[Derivation and validation of a risk score for admission to the Intensive Care Unit in patients with COVID-19]. / Derivación y validación de una puntuación de riesgo de ingreso en la Unidad de Cuidados Intensivos para pacientes con COVID-19.

BACKGROUND: This work aims to identify and validate a risk scale for admission to intensive care units (ICU) in hospitalized patients with coronavirus disease 2019 (COVID-19). METHODS: We created a derivation rule and a validation rule for ICU admission using data from a national registry of a cohort of patients with confirmed SARS-CoV-2 infection who were admitted between March and August 2020 (n = 16,298). We analyzed the available demographic, clinical, radiological, and laboratory variables recorded at hospital admission. We evaluated the performance of the risk score by estimating the area under the receiver operating characteristic curve (AUROC). Using the ß coefficients of the regression model, we developed a score (0 to 100 points) associated with ICU admission. RESULTS: The mean age of the patients was 67 years; 57% were men. A total of 1,420 (8.7%) patients were admitted to the ICU. The variables independently associated with ICU admission were age, dyspnea, Charlson Comorbidity Index score, neutrophil-to-lymphocyte ratio, lactate dehydrogenase levels, and presence of diffuse infiltrates on a chest X-ray. The model showed an AUROC of 0.780 (CI: 0.763-0.797) in the derivation cohort and an AUROC of 0.734 (CI: 0.708-0.761) in the validation cohort. A score of greater than 75 points was associated with a more than 30% probability of ICU admission while a score of less than 50 points reduced the likelihood of ICU admission to 15%. CONCLUSION: A simple prediction score was a useful tool for forecasting the probability of ICU admission with a high degree of precision.

Use of intracranial stent as rescue therapy after mechanical thrombectomy failure-9-year experience in a comprehensive stroke centre.

PURPOSE: There is no established rescue treatment in patients with mechanical thrombectomy (MT) failure. Our aim is to analyse whether the use of an intracranial stent improves prognosis in these patients. METHODS: Retrospective analysis of a prospective cohort of patients with ischemic stroke due to middle cerebral artery occlusion (MCA) or distal intracranial carotid artery (ICA) occlusion, from September 2009 to April 2019 in our comprehensive stroke care centre. Patients with MT failure were identified and dichotomized into two groups according to whether or not an intracranial stent was implanted. We analysed clinical outcomes in both groups. RESULTS: There was MT failure in 60 patients (14%) of the 433 with large vessel occlusion in distal ICA and proximal MCA. A stent was placed in 20 of them (33.3%). Compared to patients without rescue stenting, they showed better rates of independence at 3 months (mRS ≤ 2) 45% vs 2.5% (p < 0.001) and lower mortality 15% vs 50% (p = 0.009), maintaining statistical significance after multivariate analysis, without a significant increase of the rate of symptomatic intracranial haemorrhage (p = 0.209). CONCLUSION: Placement of an intracranial stent as rescue therapy after MT failure was associated with better clinical outcome without significant increase in haemorrhagic complications. We believe that this procedure should be appraised in these patients.

First-Pass Effect in M1-Occlusion Stroke Patients Treated with Combined Stent-Retriever/Large-Bore Distal Aspiration Catheter Thrombectomy.

