Heterogeneity of the Endocannabinoid System Between Cerebral Cortex and Spinal Cord Oligodendrocytes.

In the last years, regional differences have been reported between the brain and spinal cord oligodendrocytes, which should be considered when designing therapeutic strategies for myelin repair. Promising targets to achieve myelin restoration are the different components of the endocannabinoid system (ECS) that modulate oligodendrocyte biology, but almost all studies have been focused on brain-derived cells. Therefore, we compared the ECS between the spinal cord and cerebral cortex-derived oligodendrocyte precursor cells (OPCs) and mature oligodendrocytes (OLs). Cells from both regions express synthesizing and degrading enzymes for the endocannabinoid 2-arachidonoylglycerol, and degrading enzymes increase with maturation, more notably in the spinal cord (monoglyceride lipase-MGLL, alpha/beta hydrolase domain-containing 6-ABHD6, and alpha/beta hydrolase domain-containing 12-ABHD12). In addition, spinal cord OPCs express higher levels of the synthesizing enzymes diacylglycerol lipases alpha (DAGLA) and beta (DAGLB) than cortical ones, DAGLA reaching statistical significance. Cells from both the cortex and spinal cord express low levels of NAEs synthesizing enzymes, except for the glycerophosphodiester phosphodiesterase 1 (GDE-1) but high levels of the degrading enzyme fatty acid amidohydrolase (FAAH) that increases with maturation. Finally, cells from both regions show similar levels of CB1 receptor and GPR55, but spinal cord-derived cells show significantly higher levels of transient receptor potential cation channel V1 (TRPV1) and CB2. Overall, our results show that the majority of the ECS components could be targeted in OPCs and OLs from both the spinal cord and brain, but regional heterogeneity has to be considered for DAGLA, MGLL, ABHD6, ABHD12, GDE1, CB2, or TRPV1.

Persistencia a los inhibidores de la aromatasa en la cohorte SIDIAP: mortalidad e influencia de los bifosfonatos / Persistence to aromatase inhibitors in the SIDIAP cohort: mortality and influence of bisphosphonates

OBJETIVO: Evaluar la persistencia a la terapia con inhibidores de la aromatasa (IA), la mortalidad asociada a la discontinuidad al tratamiento y la influencia de los bifosfonatos (BF) orales, en la práctica clínica habitual. MATERIAL Y MÉTODOS: Estudio prospectivo observacional de mujeres con cáncer de mama en tratamiento con IA entre enero de 2006 y diciembre de 2015, registradas en la base de datos SIDIAP. Se excluyeron aquellas tratadas previamente con tamoxifeno. Se estudió la persistencia al tratamiento con IA con un análisis de supervivencia: se calculó el estimador de Kaplan-Meier, y se realizó un modelo de los riesgos proporcionales (regresión de Cox) entre usuarias y no usuarias de BF ajustando por edad. Se llevó a cabo un análisis de sensibilidad teniendo en cuenta la mortalidad como riesgo competitivo (modelos de Fine y Gray). Se comparó la diferencia de mortalidad entre grupos mediante una prueba Chi cuadrado. RESULTADOS: Se observó una persistencia a los IA del 87% a 5 años de tratamiento, con una mortalidad global del 19,75%. Se registró un 7,7% menos de mortalidad en aquellas pacientes que completaron los 5 años de tratamiento respecto a las que no. Las pacientes con BF mostraron una disminución de la mortalidad (6,6%) y una disminución del riesgo de abandono de la terapia (SHR ajustado: 0,62 [IC 95%: 0,55 a 0,70]) respecto a las no usuarias. CONCLUSIONES: La permanencia a los IA y el uso de BF está asociada a una disminución de la mortalidad global. Además, el uso de BF resulta en un aumento de la adherencia al tratamiento con IA

OBJETIVE: To assess the persistence of aromatase inhibitor (AI) therapy, mortality associated with treatment discontinuation and the influence of oral bisphosphonates (BP) in routine clinical practice. MATERIAL AND METHODS: Prospective observational study of women with breast cancer undergoing AI treatment between January 2006 and December 2015, registered in the SIDIAP database. Those previously treated with tamoxifen were excluded. AI persistence was studied with a survival analysis: the Kaplan-Meier estimator was calculated, and a proportional hazards model (Cox regression) was performed between users and non-users of BP adjusting for age. A sensitivity analysis was carried out taking into account mortality as a competitive risk (Fine and Gray models). The difference in mortality between groups was compared using a Chi square test. RESULTS: A persistence to AI of 87% was observed after 5 years of treatment, with an overall mortality of 19.75%. There was 7.7% less mortality in those patients who completed the 5 years of treatment compared to those who did not. Patients with BP showed a decrease in mortality (6.6%) and a decrease in the risk of discontinuing therapy (adjusted SHR: 0.62 [95% CI: 0.55 to 0.70]) compared to non-users. CONCLUSIONS: Persistence to AI and BP use are associated with a decrease in overall mortality. Furthermore, the use of BP increases adherence to AI treatment

