) as a secondary endpoint was 25.5 months (95% CI 19.7-29.7 months) in arm A and 16.7 months (95% CI 11.6-22.2 months) in the upfront surgery arm. This difference corresponds to a median DFS (mDFS) (ITT) of 11.5 months (95% CI 8.8-14.5 months) in arm A and 5.9 months (95% CI 3.6-11.5 months) in arm B. Treatment was safe and well tolerable in both arms. CONCLUSIONS: The primary endpoint, DFS rate of 55% at 18 months (mITT population), was not reached in either arm of the trial and numerically favored the upfront surgery arm B. mOS (ITT population), a secondary endpoint, numerically favored the neoadjuvant arm A [25.5 months (95% CI 19.7-29.7months); arm B 16.7 months (95% CI 11.6-22.2 months)]. There was a difference in chemotherapy exposure with 90% of patients in arm A completing pre-operative chemotherapy and 58% of patients starting adjuvant chemotherapy in arm B. Neoadjuvant/perioperative treatment is a novel option for patients with resectable PDAC. However, the optimal treatment regimen has yet to be defined. The trial is registered with ClinicalTrials.gov (NCT02047513) and the European Clinical Trials Database (EudraCT 2013-005559-34).
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Gemcitabina , Neoplasias Pancreáticas , Humanos , Desoxicitidina , Estudios Prospectivos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/cirugía , Neoplasias Pancreáticas/patología , Albúminas , Paclitaxel , Terapia Neoadyuvante , Adyuvantes Inmunológicos/uso terapéutico , Neoplasias PancreáticasRESUMEN
BACKGROUND: Mitochondrial disease is a rare, hereditary disease with a heterogeneous clinical presentation. However, fatigue is a common and burdensome complaint in children and adolescents with mitochondrial disease. No psychological intervention targeting fatigue exists for paediatric patients with a mitochondrial disease. We designed the PowerMe intervention, a blended cognitive behaviour therapy targeting fatigue in children and adolescents with mitochondrial disease. The aim of the intervention is to reduce perceived fatigue by targeting fatigue-related cognitions and behaviours. METHODS: A multiple baseline single case experiment will be conducted in five children (8-12 years old) and 5 adolescents (12-18 years old) with mitochondrial disease and severe fatigue. Patients will be included in the study for 33 weeks, answering weekly questions about the fatigue. Patients will be randomly assigned a baseline period of 5 to 9 weeks before starting the PowerMe intervention. The intervention consists of face-to-face and online sessions with a therapist and a website with information and assignments. The treatment will be tailored to the individual. Each patient will work on their personalized treatment plan focusing on personally relevant goals. The primary outcome is perceived fatigue. Secondary outcomes are quality of life, school presence and physical functioning. DISCUSSION: The results of the PowerMe study will provide information on the efficacy of a blended cognitive behaviour therapy on reducing perceived fatigue and its impact on daily life in children and adolescents with mitochondrial disease. Strengths and limitations of the study design are discussed. TRIAL REGISTRATION: Dutch Trial Register NTR 7675. Registered on 17 December 2018. Identifier https://www.trialregister.nl/trial/7433.
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Terapia Cognitivo-Conductual , Enfermedades Mitocondriales , Adolescente , Niño , Fatiga/diagnóstico , Fatiga/terapia , Humanos , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/terapia , Calidad de Vida , Proyectos de InvestigaciónRESUMEN
Approximately 10% of patients with ascites associated with cirrhosis fail to respond to dietary rules and diuretic treatment and therefore present with refractory ascites. In order to avoid iterative large-volume paracentesis in patients with contraindication to TIPS, the automated low flow ascites pump system (Alfapump) was developed to pump ascites from the peritoneal cavity into the urinary bladder, where it is eliminated spontaneously by normal micturition. This manuscript reports the surgical technique for placement of the Alfapump.