INTRODUCTION: Combined stent-retriever/large-bore distal aspiration catheter (LB-DAC) thrombectomy was recently introduced to treat large-vessel occlusion; however, it is unclear whether larger inner diameters improve outcomes. We compared angiographic and clinical outcomes in patients with occlusions of the M1 segment of the middle cerebral artery treated with mechanical thrombectomy using extra-LB-DAC versus LB-DAC in combination with stent-retrievers. METHODS: We analyzed consecutive patients with M1 occlusion included in the ROSSETTI registry treated with non-balloon guide catheter combined LB-DAC/stent-retriever thrombectomy between June 2019 and April 2022. We compared demographics, baseline clinical variables, procedural variables, angiographic outcomes, and clinical outcomes [National Institute of Health Stroke Scale score at 24 h (24h-NIHSS) and modified Rankin scale score at 3 months] between patients treated with extra-LB-DAC (Sofia Plus, MIVI Q6, Catalyst7; inner diameter, 0.068″-0.070″) versus LB-DAC (Sofia 5F, MIVI Q5, Catalyst 6; inner diameter, 0.055″-0.064″). Primary outcome was the first-pass effect (FPE) rate, defined as near-complete/complete reperfusion (mTICI 2c-3) after a single pass of the device. RESULTS: We included 324 patients (extra-LB-DAC, 185, 57.1% patients). Demographics, clinical data, and clinical outcomes were similar between the two groups; however, there was a trend towards improvement in National Institute of Health Stroke Scale score at 24 h (24h-NIHSS) in the cohort treated with extra-LB-DAC 9 points (IQR 4;16 points) vs. 12 points (IQR 4;18 points, P = 0.083). Patients treated with extra-LB-DAC had higher FPE rate (47% vs. 30.9%; P = 0.003) and higher modified FPE (mTICI ≥ 2b after a single pass) rate (65.9% vs 46.8%; P = 0.001). The use of extra-LB-DAC was an independent factor in predicting FPE (odds ratio 1.982, 95% confidence interval 1.250-3.143, P = 0.004). CONCLUSION: Our results suggest that in combined LB-DAC/stent-retriever thrombectomy, a larger aspiration catheter inner diameter is associated with higher rates of FPE and mFPE.

Derivation and validation of a risk score for admission to the Intensive Care Unit in patients with COVID-19.

BACKGROUND: This work aims to identify and validate a risk scale for admission to intensive care units (ICU) in hospitalized patients with coronavirus disease 2019 (COVID-19). METHODS: We created a derivation rule and a validation rule for ICU admission using data from a national registry of a cohort of patients with confirmed SARS-CoV-2 infection who were admitted between March and August 2020 (N = 16,298). We analyzed the available demographic, clinical, radiological, and laboratory variables recorded at hospital admission. We evaluated the performance of the risk score by estimating the area under the receiver operating characteristic curve (AUROC). Using the ß coefficients of the regression model, we developed a score (0-100 points) associated with ICU admission. RESULTS: The mean age of the patients was 67 years; 57% were men. A total of 1420 (8.7%) patients were admitted to the ICU. The variables independently associated with ICU admission were age, dyspnea, Charlson Comorbidity Index score, neutrophil-to-lymphocyte ratio, lactate dehydrogenase levels, and presence of diffuse infiltrates on a chest X-ray. The model showed an AUROC of 0.780 (CI: 0.763-0.797) in the derivation cohort and an AUROC of 0.734 (CI: 0.708-0.761) in the validation cohort. A score of greater than 75 points was associated with a more than 30% probability of ICU admission while a score of less than 50 points reduced the likelihood of ICU admission to 15%. CONCLUSION: A simple prediction score was a useful tool for forecasting the probability of ICU admission with a high degree of precision.

Safe and successful treatment of refractory polyarteritis nodosa with tocilizumab in a patient with past hepatitis B virus infection: a case-based review.

Polyarteritis nodosa is a primary systemic necrotizing vasculitis whose evolution follows, in many cases, a chronic remitting-recurrent course with refractoriness to conventional immunosuppressants. We report here the clinical case of a 75-year-old patient with serologies suggestive of past hepatitis B virus infection who presented a flare of polyarteritis nodosa with great secondary functional impairment. She had not responded to several previous immunosuppressants and required high doses of glucocorticoids to control the flare. After the initiation of biological therapy with tocilizumab, the patient experienced a rapid and marked clinical and analytical improvement, going into clinical remission and being able to remarkably lower the corticosteroid dose and stop the rest of the immunosuppressants. There was no evidence of hepatitis B virus reactivation or changes in the titers of any of the parameters related to the aforementioned infection. This clinical case represents the first case reported in the literature about the successful and safe treatment of polyarteritis nodosa with tocilizumab in a patient with serologies suggestive of past hepatitis B virus infection.

Clinical factors associated with discontinuation of ts/bDMARDs in rheumatic patients from the BIOBADASER III registry.

