Endovascular treatment of cerebral venous sinus thrombosis (CVST): Is a complete recanalization required for a good clinical outcome?

The usual therapy in cerebral venous sinus thrombosis (CVST) is based on anticoagulant treatment with adjusted-dose unfractionated heparin. When medical treatment fails, endovascular techniques, such as mechanical thrombectomy, are available. We report a case of a 21-year-old woman with a diagnosis of left CVST, treated by a neurointerventional approach with mechanical thrombectomy using the Penumbra(®) System. Despite the fact that only incomplete recanalization was achieved, a gradual resolution of the thrombus and a progressive clinical improvement occurred.

Factors associated with in-hospital delays in treating acute stroke with intravenous thrombolysis in a tertiary centre. / Identificación de los factores que influyen en el retraso intrahospitalario del inicio de trombólisis intravenosa en el ictus agudo en un hospital terciario.

OBJECTIVE: This study aims to determine which factors are associated with delays in door-to needle (DTN) time in our hospital. This will help us design future strategies to shorten time to treatment with intravenous thrombolysis (IVT). METHODS: Retrospective analysis of a prospective cohort of patients with ischaemic stroke treated with IVT in our hospital between 2009 and 2012. We analysed the relationship between DTN time and the following variables: age, sex, personal medical history, onset-to-door time, pre-hospital stroke code activation, blood pressure and blood glucose level, National Institutes of Health Stroke Scale (NIHSS), computed tomography angiography (CTA) and/or doppler/duplex ultrasound (DUS) performed before IVT, time to hospital arrival, and day of the week and year of stroke. RESULTS: Our hospital treated 239 patients. Median time to treatment in minutes (IQR): onset-to-door, 84 (60-120); door-to-CT, 17 (13-24.75); CT-to needle, 34 (26-47); door-to-needle, 52 (43-70); onset-to-needle, 145 (120-180). Door-to-needle time was significantly shorter when code stroke was activated, at 51 vs. 72min (P=0.008), and longer when CTA was performed, at 59 vs. 48.5min (P=0.004); it was also longer with an onset-to-door time<90min, at 58 vs. 48min (P=0.003). The multivariate linear regression analysis detected 2 factors affecting DTN: code stroke activation (26.3% reduction; P<0.001) and onset-to-door time (every 30min of onset-to-door delay corresponded to a 4.7min increase in DTN time [P=0.02]). On the other hand, CTA resulted in a 13.4% increase in DTN (P=0.03). No other factors had a significant influence on door-to-needle time. CONCLUSIONS: This study enabled us to identify CTA and the «3-hour effect¼ as the 2 factors that delay IVT in our hospital. In contrast, activating code stroke clearly reduces DTN. This information will be useful in our future attempts to reduce door-to-needle times.

Spontaneous spinal epidural haematoma: a retrospective study of a series of 13 cases.

INTRODUCTION: Spontaneous spinal epidural haematoma (SSEH) has an estimated incidence of one per million inhabitants. It is classified as spontaneous when no identifiable cause can be linked to its onset. OBJECTIVE: To describe a sample of patients with SSEH and analyse variables related to its functional prognosis. PATIENTS AND METHODS: Retrospective study carried out in patients diagnosed with SSEH between 2001 and 2013 in our hospital. RESULTS: We included 13 subjects (7 men) with a mean age of 71 years. Of the total, 62% had hypertension and 54% were treated with oral anticoagulants; of the latter, 57% had an International Normalised Ratio above 3. The most frequent manifestation was spinal column pain (85%). Nearly all subjects presented an associated neurological deficit, whether sensory-motor (70%), pure motor (15%), or pure sensory (7%). Five patients underwent surgical treatment and 8 had conservative treatment. After one year, 3 of the patients treated surgically and 4 of those on conservative treatment had a score of 2 or lower on the modified Rankin Scale. Poorer prognosis was observed in patients with anticoagulant therapy, large haematomas, location in the lumbar region, and more pronounced motor disability at onset. CONCLUSIONS: Old age, hypertension, and anticoagulant therapy are the main risk factors for SSEH. The typical presentation consists of back pain with subsequent motor deficit. In patients with established motor symptoms, surgical treatment within the first 24hours seems to be the best option.

[Aetiological classification of ischaemic strokes: comparison of the new A-S-C-O classification and the classification by the Spanish Society of Neurology's Cerebrovascular Disease Study Group]. / Clasificación etiológica del ictus isquémico: comparación entre la nueva clasificación A-S-C-O y la clasificación del Grupo de Estudio de Enfermedades Cerebrovasculares de la Sociedad Española de Neurología.