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Ascitis/cirugía , Cirrosis Hepática/complicaciones , Paracentesis/instrumentación , Paracentesis/métodos , Cavidad Peritoneal/cirugía , Vejiga Urinaria/cirugía , Anastomosis Quirúrgica/instrumentación , Anastomosis Quirúrgica/métodos , Ascitis/etiología , Ascitis/terapia , HumanosRESUMEN
BACKGROUND: Liver function tests may help to predict outcomes after liver surgery. The aim of this study was to evaluate the clinical impact on postoperative outcome and patient management of perioperative liver function testing using the LiMAx® test. METHODS: A multicentre RCT was conducted in six academic liver centres. Patients with intrahepatic tumours scheduled for open liver resection of at least one segment were eligible. Patients were randomized to undergo additional perioperative liver function tests (LiMAx® group) or standard care (control group). Patients in the intervention arm received two perioperative LiMAx® tests, one before the operation for surgical planning and another after surgery for postoperative management. The primary endpoint was the proportion of patients transferred directly to a general ward. Secondary endpoints were severe complications, length of hospital stay (LOS) and length of intermediate care/ICU (LOI) stay. RESULTS: Some 148 patients were randomized. Thirty-six of 58 patients (62 per cent) in the LiMAx® group were transferred directly to a general ward, compared with one of 60 (2 per cent) in the control group (P < 0·001). The rate of severe complications was significantly lower in the LiMAx® group (14 per cent versus 28 per cent in the control group; P = 0·022). LOS and LOI were significantly shorter in the LiMAx® group (LOS: 10·6 versus 13·3 days respectively, P = 0·012; LOI: 0·8 versus 3·0 days, P < 0·001). CONCLUSION: Perioperative use of the LiMAx® test improves postoperative management and reduces the incidence of severe complications after liver surgery. Registration number: NCT01785082 ( https://clinicaltrials.gov).
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Focal segmental glomerulosclerosis (FSGS) is one of the most common patterns of glomerular injury. FSGS can be caused by mutations in genes encoding proteins that play key roles in the function of the podocyte and glomerular basement membrane. In this case report we present a family with FSGS initially suspected to be Alport syndrome. Genetic analysis according to the Dutch guidelines of FSGS revealed a mutation in INF2.
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ADN/análisis , Glomeruloesclerosis Focal y Segmentaria/genética , Proteínas de Microfilamentos/genética , Mutación , Nefritis Hereditaria/diagnóstico , Proteínas Nucleares/genética , Adolescente , Adulto , Niño , Análisis Mutacional de ADN , Diagnóstico Diferencial , Femenino , Forminas , Pruebas Genéticas , Glomeruloesclerosis Focal y Segmentaria/diagnóstico , Glomeruloesclerosis Focal y Segmentaria/metabolismo , Humanos , Masculino , Proteínas de Microfilamentos/metabolismo , Proteínas Nucleares/metabolismo , LinajeAsunto(s)
Anemia Ferropénica/diagnóstico , Anemia Ferropénica/etiología , Granuloma de Células Plasmáticas/diagnóstico , Hepatopatías/diagnóstico , Síndrome de Respuesta Inflamatoria Sistémica/diagnóstico , Síndrome de Respuesta Inflamatoria Sistémica/etiología , Adolescente , Niño , Diagnóstico Diferencial , Femenino , Granuloma de Células Plasmáticas/patología , Granuloma de Células Plasmáticas/cirugía , Humanos , Biopsia Guiada por Imagen , Hígado/patología , Hígado/cirugía , Hepatopatías/patología , Hepatopatías/cirugía , Imagen por Resonancia Magnética , Tomografía Computarizada por Rayos X , UltrasonografíaRESUMEN
BACKGROUND AND PURPOSE: Our aim was to characterize the clinical profile, temporal changes and outcomes of patients with severe encephalitis. METHODS: A retrospective cohort study was conducted on adult patients with encephalitis admitted to the medical intensive care unit (ICU) of a university hospital over a 20-year period. Patients' characteristics and outcomes were compared between two 10-year periods: (i) 1991-2001 and (ii) 2002-2012. Multivariate logistic regression was used to analyze factors associated with a poor outcome, as defined by a modified Rankin scale (mRS) score of 4-6 (severe disability or death) 90 days after admission. RESULTS: A total of 279 patients were studied. Causes of encephalitis were infections (n = 149, 53%), immune-mediated causes (n = 41, 15%) and undetermined causes (n = 89, 32%). The distribution of causes differed significantly between the two periods, with an increase in the proportion of encephalitis recognized to be of immune-mediated causes. At day 90, 208 (75%) patients had an mRS = 0-3 and 71 (25%) had an mRS = 4-6. After adjustment for functional status before admission, the following parameters were independently associated with a poor outcome: coma [odds ratio (OR) 7.09, 95% confidence interval (95% CI) 3.06-17.03], aspiration pneumonia (OR 4.02, 95% CI 1.47-11.03), a lower body temperature (per 1 degree, OR 0.72, 95% CI 0.53-0.97), elevated cerebrospinal fluid protein levels (per 1 g/l, OR 1.55, 95% CI 1.17-2.11) and delayed ICU admission (per 1 day, OR 1.04, 95% CI 1.01-1.07). CONCLUSIONS: Indicators of outcome in adult patients with severe encephalitis reflect both the severity of illness and systemic complications. Our data suggest that patients with acute encephalitis may benefit from early ICU admission.
