Una sesión breve de ejercicio podría mejorar la memoria

Rapid stimulation of human dentate gyrus function with acute mild exercise

Abstract

Physical exercise has beneficial effects on neurocognitive function, including hippocampus-dependent episodic memory. Exercise intensity level can be assessed according to whether it induces a stress response; the most effective exercise for improving hippocampal function remains unclear. Our prior work using a special treadmill running model in animals has shown that stress-free mild exercise increases hippocampal neuronal activity and promotes adult neurogenesis in the dentate gyrus (DG) of the hippocampus, improving spatial memory performance. However, the rapid modification, from mild exercise, on hippocampal memory function and the exact mechanisms for these changes, in particular the impact on pattern separation acting in the DG and CA3 regions, are yet to be elucidated. To this end, we adopted an acute-exercise design in humans, coupled with high-resolution functional MRI techniques, capable of resolving hippocampal subfields. A single 10-min bout of very light-intensity exercise (30%V˙O2peak${\dot{V}}_{\mathrm{O}2\text{peak}}$) results in rapid enhancement in pattern separation and an increase in functional connectivity between hippocampal DG/CA3 and cortical regions (i.e., parahippocampal, angular, and fusiform gyri). Importantly, the magnitude of the enhanced functional connectivity predicted the extent of memory improvement at an individual subject level. These results suggest that brief, very light exercise rapidly enhances hippocampal memory function, possibly by increasing DG/CA3−neocortical functional connectivity.

• physical exercise
• hippocampus
• episodic memory
• pattern separation
• functional MRI

Los ritmos circadianos afectarían el momento en que ocurren las convulsiones epilépticas

Circadian and circaseptan rhythms in human epilepsy: a retrospective cohort study

Background

Epilepsy has long been suspected to be governed by cyclic rhythms, with seizure rates rising and falling periodically over weeks, months, or even years. The very long scales of seizure patterns seem to defy natural explanation and have sometimes been attributed to hormonal cycles or environmental factors. This study aimed to quantify the strength and prevalence of seizure cycles at multiple temporal scales across a large cohort of people with epilepsy.

Methods

This retrospective cohort study used the two most comprehensive databases of human seizures (SeizureTracker [USA] and NeuroVista [Melbourne, VIC, Australia]) and analytic techniques from circular statistics to analyse patients with epilepsy for the presence and frequency of multitemporal cycles of seizure activity. NeuroVista patients were selected on the basis of having intractable focal epilepsy; data from patients with at least 30 clinical seizures were used. SeizureTracker participants are self selected and data do not adhere to any specific criteria; we used patients with a minimum of 100 seizures. The presence of seizure cycles over multiple time scales was measured using the mean resultant length (R value). The Rayleigh test and Hodges-Ajne test were used to test for circular uniformity. Monte-Carlo simulations were used to confirm the results of the Rayleigh test for seizure phase.

Findings

We used data from 12 people from the NeuroVista study (data recorded from June 10, 2010, to Aug 22, 2012) and 1118 patients from the SeizureTracker database (data recorded from Jan 1, 2007, to Oct 19, 2015). At least 891 (80%) of 1118 patients in the SeizureTracker cohort and 11 (92%) of 12 patients in the NeuroVista cohort showed circadian (24 h) modulation of their seizure rates. In the NeuroVista cohort, patient 8 had a significant cycle at precisely 1 week. Two others (patients 1 and 7) also had approximately 1-week cycles. Patients 1 and 4 had 2-week cycles. In the SeizureTracker cohort, between 77 (7%) and 233 (21%) of the 1118 patients showed strong circaseptan (weekly) rhythms, with a clear 7-day period. Between 151 (14%) and 247 (22%) patients had significant seizure cycles that were longer than 3 weeks. Seizure cycles were equally prevalent in men and women, and peak seizure rates were evenly distributed across all days of the week.

Interpretation

Our results suggest that seizure cycles are robust, patient specific, and more widespread than previously understood. They align with the accepted consensus that most epilepsies have some diurnal influence. Variations in seizure rate have important clinical implications. Detection and tracking of seizure cycles on a patient-specific basis should be standard in epilepsy management practices.

Funding

Australian National Health and Medical Research Council.

