Evidence of human occupation in Mexico around the Last Glacial Maximum.

The initial colonization of the Americas remains a highly debated topic1, and the exact timing of the first arrivals is unknown. The earliest archaeological record of Mexico-which holds a key geographical position in the Americas-is poorly known and understudied. Historically, the region has remained on the periphery of research focused on the first American populations2. However, recent investigations provide reliable evidence of a human presence in the northwest region of Mexico3,4, the Chiapas Highlands5, Central Mexico6 and the Caribbean coast7-9 during the Late Pleistocene and Early Holocene epochs. Here we present results of recent excavations at Chiquihuite Cave-a high-altitude site in central-northern Mexico-that corroborate previous findings in the Americas10-17of cultural evidence that dates to the Last Glacial Maximum (26,500-19,000 years ago)18, and which push back dates for human dispersal to the region possibly as early as 33,000-31,000 years ago. The site yielded about 1,900 stone artefacts within a 3-m-deep stratified sequence, revealing a previously unknown lithic industry that underwent only minor changes over millennia. More than 50 radiocarbon and luminescence dates provide chronological control, and genetic, palaeoenvironmental and chemical data document the changing environments in which the occupants lived. Our results provide new evidence for the antiquity of humans in the Americas, illustrate the cultural diversity of the earliest dispersal groups (which predate those of the Clovis culture) and open new directions of research.

Subclinical atherosclerosis and brain health in midlife: Rationale and design of the PESA-Brain study.

RATIONALE: Cognitive decline and dementia have been reportedly linked to atherosclerosis, the main cause of cardiovascular disease. Cohort studies identifying early brain alterations associated with subclinical atherosclerosis are warranted to understand the potential of prevention strategies before cerebral damage becomes symptomatic and irreversible. METHODS & DESIGN: The Progression of Early Subclinical Atherosclerosis (PESA) study is a longitudinal observational cohort study that recruited 4184 asymptomatic middle-aged individuals (40-54 years) in 2010 in Madrid (Spain) to thoroughly characterize subclinical atherosclerosis development over time. In this framework, the PESA-Brain study has been designed to identify early structural, functional and vascular brain changes associated with midlife atherosclerosis and cardiovascular risk factors. The PESA-Brain study targets 1000 participants at the 10-year follow-up PESA visit and consists of thorough neuropsychological testing, advanced multi-modal neuroimaging, and quantification of blood-based neuropathological biomarkers. PRIMARY HYPOTHESIS: We hypothesized that, in middle-age, the presence of cardiovascular risk factors and a high burden of subclinical atherosclerosis will be associated with structural, functional and vascular brain alterations, greater amyloid burden and subtle cognitive impairment. We further hypothesize that the link between subclinical atherosclerosis and poor brain health in midlife will be mediated by cerebrovascular pathology and intracranial atherosclerosis. ENROLLMENT DATES: The PESA-Brain study started in October 2020 and is estimated to be completed by December 2024. CONCLUSION: This study is in a unique position to unveil novel relationships between cardiovascular and brain alterations in the health-to-disease transition, which may have important implications for interventional and therapeutic approaches. TRIAL REGISTRATION - REGISTRY: clinicaltrials.gov; Registration Number: NCT01410318; url: https://clinicaltrials.gov/study/NCT01410318.

A spontaneous deletion of α-synuclein is associated with an increase in CB1 mRNA transcript and receptor expression in the hippocampus and amygdala: effects on alcohol consumption.

α-Synuclein (α-syn) protein and endocannabinoid CB1 receptors are primarily located in presynaptic terminals. An association between α-syn and CB1 receptors has recently been established in Parkinson's disease, but it is completely unknown whether there is an association between these two proteins in alcohol addiction. Therefore, we aimed to examine the α-syn mRNA transcript and protein expression levels in the prefrontal cortex, striatum, amygdala and hippocampus. These brain regions are the most frequently implicated in alcohol and other drug addiction. In these studies, we used C57BL/6 mice carrying a spontaneous deletion of the α-syn gene (C57BL/6(Snca-/-) ) and their respective controls (C57BL/6(Snca) (+/) (+) ). These animals were monitored for spontaneous alcohol consumption (3-10%) and their response to a hypnotic-sedative dose of alcohol (3 g kg(-1) ) was also assessed. Compared with the C57BL/6(Snca+/+) mice, we found that the C57BL/6(Snca-/-) mice exhibited a higher expression level of the CB1 mRNA transcript and CB1 receptor in the hippocampus and amygdala. Furthermore, C57BL/6(Snca-/-) mice showed an increase in alcohol consumption when offered a 10% alcohol solution. There was no significant difference in sleep time after the injection of 3 g/kg alcohol. These results are the first to reveal an association between α-syn and the CB1 receptor in the brain regions that are most frequently implicated in alcohol and other drug addictions.

Genetic polymorphisms among C57BL/6 mouse inbred strains.

Mice from the inbred C57BL/6 strain have been commonly used for the generation and analysis of transgenic and knockout animal models. However, several C57BL/6 substrains exist, and these are genetically and phenotypically different. In addition, each of these substrains can be purchased from different animal providers and, in some cases, they have maintained their breeding stocks separated for a long time, allowing genetic differences to accumulate due to individual variability and genetic drift. With the aim of describing the differences in the genotype of several C57BL/6 substrains, we applied the Illumina(®) Mouse Medium Density Linkage Mapping panel, with 1,449 single nucleotide polymorphisms (SNPs), to individuals from ten C57BL/6-related strains: C57BL/6JArc, C57BL/6J from The Jackson Lab, C57BL/6J from Crl, C57BL6/JRccHsd, C57BL/6JOlaHsd, C57BL/6JBomTac, B6(Cg)-Tyr ( c-2j )/J, C57BL/6NCrl, C57BL/6NHsd and C57BL/6NTac. Twelve SNPs were found informative to discriminate among the mouse strains considered. Mice derived from the original C57BL/6J: C57BL/6JArc, C57BL/6J from The Jackson Lab and C57BL/6J from Crl, were indistinguishable. Similarly, all C57BL/6N substrains displayed the same genotype, whereas the additional substrains showed intermediate cases with substrain-specific polymorphisms. These results will be instrumental for the correct genetic monitoring and appropriate mouse colony handling of different transgenic and knockout mice produced in distinct C57BL/6 inbred substrains.