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Encefalitis , Unidades de Cuidados Intensivos/estadística & datos numéricos , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Adulto , Encefalitis/complicaciones , Encefalitis/etiología , Encefalitis/terapia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosRESUMEN
Urethral prolapse (UP) is a circular complete eversion of the distal urethral mucosa through the external meatus. It is a rare condition seen mostly in African-American premenarcheal girls. Both a medical and a surgical approach to this condition have been described. We present a case of a spontaneous urethral prolapse in a 60-year-old postmenopausal Caucasian woman, who failed medical management and underwent successful surgical management. The patient is asymptomatic 18 months following the procedure.
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Neurological complications are frequent in infective endocarditis (IE) and increase morbidity and mortality rates. A wide spectrum of neurological disorders may be observed, including stroke or transient ischemic attack, cerebral hemorrhage, mycotic aneurysm, meningitis, cerebral abscess, or encephalopathy. Most complications occur early during the course of IE and are a hallmark of left-sided abnormalities of native or prosthetic valves. Ischemic lesions account for 40% to 50% of IE central nervous system complications. Systematic brain MRI may reveal cerebral abnormalities in up to 80% of patients, including cerebral embolism in 50%, mostly asymptomatic. Neurological complications affect both medical and surgical treatment and should be managed by an experimented multidisciplinary team including cardiologists, neurologists, intensive care specialists, and cardiac surgeons. Oral anticoagulant therapy given to patients presenting with cerebral ischemic lesions should be replaced by unfractionated heparin for at least 2 weeks, with a close monitoring of coagulation tests. Recently published data suggest that after an ischemic stroke, surgery indicated for heart failure, uncontrolled infection, abscess, or persisting high emboli risk should not be delayed, provided that the patient is not comatose or has no severe deficit. Surgery should be postponed for 2 to 3 weeks for patients with intracranial hemorrhage. Endovascular treatment is recommended for cerebral mycotic aneurysms, if there is no severe mass effect. Recent data suggests that neurological failure, which is associated with the location and extension of brain injury, is a major determinant for short-term prognosis.
