[Clinical characteristics of patients with stroke code activation not identified by the emergency medical service]. / Características clínicas de los pacientes con activación de código ictus no identificados por el servicio de emergencias médicas.

AIMS: To determine the sensitivity of stroke detection by emergency medical services (EMS) and to analyse the clinical characteristics of unidentified patients with suspected stroke. PATIENTS AND METHODS: Prospective register of patients with suspected stroke in our area (850,000 inhabitants) from 2011 to 2017. The population that notified the EMS was selected. Of this population, patients with and without stroke code activation by the EMS were compared (EMS+ versus EMS-). Demographics, time to progression, clinical characteristics of the episode and reperfusion therapy administered were recorded. RESULTS: Of a total of 5,497 patients with suspected stroke, 2,087 alerted the EMS: 1,611 (77%) EMS+ and 476 (33%) EMS-. The EMS- patients presented lower scores on the National Institute of Health Stroke Scale (8 vs. 11) and a greater frequency of clinical features of the vertebrobasilar territory (14.1% vs. 8.7%) and partial hemispheric clinical features (23.5% vs. 18.4%), especially in the left hemisphere (78.1% vs. 48.4%). Reperfusion treatment was administered in 29% of EMS+ and 23% of EMS-. The time from symptom onset to treatment was 42 minutes longer in the EMS group (175 versus 133 minutes). CONCLUSIONS: The sensitivity of EMS to detect stroke patients in our series is 77%. We have identified clinical features associated with lack of sensitivity, such as vertebrobasilar territory symptoms or isolated language disorder.

TITLE: Características clínicas de los pacientes con activación de código ictus no identificados por el servicio de emergencias médicas.Objetivos. Determinar la sensibilidad de detección de ictus por parte de los servicios de emergencias médicas (SEM) y analizar las características clínicas de los pacientes con sospecha de ictus no identificados. Pacientes y métodos. Registro prospectivo de pacientes con sospecha de ictus de nuestra área (850.000 habitantes) desde 2011 hasta 2017. Se seleccionó a la población que avisó al SEM. De ésta, se compararon los pacientes con y sin activación de código ictus por parte del SEM (SEM+ frente a SEM-). Se registraron los datos demográficos, el tiempo de evolución, las características clínicas del episodio y el tratamiento de reperfusión administrado. Resultados. De un total de 5.497 pacientes con sospecha de ictus, 2.087 alertaron al SEM: 1.611 (77%) SEM+ y 476 (33%) SEM-. Los pacientes SEM- presentaron menor puntuación en la National Institute of Health Stroke Scale (8 frente a 11) y mayor frecuencia de clínica de territorio vertebrobasilar (14,1% frente a 8,7%) y de clínica hemisférica parcial (23,5% frente a 18,4%), especialmente del hemisferio izquierdo (78,1% frente a 48,4%). Se administró tratamiento de reperfusión en el 29% de los SEM+ y en el 23% de los SEM-. El tiempo desde el inicio de los síntomas hasta el tratamiento fue 42 minutos más largo en el grupo de pacientes SEM- (175 frente a 133 minutos). Conclusiones. La sensibilidad del SEM para detectar pacientes con ictus en nuestra serie es del 77%. Hemos identificado características clínicas asociadas a la falta de sensibilidad, como los síntomas de territorio vertebrobasilar o el trastorno de lenguaje aislado.

Dysregulated liver lipid metabolism and innate immunity associated with hepatic steatosis in neonatal BBdp rats and NOD mice.