INTRODUCTION: The A-S-C-O classification may be better than other methods for classifying ischaemic stroke by aetiology. Our aims are to describe A-S-C-O phenotype distribution (A: atherosclerosis, S: small vessel disease, C: cardiac source, O: other causes; 1: potential cause, 2: causality uncertain, 3: unlikely to be a direct cause although disease is present) and compare them to the Spanish Society of Neurology's Cerebrovascular Disease Study Group (GEECV/SEN) classification. We will also find the degree of concordance between these classification methods and determine whether using the A-S-C-O classification delivers a smaller percentage of strokes of undetermined cause. METHODS: We analysed those patients with ischaemic stroke admitted to our stroke unit in 2010 with strokes that were classified according to GEECV/SEN and A-S-C-O criteria. RESULTS: The study included 496 patients. The percentages of strokes caused by atherosclerosis and small vessel disease according to GEECV/SEN criteria were higher than the percentages for potential atherosclerotic stroke (A1) (14.1 vs. 11.9%; P=.16) and potential small vessel stroke (S1) (14.3 vs. 3%; P<.001). Cardioembolic stroke (C1) was more frequent (22.2 vs. 31%; P<.001). No differences between unusual cause of stroke and other potential causes (O1) were observed. Some degree of atherosclerosis was present in 53.5% of patients (A1, A2, or A3); 65.5% showed markers of small vessel disease (S1, S2, or S3), and 74.9% showed signs of cardioembolism (C1, C2, or C3). Fewer patients in the group without scores of 1 or 2 for any of the A-S-C-O phenotypes were identified as having a stroke of undetermined cause (46.6 vs. 29.2%; P<.001). The agreement between the 2 classifications ranged from κ<0.2 (small vessel and S1) to κ>0.8 (unusual causes and O1). CONCLUSION: Our results show that GEECV/SEN and A-S-C-O classifications are neither fully comparable nor consistent. Using the A-S-C-O classification provided additional information on co-morbidities and delivered a smaller percentage of strokes classified as having an undetermined cause.

Fatal intracerebral haemorrhage associated with thrombosis with thrombocytopenia syndrome after ChAdOx1-S vaccine. / Hemorragia intracerebral fatal asociada al síndrome de trombosis con trombocitopenia tras la vacuna ChAdOx1-S.

INTRODUCTION: The COVID-19 pandemic has had a devastating impact on health, society and economics worldwide. Therefore, vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have recently emerged as an important measure to fight the pandemic. ChAdOx1-S (Oxford-AstraZeneca) is an adenovirus-vectored vaccine that expresses the SARS-CoV-2 spike protein. It shows an acceptable safety profile. Nevertheless, several cases of unusual thrombosis and thrombocytopenia have been reported after initial vaccination with ChAdOx1-S mimicking autoimmune heparin-induced thrombocytopenia. This condition has been called thrombosis with thrombocytopenia syndrome (TTS) and complications such as intracerebral haemorrhage have been described. CASE REPORT: We present a case of intracerebral haemorrhage after ChAdOx1-S vaccination. Middle-aged patient with no prior medical history was seen in the emergency room 16 days after the first dose of ChAdOx1-S vaccine with sudden onset left hemiplegia and severe holocranial oppressive headache. She did not receive heparin treatment in the previous 100 days. Blood test showed moderate thrombocytopenia and a right frontal lobar haemorrhage was seen on computed tomography scan, computed tomography venography was negative for thrombosis. The presence of antibodies against platelet factor 4 was confirmed. The patient's neurological condition progressively worsened. She developed a treatment resistant intracranial hypertension syndrome and she died three weeks later. CONCLUSIONS: TTS is a rare adverse effect of ChAdOx1-S vaccine, defined by the presence of thrombosis in uncommon locations. In our case we report an spontaneous intracerebral haemorrhage probable due to the thrombocytopenia related to probable TTS. It represents a rare clinical presentation of TTS.