Biologic and targeted synthetic disease-modifying antirheumatic drugs (ts/bDMARDs) play a pivotal role in the treatment of rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS). Persistence of therapy provides an index of a drug's overall effectiveness. The objective of the study was to identify factors associated with discontinuation of ts/bDMARDs in a real-world dataset. The study population comprised patients diagnosed with RA, PsA, and AS included in the BIOBADASER registry for whom follow-up data were available until November 2019. Patient features and treatment data were included in the analysis. The Kaplan-Meier method was used to study survival of the different drugs according to the reason for discontinuation. Factors associated with discontinuation were studied using Cox regression models and bivariate and multivariate analyses. P values of less than 0.05 were regarded as statistically significant. The study population comprised 4,752 patients who received a total of 8,377 drugs, of which 4,411 (52.65%) were discontinued. The Kaplan-Meier curves showed that survival for first-line treatment was greater in all 3 groups (p < 0.001). Patients with RA had a greater risk of discontinuation if they were younger (HR, 0.99; 95% CI 0.99-1.00), if they were receiving anti-TNFα agents (HR, 0.61; 95% CI 0.54-0.70), and if they had more comorbid conditions (HR, 1.09; 95% CI 1.00-1.17). Patients with PsA had a higher risk if they were women (HR, 1.36; 95% CI 1.15-1.62) and if they were receiving other ts/bDMARDs (HR, 1.29; 95% CI 1.05-1.59). In patients with AS, risk increased with age (HR, 1.01; 95% CI 1.00-1.02), as did the number of comorbid conditions (HR, 1.27; 95% CI 1.12-1.45). The factors that most affected discontinuation of ts/bDMARDs were line of treatment, age, type of drug, sex, comorbidity and the year of initiation of treatment. The association with these factors differed with each disease, except for first-line treatment, which was associated with a lower risk of discontinuation in all 3 diseases.

AMPA receptor downregulation induced by ischaemia/reperfusion is attenuated by age and blocked by meloxicam.

AIM: Stroke prevalence increases with age, while alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR) and inflammation have been related to ischaemia-induced damage. This study shows how age and treatment with an anti-inflammatory agent (meloxicam) modify the levels of AMPAR subunits GluR1 and GluR2, as well as the mRNA levels of the GluR2-editing enzyme, ADAR2, in a global brain ischaemia/reperfusion (I/R) model. METHODS: Two days after global ischaemia CA1, CA3, dentate gyrus and cerebral cortex were obtained from sham-operated and I/R-injured 3- and 18-month-old Sprague-Dawley rats. Real time polymerase chain reaction, Western blotting and immunohistochemical assays were performed. Meloxicam treatment was assayed on young animals. RESULTS: Data showed that age attenuates the downregulation induced by I/R in the AMPAR subunits GluR1 and GluR2 and modifies the GluR1/GluR2 mRNA level ratio in a structure-dependent way. The study of the ADAR2 mRNA levels showed more downregulation in older animals than young ones. Meloxicam treatment prevented the transcriptional arrest induced by I/R. CONCLUSION: Our data suggest that changes in the AMPAR isoforms could be associated with ageing in the different structures studied. Although GluR2 editing seems to be involved in age-dependent vulnerability to ischaemia supporting the 'GluR2 hypothesis', this alone does not explain the differential vulnerability in the different brain regions. Finally, inflammation could play a role in protection from I/R-induced injury.

Dual SAVE technique for mechanical thrombectomy rescue on MCA bifurcation clots.

The Stent retriever Assisted Vacuum-locked Extraction (SAVE) technique in mechanical thrombectomy consists of the simultaneous use of a stent retriever and a distal aspiration catheter, with the removal of both as a unit when performing the thrombectomy pass. This is a safe procedure that provides a high rate of first-pass reperfusion.1 In the distal M1 segment of the middle cerebral artery (MCA) occlusions, with the distal portion of the clot extending to the upper and lower MCA branches, mechanical thrombectomy can be challenging since the thrombus is not fully trapped, with risk of distal clot migration to the branch in which the retriever is not placed. In these cases the double stent-retriever technique has been described as a rescue strategy.2-4 We describe a case of the combined use of SAVE and double stent-retriever techniques as a rescue strategy in a patient with tandem occlusion of the proximal internal carotid artery and distal MCA-the D-SAVE technique. (video 1).

Aortic dissection class 3: a little-known entity. Presentation of 4 cases. / Disección aórtica de clase 3: una entidad poco conocida. Presentación de 4 casos.

