Effects of cannabidiol in post-stroke mood disorders in neonatal rats.

BACKGROUND: Neonatal rats can manifest post-stroke mood disorders (PSMD) following middle cerebral artery occlusion (MCAO). We investigated whether cannabidiol (CBD) neuroprotection, previously demonstrated in neonatal rats after MCAO, includes prevention of PSMD development. METHODS: Seven-day-old Wistar rats (P7) underwent MCAO and received either vehicle or 5 mg/kg CBD treatment. Brain damage was quantified by MRI, and neurobehavioral and histological (TUNEL) studies were performed at P14 and P37. PSMD were assessed using the tail suspension test, forced swimming test, and open field tests. The dopaminergic system was evaluated by quantifying dopaminergic neurons (TH+) in the Ventral Tegmental Area (VTA), measuring brain dopamine (DA) concentration and DA transporter expression, and assessing the expression and function D2 receptors (D2R) through [35S]GTPγS binding. Animals without MCAO served as controls. RESULTS: CBD reduced MCAO-induced brain damage and improved motor performance. At P14, MCAO induced depressive-like behavior, characterized by reduced TH+ cell population and DA levels, which CBD did not prevent. However, CBD ameliorated hyperactivity observed at P37, preventing increased DA concentration by restoring D2R function. CONCLUSIONS: These findings confirm the development of PSMD following MCAO in neonatal rats and highlight CBD as a neuroprotective agent capable of long-term functional normalization of the dopaminergic system post-MCAO. IMPACT: MCAO in neonatal rats led to post-stroke mood disorders consisting in a depression-like picture in the medium term evolving towards long-term hyperactivity, associated with an alteration of the dopaminergic system. The administration of CBD after MCAO did not prevent the development of depressive-like behavior, but reduced long-term hyperactivity, normalizing dopamine receptor function. These data point to the importance of considering the development of depression-like symptoms after neonatal stroke, a well-known complication after stroke in adults. Our work confirms the interest of CBD as a possible treatment for neonatal stroke.

The Role of the Dopamine System in Post-Stroke Mood Disorders in Newborn Rats.

Post-stroke mood disorders (PSMD) affect disease prognosis in adults. Adult rodent models underlie the importance of the dopamine (DA) system in PSMD pathophysiology. There are no studies on PSMD after neonatal stroke. We induced neonatal stroke in 7-day-old (P7) rats by temporal left middle cerebral artery occlusion (MCAO). Performance in the tail suspension test (TST) at P14 and the forced swimming test (FST) and open field test (OFT) at P37 were studied to assess PSMD. DA neuron density in the ventral tegmental area, brain DA concentration and DA transporter (DAT) expression as well as D2 receptor (D2R) expression and G-protein functional coupling were also studied. MCAO animals revealed depressive-like symptoms at P14 associated with decreased DA concentration and reduced DA neuron population and DAT expression. At P37, MCAO rats showed hyperactive behavior associated with increased DA concentration, normalization of DA neuron density and decreased DAT expression. MCAO did not modify D2R expression but reduced D2R functionality at P37. MCAO-induced depressive-like symptoms were reversed by the DA reuptake inhibitor GBR-12909. In conclusion, MCAO in newborn rats induced depressive-like symptoms and hyperactive behavior in the medium and long term, respectively, that were associated with alterations in the DA system.

Monitoring tert-Butylhydroquinone Content and Its Effect on a Biolubricant during Oxidation.

The use of biolubricants as a replacement for petroleum-based products is becoming more and more important, due to the current global energy and crude oil scenario. Thus, the production of biolubricants (which could take place in biorefineries) should be as efficient as possible, obtaining high-quality products with suitable viscosity or oxidation stability values to compete with oil refineries. One of the ways to produce biolubricants is through double transesterification from vegetable oils, where the role of catalysts (usually homogeneous) is vital, as they can improve the yield of the process. However, they should be removed after the chemical reaction, which is difficult once the biolubricant is obtained. Otherwise, they could act as catalysts during oxidation, contributing to a further decrease in oxidation stability and provoking significant changes. To avoid this, antioxidant addition could be an interesting choice. The aim of this work was to assess TBHQ addition in frying oil biolubricants, monitoring properties such as viscosity, acid number, absorbance or TBHQ content (through voltammetry) during oxidation. TBHQ addition (2114 mg·L-1) kept the main quality parameters during oxidation compared to control samples. In contrast, TBHQ content decreased during oxidation (to 160 mg·L-1), which proved its antioxidant effect.