TITLE: Hemorragia intracerebral fatal asociada al síndrome de trombosis con trombocitopenia tras la vacuna ChAdOx1-S.Introducción. La pandemia por COVID-19 ha tenido un impacto devastador en la salud, la sociedad y la economía en el mundo. Por ello, las vacunas contra el coronavirus del síndrome respiratorio agudo grave 2 (SARS-CoV-2) han surgido como medida importante para combatir la pandemia. ChAdOx1-S (Oxford-AstraZeneca) es una vacuna vectorizada por adenovirus que expresa la proteína de espiga del SARS-CoV-2. Se han notificado varios casos de trombosis y trombocitopenia inusuales tras la ChAdOx1-S que imitan la trombocitopenia autoinmune inducida por heparina. Esta situación se denomina síndrome de trombosis con trombocitopenia (STT), y se han descrito casos de hemorragia intracerebral secundaria. Caso clínico. Presentamos un caso de hemorragia intracerebral tras la vacunación con ChAdOx1-S. Una paciente de mediana edad sin antecedentes médicos de interés fue atendida en urgencias 16 días después de la primera dosis de ChAdOx1-S con una hemiplejía izquierda de inicio repentino y una cefalea opresiva holocraneal grave. No recibió heparina los 100 días anteriores. El análisis de sangre mostró trombocitopenia moderada y en la tomografía computarizada se observó una hemorragia lobar frontal derecha sin trombosis en la venografía por tomografía computarizada. Se confirmó la presencia de anticuerpos contra el factor 4 de las plaquetas en la sangre. La paciente presentó un síndrome de hipertensión intracraneal resistente al tratamiento y falleció tres semanas después. Conclusiones. El STT es un efecto adverso infrecuente de la vacuna ChAdOx1-S que se define por la presencia de trombosis en localizaciones infrecuentes. En nuestro caso, describimos una hemorragia intracerebral espontánea secundaria a la trombocitopenia desencadenada por el STT. Representa una presentación clínica poco frecuente del STT.

[The use of a pro-forma improves the quality of the emergency medical charts of patients with acute stroke]. / El empleo de un formulario estructurado mejora la calidad de la historia clínica de urgencias de pacientes con ictus agudos.

INTRODUCTION: The information obtained from the Emergency Medical Chart (EMC) is a key factor for the correct management of acute stroke. Our aim is to determine if the use of a pro-forma (PF) for filling in the EMC improves the quality of the clinical information. MATERIAL AND METHODS: A PF was created from a list of 26 key-items considered important to be recorded in an EMC. We compared the number of items recorded in the EMC of patients admitted to our Stroke Unit (SU) in January-February 2009 (before PF was introduced) with the data obtained with the PF (April-May, 2009). We also analysed the agreement with the final diagnosis on discharge from the SU. RESULTS: A total of 128 EMC were analysed, and the PF was used in 48 cases. The mean number of recorded items was 20.5 for the PF group and 13.7 for the non-PF charts (P<.001). Sixteen of the 26 items were recorded significant more frequently (P<.05) in the PF Group. The most notable scores being: previous baseline situation (100% vs. 51%), previous Modified Rankin scale score (94% vs. 1%), time of symptom onset (100% vs. 85%), time of neurological evaluation (100% vs. 39%), NIHSS score (92% vs. 30%), ECG results (88% vs. 59%), time of perform brain scan (60% vs. 1%). Diagnostic agreement: nosological/syndromic diagnosis: PF group: 94%, Non-PF group: 60% (P<.001), topographic diagnosis: PF: 71%, Non-PF: 53% (P=.03), aetiological diagnosis: PF: 25%, Non-PF: 9% (P=.01). CONCLUSIONS: The use of a PF improves the quantity and quality of the information, and offers a better diagnostic accuracy.

A new protocol reduces median door-to-needle time to the benchmark of 30 minutes in acute stroke treatment.

INTRODUCTION: Recent analyses emphasise that The Benchmark Stroke Door-to-Needle Time (DNT) should be 30min. This study aimed to determine if a new in-hospital IVT protocol is effective in reducing door-to-needle time and correcting previously identified factors associated with delays. MATERIAL AND METHODS: In 2014, we gradually introduced a series of measures aimed to reduce door-to-needle time for patients receiving IVT, and compared it before (2009-2012) and after (2014-2017) the new protocol was introduced. RESULTS: The sample included 239 patients before and 222 after the introduction of the protocol. Median overall door-to-needle time was 27min after the protocol was fully implemented (a 48% reduction on previous door-to-needle time [52min], P<.001)]. Median door-to-needle time was lower when pre-hospital code stroke was activated (22min). We observed a 26-min reduction in the median time from onset to treatment (P<.001). After the protocol was implemented, the "3-hour-effect" did not affect door-to-needle time (P=.98). Computed tomography angiography studies performed before IVT were associated with increased door-to-needle time (P<.001); however, the test was performed after IVT was started in most cases. CONCLUSIONS: Hospital reorganisation and multidisciplinary collaboration brought median door-to-needle time below 30min and corrected previously identified delay factors. Furthermore, overall time from onset to treatment was also reduced and more stroke patients were treated within 90min of symptom onset.

Syndrome of transient headache and neurological deficits with cerebrospinal fluid lymphocytosis (HaNDL) in a patient with confusional symptoms, diffuse EEG abnormalities, and bilateral vasospasm in transcranial Doppler ultrasound: A case report and literature review. / Síndrome de cefalea transitoria con déficits neurológicos asociados y pleocitosis en líquido cefalorraquídeo (HaNDL) con cuadro confusional, EEG compatible con afectación difusa y datos de vasoespasmo bilateral en estudio Doppler transcraneal: presentación de un caso y revisión de la literatura.