Aortic dissection (AD) is the most common acute condition of the aorta and has a high mortality. Therefore, it is a radiological emergency of vital importance. Currently, five subtypes are distinguished, among which AD class 3 -also known as limited or subtle AD- is the less recognised. This type of dissection is infrequent and needs to be acknowledged radiologically in order not to go unnoticed. Regarding its imaging features, this entity is characterized by a small focal bulging of the aortic wall outline and/or a limited round dilation at the region affected by the intimal tear. Recently, the low familiarity of the radiologist with this condition has been emphasized. With the aim of illustrating the main imaging findings of this entity and reviewing its most relevant aspects, we present four cases of AD class 3 diagnosed in our hospital.

A GC-rich satellite DNA and karyology of the bivalve mollusk Donax trunculus: a dominance of GC-rich heterochromatin.

We characterized the DTF2 satellite DNA family of the clam Donaxtrunculus and compared its chromosomal localization with cytogenetic data revealed by fluorochrome banding, C-banding, and 28S rDNA FISH. In contrast to the other satellites detected previously in this species, DTF2 is an abundant (2%) GC-rich satellite that exhibits CpG methylation. Sequence characteristics of DTF2 indicate that its evolution is not affected by constraints that might indicate some functional interactions. Fluorescence in situ hybridization revealed subtelomeric location of this satellite on a subset of 14 out of 19 D. trunculus chromosome pairs. The chromomycin A(3) (CMA) staining of GC-rich regions on D. trunculus chromosomes revealed a complex banding pattern that overlaps completely with C-bands. In total, only three bands show subtelomeric location, while 13 bands are located interstitially, one of them being coincident with the 28S rDNA hybridization signal. No bands, either CMA positive (GC-rich) or DAPI positive (AT-rich) were detected at centromeric chromosomal positions. Only two of the CMA-positive bands co-localize with the DTF2 satellite, showing a) the presence of small islands of GC-rich repetitive sequences that remained undetected by CMA/C-banding and b) the abundance of DTF2-divergent GC-rich sequences at interstitial chromosomal locations.

Rectal culture-directed antibiotic prophylaxis before transrectal prostate biopsy: Reduced infectious complications and healthcare costs. / Profilaxis antibiótica «dirigida¼ por cultivos rectales antes de la biopsia prostática transrectal: reducción de complicaciones infecciosas y costes de atención sanitaria.

BACKGROUND: Transrectal ultrasound-guided prostate biopsy (TUPB) is associated with infectious complications (ICs), which are related to a greater prevalence of ciprofloxacin-resistant bacteria (CRB) in rectal flora. We examined the ICs that occurred in 2 groups: A guided antibiotic prophylaxis (GP) group and an empiric prophylaxis (EP) group. We assessed the financial impact of GP. MATERIAL AND METHODS: The GP group was studied prospectively (June 2013 to July 2014). We collected rectal cultures (RCs) before the TUPB, which were seeded on selective media with ciprofloxacin to determine the presence of CRB. The patients with sensitive bacteria were administered ciprofloxacin. Patients with resistant bacteria were administered GP according to the RC antibiogram. The EP group was studied retrospectively (January 2011 to June 2009). RCs were not performed, and all patients were treated with ciprofloxacin as prophylaxis. The ICs in both groups were recorded during a period no longer than 30 days following TUPB (electronic medical history). RESULTS: Three hundred patients underwent TUPB, 145 underwent GP, and 155 underwent EP. In the GP group, 23 patients (15.86%) presented CRB in the RCs. Only one patient (0.7%) experienced a UTI. In the EP group, 26 patients (16.8%) experienced multiple ICs (including 2 cases of sepsis) (P<.005). The estimated total cost, including the management of the ICs, was €57,076 with EP versus €4802.33 with GP. The average cost per patient with EP was €368.23 versus €33.11 with GP. GP achieved an estimated total savings of €52,273.67. Six patients had to undergo GP to prevent an IC. CONCLUSIONS: GP is associated with a marked decrease in the incidence of ICs caused by CRB and reduced healthcare costs.

[Benign tumors that cause fractures in children]. / Tumores benignos que producen fracturas en niños.