Pharmacological activation of CB1 and D2 receptors in rats: predominant role of CB1 in the increase of alcohol relapse.

The classical dopamine D2 receptor has been widely studied in alcoholism. Recently, different studies have explored the role of the CB1 receptor in alcohol-related behavior. In alcohol addiction, relapse is one of the central features. In light of this, we investigated the functional roles of and interactions between CB1 and D2 receptors in alcohol relapse. We used the learned task of alcohol operant self-administration in Wistar rats. In order to evaluate alcohol relapse, we set up a protocol essentially based on the alcohol deprivation effect. We found that subchronic activation of CB1 (WIN 55,212-2, 2 mg/kg), but not D2 receptors (quinpirole, 1 mg/kg), during a period of alcohol deprivation increased long-lasting alcohol relapse. The cannabinoid-induced potentiation of alcohol relapse was mediated by a motivational and appetitive component, and not merely by alcohol consumption. This potentiation was prevented by the pharmacological inactivation of D2 receptors (raclopride, 0.1-0.3 mg/kg). Together, these results essentially demonstrate that activation of CB1 receptors plays a key role in the increase of alcohol relapse, whereas inactivation of D2 receptors modulates this aberrant behavior. We suggest that there exists a functional and interactive relationship between both receptor systems, which controls alcohol relapse and alcohol-learned tasks.

Developmentally-induced hypothyroidism alters the expression of Egr-1 and Arc genes and the sensitivity to cannabinoid agonists in the hippocampus. Possible implications for memory and learning.

We analyzed the role of the cannabinoid system in the cognitive deficits caused by developmentally-induced hypothyroidism. We studied in control and hypothyroid rats the effect of a cannabinoid agonist on spatial memory, hippocampal phosphorylation of CREB and expression of early genes. Our results show that, 1-basal hippocampal expression of early genes and spatial learning are decreased in hypothyroid rats; 2-hypothyroid rats are very sensitive to cannabinoid agonists. Low dose of cannabinoid agonist ineffective in controls altered spatial memory, CREB's phosphorylation and early gene expression in hypothyroids. These effects are not due a change in CB1 receptor (CB1R) content. 3-Treatment of hypothyroid rats with thyroid hormones normalized the biochemical and behavioral responses to cannabinoid agonists but did not correct the low basal levels of early gene transcripts and the deficits in spatial learning. All these data suggest that the hippocampal deregulation of early genes expression could play an important role in the basal cognitive deficits of hypothyroid rats.

Seguridad y utilidad de la maniobra de retrovisión en ciego y colon ascendente / Safety and usefulness of the retrograde-viewing maneuver in the cecum and ascending colon

Objetivo: Analizar la utilidad y seguridad de la maniobra de retrovisión en ciego y colon realizada en una serie de 20 pacientes. Sede: Centro Hospitalario del Estado Mayor Presidencial y Hospital Ángeles Lomas. Tipo de estudio: Prospectivo, comparativo, transversal y observacional. Análisis estadístico: Por porcentajes. Pacientes y método: Veinte pacientes con indicación de colonoscopia. Las variables evaluadas fueron: factibilidad de realizar la maniobra, complicaciones presentadas y comparación de lesiones localizadas con la endoscopia convencional y por medio de la retrovisión. Resultados: Edad promedio de 53 años (33 a 72 años); 12 mujeres y 8 varones. La maniobra de retrovisión fue factible en l6 de las colonoscopias (80%). La complicación más frecuentemente observada fue erosión leve de la mucosa por fricción de la punta del endoscopio en el ciego, en cuatro enfermos (20%), lo que no ameritó ningún tratamiento. No hubo perforación ni sangrado en caso alguno. La maniobra de retrovisión aportó un diagnóstico endoscópico adicional en tres enfermos (15%), siendo dos pólipos pequeños y un divertículo del ciego. Conclusiones: La maniobra de retrovisión en ciego fue útil y segura, ya que permitió diagnosticar un 15% más de lesiones que no fueron observadas antes de realizar la maniobra; esto sin presentar complicaciones.

Objective: To analyze the usefulness and safety of the retrograde-viewing maneuver in the cecum and colon performed in a series of 20 patients. Setting: Third level health care center. Type of study: Prospective, comparative, cross-sectional, and observational. Statistical analysis: Percentages. Patients and method: Twenty patients with indication for colonoscopy. Assessed variables were: feasibility of the maneuver. Complications and comparison of injuries localized with conventional endoscopy and by means of the retrograde-viewing device. Results: Average age was 53 years (33 to 72 years), 12 women and 8 men. The retrograde viewing maneuver was feasible in 16 of the colonoscopies (80%). The most frequent complication observed was slight erosion of the mucosa due to the friction caused by the tip of the endoscope in the cecum in four patients (20%), which did not need any treatment. There was no perforation or bleeding in any case. The retrograde-viewing maneuver provided an additional endoscopic diagnosis in three patients (15%), being these small polyps and a diverticulum in the cecum. Conclusions: Retrograde-viewing in the cecum was useful and safe, as it allowed to diagnose 15% more lesions than those observed before performing the maneuver; without presenting complications.