In a previous study we reported that prediabetic rats have a unique gene signature that was apparent even in neonates. Several of the changes we observed, including enhanced expression of pro-inflammatory genes and dysregulated UPR and metabolism genes were first observed in the liver followed by the pancreas. In the present study we investigated further early changes in hepatic innate immunity and metabolism in two models of type 1 diabetes (T1D), the BBdp rat and NOD mouse. There was a striking increase in lipid deposits in liver, particularly in neonatal BBdp rats, with a less striking but significant increase in neonatal NOD mice in association with dysregulated expression of lipid metabolism genes. This was associated with a decreased number of extramedullary hematopoietic clusters as well as CD68+ macrophages in the liver of both models. In addition, PPARÉ£ and phosphorylated AMPKα protein were decreased in neonatal BBdp rats. BBdp rats displayed decreased expression of antimicrobial genes in neonates and decreased M2 genes at 30 days. This suggests hepatic steatosis could be a common early feature in development of T1D that impacts metabolic homeostasis and tolerogenic phenotype in the prediabetic liver.

Ultrasound features of retroareolar breast carcinoma.

PURPOSE: The goal of this study was to report the ultrasound features of retroareolar breast carcinoma (RABC). MATERIALS AND METHODS: The ultrasound examinations of the breast of 53 women with RABC were reviewed. They had a mean age of 67.2 years±13.4 (standard deviation [SD]) (range: 46-85 years). RABC were defined as carcinomas located less than 2cm from the nipple on mammogram. RESULTS: Among the 53 RABC, 42 (42/53; 79%) were invasive ductal carcinomas, 6 (6/53; 11%) were invasive lobular carcinomas, 4 (4/53; 8%) were ductal carcinomas in situ and 1 (1/53; 2%) was intracystic papillary carcinoma. The mean size of RABCs was 22.5mm±8.2 (SD) (range: 7.2-54.8mm). RABCs presented as a mass (53/53; 100%) with an irregular shape (44/53; 83%), a non-parallel orientation (37/53; 70%), non-circumscribed margins (50/53; 94%), a hypoechoic echotexture (46/53; 87%,) posterior attenuation (45/53; 85%) and increased vascularity (37/53; 70%) on Doppler ultrasound. CONCLUSION: On ultrasound, RABC have a presentation similar to that of breast carcinoma in other locations.

Effect of acute and chronic autophagy deficiency on skeletal muscle apoptotic signaling, morphology, and function.

Autophagy is a catabolic process that targets and degrades cytoplasmic materials. In skeletal muscle, autophagy is required for the control of mass under catabolic conditions, but is also basally active in the maintenance of myofiber homeostasis. In this study, we found that some specific autophagic markers (LC3-I, LC3-II, SQSTM1) were basally lower in glycolytic muscle compared to oxidative muscle of autophagy competent mice. In contrast, basal autophagic flux was higher in glycolytic muscle. In addition, we used several skeletal muscle-specific Atg7 transgenic mouse models to investigate the effect of acute (iAtg7-/-) and chronic (cAtg7-/-) autophagy deficiency on skeletal muscle morphology, contractility, and apoptotic signaling. While acute autophagy ablation (iAtg7-/-) resulted in increased centralized nuclei in glycolytic muscle, it did not alter contractile properties or measures of apoptosis and proteolysis. In contrast, with chronic autophagy deficiency (cAtg7-/-) there was an increased proportion of centralized nuclei, as well as reduced force and altered twitch kinetics in glycolytic muscle. Glycolytic muscle of cAtg7-/- mice also displayed an increased level of the pro-apoptotic protein BAX, as well as calpain and proteasomal enzymatic activity. Collectively, our data demonstrate cumulative damage from chronic skeletal muscle-specific autophagy deficiency with associated apoptotic and proteasomal upregulation. These findings point towards the importance of investigating different muscle/fiber types when studying skeletal muscle autophagy, and the critical role of autophagy in the maintenance of myofiber function, integrity, and cellular health.

Neuromuscular blocking effects of cisatracurium and its antagonism with neostigmine in a canine model of autosomal-recessive centronuclear myopathy.