INTRODUCTION: A pathological fracture is defined as that which occurs through an abnormal bone. Approximately 20,000 benign neoplasms of the musculoskeletal system are diagnosed each year. Often the pain of the fracture is the first symptom of a pathological process in the bone. The site, age and radiographic appearance create a differential diagnosis for pathological fractures that remains broad. The clinical examination evaluates the condition of the skin, palpating any tissue mass and determining if there are local inflammatory signs such as erythema, heat or edema. The biopsy is highly recommended to confirm the diagnosis of a pathological fracture. OBJECTIVE: To determine which benign bone tumors and pseudotumoral lesions produce fractures in childrens bones more frequently in our institution. MATERIAL AND METHODS: Cross-sectional retrospective study, review of records of patients with diagnosis of pathological fracture, attended in the period from March 2013 to March 2017, were reviewed. Results: The benign tumors that caused fractures in previously damaged areas were: aneurysmal bone cyst 13, enchondroma 5, osteoid osteoma 3, giant cell tumor 2. CONCLUSION: At our institution, aneurysmal bone cysts were the benign tumors that most frequently produce pathological fractures in children, with predominance in males.

INTRODUCCIÓN: Se define fractura patológica a la que se produce a través de un hueso anormal. Cada año se diagnostican aproximadamente 20,000 neoplasias benignas del sistema musculoesquelético. A menudo, el dolor de la fractura es el primer síntoma de un proceso patológico en el hueso. El sitio, la edad y la apariencia radiográfica crean un diagnóstico diferencial para las fracturas patológicas que sigue siendo amplio. El examen clínico evalúa la condición de la piel, palpar cualquier masa de tejido y determinar si hay signos inflamatorios locales como eritema, calor o edema. La toma de biopsia es muy recomendable para confirmar el diagnóstico de una fractura patológica. OBJETIVO: Determinar qué tumores óseos benignos y qué lesiones seudotumorales producen fracturas en huesos de niños con mayor frecuencia en nuestro hospital. MATERIAL Y MÉTODOS: Estudio retrospectivo transversal, se revisaron expedientes de pacientes con diagnóstico de fractura en terreno patológico, atendidos en el período de Marzo de 2013 a Marzo de 2017. RESULTADOS: Los tumores benignos que ocasionaron fracturas en terreno previamente dañado fueron: quiste óseo aneurismático 13, encondroma cinco, osteoma osteoide tres, tumor de células gigantes dos. CONCLUSIÓN: En nuestra institución, los quistes óseos aneurismáticos fueron los tumores benignos que con mayor frecuencia producen fracturas patológicas en niños, con predominio en el sexo masculino.

Derivación y validación de una puntuación de riesgo de ingreso en la Unidad de Cuidados Intensivos para pacientes con COVID-19 / Derivation and validation of a risk score for admission to the Intensive Care Unit in patients with COVID-19

Fundamento: Identificar y validar una escala de riesgo de ingreso en las unidades de cuidados intensivos (UCI) en pacientes hospitalizados con enfermedad por coronavirus 2019 (COVID-19). Métodos: Realizamos una regla de derivación y otra de validación para ingreso en UCI, utilizando los datos de un registro nacional de cohortes de pacientes con infección confirmada por SARS-CoV-2 ingresados entre marzo y agosto del año 2020 (n = 16.298). Analizamos variables demográficas, clínicas, radiológicas y de laboratorio disponibles en el ingreso hospitalario. Evaluamos el rendimiento de la escala de riesgo mediante estimación del área bajo la curva de característica operativa del receptor (AROC). Utilizamos los coeficientes β del modelo de regresión para elaborar una puntuación (0 a 100 puntos) asociada con ingreso en UCI. Resultados: La edad media de los pacientes fue de 67 años; 57% varones. Un total de 1.420 (8,7%) pacientes ingresaron en la UCI. Las variables independientes asociadas con el ingreso en UCI fueron: edad, disnea, índice de comorbilidad de Charlson, cociente neutrófilos-linfocitos, lactato deshidrogenasa e infiltrados difusos en la radiografía de tórax. El modelo mostró un AROC de 0,780 (IC: 0,763-0,797) en la cohorte de derivación y un AROC de 0,734 (IC: 0,708-0,761) en la cohorte de validación. Una puntuación > 75 se asoció con una probabilidad de ingreso en UCI superior a un 30%, mientras que una puntuación < 50 redujo la probabilidad de ingreso en UCI al 15%. Conclusiós: Una puntuación de predicción simple proporcionó una herramienta útil para predecir la probabilidad de ingreso en la UCI con un alto grado de precisión (AU)