Formation of In Vitro Mixed-Species Biofilms by Lactobacillus pentosus and Yeasts Isolated from Spanish-Style Green Table Olive Fermentations.

The present work details the in vitro interactions between Lactobacillus pentosus and yeast strains isolated from table olive processing to form mixed biofilms. Among the different pairs assayed, the strongest biofilms were obtained from L. pentosus and Candida boidinii strain cocultures. However, biofilm formation was inhibited in the presence of d-(+)-mannose. In addition, biofilm formation by C. boidinii monoculture was stimulated in the absence of cell-cell contact with L. pentosus. Scanning electron microscopy revealed that a sort of "sticky" material formed by the yeasts contributed to substrate adherence. Hence, the data obtained in this work suggest that yeast-lactobacilli biofilms may be favored by the presence of a specific mate of yeast and L. pentosus, and that more than one mechanism might be implicated in the biofilm formation. This knowledge will help in the design of appropriate mixed starter cultures of L. pentosus-yeast species pairs that are able to improve the quality and safety of Spanish-style green table olive processing.

Neuroprotective effects of VCE-004.8 in a rat model of neonatal stroke.

BACKGROUND: Currently there is no effective treatment for neonatal stroke, an acute neurologic syndrome with sequelae, due to focal ischemic, thrombotic, or hemorrhagic event occurring in the perinatal period. VCE-004.8, an aminoquinone exhibiting activity on CB2 and PPARγ receptors, is neuroprotective in adult mice models of acute and chronic brain damaging conditions. We hereby aimed to study VCE-004.8 neuroprotection in a rat model of neonatal stroke. METHODS: 7-day-old (P7) Wistar rats of both sexes were submitted to Middle Cerebral Artery Occlusion (MCAO), receiving i.p. 30 min after vehicle (MCAO + VEH) or VCE-004.8 5 mg/kg (MCAO + VCE). Non-occluded rats served as controls (SHAM). MCAO consequences were assessed at P14 by MRI, histological (TUNEL staining), biochemical (lactate/n-acetyl aspartate ratio by 1H-NMR spectroscopy) and motor studies (grasp test), and at P37 assessing myelination (MBP signal), hemiparesis and hyperlocomotion. Effects of VCE-004.8 on excitotoxicity (glutamate/n-acetyl aspartate, 1H-NMR), oxidative stress (protein nitrosylation, Oxyblot) and neuroinflammation (Toll-like receptor 4 and TNFa expression, Western blot) were assessed at P14. Therapeutic window was assessed by delaying drug administration for 12 or 18 h. RESULTS: Post-MCAO administration of VCE-004.8 reduced the volume of infarct and histological and biochemical brain damage, reducing hyperlocomotion, restoring motor performance and preserving myelination, in a manner linked to the modulation of excitotoxicity, oxidative stress and neuroinflammation. VCE-004.8 was still effective being administered 12-18 h post-insult. CONCLUSIONS: These data suggest that this drug could be effective for the treatment of stroke in newborns.

Cannabidiol reduces intraventricular hemorrhage brain damage, preserving myelination and preventing blood brain barrier dysfunction in immature rats.

Intraventricular hemorrhage (IVH) is an important cause of long-term disability in extremely preterm infants, with no current treatment. This study assessed the potential neuroprotective effects of cannabidiol (CBD) in an IVH model using immature rats. IVH was induced in 1-day-old (P1) Wistar rats by left periventricular injection of Clostridial collagenase. Some rats received CBD prenatally (10 â€‹mg/kg i.p. to the dam) and then 5 â€‹mg/kg i.p. 6, 30 and 54 â€‹h after IVH (IVH+CBD, n â€‹= â€‹30). Other IVH rats received vehicle (IVH+VEH, n â€‹= â€‹34) and vehicle-treated non-IVH rats served as controls (SHM, n â€‹= â€‹29). Rats were humanely killed at P6, P14 or P45. Brain damage (motor and memory performance, area of damage, Lactate/N-acetylaspartate ratio), white matter injury (ipsilateral hemisphere and corpus callosum volume, oligodendroglial cell density and myelin basic protein signal), blood-brain barrier (BBB) integrity (Mfsd2a, occludin and MMP9 expression, gadolinium leakage), inflammation (TLR4, NFκB and TNFα expression, infiltration of pro-inflammatory cells), excitotoxicity (Glutamate/N-acetylspartate ratio) and oxidative stress (protein nitrosylation) were then evaluated. CBD prevented the long-lasting motor and cognitive consequences of IVH, reduced brain damage in the short- and long-term, protected oligodendroglial cells preserving adequate myelination and maintained BBB integrity. The protective effects of CBD were associated with the modulation of inflammation, excitotoxicity and oxidative stress. In conclusion, in immature rats, CBD reduced IVH-induced brain damage and its short- and long-term consequences, showing robust and pleiotropic neuroprotective effects. CBD is a potential candidate to ameliorate IVH-induced immature brain damage.