BACKGROUND: Centronuclear myopathy (CNM) is a rare congenital condition associated with skeletal muscle weakness. Patients with CNM may have decreased acetylcholine receptor expression and a reduced number of releasable quanta. Such perturbations could affect the time-course of neuromuscular blocking agents (NMBAs) and their antagonism with cholinesterase inhibitors. As a result of the rarity of CNM, prospective data regarding NMBA use in this subpopulation is scarce. We evaluated the neuromuscular blocking effects of cisatracurium and its antagonism with neostigmine in a canine model of CNM. METHODS: Six dogs with congenital autosomal-recessive CNM and six controls received cisatracurium 0.15 mg kg(-1) i.v. under general anaesthesia and intermittent positive pressure ventilation. Neuromuscular function was monitored with acceleromyography.When the second response (T2) to train-of-four (TOF) stimulation returned, neostigmine 0.04 mg kg(-1) (with glycopyrrolate) were administered i.v. The onset time, time to spontaneous return of T2, and the time to reach a TOF ratio ≥0.9 after neostigmine administration were recorded. RESULTS: Onset time was no different between groups. Median (interquartile range) time to return of T2 was 27 (24-31) min for control dogs and 26 (22-31) min for CNM dogs (P=0.93).After neostigmine administration, a TOF ratio ≥0.9 was reached in 12 (10-15) min and 17 (16-19) min in control and CNM, respectively (P=0.005). CONCLUSIONS: The spontaneous return of T2 was not different between groups. However, neostigmine-facilitated recovery was significantly slower in dogs with CNM. Canine autosomal-recessive CNM does not preclude the use of cisatracurium or its antagonism with neostigmine.

Investigating a race model account of executive control in rats with the countermanding paradigm.

The countermanding paradigm investigates the ability to withhold a response when a stop signal is presented occasionally. The race model (Logan and Cowan, 1984) was developed to account for performance in humans and to estimate the stop signal response time (SSRT). This model has yet to be fully validated for countermanding performance in rats. Furthermore, response adjustments observed in human performance of the task have not been examined in rodents. Male Wistar rats were trained to respond to a visual stimulus (go signal) by pressing a lever below that stimulus, but to countermand the lever press (25% of trials) subsequent to an auditory tone (stop signal) presented after a variable delay. We found decreased inhibitory success as stop signal delay (SSD) increased and estimated a SSRT of 157ms. As expected by the race model, response time (RT) of movements that escaped inhibition: (1) were faster than responses made in the absence of a stop signal; (2) lengthened with increasing SSD; and (3) were predictable by the race model. In addition, responses were slower after stop trial errors, suggestive of error monitoring. Amphetamine (AMPH) (0.25, 0.5mg/kg) resulted in faster go trial RTs, baseline-dependent changes in SSRT and attenuated response adjustments. These findings demonstrate that the race model of countermanding performance, applied successfully in human and nonhuman primate models, can be employed in the countermanding performance of rodents. This is the first study to reveal response adjustments and AMPH-induced alterations of response adjustments in rodent countermanding.

Controlled movement processing: evidence for a common inhibitory control of finger, wrist, and arm movements.

We used the behavioral task and theoretical construct of the countermanding paradigm to test whether there is any difference between the inhibitory control of the finger, wrist, and arm. Participants were instructed (primary task) to respond to a directional go signal presented at the fovea by pressing a button with either their index or middle fingers, moving a joystick with their wrists, or reaching to a stimulus on a touch screen with their arms. They were also instructed (secondary task) to withhold their responses when a stop signal was presented on 25% of trials. The participants' ability to inhibit each of the commanded movements was captured by their inhibition probability function, which describes how withholding is increasingly difficult as the delay between the go and stop signals increased. By modeling each participant's inhibition function, we estimated that the time needed to inhibit a commanded movement was about 240 ms, a variable that did not differ significantly between the three limb segments. Moreover, we found that the best-fit model of each segment's inhibition function could fit equally well the inhibition functions obtained with the other two segments. These results provide evidence that the upper limb segments share a common inhibitory control, which may facilitate the regulation of neuronal activity within the distributed motor cortical representations and thus simplify the voluntary control of multi-segmental movements.

Audiovisual integration of speech in a bistable illusion.