Vinculan el TDAH con un mayor riesgo de enfermedad de Parkinson de inicio precoz

Increased risk of diseases of the basal ganglia and cerebellum in patients with a history of attention-deficit/hyperactivity disorder

Abstract

Attention-deficit/hyperactivity disorder (ADHD) is marked by an ongoing pattern of inattention and/or hyperactivity and involves dysregulated dopaminergic pathways. Dopaminergic agents (i.e., amphetamine and methylphenidate) are thus prescribed to treat ADHD. As little is known regarding long-term consequences of either ADHD or its treatment, the objective of this study was to determine if either alters the risk of diseases of the basal ganglia and cerebellum, including Parkinson’s disease. Statewide medical records from 1996 to 2016 were retrieved from the Utah Population Database to conduct a retrospective cohort study. Participants included ADHD patients (International Classification of Diseases, 9th revision (ICD-9) diagnosis codes 314.0–314.2, 314.8, 314.9) and 5:1 random sex-matched and age-matched subjects with no ADHD diagnosis history. Both patients and non-ADHD subjects met the following eligibility criteria: (1) no prior diagnosis of Parkinson’s disease, secondary parkinsonism, basal ganglia disease, or essential tremor (ICD-9 codes 332.0, 332.1, 333.0, 333.1), (2) born in 1950 or later and age ≥20 years at last follow-up, and (3) no history of substance abuse (illicit drugs or alcohol). Outcomes were measured as time to diagnosis of diseases of the basal ganglia and cerebellum, death, or study-end. A Cox model incorporating a competing risk of death was used to provide hazard ratio estimates. Patients with ADHD (N = 31,769) had a 2.4-fold increased risk of basal ganglia and cerebellum diseases (95% confidence interval (CI): 2.0–3.0; P < 0.0001) compared with 158,790 non-ADHD persons, after controlling for sex and age and adjusting for tobacco use and psychotic conditions. In 4960 ADHD patients prescribed psychostimulants, risk of basal ganglia and cerebellum diseases between ages 21 and 49 years was especially pronounced, at 8.6-fold (95% CI: 4.8–15.6; P < 0001). The association of ADHD patients prescribed psychostimulants with higher risk of diseases of the basal ganglia and cerebellum may reflect a more severe ADHD phenotype rather than a direct association between prescribed stimulant use and basal ganglia or cerebellum disorders. Future studies to assess and stratify patient risk so as to inform treatment are warranted.

Factores de estabilidad del cociente intelectual en los trastornos del espectro autista

Autism and intelligence quotient: stability?

INTRODUCTION:

Autism is a heterogeneous disorder. The possibility of determining its characteristics over time will have a great impact on the prognosis and predictions that can be made. In that regard, the intelligence quotient and its possible stability throughout the life cycle can help to better define the phenotype of the disorder and its associated needs.

DEVELOPMENT:

Longitudinal studies show a certain level of stability in intelligence quotient scores, especially starting from the school years. Before, in the preschool stage, there is greater variability, especially in those children who have a borderline intellectual functioning or moderate intellectual disability.

CONCLUSION:

More research should continue to be developed to know the cognitive profile of people with autism spectrum disorder and be able to make predictions based on their intellectual functioning.

Pacientes con esclerosis lateral amiotrófica también sufren cambios cognitivos o conductuales

ALS-specific cognitive and behavior changes associated with advancing disease stage in ALS

Abstract

Objective To elucidate the relationship between disease stage in amyotrophic lateral sclerosis (ALS), as measured with the King's Clinical Staging System, and cognitive and behavioral change, measured with the Edinburgh Cognitive and Behavioural ALS Screen (ECAS).

Methods A large multicenter observational cohort of 161 cross-sectional patients with ALS and 80 healthy matched controls were recruited across 3 research sites (Dublin, Edinburgh, and London). Participants were administered the ECAS and categorized into independent groups based on their King's clinical disease stage at time of testing.

Results Significant differences were observed between patients and controls on all subtests of the ECAS except for visuospatial functioning. A significant cross-sectional effect was observed across disease stages for ALS-specific functions (executive, language, letter fluency) and ECAS total score but not for ALS-nonspecific functions (memory, visuospatial). Rates of ALS-specific impairment and behavioral change were also related to disease stage. The relationship between cognitive function and disease stage may be due to letter fluency impairment, whereas higher rates of all behavioral domains were seen in later King's stage. The presence of bulbar signs, but not site of onset, was significantly related to ALS-specific, ECAS total, and behavioral scores.

Conclusion ALS-specific cognitive deficits and behavioral impairment are more frequent with more severe disease stage. By end-stage disease, only a small percentage of patients are free of neuropsychological impairment. The presence of bulbar symptoms exaggerates the differences observed between disease stages. These findings suggest that cognitive and behavioral change should be incorporated into ALS diagnostic criteria and should be included in future staging systems.

La reserva cognitiva podría predecir la evolución de trastornos mentales graves

Cognitive reserve as an outcome predictor: first‐episode affective versus non‐affective psychosis

Abstract

Objective

Cognitive reserve (CR) refers to the brain's capacity to cope with pathology in order to minimize the symptoms. CR is associated with different outcomes in severe mental illness. This study aimed to analyze the impact of CR according to the diagnosis of first‐episode affective or non‐affective psychosis (FEP).