Protein Carbonylation as a Biomarker of Oxidative Stress and a Therapeutic Target in Neonatal Brain Damage.

Oxidative stress (OS) constitutes a pivotal factor within the mechanisms underlying brain damage, for which the immature brain is particularly vulnerable. This vulnerability is caused by the abundance of immature oligodendrocytes in the immature brain, which are highly susceptible to OS-induced harm. Consequently, any injurious process involving OS within the immature brain can lead to long-term myelination impairment. Among the detrimental repercussions of OS, protein carbonylation stands out as a prominently deleterious consequence. Noteworthy elevation of protein carbonylation is observable across diverse models of neonatal brain injury, following both diffuse and focal hypoxic-ischemic insults, as well as intraventricular hemorrhage, in diverse animal species encompassing rodents and larger mammals, and at varying stages of brain development. In the immature brain, protein carbonylation manifests as a byproduct of reactive nitrogen species, bearing profound implications for cell injury, particularly in terms of inflammation amplification. Moreover, protein carbonylation appears as a therapeutic target for mitigating neonatal brain damage. The administration of a potent antioxidant, such as cannabidiol, yields substantial neuroprotective effects. These encompass the reduction in cerebral damage, restoration of neurobehavioral performance, and preservation of physiological myelination. Such effects are linked to the modulation of protein carbonylation. The assessment of protein carbonylation emerges as a reliable method for comprehending the intricate mechanisms underpinning damage and neuroprotection within neonatal brain injury.

Role of 5HT1A Receptors in the Neuroprotective and Behavioral Effects of Cannabidiol in Hypoxic-Ischemic Newborn Piglets.

Background: Hypoxic-ischemic (HI) insults have important deleterious consequences in newborns, including short-term morbidity with neuromotor and cognitive disturbances. Cannabidiol (CBD) has demonstrated robust neuroprotective effects and shows anxiolytic/antidepressant effects as well. These effects are thought to be related to serotonin 5-HT1A receptor (5HT1AR) activation. We hereby aimed to study the role of 5HT1AR in the neuroprotective and behavioral effects of CBD in HI newborn piglets. Methods: 1-day-old piglets submitted to 30 min of hypoxia (FiO2 10%) and bilateral carotid occlusion were then treated daily with vehicle, CBD 1 mg/kg, or CBD with the 5HT1AR antagonist WAY 100635 1 mg/kg 72 h post-HI piglets were studied using amplitude-integrated EEG to detect seizures and a neurobehavioral test to detect neuromotor impairments. In addition, behavioral performance including social interaction, playful activity, hyperlocomotion, and motionless periods was assessed. Then, brain damage was assessed using histology (Nissl and TUNEL staining) and biochemistry (proton magnetic resonance spectroscopy studies. Results: HI led to brain damage as assessed by histologic and biochemistry studies, associated with neuromotor impairment and increased seizures. These effects were not observed in HI piglets treated with CBD. These beneficial effects of CBD were not reversed by the 5HT1AR antagonist, which is in contrast with previous studies demonstrating that 5HT1AR antagonists eliminated CBD neuroprotection as assessed 6 h after HI in piglets. HI led to mood disturbances, with decreased social interaction and playfulness and increased hyperlocomotion. Mood disturbances were not observed in piglets treated with CBD, but in this case, coadministration of the 5HT1AR antagonist eliminates the beneficial effects of CBD. Conclusion: CBD prevented HI-induced mood disturbances in newborn piglets by acting on 5HT1AR. However, 5HT1AR activation seems to be necessary for CBD neuroprotection only in the first hours after HI.