Visible speech enhances the intelligibility of auditory speech when listening conditions are poor [1], and can modify the perception of otherwise perfectly audible utterances [2]. This audiovisual perception is our most natural form of communication and one of our most common multisensory phenomena. However, where and in what form the visual and auditory representations interact is still not completely understood. Although there are longstanding proposals that multisensory integration occurs relatively late in the speech-processing sequence [3], considerable neurophysiological evidence suggests that audiovisual interactions can occur in the brain stem and primary sensory cortices [4, 5]. A difficulty testing such hypotheses is that when the degree of integration is manipulated experimentally, the visual and/or auditory stimulus conditions are drastically modified [6, 7]; thus, the perceptual processing within a modality and the corresponding processing loads are affected [8]. Here, we used a bistable speech stimulus to examine the conditions under which there is a visual influence on auditory perception in speech. The results indicate that visual influences on auditory speech processing, at least for the McGurk illusion, necessitate the conscious perception of the visual speech gestures, thus supporting the hypothesis that multisensory speech integration is not completed in early processing stages.

Effect of age on the conformity rate to short-acting beta-agonist use criteria in asthma.

STUDY OBJECTIVES: Assess compliance to asthma guidelines and influence of age concerning inhaled short-acting beta2-agonist (SABA) utilization in 5 to 45-year-old asthmatic subjects in the province of Quebec. DESIGN: Population-based retrospective drug utilization review using a computerized database of claims submitted to a private prescription drug insurance plan. PATIENTS: Subjects who received at least one outpatient prescription of SABA (age range, 5 to 45 years) for the treatment of asthma between January 1996 and December 1997. MEASUREMENTS: Percentages of patients whose use was appropriate according to the criteria regarding the average daily dose of SABA. Use was considered appropriate if the consumption rate corresponded to a maximum of two puffs per day (Salbutamol equivalent) in subjects who did or did not use inhaled corticosteroids (ICS) at an estimated maximum dose of 800 mcg/day of Beclomethasone (BDP) equivalent for the 5 to 11-year-olds and 1000 mcg/day for the 12 to 45-year-olds. RESULTS: In 1996, use was found to be appropriate for 74.4% of the 394 patients who received an SABA without ICS as compared with 70.7% for 593 patients in 1997. If we consider those who received an ICS at low to moderate doses, appropriate use was found for 51% of the 375 patients in 1996 and 57.6% for 254 patients in 1997. If we exclude patients who did not renew their SABA, appropriate use drops to 46.3% for 1996 and 34.3% for 1997 for the group who receive SABA without ICS (29.4% and 37.6%, respectively, for those with ICS). There is a relationship between age and appropriateness; the percentage of appropriateness was higher for the younger ones (5 to 14-year-old group; 83% in 1996 and 86% in 1997 for the patients who received a SABA without IS and 58.5% in 1996 and 73% in 1997 for the patients who received a SABA using ICS (p < 0.05). CONCLUSION: Our results indicate that adherence to asthma guidelines concerning SABA is poor. SABA are still overused, particularly among ICS users, which might be explained by undertreatment or poor compliance. Appropriate SABA use was significantly more common among younger groups (p < 0.05). This can be explained by better treatment in that age group, better compliance or less severe asthma.

Signal transformations from cerebral cortex to superior colliculus for the generation of saccades.

The ability of primates to make rapid and accurate saccadic eye movements for exploring the natural world is based on a neuronal system in the brain that has been studied extensively and is known to include multiple brain regions extending throughout the neuraxis. We examined the characteristics of signal flow in this system by recording from identified output neurons of two cortical regions, the lateral intraparietal area (LIP) and the frontal eye field (FEF), and from neurons in a brainstem structure targeted by these output neurons, the superior colliculus (SC). We compared the activity of neurons in these three populations while monkeys performed a delayed saccade task that allowed us to quantify visual responses, motor activity, and intervening delay activity. We examined whether delay activity was related to visual stimulation by comparing the activity during interleaved trials when a target was either present or absent during the delay period. We examined whether delay activity was related to movement by using a Go/Nogo task and comparing the activity during interleaved trials in which a saccade was either made (Go) or not (Nogo). We found that LIP output neurons, FEF output neurons, and SC neurons can all have visual responses, delay activity, and presaccadic bursts; hence in this way they are all quite similar. However, the delay activity tended to be more related to visual stimulation in the cortical output neurons than in the SC neurons. Complementing this, the delay activity tended to be more related to movement in the SC neurons than in the cortical output neurons. We conclude, first, that the signal flow leaving the cortex represents activity at nearly every stage of visuomotor transformation, and second, that there is a gradual evolution of signal processing as one proceeds from cortex to colliculus.