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Encefalopatías/etiología , Endocarditis/complicaciones , Meningitis/etiología , Antiinfecciosos/uso terapéutico , Anticoagulantes/uso terapéutico , Absceso Encefálico/diagnóstico , Absceso Encefálico/etiología , Absceso Encefálico/terapia , Encefalopatías/diagnóstico , Encefalopatías/terapia , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/etiología , Isquemia Encefálica/terapia , Hemorragia Cerebral/diagnóstico , Hemorragia Cerebral/etiología , Hemorragia Cerebral/terapia , Terapia Combinada , Vendajes de Compresión , Manejo de la Enfermedad , Endocarditis/tratamiento farmacológico , Endocarditis/cirugía , Fibrinolíticos/uso terapéutico , Humanos , Aneurisma Intracraneal/diagnóstico , Aneurisma Intracraneal/tratamiento farmacológico , Aneurisma Intracraneal/etiología , Meningitis/diagnóstico , Meningitis/tratamiento farmacológico , Neuroimagen/métodos , Trombofilia/tratamiento farmacológico , Trombofilia/terapiaRESUMEN
BACKGROUND AND PURPOSE: Neurologic complications in infective endocarditis are frequent and affect patient prognosis negatively. Additionally, detection of asymptomatic lesions by MR imaging could help early management of this condition. The objective of our study was to describe MR imaging characteristics of cerebral lesions in a neurologically asymptomatic population with infective endocarditis. MATERIALS AND METHODS: One hundred nine patients at the acute phase of a definite or possible infective endocarditis according to the Duke modified criteria and without neurologic manifestations according to the NIHSS were prospectively included. Each patient underwent cerebral MR imaging and MRA within 7 days of admission. RESULTS: MR imaging showed abnormalities in 78 patients (71.5%). Acute ischemic lesions (40 patients, 37%) and cerebral microbleeds (62 patients, 57%) were the most frequent lesions. Eight patients had an acute SAH, 3 patients had brain microabscesses, 3 had a small cortical hemorrhage, and 3 had a mycotic aneurysm. Acute ischemic lesions mostly appeared as multiple small infarcts disseminated in watershed territories (25/40, 62.5%) and as lesions of different ages (21/40, 52.5%). Cerebral microbleeds were preferentially distributed in cortical areas (362/539 cerebral microbleeds, 67%). No significant correlation was found among lesions, in particular between acute ischemia and cerebral microbleeds. CONCLUSIONS: Occult cerebral lesions, in particular cerebral microbleeds and acute ischemic lesions, are frequent in infective endocarditis. The MR imaging pattern of acute small infarcts of different ages predominating in watershed territories and cortical cerebral microbleeds may represent a surrogate imaging marker of infective endocarditis.
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Encefalopatías/epidemiología , Encefalopatías/patología , Encéfalo/patología , Endocarditis/epidemiología , Endocarditis/patología , Imagen por Resonancia Magnética/estadística & datos numéricos , Adulto , Anciano , Anciano de 80 o más Años , Causalidad , Comorbilidad , Femenino , Francia/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Reproducibilidad de los Resultados , Factores de Riesgo , Sensibilidad y EspecificidadRESUMEN
BACKGROUND: Cerebral complications are well-identified causes of morbidity and mortality in patients with infective endocarditis (IE). Few studies have analysed the impact of brain magnetic resonance imaging (MRI) in IE patients with neurological manifestations. OBJECTIVES: The aims of this study were to assess the MRI contribution to the management of patients with IE neurological manifestations and to compare cerebral CT and MRI findings. MATERIAL AND METHODS: Patients with definite or probable IE and neurological manifestations were prospectively enrolled from 2005 to 2008, in a university hospital (Bichat Claude Bernard Hospital, Paris). Clinical and radiological characteristics and echocardiographic findings were systematically recorded. Brain MRI with angiography was performed and compared to available CT scans. The contribution of MRI results to cerebral involvement staging and to therapeutic plans was evaluated. RESULTS: Thirty patients, 37-89 years old, were included. Nineteen suffered from pre-existing heart disease. Blood cultures were positive in 29 cases and the main micro-organisms were streptococci (n = 14) and staphylococci (n = 13). The IE was mainly located on mitral (n = 15) and aortic valves (n = 13). Neurological events were strokes (n = 12), meningitis (n = 5), seizures (n = 1), impaired consciousness (n = 11) and severe headache (n = 1). MRI findings included ischaemic lesions (n = 25), haemorrhagic lesions (n = 2), subarachnoid haemorrhage (n = 5), brain abscess (n = 6), mycotic aneurysm (n = 7), vascular occlusion (n = 3) and cerebral microbleeds (n = 17). In 19/30 cases, neurological manifestations were observed before the diagnosis of IE. MRI was more sensitive than CT scan in detecting both clinically symptomatic cerebral lesions (100 and 81%, respectively) and additional asymptomatic lesions (50 and 23%, respectively). Therapeutic plans were modified according to MRI results in 27% of patients: antibiotherapy regimen modifications in 7% (switch for molecules with high cerebral diffusion) and surgical plan modifications in 20% (indication of valvular replacement due to the embolic nature of the vegetations revealed by MRI or postponement of surgery due to haemorrhagic lesions). None of the 16/30 (51%) operated-on patients experienced postoperative neurological worsening. In-hospital death occurred in 4 patients. CONCLUSION: In patients with IE neurological manifestations, MRI revealed a broader involvement of the brain (type and number of lesions) than indicated by clinical signs and/or CT scan. With a better disease staging of neurological manifestations, MRI brain imaging may help in patient management and the decision-making process especially for cardiac surgery indication and timing of valve replacement.