PULSE-HF: A Simple Clinical and Geriatric Score to Predict Systolic Dysfunction in the Elderly Without Heart Failure.

To develop a clinical score to determine preclinical predictors of systolic dysfunction in an outpatient elderly population without a diagnosis of heart failure (HF). PULSE-HF is a cross-sectional study in elderly at-risk (coronary artery disease, diabetes or hypertension) outpatients without a diagnosis of heart failure (HF). The objective in this population was to develop a clinical score to determine preclinical predictors of systolic dysfunction. Clinical and geriatric variables were analyzed; independent predictive factors in the logistic regression analysis were included for the score calculation. Of the 722 subjects enrolled, 47 (6.5%) had a left ventricular ejection fraction (LVEF) < 50%, and 15 (2.1%) a LVEF < 40%. Mean age was 76.5 years (5.18) and 445 (61.6%) were female. Multiple logistic regression analysis identified abnormal Q waves (odds ratio [OR]: 4.36; P = 0.003), cardiomegaly (OR: 3.32; P < 0.001), right bundle branch block (OR: 2.84; P = 0.011), cognitive dysfunction (OR: 2.14; P = 0.027) and NT-proBNP (OR 5.43; P < 0.001) as independent predictors of LVEF < 50%. Two prediction scores were built, without and with NT-proBNP inclusion; the area under ROC curves were 0.70 and 0.76, respectively. As the score increased, the sensitivity decreases but increases specificity, and accuracy (97.17% and 91.64% respectively in ≥6 points). NT-proBNP was associated with an increment in the performance (accuracy of 93.18% for score ≥10). We conclude that a simple score using clinical information might be useful to predicting asymptomatic systolic dysfunction in the elderly.

Neuroprotective Effects of Betulinic Acid Hydroxamate in Intraventricular Hemorrhage-Induced Brain Damage in Immature Rats.

Intraventricular hemorrhage (IVH) is an important cause of long-term disability in extremely preterm infants, with no current treatment. We aimed to study in an IVH model in immature rats the neuroprotective effect of betulinic acid hydroxamate (BAH), a B55α/PP2A activator that inhibits the activity of the hypoxia-inducing factor prolyl-hydroxylase type 2. IVH was induced in 1-day-old (P1) Wistar rats by the left periventricular injection of Clostridial collagenase. Then, pups received i.p. vehicle or BAH 3 mg/kg single dose. At P6, P14 and P45, brain damage (area of damage, neurobehavioral deficits, Lactate/N-acetylaspartate ratio), white matter injury (WMI: corpus callosum atrophy and myelin basic protein signal reduction) and inflammation (TLR4, NF-κB and TNFα expression), excitotoxicity (Glutamate/N-acetylspartate) and oxidative stress (protein nitrosylation) were evaluated. BAH treatment did not reduce the volume of brain damage, but it did reduce perilesional tissue damage, preventing an IVH-induced increase in Lac/NAA. BAH restored neurobehavioral performance at P45 preventing WMI. BAH prevented an IVH-induced increase in inflammation, excitotoxicity and oxidative stress. In conclusion, in immature rats, BAH reduced IVH-induced brain damage and prevented its long-term functional consequences, preserving normal myelination in a manner related to the modulation of inflammation, excitotoxicity and oxidative stress.

Brain electrophysiological responses associated with the retrieval of temporal and spatial contexts in episodic memory.

Episodic memory allows us to remember three main elements regarding an event: what (it is), where (it is in space), and when (it appears). The brain's electrical activity signaling the occurrence of these processes has been studied separately, revealing different patterns of ERP components and changes in the EEG theta band amplitude. However, how these patterns signal the retrieval of the temporal and spatial contexts of the same episode is unknown. The objective of this study was to evaluate the ERP components and the EEG theta band in association to the retrieval of the what, where, and when of the same episode through a source memory task. Three types of trials were identified here: total retrieval (what, where, and when), spatial retrieval (what and where), and correct rejections (correctly identified as new items). Attentional components, N200 and P300, and theta band were sensitive to the amount of information retrieved from episodic memory. Total retrieval and spatial trials elicited higher mean amplitude of FN400 and LPC, familiarity and recollection markers, respectively, than correct rejections. Our results suggest that early attention mechanisms can discern the strength of retrieval; in turn, familiarity and recollection mechanisms participate in the retrieval of the main contexts of episodic memory, but not in a cumulative way.