The Meissner corpuscle revised: a multiafferented mechanoreceptor with nociceptor immunochemical properties.

Meissner corpuscles (MCs) in the glabrous skin of monkey digits have at least three types of innervation as revealed by immunofluorescence. The previously well known Aalphabeta-fiber terminals are closely intertwined with endings from peptidergic C-fibers. These intertwined endings are segregated into zones that alternate with zones containing a third type of ending supplied by nonpeptidergic C-fibers. Although MCs are widely regarded as low-threshold mechanoreceptors, all three types of innervation express immunochemical properties associated with nociception. The peptidergic C-fiber endings have readily detectable levels of immunoreactivity (IR) for calcitonin gene-related peptide (CGRP) and substance P (SP). The Aalphabeta endings have relatively lower levels of IR for CGRP and SP as well as the SP neurokinin 1 receptor and vanilloid-like receptor 1. Both the Aalphabeta and peptidergic C-fiber endings were also labeled with antibodies for different combinations of adrenergic, opioid, and purinergic receptors. The nonpeptidergic C-fiber endings express IR for vanilloid receptor 1, which has also been implicated in nociception. Thus, MCs are multiafferented receptor organs that may have nociceptive capabilities in addition to being low-threshold mechanoreceptors.

Activity in ventral and dorsal premotor cortex in response to predictable force-pulse perturbations in a precision grip task.

This study compared the responses of ventral and dorsal premotor cortex (PMv and PMd) neurons to predictable force-pulse perturbations applied during a precision grip. Three monkeys were trained to grasp an unseen instrumented object between the thumb and index finger and to lift and hold it stationary within a position window for 2-2.5 s. The grip and load forces and the object displacement were measured on each trial. Single-unit activity was recorded from the hand regions in the PMv and PMd. In some conditions a predictable perturbation was applied to the object after 1,500 ms of static holding, whereas in other conditions different random combinations of perturbed and unperturbed trials were given. In the perturbed conditions, some were randomly and intermittently presented with a warning flash, whereas some were unsignaled. The activities of 198 cells were modulated during the task performance. Of these cells, 151 were located in the PMv, and 47 were located in the PMd. Although both PMv and PMd neurons had similar discharge patterns, more PMd neurons (84 vs. 43%) showed early pregrip activity. Forty of 106 PMv and 10/30 PMd cells responded to the perturbation with reflexlike triggered reactions. The latency of this response was always <100 ms with a mean of about 55 ms in both the PMv and the PMd. In contrast, 106 PMv and 30 PMd cells tested with the perturbations, only 9 and 10%, respectively, showed significant but nonspecific adaptations to the perturbation. The warning stimulus did not increase the occurrence of specific responses to the perturbation even though 21 of 42 cells related to the grip task also responded to moving visual stimuli. The responses were retinal and frequently involved limited portions of both foveal and peripheral visual fields. When tested with a 75 x 5.5-cm dark bar on a light background, these cells were sensitive to the direction of movement. In summary, the periarcuate premotor area activity to related to predictable force-pulse perturbations seems to reflect a general increase in excitability in contrast to a more specific anticipatory activity such as recorded in the cerebellum. In spite of the strong cerebello-thalamo-cortical projections, the results of the present study suggest that the cortical premotor areas are not involved in the elaboration of adaptive internal models of hand-object dynamics.