INTRODUCTION: HaNDL syndrome (transient headache and neurological deficits with cerebrospinal fluid lymphocytosis) is characterised by one or more episodes of headache and transient neurological deficits associated with cerebrospinal fluid lymphocytosis. To date, few cases of HaNDL manifesting with confusional symptoms have been described. Likewise, very few patients with HaNDL and confusional symptoms have been evaluated with transcranial Doppler ultrasound (TCD). TCD data from patients with focal involvement reveal changes consistent with vasomotor alterations. DEVELOPMENT: We present the case of a 42-year-old man who experienced headache and confusional symptoms and displayed pleocytosis, diffuse slow activity on EEG, increased blood flow velocity in both middle cerebral arteries on TCD, and single-photon emission computed tomography (SPECT) findings suggestive of diffuse involvement, especially in the left hemisphere. CONCLUSIONS: To our knowledge, this is the first description of a patient with HaNDL, confusional symptoms, diffuse slow activity on EEG, and increased blood flow velocity in TCD. Our findings suggest a relationship between cerebral vasomotor changes and the pathophysiology of HaNDL. TCD may be a useful tool for early diagnosis of HaNDL.

Prediction of HIV-1 drug susceptibility phenotype from the viral genotype using linear regression modeling.

Linear regression modeling on a database of HIV-1 genotypes and phenotypes was applied to predict the HIV-1 resistance phenotype from the viral genotype. In this approach, the phenotypic measurement is estimated as the weighted sum of the effects of individual mutations. Higher order interaction terms (mutation pairs) were included to account for synergistic and antagonistic effects between mutations. The most significant mutations and interactions identified by the linear regression models for 17 approved antiretroviral drugs are reported. Although linear regression modeling is a statistical data-driven technique focused on obtaining the best possible prediction, many of these mutations are also known resistance-associated mutations, indicating that the statistical models largely reflect well characterized biological phenomena. The performance of the models in predicting in vitro susceptibility phenotype and virologic response in treated patients is described. In addition to a high concordance with in vitro measured fold change, which was the primary aim of model design, the models per drug show good predictivity of therapy response for regimens including that drug, even in the absence of other clinically relevant factors such as background regimen.

The androgen receptor amino-terminal domain plays a key role in p160 coactivator-stimulated gene transcription.

Steroid receptors are conditional transcription factors that, upon binding to their response elements, regulate the expression of target genes via direct protein interactions with transcriptional coactivators. We have analyzed the functional interactions between the androgen receptor (AR) and 160-kDa nuclear receptor coactivators. Upon overexpression in mammalian cells, these coactivators enhance the transcriptional activity of both the amino-terminal domain (NTD) and the ligand-binding domain (LBD) of the AR. The coactivator activity for the LBD is strictly ligand-controlled and depends on the nature of the DNA-binding domain to which it is fused. We demonstrate that the NTD physically interacts with coactivators and with the LBD and that this interaction, like the functional interaction between the LBD and p160 coactivators, relies on the activation function 2 (AF2) core domain. The mutation of a highly conserved lysine residue in the predicted helix 3 of the LBD (K720A), however, blunts the functional interaction with coactivators but not with the NTD. Moreover, this mutation does not affect the transcriptional activity of the full-size AR. A mutation in the NTD of activation function AF1a (I182A/L183A), which dramatically impairs the activity of the AR, has no effect on the intrinsic transcriptional activity of the NTD but interferes with the cooperation between the NTD and the LBD. Finally, p160 proteins in which the three LXXLL motifs are mutated retain most of their coactivator activity for the full-size AR, although they are no longer functional for the isolated LBD. Together, these data suggest that in the native AR the efficient recruitment of coactivators requires a functional association of the NTD with the LBD and that the binding of coactivators occurs primarily through the NTD.

Hemorragia intracerebral fatal asociada al síndrome de trombosis con trombocitopenia tras la vacuna ChAdOx1-S / Fatal intracerebral haemorrhage associated with thrombosis with thrombocytopenia syndrome after ChAdOx1-S vaccine