Physiological Assessment of Water Stress in Potato Using Spectral Information.

Water stress in potato (Solanum tuberosum L.) causes considerable losses in yield, and therefore, potato is often considered to be a drought sensitive crop. Identification of water deficit tolerant potato genotypes is an adaptation strategy to mitigate the climatic changes that are occurring in the Cundiboyacense region in Colombia. Previous studies have evaluated potato plants under water stress conditions using physiological analyses. However, these methodologies require considerable amounts of time and plant material to perform these measurements. This study evaluated and compared the physiological and spectral traits between two genotypes, Diacol Capiro and Perla Negra under two drought levels (10 and 15 days without irrigation from flowering). Reflectance information was used to calculate indexes which were associated with the physiological behavior in plants. The results showed that spectral information was correlated (ρ < 0.0001) with physiological variables such as foliar area (FA), total water content (H2Ot), relative growth rate of potato tubers (RGTtub), leaf area ratio (LAR), and foliar area index (AFI). In general, there was a higher concentration of chlorophyll under drought treatments. In addition, Perla Negra under water deficit treatments did not show significant differences in its physiological variables. Therefore, it could be considered a drought tolerant genotype because its physiological performance was not affected under water stress conditions. However, yield was affected in both genotypes after being subject to 15 days of drought. The results suggested that reflectance indexes are a useful and affordable approach for potato phenotyping to select parent and segregant populations in breeding programs.

Effects of troglitazone on intracellular cholesterol distribution and cholesterol-dependent cell functions in MA-10 Leydig tumor cells.

Troglitazone treatment of MA-10 Leydig tumor cells resulted in cellular cholesteryl esters decreasing and cell free cholesterol increasing. This was not an effect unique to this chemical entity; rosiglitazone and pioglitazone caused these changes also. The excess free cholesterol was recovered largely in the cholesterol oxidase susceptible, plasma membrane cholesterol pool. This effect of troglitazone probably is not mediated by activation of peroxisome proliferator activated receptors since it immediately reversed with washing and did not occur at all in cells treated with the peroxisome proliferator activated receptor agonist, 15-deoxy Delta 12,14 prostaglandin J-2. Plasma membrane cholesterol esterification was inhibited by troglitazone in a dose-dependent manner. Plasma membrane cholesterol esterification was inhibited half-maximally by 14 microM troglitazone and by more than 90% by 40 microM troglitazone. This effect was not unique for MA-10 cells. Similar results were found using fibroblasts. Troglitazone was not simply inhibiting internalization of plasma membrane cholesterol. Dibutyryl-cAMP stimulation of troglitazone-treated cells resulted in more progesterone synthesis than in stimulated control cells; moreover, radioactive plasma membrane cholesterol was readily converted into progesterone in troglitazone-treated cells. Studies of LDL uptake in troglitazone-treated cells indicated that intracellular membranes were cholesterol replete. Troglitazone inhibited plasma membrane cholesterol esterification with kinetics similar to 58-035, a known inhibitor of the acyl coenzyme A: cholesterol acyltranserase (ACAT) enzyme. It is not likely an ACAT inhibitor since troglitazone did not block incorporation of exogenous free fatty acids into cholesteryl esters. Thus, it appears that troglitazone prevented presentation of free fatty acid to the ACAT enzyme.

Biofilm formation on abiotic and biotic surfaces during Spanish style green table olive fermentation.

In this work, the establishment of polymicrobial communities on the surfaces which come into contact with the brine during Spanish style Gordal cv. green olive fermentation when subjected to spontaneous or controlled processes (inoculated with Lactobacillus pentosus LPCO10 or 128/2) was studied. Scanning electron microscopy showed that L. pentosus and yeast populations were able to form mixed biofilms throughout the fermentation process on both abiotic (glass slide) and biotic (olive skin) surfaces. The biofilm architectures in both supports were completely different: on the glass slides only aggregates of L. pentosus and yeasts without any polymeric matrix surrounding them were found while on the skin of the fruits, true mature biofilms were observed. During fermentation, the lactic acid bacteria (LAB) population on the olives remained similar while that of yeasts increased progressively to reach similar levels at the end of the process (8-9 log CFU/cm(2)). Molecular analysis showed that different populations of L. pentosus and yeasts were the only microbial members of the biofilm formed during fermentation, regardless of inoculation. Hence, the green olive surface provides an appropriate environmental condition for the suitable development and formation of complex biofilms during controlled or natural table olive processing.