Method

A total of 247 FEP patients (211 non‐affective and 36 affective) and 205 healthy controls were enrolled. To assess CR, common proxies have been integrated (premorbid IQ; education–occupation; leisure activities). The groups were divided into high and low CR.

Results

In non‐affective patients, those with high CR were older, had higher socioeconomic status (SES), shorter duration of untreated psychosis, and a later age of onset. They also showed greater performance in most cognitive domains. In affective patients, those with a greater CR showed a higher SES, better functioning, and greater verbal memory performance.

Conclusion

CR plays a differential role in the outcome of psychoses according to the diagnosis. Specifically, in order to address the needs of non‐affective patients with low CR, cognitive rehabilitation treatments will need to be ‘enriched’ by adding pro‐cognitive pharmacological agents or using more sophisticated approaches. However, a functional remediation therapy may be of choice for those with an affective psychosis and low CR.

Vinculan la septicemia con el ictus y el infarto de miocardio

Susceptible period for cardiovascular complications in patients recovering from sepsis

Abstract

BACKGROUND: 

Patients are at increased risk of cardiovascular complications while recovering from sepsis. We aimed to study the temporal change and susceptible periods for cardiovascular complications in patients recovering from sepsis by using a national database.

METHODS: 

In this retrospective population-based cohort study, patients with sepsis were identified from the National Health Insurance Research Database in Taiwan. We estimated the risk of myocardial infarction (MI) and stroke following sepsis by comparing a sepsis cohort to a matched population and hospital control cohort. The primary outcome was first occurrence of MI or stroke requiring admission to hospital during the 180-day period following discharge from hospital after sepsis. To delineate the risk profile over time, we plotted the weekly risk of MI and stroke against time using the Cox proportional hazards model. We determined the susceptible period by fitting the 2 phases of time-dependent risk curves with free-knot splines, which highlights the turning point of the risk of MI and stroke after discharge from the hospital.

RESULTS: 

We included 42 316 patients with sepsis; stroke developed in 831 of these patients and MI developed in 184 within 180 days of discharge from hospital. Compared with population controls, patients recovering from sepsis had the highest risk for MI or stroke in the first week after discharge (hazard ratio [HR] 4.78, 95% confidence interval [CI] 3.19 to 7.17; risk difference 0.0028, 95% CI 0.0021 to 0.0034), with the risk decreasing rapidly until the 28th day (HR 2.38, 95% CI 1.94 to 2.92; risk difference 0.0045, 95% CI 0.0035 to 0.0056) when the risk stabilized. In a repeated analysis comparing the sepsis cohort with the nonsepsis hospital control cohort, we found an attenuated but still marked elevated risk before day 36 after discharge (HR 1.32, 95% CI 1.15 to 1.52; risk difference 0.0026, 95% CI 0.0013 to 0.0039). The risk of MI or stroke was found to interact with age, with younger patients being associated with a higher risk than older patients (interaction p = 0.0004).

Un estudio no pudo establecer una relación causal entre el síndrome de Guillain-Barré y el virus del Zika

The most frequent causative agents of Guillain-Barre syndrome in a Mexican general hospital

INTRODUCTION:

After Zika virus outbreak and the increase in the incidence of Guillain-Barre syndrome (GBS), the causal relationship has been studied, however a full etiological correlation has not been found.

PATIENTS AND METHODS:

From January 1 to December 31, 2017, patients with GBS were included. In addition to the basic serologies, enterovirus, herpes, Campylobacter, hepatitis B and C, TORCH, HIV, Brucella and Salmonella were requested.

RESULTS:

Cohort of seven male patients. Five patients analyzed cerebrospinal fluid reporting normal; all of them underwent brain scan, reporting normal. Neuroconduction was performed, resulting in acute inflammatory demyelinating polyneuropathy in four cases and acute motor axonal neuropathy in one case. All received intravenous immunoglobulins, five cases had a good prognosis and two deaths. No positive cases were reported to Zika virus. A positive case was reported to dengue and another to chikungunya. Five positive cases were reported to Campylobacter. One case positive to enterovirus. Dengue + Campylobacter coinfections were reported in one case and chikungunya + Campylobacter in another case.

CONCLUSIONS:

The present cohort shows that it was not possible to establish a causal relationship between GBS and Zika virus, but other viral and bacterial causal agents were identified, such as dengue, chikungunya and enterovirus, with the identification of Campylobacter cases even more remarkable.