Introducción: La pandemia por COVID-19 ha tenido un impacto devastador en la salud, la sociedad y la economía en el mundo. Por ello, las vacunas contra el coronavirus del síndrome respiratorio agudo grave 2 (SARS-CoV-2) han surgido como medida importante para combatir la pandemia. ChAdOx1-S (Oxford-AstraZeneca) es una vacuna vectorizada por adenovirus que expresa la proteína de espiga del SARS-CoV-2. Se han notificado varios casos de trombosis y trombocitopenia inusuales tras la ChAdOx1-S que imitan la trombocitopenia autoinmune inducida por heparina. Esta situación se denomina síndrome de trombosis con trombocitopenia (STT), y se han descrito casos de hemorragia intracerebral secundaria. Caso clínico: Presentamos un caso de hemorragia intracerebral tras la vacunación con ChAdOx1-S. Una paciente de mediana edad sin antecedentes médicos de interés fue atendida en urgencias 16 días después de la primera dosis de ChAdOx1-S con una hemiplejía izquierda de inicio repentino y una cefalea opresiva holocraneal grave. No recibió heparina los 100 días anteriores. El análisis de sangre mostró trombocitopenia moderada y en la tomografía computarizada se observó una hemorragia lobar frontal derecha sin trombosis en la venografía por tomografía computarizada. Se confirmó la presencia de anticuerpos contra el factor 4 de las plaquetas en la sangre. La paciente presentó un síndrome de hipertensión intracraneal resistente al tratamiento y falleció tres semanas después. Conclusiones: El STT es un efecto adverso infrecuente de la vacuna ChAdOx1-S que se define por la presencia de trombosis en localizaciones infrecuentes. En nuestro caso, describimos una hemorragia intracerebral espontánea secundaria a la trombocitopenia desencadenada por el STT. Representa una presentación clínica poco frecuente del STT.(AU)

INTRODUCTION: The COVID-19 pandemic has had a devastating impact on health, society and economics worldwide. Therefore, vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have recently emerged as an important measure to fight the pandemic. ChAdOx1-S (Oxford-AstraZeneca) is an adenovirus-vectored vaccine that expresses the SARS-CoV-2 spike protein. It shows an acceptable safety profile. Nevertheless, several cases of unusual thrombosis and thrombocytopenia have been reported after initial vaccination with ChAdOx1-S mimicking autoimmune heparin-induced thrombocytopenia. This condition has been called thrombosis with thrombocytopenia syndrome (TTS) and complications such as intracerebral haemorrhage have been described. CASE REPORT: We present a case of intracerebral haemorrhage after ChAdOx1-S vaccination. Middle-aged patient with no prior medical history was seen in the emergency room 16 days after the first dose of ChAdOx1-S vaccine with sudden onset left hemiplegia and severe holocranial oppressive headache. She did not receive heparin treatment in the previous 100 days. Blood test showed moderate thrombocytopenia and a right frontal lobar haemorrhage was seen on computed tomography scan, computed tomography venography was negative for thrombosis. The presence of antibodies against platelet factor 4 was confirmed. The patient’s neurological condition progressively worsened. She developed a treatment resistant intracranial hypertension syndrome and she died three weeks later. CONCLUSIONS: TTS is a rare adverse effect of ChAdOx1-S vaccine, defined by the presence of thrombosis in uncommon locations. In our case we report an spontaneous intracerebral haemorrhage probable due to the thrombocytopenia related to probable TTS. It represents a rare clinical presentation of TTS.(AU)

Un nuevo protocolo intrahospitalario reduce el tiempo puerta-aguja en el ictus agudo tratado con trombolisis intravenosa a menos de 30 minutos / A new protocol reduces median door-to-needle time to the benchmark of 30 minutes in acute stroke treatment

Introducción: El objetivo del tiempo puerta-aguja en el ictus isquémico agudo tratado con trombólisis intravenosa (TIV) tiende a situarse actualmente en los 30 min. Determinamos si un nuevo protocolo de actuación intrahospitalario es eficaz para reducir el intervalo puerta-aguja y corregir los factores de demora previamente identificados.Material y métodosEn 2014 se implantaron gradualmente unas medidas diseñadas para acortar los tiempos de actuación intrahospitalarios en los pacientes tratados con TIV. Se compararon los tiempos de actuación antes (2009-2012) y después (febrero 2014-abril 2017) de la introducción del nuevo protocolo.ResultadosSe incluyeron 239 pacientes antes y 222 después. Cuando todas las medidas fueron introducidas, la mediana global de tiempo puerta-aguja fue de 27 min (previa 52 min, 48% menos, p < 0,001) y de 22 min cuando se activó el código ictus extrahospitalario. El tiempo global al tratamiento (inicio-aguja) se redujo en 26 min de mediana (p < 0,001). En el período postintervención ya no se objetivó el «efecto de fin de ventana» (p = 0,98). Aunque la angio-TC antes de la TIV continuó retrasando los tiempos de actuación (p < 0,001), tras el nuevo protocolo, esta prueba se realizó después del inicio del tratamiento en la mayoría de los casos.ConclusionesLa reorganización intrahospitalaria y la colaboración multidisciplinar han situado la mediana de tiempo puerta-aguja por debajo de los 30 min y han corregido los factores de demora identificados previamente. Además, se ha reducido el tiempo global al tratamiento y una mayor proporción de pacientes son tratados en los primeros 90 min desde el inicio de los síntomas. (AU)