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Encefalopatías/diagnóstico , Encéfalo/irrigación sanguínea , Encéfalo/patología , Angiografía Cerebral/métodos , Arterias Cerebrales/patología , Imagen de Difusión por Resonancia Magnética , Endocarditis Bacteriana/complicaciones , Angiografía por Resonancia Magnética , Adulto , Anciano , Anciano de 80 o más Años , Encéfalo/diagnóstico por imagen , Encefalopatías/etiología , Encefalopatías/mortalidad , Encefalopatías/patología , Encefalopatías/terapia , Arterias Cerebrales/diagnóstico por imagen , Trastornos Cerebrovasculares/diagnóstico , Trastornos Cerebrovasculares/etiología , Ecocardiografía , Endocarditis Bacteriana/diagnóstico , Endocarditis Bacteriana/microbiología , Endocarditis Bacteriana/mortalidad , Endocarditis Bacteriana/terapia , Femenino , Hospitales Universitarios , Humanos , Masculino , Persona de Mediana Edad , Paris , Valor Predictivo de las Pruebas , Pronóstico , Estudios Prospectivos , Tomografía Computarizada por Rayos XRESUMEN
The blatant problem of organ shortage leads to an increasing acceptance of organs from extended criteria donors. This increases the importance of the process of organ donation and retrieval. A working group of representatives of Bavarian retrieval surgeons and the procurement organization German Foundation of Organ Transplantation (DSO) was initiated to develop consensus-based recommendations for quality improvements in the field of organ retrieval on the basis of regional data. The main aim was to professionalize retrieval teams by specified training standards and to define objective qualifications for retrieval surgeons. Initial measures of the working group included agreement on standardized retrieval techniques and improvement of documentation in terms of quality forms and the return rate of the forms. Quality data are being analyzed prospectively with a new categorization of complications. Communication among centers and teams and complication reporting has already been improved and initial structural changes have been set up.
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Trasplante de Órganos/normas , Mejoramiento de la Calidad/normas , Recolección de Tejidos y Órganos/normas , Factores de Edad , Documentación/normas , Alemania , Humanos , Trasplante de Órganos/métodos , Complicaciones Posoperatorias/clasificación , Complicaciones Posoperatorias/etiología , Estudios Prospectivos , Donantes de Tejidos/provisión & distribución , Recolección de Tejidos y Órganos/métodos , Obtención de Tejidos y Órganos/normasRESUMEN
Surgical problems during organ procurement may propagate complications in the transplant recipient. Ultimately, these problems may result in the complete loss of already scarce donor organs.Donor reports (Eurotransplant donor report) of 1,492 donor organs from January 2010 to August 2012 in the German Foundation of Organ Transplantation (DSO) region of Bavaria and corresponding organ quality forms were analyzed. Surgical problems were classified into 3 categories: (I) surgical problems recognized and reported by the donor surgeon, (II) surgical problems observed by the recipient surgeon but not reported by the donor surgeon and (III) surgical problems leading to organ loss. Surgical problems during this 20-month time period were reported for 17.6 % of organs; category I in 5.5 %, category II in 11.1 % and category III in 1 %. Damage of graft vasculature in 9.1 % was the most frequently reported problem. The mean error index for individual surgeons was 16 % and one out of the five Bavarian organ procurement centers had significantly more problems in all categories (30 %). Interestingly, surgeons who performed rapid retrieval procedures had more problems with quality than surgeons who took more time. Organ retrieval is prone to surgical problems. Especially in a system of organ transport, consistent reporting of surgical problems and quality assurance is needed to maintain and to improve surgical quality.