La resistencia mecánica tisular ósea es independiente de la edad en individuos sanos / Bone tissue mechanical strength is in dependent of age in healthy individuals

Objetivo: La microindentación de impacto (MII) es una técnica que permite medir in vivo la resistencia tisular mecánica ósea. Se ha demostrado que la MII proporciona información útil sobre la evaluación de enfermedades esqueléticas, pero se desconoce el efecto que la edad puede ejercer sobre la propiedad ósea medida. El objetivo del estudio es analizar la relación entre la edad y la MII. Material y métodos: El índice de Resistencia Mineral Ósea (BMSi), la variable de medición de MII, se midió en 69 mujeres (mediana de edad: 49 años; rango: 30-81 años) y 19 varones (mediana de edad: 34 años; rango: 24-98 años) sanos. La correlación entre BMSi y la edad se analizó mediante regresión lineal. La asociación entre BMSi y edad se evaluó mediante ANOVA tras ajustar por el índice de masa corporal. El posible efecto de depleción estrogénica postmenopáusica sobre el BMSi se estudió comparando el subgrupo de mujeres más jóvenes con las más mayores mediante la prueba t de Student. Resultados: Los análisis de regresión lineal mostraron que la BMSi no se correlaciona con la edad en varones (R2=0,0016, p=0,74) ni en mujeres (R2=0,076, p=0,25). Asimismo, el análisis ajustado de ANOVA no demostró asociación entre la BMSi y la edad ni en varones (p=0,78) ni en mujeres (p=0,73). Finalmente, no se encontraron diferencias entre la BMSi entre las mujeres más jóvenes y las mayores (p=0,8). Conclusiones: La resistencia tisular mecánica ósea en individuos sanos es independiente a la edad y a la depleción estrogénica postmenopáusica

Objective: Impact microindentation (IMI) is a technique that allows the measurement of mechanicalbone tissue resistance in vivo. IMI has proven to provide useful information on the evaluation of skeletal diseases, but the effect of age on the bone property that is measured by this technique is unknown. This study aims to analyzethe relationship between age and MIH. Material and methods: Bone Material Strength index (BMSi), IMI’s output variable, was measured in 69 healthy women (median age: 49 years, range: 30-81 years) and 19 healthy men median age: 34 years, range: 24-98 years). The correlation between BMSi and age was analyzed by linear regression. The association between BMSi and age was evaluated by ANOVA after adjusting for body mass index. The potential effect of postmenopausal estrogenic depletion on BMSi was studied by comparing the younger vs the older subset of women through a t-student test. Results: Linear regression analysis showed that BMSi was not correlated with age in either men (R2=0.0016, p=0.74) or women (R2=0.076, p=0.25). Similarly, the BMI-adjusted ANOVA model revealed a lack of asso-ciation of BMSi with age in men (p=0.78) and women (p=0.73). Finally, there were not significant differences on BMSi detected between the younger and the older subset of women (p=0.8). Conclusions: Bone tissue mechanical resistance in healthy individuals is independent of age and postmenopausal estrogenic depletion

Cutaneous skeletal hypophosphatemia syndrome: clinical spectrum, natural history, and treatment.