Introduction: Recent analyses emphasize that The Benchmark Stroke Door-to-Needle Time (DNT) should be 30 min. This study aimed to determine if a new in-hospital IVT protocol is effective in reducing door-to-needle time and correcting previously identified factors associated with delays.Material and methodsIn 2014, we gradually introduced a series of measures aimed to reduce door-to-needle time for patients receiving IVT, and compared it before (2009-2012) and after (2014-2017) the new protocol was introduced.ResultsThe sample included 239 patients before and 222 after the introduction of the protocol. Median overall door-to-needle time was 27 min after the protocol was fully implemented (a 48% reduction on previous door-to-needle time [52 minutes], P<.001)]. Median door-to-needle time was lower when pre-hospital code stroke was activated (22 min). We observed a 26-min reduction in the median time from onset to treatment (P<.001). After the protocol was implemented, the «3-hour-effect» did not affect door-to-needle time time (P=.98). Computed tomography angiography studies performed before IVT were associated with increased door-to-needle time (P<.001); however, the test was performed after IVT was started in most cases.ConclusionsHospital reorganisation and multidisciplinary collaboration brought median door-to-needle time below 30 min and corrected previously identified delay factors. Furthermore, overall time from onset to treatment was also reduced and more stroke patients were treated within 90 min of symptom onset. (AU)

[Diagnostic, prognostic and therapeutic implications of transcranial color-coded duplex sonography in acute ischemic stroke: TIBI and COGIF scores validation]. / Implicaciones diagnosticas, pronosticas y terapeuticas del duplex color transcraneal en el ictus isquemico agudo: validacion de los grados TIBI y COGIF.

AIM: To describe the information provided by transcranial color-coded duplex (TCCD) sonography for therapeutic decision-making in patients with acute ischemic stroke and to analyze the relationship between TCCD findings and the severity and prognosis of stroke. PATIENTS AND METHODS: TCCD performed within the six first hours after an acute ischemic stroke were analyzed in our institution. The presence of an arterial occlusion and its location were collected using TIBI (Thrombolysis in Brain Ischemia) and COGIF (Consensus on Grading Intracranial Flow Obstruction) criteria. Arterial recanalization within 24 hours after stroke was determined using TIBI and COGIF criteria. Favorable functional outcome was defined as a modified Rankin scale from 0 to 2 at three months. RESULTS: TCCD was performed in 104 patients, 85 were treated with intravenous thrombolysis. Arterial occlusion was detected in 79.8% of patients. The detection of arterial occlusion with TCCD allowed the selection for endovascular treatment in 23.1% of patients. Arterial occlusion was associated with a higher severity of stroke. Recanalization was detected in 44.1% using TIBI and 45.8% according to COGIF criteria. 80.8% of recanalized patients and only 39.5% of not recanalized had a favorable functional outcome at three months. Recanalization rate depended on the location of arterial occlusion. CONCLUSION: TCCD is a useful technique for the detection and location of arterial occlusion. It provides valuable prognostic information and allows selecting patients for endovascular recanalizing therapies. TIBI and COGIF scores provide a comparable information.

TITLE: Implicaciones diagnosticas, pronosticas y terapeuticas del duplex color transcraneal en el ictus isquemico agudo: validacion de los grados TIBI y COGIF.Objetivo. Describir la informacion aportada por el duplex color transcraneal (DCTC) en pacientes con ictus isquemico agudo, analizando la relacion entre los hallazgos del DCTC, la gravedad y el pronostico, asi como su utilidad en la toma de decisiones terapeuticas. Pacientes y metodos. Analizamos los DCTC realizados a pacientes con ictus agudo de menos de seis horas de evolucion. Recogimos la existencia de oclusion arterial empleando las clasificaciones TIBI (Thrombolysis in Brain Ischemia) y COGIF (Consensus on Grading Intracranial Flow Obstruction). Determinamos la recanalizacion arterial a las 24 horas del ictus empleando criterios TIBI y COGIF. Consideramos buena evolucion funcional puntuaciones en la escala de Rankin de 0 a 2 a los tres meses. Resultados. Realizamos DCTC en 104 pacientes, 85 tratados con trombolisis intravenosa. Objetivamos oclusion arterial en el 79,8%. La deteccion de una oclusion arterial mediante DCTC permitio indicar tratamiento endovascular en el 23,1% de los pacientes. La presencia de oclusion arterial se asocio a mayor gravedad del ictus. Detectamos recanalizacion arterial en el 44,1% segun los criterios TIBI y en el 45,8% segun los criterios COGIF. El 80,8% de los pacientes que recanalizaron y solo el 39,5% de los que no recanalizaron obtuvieron una buena evolucion funcional a los tres meses. La recanalizacion dependio de la localizacion de la oclusion arterial. Conclusiones. El DCTC es util para deteccion y localizacion de oclusion arterial, aporta informacion pronostica valiosa y permite seleccionar pacientes para el empleo de terapias endovasculares. La informacion aportada por las clasificaciones TIBI y COGIF es equiparable.