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Garantía de la Calidad de Atención de Salud/normas , Recolección de Tejidos y Órganos/normas , Obtención de Tejidos y Órganos/normas , Competencia Clínica/normas , Estudios Transversales , Documentación/normas , Alemania , Humanos , Complicaciones Intraoperatorias/epidemiología , Complicaciones Intraoperatorias/etiología , Errores Médicos/estadística & datos numéricos , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Encuestas y Cuestionarios , Estudios de Tiempo y Movimiento , Donantes de Tejidos , Supervivencia Tisular/fisiología , Recolección de Tejidos y Órganos/estadística & datos numéricos , Obtención de Tejidos y Órganos/estadística & datos numéricosAsunto(s)
Aspergilosis/diagnóstico , Aspergillus fumigatus/aislamiento & purificación , Dermatosis de la Mano/diagnóstico , Mano/patología , Huésped Inmunocomprometido , Leucemia-Linfoma Linfoblástico de Células Precursoras/complicaciones , Úlcera Cutánea/diagnóstico , Adulto , Aspergilosis/complicaciones , Aspergilosis/inmunología , Biopsia , Diagnóstico Diferencial , Mano/microbiología , Dermatosis de la Mano/etiología , Dermatosis de la Mano/inmunología , Humanos , Masculino , Necrosis , Leucemia-Linfoma Linfoblástico de Células Precursoras/diagnóstico , Leucemia-Linfoma Linfoblástico de Células Precursoras/inmunología , Úlcera Cutánea/complicaciones , Úlcera Cutánea/inmunologíaRESUMEN
Susac syndrome is a mysterious vasculopathy affecting brain, retina and inner ear in young women. Main features of the disease are increasingly recognized: subacute encephalopathy often mimicking psychosis and frequently heralded with unusual ophthalmic migraine; frequent subclinical meningitis; brain MRI with multiple and bilateral white and gray matter nuclei lesions, with prominent involvement of corpus callosum; bilateral involvement of central retina artery branches, not only with occlusions but also with peculiar leakage of fluorescein through arteriolar walls on late stages of angiography; non-specific bilateral cochleovestibular symptoms with audiogram showing perception hypoacousia that predominates on low frequencies. Outcome, prognosis, pathogenesis and a rational basis for treatment are discussed in this review. A key message for the clinician should be to perform brain MRI, audiogram and retinal angiography whatever the mode of entry, in order not to miss one (or two) features of this syndrome triad.
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Encéfalo/patología , Oído Interno/patología , Retina/patología , Síndrome de Susac/patología , Angiografía , Audiometría , Diagnóstico Diferencial , Femenino , Humanos , Factores Inmunológicos/uso terapéutico , Imagen por Resonancia Magnética , Pronóstico , Síndrome de Susac/tratamiento farmacológicoRESUMEN
There is significant interest in development of thyroid hormone analogues to harness specific properties as therapeutic agents for a variety of clinical indications including obesity, hypercholesterolemia, heart failure, and thyrotoxicosis. To date, most analogues have been designed to target liver specific effects, which can promote weight loss and lipid lowering through either tissue specific uptake or thyroid hormone receptor (TR) ß isoform selectivity at the same time minimizing the unwanted cardiac and bone effects. We have developed a molecular biomarker assay to study the induction of the transcription of the cardiac specific α-myosin heavy chain (MHC) gene as a more sensitive and specific measure of thyroid hormone action on cardiac myocytes. We tested 5 TRß and 1 TRα selective agonists as well as 2 putative TR antagonists in our α-MHC hnRNA assay. Using reverse transcription and polymerase chain reaction, we measured the induction of the α-MHC primary transcript in response to administration of drug. The TRα and only 2 of the TRß agonists were highly active, when compared to the effect of T3, at the level of the cardiac myocyte. In addition, our data suggests that the reason that the antagonist NH-3 is not able to block the T3-mediated induction of α-MHC is that it does not get transported into the cardiac myocyte. Our data suggest that this assay will be useful in preclinical studies of the potential cardiac specific effects of thyroid hormone analogues and that predictions of function based on structure are not necessarily accurate or complete.