Background: This work aims to identify and validate a risk scale for admission to intensive care units (ICU) in hospitalized patients with coronavirus disease 2019 (COVID-19). Methods: We created a derivation rule and a validation rule for ICU admission using data from a national registry of a cohort of patients with confirmed SARS-CoV-2 infection who were admitted between March and August 2020 (n = 16,298). We analyzed the available demographic, clinical, radiological, and laboratory variables recorded at hospital admission. We evaluated the performance of the risk score by estimating the area under the receiver operating characteristic curve (AUROC). Using the β coefficients of the regression model, we developed a score (0 to 100 points) associated with ICU admission. Results: The mean age of the patients was 67 years; 57% were men. A total of 1,420 (8.7%) patients were admitted to the ICU. The variables independently associated with ICU admission were age, dyspnea, Charlson Comorbidity Index score, neutrophil-to-lymphocyte ratio, lactate dehydrogenase levels, and presence of diffuse infiltrates on a chest X-ray. The model showed an AUROC of 0.780 (CI: 0.763-0.797) in the derivation cohort and an AUROC of 0.734 (CI: 0.708-0.761) in the validation cohort. A score of greater than 75 points was associated with a more than 30% probability of ICU admission while a score of less than 50 points reduced the likelihood of ICU admission to 15%. Conclusion: A simple prediction score was a useful tool for forecasting the probability of ICU admission with a high degree of precision (AU)

Effect of the arterial hypertension and captopril treatment on the angiotensin II content in the subfornical organ. A study in SHR rats.

We studied the effects of spontaneous high blood pressure and the captopril treatment on the subfornical organ (SFO) of rats. The brains of control Wistar-Kyoto rats (WKY), WKY rats treated with captopril (WKY-T), spontaneously hypertensive rats (SHR) and SHR rats treated with captopril (SHR-T) were processed immunohistochemically using anti-angiotensin II as primary antibody. Immunorective material (IRM) for angiotensin II was observed in a group of neurons and some cells of the ependymal layer of the SFO in WKY rats. The angiotensin II immunoreactive (AGII-ir) in the SHR rats was decreased, showing positive reaction only in a few neurons, while captopril treatment induced an increase in immunoreactive material in hypertensive rats, but contrarily, the expression of AGII-ir in the WKY-T group was scarce. The variations of the angiotensin II observed in the SFO could be owing to an interaction between the hypertension and its captopril treatment.

Development of a comet-FISH assay for the detection of DNA damage in hemocytes of Crassostrea gigas.

In this work, the DNA-damaging effect of hydrogen peroxide on the structural integrity of nucleolar organizer regions (NORs) was studied for the first time by comet-FISH in the Pacific oyster Crassostrea gigas. Global DNA damage was assessed in hemocytes using an alkaline version of the comet assay. Next, NOR sensitivity was analyzed by mapping major rDNA repeat unit by fluorescence in situ hybridization (FISH) on the same comet slides. Exposure of hemocytes to 100 µM of hydrogen peroxide induced a significant increase in both DNA damage and number of FISH-signals of major ribosomal genes versus the control. Moreover, a significant positive correlation was shown between DNA damage as measured by the comet assay (percentage of DNA in comet tail) and the number of signals present in comet tails. This study demonstrates the potential value of the comet-FISH assay for the study of DNA damage induced by genotoxicant exposure of target genes. It offers a perspective for better understanding the impact of genotoxicity on animal physiology and fitness.

Histamine H3 receptor: a potential drug target for the treatment of central nervous system disorders.

Histamine H(3) receptors were first described in the eighties but finally cloned four years ago. They are G-protein coupled, mostly presynaptic, and are involved in the control of the synthesis and/or release of different neurotransmitters both in the central nervous system and the periphery. The availabiliy of specific ligands has permitted the study of potential therapeutic applications of either stimulating or blocking the function of these receptors. There is experimental evidence that drugs targeted at histamine H(3) receptors could be beneficial for neurodegenerative diseases such as Alzheimer and Parkinson's disease, epilepsy, drug abuse and several affective, appetite and sleeping disorders, among others. This review presents recent advances in this field.

Effects of yohimbine on the antinociceptive and place conditioning effects of opioid agonists in rodents.