Cutaneous skeletal hypophosphatemia syndrome (CSHS), caused by somatic RAS mutations, features excess fibroblast growth factor-23 (FGF23) and skeletal dysplasia. Records from 56 individuals were reviewed and demonstrated fractures, scoliosis, and non-congenital hypophosphatemia that in some cases were resolved. Phosphate and calcitriol, but not skin lesion removal, were effective at controlling hypophosphatemia. No skeletal malignancies were found. PURPOSE: CSHS is a disorder defined by the association of epidermal and/or melanocytic nevi, a mosaic skeletal dysplasia, and an FGF23-mediated hypophosphatemia. To date, somatic RAS mutations have been identified in all patients whose affected tissue has undergone DNA sequencing. However, the clinical spectrum and treatment are poorly defined in CSHS. The purpose of this study is to determine the spectrum of the phenotype, natural history of the disease, and response to treatment of hypophosphatemia. METHODS: Five CSHS subjects underwent prospective data collection at clinical research centers. A review of the literature identified 45 reports that included a total of 51 additional patients, in whom the findings were compatible with CSHS. Data on nevi subtypes, bone histology, mineral and skeletal disorders, abnormalities in other tissues, and response to treatment of hypophosphatemia were analyzed. RESULTS: Fractures, limb deformities, and scoliosis affected most CSHS subjects. Hypophosphatemia was not present at birth. Histology revealed severe osteomalacia but no other abnormalities. Skeletal dysplasia was reported in all anatomical compartments, though less frequently in the spine; there was no clear correlation between the location of nevi and the skeletal lesions. Phosphate and calcitriol supplementation was the most effective therapy for rickets. Convincing data that nevi removal improved blood phosphate levels was lacking. An age-dependent improvement in mineral abnormalities was observed. A spectrum of extra-osseous/extra-cutaneous manifestations that included both benign and malignant neoplasms was present in many subjects, though osteosarcoma remains unreported. CONCLUSION: An understanding of the spectrum, natural history, and efficacy of treatment of hypophosphatemia in CSHS may improve the care of these patients.

Spinal cord injury induces a long-lasting upregulation of interleukin-1ß in astrocytes around the central canal.

Under inflammatory conditions, interleukin-1ß (IL-1ß) modulates neural stem cells at neurogenic niches. Here we show that spinal cord injury in rats increases IL-1ß expression in astrocytes located around the spinal cord ependyma, a region that also holds a neurogenic potential. IL-1ß increases from day 1 after lesion, reaches maximal levels between days 3 and 7, and declines from 14 days to low levels after 28 days. At the time of maximal expression, periependymal upregulation of IL-1ß extends beyond 5 mm from the epicenter of the lesion both rostral and caudally. Since IL-1ß controls proliferation and cell fate of neural stem/precursor cells, its modulation in periependymal astrocytes might create an appropriate environment for cell replacement after injury.

CB1 receptor antagonism/inverse agonism increases motor system excitability in humans.

CB1 receptor is highly expressed in cerebral structures related to motor control, such as motor cortex, basal ganglia and cerebellum. In the spinal cord, the expression of CB1 receptors has also been observed in ventral motor neurons, interneurons and primary afferents, i.e., in the cells that may be part of the circuits involved in motor control. It is known that the antagonist/inverse agonist of CB1 receptors Rimonabant penetrates the blood-brain barrier and produces a broad range of central psychoactive effects in humans. Based on the occurrence of central effects in humans treated with Rimonabant and on the location of CB1 receptors, we hypothesized that the application of Rimonabant can also affect the motor system. We tested the effects of a single dose of 20mg of Rimonabant on the excitability of motor cortex and of spinal motor neurons in order to detect a possible drug action on motor system at cortical and spinal levels. For this purpose we use classical protocols of transcranial magnetic and electrical stimulation (TMS and TES). Single and paired pulse TMS and TES were used to assess a number of parameters of cortical inhibition and cortical excitability as well as of the excitability of spinal motor neurons. We demonstrated that a single oral dose of 20mg of Rimonabant can increase motor system excitability at cortical and spinal levels. This opens new avenues to test the CB1R antagonists/inverse agonists for the treatment of a number of neurological dysfunctions in which can be useful to increase the excitability levels of motor system. Virtually all the disorders characterized by a reduced output of the motor cortex can be included in the list of the disorders that can be treated using CB1 antagonists/reverse agonists (e.g. stroke, traumatic brain injury, spinal cord injury, multiple sclerosis, fatigue syndromes, parkinsonisms, etc.).

CB2 cannabinoid receptors as an emerging target for demyelinating diseases: from neuroimmune interactions to cell replacement strategies.

Amongst the various demyelinating diseases that affect the central nervous system, those induced by an inflammatory response stand out because of their epidemiological relevance. The best known inflammatory-induced demyelinating disease is multiple sclerosis, but the immune response is a common pathogenic mechanism in many other less common pathologies (e.g., acute disseminated encephalomyelitis and acute necrotizing haemorrhagic encephalomyelitis). In all such cases, modulation of the immune response seems to be a logical therapeutic approach. Cannabinoids are well known immunomodulatory molecules that act through CB1 and CB2 receptors. While activation of CB1 receptors has a psychotropic effect, activation of CB2 receptors alone does not. Therefore, to bypass the ethical problems that could result from the treatment of inflammation with psychotropic molecules, considerable effort is being made to study the potential therapeutic value of activating CB2 receptors. In this review we examine the current knowledge and understanding of the utility of cannabinoids as therapeutic molecules for inflammatory-mediated demyelinating pathologies. Moreover, we discuss how CB2 receptor activation is related to the modulation of immunopathogenic states.