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Diseño de Fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Ventrículos Cardíacos/efectos de los fármacos , Hipotiroidismo/metabolismo , Receptores de Hormona Tiroidea/agonistas , Receptores de Hormona Tiroidea/antagonistas & inhibidores , Triyodotironina/análogos & derivados , Animales , Fármacos Antiobesidad/efectos adversos , Fármacos Antiobesidad/química , Fármacos Antiobesidad/uso terapéutico , Biomarcadores/metabolismo , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Ventrículos Cardíacos/metabolismo , Hipolipemiantes/efectos adversos , Hipolipemiantes/química , Hipolipemiantes/uso terapéutico , Hipotiroidismo/tratamiento farmacológico , Masculino , Cadenas Pesadas de Miosina/genética , Cadenas Pesadas de Miosina/metabolismo , Isoformas de Proteínas/agonistas , Isoformas de Proteínas/antagonistas & inhibidores , Precursores del ARN/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores alfa de Hormona Tiroidea/agonistas , Receptores beta de Hormona Tiroidea/agonistas , Tiroidectomía/efectos adversos , Triyodotironina/efectos adversos , Triyodotironina/química , Triyodotironina/uso terapéutico , Miosinas Ventriculares/genética , Miosinas Ventriculares/metabolismoRESUMEN
INTRODUCTION: Hypoplastic basilar (BA) and vertebral arteries (VA) can cause posterior circulation infarctions. Distinction between hypoplastic and atherosclerotic BA can be difficult with usual angiographic methods (MR, CT or conventional angiographies), only showing arterial luminogram. High-resolution MRI (HRMRI) of the arterial wall is promising in identifying intracranial artery plaques. OBSERVATION: A 70-year-old man with vascular risk factors suddenly presented with vertigo. MRI showed no brain infarction. Contrast-enhanced MRA showed small and irregular BA lumen compatible with severe atherosclerotic stenosis. An associated persistent primitive trigeminal artery was noticed. HRMRI of the BA rectified the initial angiographic diagnosis by showing a normal vessel wall without any thickening that could suggest atherosclerotic plaque. CONCLUSION: In the event of BA lumen narrowing, HRMRI may help distinguish between hypoplastic and atherosclerotic artery.
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Arteria Basilar/anomalías , Imagen por Resonancia Magnética , Insuficiencia Vertebrobasilar/diagnóstico , Anciano , Antihipertensivos/uso terapéutico , Aterosclerosis/patología , Arteria Basilar/patología , Diagnóstico Diferencial , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Angiografía por Resonancia Magnética , Masculino , Inhibidores de Agregación Plaquetaria/uso terapéutico , Tomografía Computarizada por Rayos X , Insuficiencia Vertebrobasilar/tratamiento farmacológico , Insuficiencia Vertebrobasilar/patología , Vértigo/etiologíaRESUMEN
OBJECTIVE: We aimed to investigate the prognosis of HIV-infected patients with acute neurological complications at the highly active antiretroviral therapy (HAART) era. METHODS: We performed a retrospective study in HIV-infected patients admitted to a medical ICU with neurological complications between 2001 and 2008. RESULTS: Among the 210 studied patients (median [interquartile range] CD4-cell count: 80 [18-254]/µL; HIV viral load: 4.8 [2-5.3] log10/mL), 40 (19%) had unknown HIV status at admission. Neurological complications consisted in delirium (45%), coma (39%), seizures (32%) and/or intracranial hypertension (21%). Admission diagnoses were AIDS-defining CNS disease for 88 (42%) patients, non-AIDS-defining CNS disease for 45 (21%), and systemic disease with neurological signs for 77 (37%). Seizures (p=0.003), focal deficit (p<0.001) and intracranial hypertension (p<0.001) were more frequently observed in patients with AIDS-defining CNS disease. Factors independently associated with ICU mortality (29.5%) were intracranial hypertension [odds ratio (OR), 5.09; 95% confidence interval (95% CI), 2.17-11.91], vasopressor use [OR, 3.92; 95% CI, 1.78-8.60] and SAPS II score [per 10-point increment, OR, 1.59; 95% CI, 1.31-1.93]. CONCLUSIONS: Prognosis of HIV-infected patients with neurological complications depends rather on clinical presentation than on HIV-related parameters. Intracranial hypertension symptoms at admission have a major impact on outcome.