1. The pharmacological modulation of opioid actions by drugs acting on heterologous mechanisms could be useful to overcome some of the main problems associated with the use of opiate agonists. Based on previous findings on the interactions between yohimbine and opioid drugs, we have further studied the effects of yohimbine on the antinociceptive and positive-negative reinforcing effects of morphine (mu opioid receptor-preferring agonist), U-50,488 (kappa agonist) and SNC80 (delta agonist). 2. Pretreatment with yohimbine completely blocked the antinociception provided by the three opioid agonists in the mouse tail-immersion test. 3. A similar blockade of SNC80 and U-50,488-induced antinociception was observed with yohimbine in the mouse hot plate test at the same doses. In this paradigm, the effect of the kappa agonist was very slight and the actions of yohimbine rather variable. 4. In place conditioning experiments with SD (Sprague -- Dawley) male rats, yohimbine alone was inactive but it limited the preference induced by morphine and SNC80 and the aversive effect of U-50,488. Impaired novelty preference was also observed with the combination of yohimbine and U-50,488. 5. It is concluded that yohimbine tends to limit opioid antinociception and the addictive potential of mu and delta opioid agonists. More selective drugs could help to understand the mechanisms involved in these actions.

Reelin-immunoreactive neurons in the adult vertebrate pallium.

Reelin, an extracellular matrix protein, plays a crucial role in cortical development. By using Reelin-immunohistochemistry in different vertebrates (fish, amphibians, reptiles, and mammals : insectivores, odontocetes, rodents, carnivores and man) we show here that Reelin is also expressed by a variety of neurons in the adult pallium. In the everted telencephalon of the zebrafish, Reelin-positive neurons are widely distributed over the dorsal pallium. In land vertebrates, the most consistent and evolutionary conserved location of Reelin-expressing neurons is in the cell-sparse molecular layer associated with laminated cortical organization. We describe an additional heterogeneous population of Reelin-positive neurons outside the molecular layer, the location and distribution of which are more variable, and which may reflect major evolutionary changes in cortical architecture. In squamate reptiles, the Reelin-negative main cell layer is flanked by a superficial and a deep plexiform layer which both contain Reelin-expressing neurons. In mammals, Reelin-positive interneurons are dispersed throughout layers II--VI; the human neocortex is particularly poor in Reelin-positive interneurons. Reelin is also expressed by large stellate and modified pyramidal neurons in layer II of the mammalian entorhinal cortex, and in the superficial lateral cortex of lizards. Examination of this cell population (layer II Pre-alpha) in human brains of different age groups points to a decrease in Reelin-expression in the course of adult life.

Effects of histamine H3 receptor ligands in experimental models of anxiety and depression.

Histamine H3 receptor ligands have been proposed to be of potential therapeutic interest for the treatment of different central nervous system disorders; however, the psychopharmacological properties of these drugs have not been studied extensively. In this work, we investigated the possible involvement of histamine H3 receptor function in experimental models of anxiety (elevated plus-maze) and depression (forced swimming test). Male Sprague-Dawley rats were treated i.p. with the histamine H3 receptor agonist R-alpha-methylhistamine (10 mg/kg) or the histamine H3 receptor antagonist thioperamide (0.2, 2 and 10 mg/kg) and 30 min afterwards the time spent in the open arms of an elevated plus-maze was registered for 5 min. The immobility time of male OF1 mice in the forced swimming test was recorded for 6 min, 1 h after the i.p. administration of R-alpha-methylhistamine (10 and 20 mg/kg), thioperamide (0.2, 2, 10 and 20 mg/kg) or another histamine H3 receptor antagonist, clobenpropit (5 mg/kg). The locomotor activity of mice was checked in parallel by means of an activity meter. Both saline controls and active drug controls were used in all the paradigms. Neither thioperamide nor R-alpha-methylhistamine significantly changed animal behaviour in the elevated plus-maze. R-alpha-methylhistamine and the higher dose of thioperamide assayed (20 mg/kg) were also inactive in the forced swimming test. By contrast, thioperamide (0.2-10 mg/kg) dose-dependently decreased immobility, the effect being significant at 10 mg/kg (33% reduction of immobility); clobenpropit produced an effect qualitatively similar (24% reduction of immobility). None of these histamine H3 receptor antagonists affected locomotor activity. These preliminary results suggest that the histamine H3 receptor blockade could be devoid of anxiolytic potential but have antidepressant effects. Besides, the stimulation of these receptors does not seem to be followed by changes in the behavioural parameters studied.