Fluctuation of synapse density in the arcuate nucleus during the estrous cycle.

The hypothalamic arcuate nucleus integrates different hormonal and neural signals to control neuroendocrine events, feeding, energy balance and reproduction. Previous studies have shown that in adult female rats the arcuate nucleus undergoes a cyclic fluctuation in the number of axo-somatic synapses during the estrous cycle, in parallel to the variation of ovarian hormone levels in plasma. In the present study we have used an unbiased stereological analysis in conjunction with postembedding immunocytochemistry to assess whether the synaptic remodeling during the estrous cycle in rats is specific for certain types of synapses. Our findings indicate that there is a significant decrease in the number of GABAergic axo-somatic synapses on proestrus afternoon and estrus day compared with other days of the estrous cycle. This decrease in GABAergic synapses is accompanied by an increase in the number of dendritic spine synapses. The synaptic density appears to cycle back to proestrus morning values on metestrus day. In contrast, the number of synapses on dendritic shafts does not change during the cycle. These results indicate that a rapid and selective synaptic turnover of arcuate synapses occurs in physiological circumstances.

Novel cellular phenotypes and subcellular sites for androgen action in the forebrain.

Historically, morphological studies of the distribution of androgen receptors in the brain led to conclusions that the major regional targets of androgen action are involved in reproduction, that the primary cellular targets are neurons, and that functional androgen receptors are exclusively nuclear, consistent with the classical view of steroid receptors as ligand-dependent transcription factors. In this review, we discuss three separate but interrelated recent studies highlighting observations made with newer methodologies while assessing the regional, cellular or subcellular distribution of androgen receptors containing cells in the forebrain. Regional studies demonstrated that the largest forebrain target for androgen action in terms of the number of androgen receptor expressing cells is the cerebral cortex, rather than the main hypothalamic and limbic centers for reproductive function. Cellular studies to determine the phenotype of androgen receptor expressing cells confirmed that most of these cells are neurons but also revealed that small subpopulations are astrocytes. The expression of androgen receptors in astrocytes is both region and age dependent. In contrast, reactive astrocytes in the lesioned adult rat brain do not express androgen receptors whereas reactive microglia do. Finally, androgen receptor immunoreactive axons were identified in the cerebral cortex of the rat and human. These observations do not overturn classical views of the cellular and subcellular locus of steroid action in the nervous system, but rather broaden our view of the potential direct impact of gonadal steroid hormones on cellular function and emphasize the regional and developmental specificity of these effects on the nervous system.

Space flight affects magnocellular supraoptic neurons of young prepuberal rats: transient and permanent effects.

Effects of microgravity on postural control and volume of extracellular fluids as well as stress associated with space flight may affect the function of hypothalamic neurosecretory neurons. Since environmental modifications in young animals may result in permanent alterations in neuroendocrine function, the present study was designed to determine the effect of a space flight on oxytocinergic and vasopressinergic magnocellular hypothalamic neurons of prepuberal rats. Fifteen-day-old Sprague-Dawley female rats were flown aboard the Space Shuttle Columbia (STS-90, Neurolab mission, experiment 150) for 16 days. Age-matched litters remained on the ground in cages similar to those of the flight animals. Six animals from each group were killed on the day of landing and eight animals from each group were maintained under standard vivarium conditions and killed 18 weeks after landing. Several signs of enhanced transcriptional and biosynthetic activity were observed in magnocellular supraoptic neurons of flight animals on the day of landing compared to control animals. These include increased c-Fos expression, larger nucleoli and cytoplasm, and higher volume occupied in the neuronal perikaryon by mitochondriae, endoplasmic reticulum, Golgi apparatus, lysosomes and cytoplasmic inclusions known as nematosomes. In contrast, the volume occupied by neurosecretory vesicles in the supraoptic neuronal perikarya was significantly decreased in flight rats. This decrease was associated with a significant decrease in oxytocin and vasopressin immunoreactive levels, suggestive of an increased hormonal release. Vasopressin levels, cytoplasmic volume and c-Fos expression returned to control levels by 18 weeks after landing. These reversible effects were probably associated to osmotic stimuli resulting from modifications in the volume and distribution of extracellular fluids and plasma during flight and landing. However, oxytocin levels were still reduced at 18 weeks after landing in flight animals compared to controls. This indicates that space flight during prepuberal age may induce irreversible modifications in the regulation of oxytocinergic neurons, which in turn may result in permanent endocrine and behavioral impairments.