Identification of a functional androgen-response element in the exon 1-coding sequence of the cystatin-related protein gene crp2.

Two hormone-responsive segments, one in the region of the promoter and one in intron 1, are identified in two homologous androgen-regulated and differentially expressed rat genes encoding the cystatin-related proteins (CRPs). Footprint analysis with the androgen receptor (AR) DNA-binding domain on the promoter-containing fragments reveals an AR-binding site downstream of the transcription start point in the crp2 gene (ARBSd/crp2, +40/+63). It displays an androgen response element-like sequence motif 5'-AGAAGAaaaTGTACA-3' and overlaps with the ATG translation start codon. A double-stranded oligonucleotide containing this sequence forms a DNA-protein complex with the full-length AR synthesized by vaccinia, as seen in band shift assays. Additional AR-binding sites, ARBSu/crp1 and ARBSu/crp2, occur 5' upstream of the transcription start point and are located at an identical position (-142/ -120) in crp1 and crp2. The AR affinity for these two slightly different sequence motifs is relatively weak. The biological function of all three AR-binding sites as transcription control elements has been studied. The ARBSd/crp2 element clearly shows androgen-response element characteristics. The contribution of the common upstream element to the androgen-dependent control of reporter gene transcription is less clear. The transcription of a reporter gene construct containing the crp2 footprint fragment crp2F (-273/+88) is hormonally regulated as determined by transfection into the human breast cancer cell line T-47D. Androgens, but also glucocorticoids, efficiently stimulate steroid-dependent transcription of the chloramphenicol acetyltransferase gene. Mutation of the 5'-TGTACA-3' sequence in ARBSd/crp2 destroys the AR binding and abolishes the androgen-dependent synthesis of chloramphenicol acetyltransferase. A large fragment derived from intron 1 of the crp1 and crp2 gene can also provide the androgen-dependent transcription of chimeric constructs in T-47D cells. However, the induction measured is less than the one observed with crp2F (-273/+88), and this activity seems to reside in several subfragments that each display a low but consistent androgen responsiveness.

Androgen specificity of a response unit upstream of the human secretory component gene is mediated by differential receptor binding to an essential androgen response element.

The expression of secretory component (SC), the epithelial receptor for poly-immunoglobulins, is regulated in a highly tissue-specific manner. In several tissues, e.g. lacrimal gland and prostate, SC synthesis is enhanced by androgens at the transcriptional level. In this study, we describe the presence of an androgen response unit, located 3.3 kb upstream of the sc transcription initiation site and containing several 5'-TGTTCT-3'-like motifs. Although each of these elements is implicated in the enhancer function, one element, the ARE1.2 motif, is found to be the main interaction site for the androgen receptor as demonstrated in in vitro binding assays as well as in transient transfection assays. A high-affinity binding site for nuclear factor I, adjacent to this ARE, is also involved in the correct functioning of the sc upstream enhancer. The ARE1.2 motif consists of an imperfect direct repeat of two core binding elements with a three-nucleotide spacer and therefore constitutes a nonconventional ARE. We demonstrate that this element displays selectivity for the androgen receptor as opposed to glucocorticoid receptor both in in vitro binding assays and in transfection experiments. Mutational analysis suggests that the direct nature of the half-site repeat is responsible for this selectivity. We have thus determined a complex and androgen-specific response unit in the far upstream region of the human SC gene, which we believe to be involved in its androgen responsiveness in epithelial cells of different organs such as prostate and lacrimal gland. We were also able to demonstrate that the primary sequence of a single nonconventional ARE motif within the enhancer is responsible for its androgen specificity.

Interaction of the putative androgen receptor-specific coactivator ARA70/ELE1alpha with multiple steroid receptors and identification of an internally deleted ELE1beta isoform.