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Complejo SIDA Demencia/fisiopatología , Infecciones Oportunistas Relacionadas con el SIDA/fisiopatología , Enfermedades del Sistema Nervioso Central/fisiopatología , Enfermedad Crítica , Infecciones por VIH/complicaciones , Complejo SIDA Demencia/diagnóstico , Infecciones Oportunistas Relacionadas con el SIDA/diagnóstico , Adulto , Terapia Antirretroviral Altamente Activa , Enfermedades del Sistema Nervioso Central/diagnóstico , Coma/diagnóstico , Delirio/diagnóstico , Femenino , Infecciones por VIH/tratamiento farmacológico , Mortalidad Hospitalaria , Humanos , Unidades de Cuidados Intensivos , Hipertensión Intracraneal/diagnóstico , Masculino , Persona de Mediana Edad , Pronóstico , Convulsiones/diagnósticoRESUMEN
BACKGROUND: A substantial proportion of ischemic strokes have an embolic mechanism, but the source of embolism is not detected. Coexistence of subdiaphragmatic visceral infarction (SDVI; e.g., renal, splenic, hepatic, bowel infarction) may be a suggestion of a common source of embolism. One large autopsy study found SDVI in 21.5% of patients with fatal stroke. METHOD: We performed diffusion-weighted magnetic resonance abdominal imaging and subsequently performed it in consecutive patients with stroke or TIA and a history of nonvalvular atrial fibrillation. RESULTS: Among 27 patients, 6 had SDVI (3 recent renal, 1 recent splenic, and 3 old splenic infarction). The median time between onset of ischemic stroke and abdominal MRI was 8 days (interquartile range 3-15 days). No predictive factor of SDVI was found in this study population with respect to demographic or ultrasound characteristics. CONCLUSIONS: One in 5 patients with nonfatal cardioembolic stroke or TIA may be associated with subdiaphragmatic visceral infarction (SDVI). Further study should evaluate the frequency of SDVI in patients with stroke of unknown cause.
Asunto(s)
Fibrilación Atrial/epidemiología , Isquemia Encefálica/epidemiología , Infarto/epidemiología , Embolia Intracraneal/epidemiología , Accidente Cerebrovascular/epidemiología , Vísceras/irrigación sanguínea , Anciano , Anciano de 80 o más Años , Fibrilación Atrial/patología , Isquemia Encefálica/patología , Imagen de Difusión por Resonancia Magnética , Femenino , Humanos , Embolia Intracraneal/patología , Ataque Isquémico Transitorio/epidemiología , Ataque Isquémico Transitorio/patología , Masculino , Persona de Mediana Edad , Prevalencia , Accidente Cerebrovascular/patología , Factores de TiempoRESUMEN
The immortalized human cerebral microvessel endothelial cell line hCMEC/D3 has been repeatedly used as a model of human blood-brain barrier (BBB). hCMEC/D3 cells between passage 25 and 35 are most often applied in research, remained phenotypically nontransformed, and cells maintained many characteristics of human brain endothelial cells. Also hCMEC/D3 was thought to have conserved a normal diploid karyotype over all these passages. Here we characterized the cell line using high-resolution multicolor fluorescence in situ hybridization (FISH) approaches and revealed a complex karyotype in the 30th passage. Clonal cryptic unbalanced structural rearrangements and numerical aberrations were discovered and described as follows: 45 approximately 48,XX, -X,del(5)(q11)[2],del(9)(q11)[3],+9[3],del(11)(q13 approximately 14)[2], der(14)t(14;21)(q32.33;q22.3)[28],der(15)t(9;15)(p11;p11)[13], dup(15)(p11q11)[5],der(21)t(17;21)(p12;q22)[9],-22[6][cp28]. In summary, a complex karyotype with clonal unbalanced chromosomal rearrangements is present in hCMEC/D3. Thus, we solicit to include molecular cytogenetics in the testing of all cell lines prior to application of their use in complex studies.