Progression in neuronal processing for saccadic eye movements from parietal cortex area lip to superior colliculus.

Neurons in both the lateral intraparietal area (LIP) of the monkey parietal cortex and the intermediate layers of the superior colliculus (SC) are activated well in advance of the initiation of saccadic eye movements. To determine whether there is a progression in the covert processing for saccades from area LIP to SC, we systematically compared the discharge properties of LIP output neurons identified by antidromic activation with those of SC neurons collected from the same monkeys. First, we compared activity patterns during a delayed saccade task and found that LIP and SC neurons showed an extensive overlap in their responses to visual stimuli and in their sustained activity during the delay period. The saccade activity of LIP neurons was, however, remarkably weaker than that of SC neurons and never occurred without any preceding delay activity. Second, we assessed the dependence of LIP and SC activity on the presence of a visual stimulus by contrasting their activity in delayed saccade trials in which the presentation of the visual stimulus was either sustained (visual trials) or brief (memory trials). Both the delay and the presaccadic activity levels of the LIP neuronal sample significantly depended on the sustained presence of the visual stimulus, whereas those of the SC neuronal sample did not. Third, we examined how the LIP and SC delay activity relates to the future production of a saccade using a delayed GO/NOGO saccade task, in which a change in color of the fixation stimulus instructed the monkey either to make a saccade to a peripheral visual stimulus or to withhold its response and maintain fixation. The average delay activity of both LIP and SC neuronal samples significantly increased by the advance instruction to make a saccade, but LIP neurons were significantly less dependent on the response instruction than SC neurons, and only a minority of LIP neurons was significantly modulated. Thus despite some overlap in their discharge properties, the neurons in the SC intermediate layers showed a greater independence from sustained visual stimulation and a tighter relationship to the production of an impending saccade than the LIP neurons supplying inputs to the SC. Rather than representing the transmission of one processing stage in parietal cortex area LIP to a subsequent processing stage in SC, the differences in neuronal activity that we observed suggest instead a progressive evolution in the neuronal processing for saccades.

Expression of a re-centering bias in saccade regulation by superior colliculus neurons.

In previous studies of saccadic eye movement reaction time, the manipulation of initial eye position revealed a behavioral bias that facilitates the initiation of movements towards the central orbital position. An interesting hypothesis for this re-centering bias suggests that it reflects a visuo-motor optimizing strategy, rather than peripheral muscular constraints. Given that the range of positions that the eyes can take in the orbits delimits the extent of visual exploration by head-fixed subjects, keeping the eyes centered in the orbits may indeed permit flexible orienting responses to engaging stimuli. To investigate the influence of initial eye position on central processes such as saccade selection and initiation, we examined the activity of saccade-related neurons in the primate superior colliculus (SC). Using a simple reaction time paradigm wherein an initially fixated visual stimulus varying in position was extinguished 200 ms before the presentation of a saccadic target, we studied the relationship between initial eye position and neuronal activation in advance of saccade initiation. We found that the magnitude of the early activity of SC neurons, especially during the immediate pre-target period that followed the fixation stimulus disappearance, was correlated with changes in initial eye position. For the great majority of neurons, the pre-target activity increased with changes in initial eye position in the direction opposite to their movement fields, and it was also strongly correlated with the concomitant reduction in reaction time of centripetal saccades directed within their movement fields. Taking into account the correlation with saccadic reaction time, the relationship between neuronal activity and initial eye position remained significant. These results suggest that eye-position-dependent changes in the excitability of SC neurons could represent the neural substrate underlying a re-centering bias in saccade regulation. More generally, the low frequency SC pre-target activity could use eccentric eye position signals to regulate both when and which saccades are produced by promoting the emergence of a high frequency burst of activity that can act as a saccadic command. However, only saccades initiated within approximately 200 ms of target presentation were associated with SC pre-target activity. This eye-dependent pre-target activation mechanism therefore appears to be restricted to the initiation of saccades with relatively short reaction times, which specifically require the integrity of the SC.