Steroid-regulated gene transcription requires the coordinate physical and functional interaction of hormone receptors, basal transcription factors, and transcriptional coactivators. In this context ARA70, previously called RFG and ELE1, has been described as a putative coactivator that specifically enhances the activity of the androgen receptor (AR) but not that of the glucocorticoid receptor (GR), the progesterone receptor, or the estrogen receptor (ER). Here we describe the cloning of the cDNA for ELE1/ARA70 by RT-PCR from RNA derived from different cell lines (HeLa, DU-145, and LNCaP). In accordance with the previously described sequence, we obtained a 1845-bp PCR product for the HeLa and the LNCaP RNA. Starting from T-47D RNA, however, an 860-bp PCR product was obtained. This shorter variant results from an internal 985-bp deletion and is called ELE1beta; accordingly, the longer isoform is referred to as ELE1alpha. The deduced amino acid sequence of ELE1alpha, but not that of ELE1beta, differs at specific positions from the one previously published by others, suggesting that these two proteins are encoded by different nonallelic genes. ELE1alpha is expressed in the three prostate-derived cell lines examined (PC-3, DU-145, and LNCaP), and this expression is not altered by androgen treatment. Of all rat tissues examined, ELE1alpha expression is highest in the testis. This is also the only tissue in which we could demonstrate ELE1beta expression. Both ELE1alpha and ELE1beta interact in vitro with the AR, but also with the GR and the ER, in a ligand-independent way. Overexpression of either ELE1 isoform in DU-145, HeLa, or COS cells had only minor effects on the transcriptional activity of the human AR. ELE1alpha has no intrinsic transcription activation domain or histone acetyltransferase activity, but it does interact with another histone acetyltransferase, p/CAF, and the basal transcription factor TFIIB. The interaction with the AR occurs through the ligand-binding domain and involves the region corresponding to the predicted helix 3. Mutation in this domain of leucine 712 to arginine greatly reduces the affinity of the AR for ELE1alpha but has only moderate effects on its transcriptional activity. Taken together, we have identified two isoforms of the putative coactivator ARA70/ELE1 that may act as a bridging factor between steroid receptors and components of the transcription initiation complex but which lack some fundamental properties of a classic nuclear receptor coactivator. Further experiments will be required to highlight the in vivo role of ELE1 in nuclear receptor functioning.

The first exon of the human sc gene contains an androgen responsive unit and an interferon regulatory factor element.

Secretory component (SC) plays a key role in the transport of IgA and IgM to the lumina of many glands. The gene is constitutively expressed, but can be modulated by hormonal and immunological stimuli. Recently, the promoter and the first exon of the human sc gene have been cloned. The first exon contains a putative androgen/glucocorticoid response element (ARE/GRE) and an Interferon Regulatory Factor Element (IRF-E). Here we show that the ARE/GRE can bind the DNA-binding domain (DBD) of both the androgen (AR) and glucocorticoid receptor (GR) with a preference for the AR-DBD. In transient transfection experiments, this element confers higher responsiveness to androgens than to glucocorticoids. The IRF-E can function as an IRF-2, but surprisingly not as an IRF-I responsive element. We postulate that these two regulatory elements play a key role in the complex regulation of the sc gene in vivo.

[A study made on a data base of 2,471 patients with Parkinson disease and disorders of movement in Health District 1 of the autonomous region of Madrid. Observed demographic changes over 8 year-period]. / Estudio sobre una base de datos de 2.471 pacientes con enfermedad de Parkinson y trastornos del movimiento en el Area Sanitaria 1 de la Comunidad de Madrid. Cambios demográficos observados a lo largo de ocho años.

INTRODUCTION: A specialised unit may influence favourably primary levels of health system by alerting physicians and patients on the existence of those pathologies most commonly seen. OBJECTIVES: To determine demographic changes and referral patterns observed in a hospital-based monographic outpatient clinic on Parkinson's disease and movement disorders along an eight-year period (1991-1998). PATIENTS AND METHODS: Database analysis of 2,471 patients attending a specialised unit covering an urban and rural population of 630,000 people in South-East Madrid city and county. RESULTS: We observed a slight, albeit non-significant reduction in the incidence of secondary parkinsonisms (40% of all parkinsonisms observed). This occurred despite a drastic reduction in drug-induced parkinsonisms, particularly those caused by cinnarizine/flunarizine and flupentixol. The reduction was balanced by a relative increase in neurodegenerative parkinsonisms, particularly Lewy body dementia. There was a sustained decrease in the time elapsed between onset of symptoms and identification of parkinsonisms as well as identification of its primary or symptomatic nature. The incidence of tardive dystonia (46.7%) of all symptomatic dystonias) remained unchanged. Essential tremor referrals markedly increased along the study period. CONCLUSIONS: Demographics features of patients attending a Parkinson's disease and movement disorder unit are submitted to changes over time. These probably reflect better awareness about these conditions by patients and physicians, ready access to hospital-based specialised units, and a greater demand for specialised care by the aged.