Sífilis maligna precoz y enfermedad de Hodgkin / Early malignant syphilis and Hodgkin's disease

Se realiza una revisión bibliográfica sobre la sífilis maligna precoz, forma clínica muy rara en nuestros días, que aparece en aquellas personas que adquieren la sífilis y padecen, además, de otras afecciones crónicas, como tuberculosis, desnutrición, alcoholismo, paludismo, adicción a drogas, etcétera. Se presenta un paciente que, con el diagnóstico previo de una enfermedad de Hodgkin, adquirió una sífilis reciente confirmada por los resultados de laboratorio y epidemiológicos y con manifestaciones clínicas que corresponden a una sífilis maligna precoz

Atrofia cutánea secundaria debido a inyección intramuscular de corticoide / Secondary cutaneous atrophy due to intramuscular injection of corticoids

Se establecen conceptos acerca de los efectos beneficiosos de los corticoides, tanto desde el punto de vista local como sistémico. Se presenta el caso de un paciente del sexo femenino de 25 años de edad con antecedentes de asma desde hace alrededor de 8 años, por lo que en varias ocasiones utilizó como tratamiento inyección intramuscular de Kanelog-40; con posterioridad a la administración del mismo notó alteraciones en la piel de la región glútea, y asiste al Servicio de Dermatología de nuestro hospital, donde se decide realizar biopsia de piel con la impresión diagnóstica de atrofia residual medicamentosa, lo cual fue corroborado con dicho estudio

Sarcoidosis: a propósito de un caso interesante / Sarcoidosis: apropos of an interesting case

La sarcoidosis es una enfermedad granulomatosa, sistémica, de origen indeterminado. Se realiza una revisión del tema, tanto del tipo transitorio o subagudo como del tipo persistente o crónico. Se ilustra con un paciente diagnosticado de sarcoidosis en el Servicio de Dermatología del Hospital Docente Clinicoquirúrgico "10 de Octubre" con manifestaciones sistémicas en ganglios, hilios pulmonares y piel. Se trata de un paciente de 49 años de edad, de la raza negra, con antecedentes de padecer drepanocitemia y asma bronquial. El diagnóstico se sospecha por la clínica de las lesiones cutáneas y se confirma con el estudio histopatológico. Como dato de interés está el hecho de que hace unos 4 años fue diagnosticado de padecer de un linfoma folicular gigante y posteriormente como una enfermedad de Hodgkin. Recibió tratamiento basado en dichos diagnósticos

Hemangioendotelioma maligno / Malignant hemangioendothelioma

Se presenta el caso de un hemangioendotelioma, valorado inicialmente como un angioma cavernoso, cuya evolución clínica agresiva y su falta de respuesta a las terapéuticas empleadas, hizo que se interpretara como un proceso maligno. La paciente posteriormente fallece, se comprueba entonces la existencia de este tumor maligno mediante el estudio necrópsico realizado

Evaluación de conocimientos y actitudes respecto a sexualidad en estudiantes de odontología y medicina de la escuela colombiana de medicina / Evaluation of knowledge and attitudes in relation to sexuality in students of ECM

Este es un estudio epidemiológico, descriptivo, evaluativo y exploratorio diseñado para evaluar los diferentes aspectos de la sexualidad humana, en estudiantes de Medicina (que tienen una cátedra de sexología dentro del pensum) y Odontología (que no la tienen) pertenecientes a los semestres I,II, IX y X de la Escuela Colombiana de Medicina. También se buscó evaluar las posibles diferencias entre ambas facultades. Con estos propósitos se diseñó y aplicó una encuesta en 417 sujetos. Los resultados obtenidos mostraron pequeñas diferencias entre todos los grupos. Estos hallazgos nos llevan a sospechar que no solo la información obtenida antes del ingreso a la universidad es deficiente sino que tambien la información brindada por esta institución no es suficiente para aclarar las dudas de los estudiantes, y por lo tanto su conocimiento sobre este tambien es deficiente