Un fármaco frena la atrofia cerebral en la esclerosis múltiple progresiva

Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis

Abstract

BACKGROUND

There are limited treatments for progressive multiple sclerosis. Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll-like receptor 4 and can cross the blood–brain barrier, with potential salutary effects in progressive multiple sclerosis.

METHODS

We enrolled patients with primary or secondary progressive multiple sclerosis in a phase 2 randomized trial of oral ibudilast (≤100 mg daily) or placebo for 96 weeks. The primary efficacy end point was the rate of brain atrophy, as measured by the brain parenchymal fraction (brain size relative to the volume of the outer surface contour of the brain). Major secondary end points included the change in the pyramidal tracts on diffusion tensor imaging, the magnetization transfer ratio in normal-appearing brain tissue, the thickness of the retinal nerve-fiber layer, and cortical atrophy, all measures of tissue damage in multiple sclerosis.

RESULTS

Of 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 to placebo. A total of 53% of the patients in the ibudilast group and 52% of those in the placebo group had primary progressive disease; the others had secondary progressive disease. The rate of change in the brain parenchymal fraction was −0.0010 per year with ibudilast and −0.0019 per year with placebo (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P=0.04), which represents approximately 2.5 ml less brain-tissue loss with ibudilast over a period of 96 weeks. Adverse events with ibudilast included gastrointestinal symptoms, headache, and depression.

CONCLUSIONS

In a phase 2 trial involving patients with progressive multiple sclerosis, ibudilast was associated with slower progression of brain atrophy than placebo but was associated with higher rates of gastrointestinal side effects, headache, and depression. (Funded by the National Institute of Neurological Disorders and Stroke and others; NN102/SPRINT-MS ClinicalTrials.gov number, NCT01982942.)

La estación del año influiría en el estado cognitivo de pacientes con enfermedad de Alzheimer

Seasonal plasticity of cognition and related biological measures in adults with and without Alzheimer disease: Analysis of multiple cohorts

Background

There are few data concerning the association between season and cognition and its neurobiological correlates in older persons—effects with important translational and therapeutic implications for the diagnosis and treatment of Alzheimer disease (AD). We aimed to measure these effects.

Methods and findings

We analyzed data from 3,353 participants from 3 observational community-based cohort studies of older persons (the Rush Memory and Aging Project [MAP], the Religious Orders Study [ROS], and the Minority Aging Research Study [MARS]) and 2 observational memory-clinic-based cohort studies (Centre de Neurologie Cognitive [CNC] study at Lariboisière Hospital and the Sunnybrook Dementia Study [SDS]). We performed neuropsychological testing and, in subsets of participants, evaluated cerebrospinal fluid AD biomarkers, standardized structured autopsy measures, and/or prefrontal cortex gene expression by RNA sequencing. We examined the association between season and these variables using nested multiple linear and logistic regression models. There was a robust association between season and cognition that was replicated in multiple cohorts (amplitude = 0.14 SD [a measure of the magnitude of seasonal variation relative to overall variability; 95% CI 0.07–0.23], p = 0.007, in the combined MAP, ROS, and MARS cohorts; amplitude = 0.50 SD [95% CI 0.07–0.66], p =0.017, in the SDS cohort). Average composite global cognitive function was higher in the summer and fall compared to winter and spring, with the difference equivalent in cognitive effect to 4.8 years’ difference in age (95% CI 2.1–8.4, p = 0.002). Further, the odds of meeting criteria for mild cognitive impairment or dementia were higher in the winter and spring (odds ratio 1.31 [95% CI 1.10–1.57], p = 0.003). These results were robust against multiple potential confounders including depressive symptoms, sleep, physical activity, and thyroid status and persisted in cases with AD pathology. Moreover, season had a marked effect on cerebrospinal fluid Aβ 42 level (amplitude 0.30 SD [95% CI 0.10–0.64], p = 0.003), which peaked in the summer, and on the brain expression of 4 cognition-associated modules of co-expressed genes (m6: amplitude = 0.44 SD [95% CI 0.21–0.65], p = 0.0021; m13: amplitude = 0.46 SD [95% CI 0.27–0.76], p = 0.0009; m109: amplitude = 0.43 SD [95% CI 0.24–0.67], p = 0.0021; and m122: amplitude 0.46 SD [95% CI 0.20–0.71], p = 0.0012), which were in phase or anti-phase to the rhythms of cognition and which were in turn associated with binding sites for several seasonally rhythmic transcription factors including BCL11A, CTCF, EGR1, MEF2C, and THAP1. Limitations include the evaluation of each participant or sample once per annual cycle, reliance on self-report for measurement of environmental and behavioral factors, and potentially limited generalizability to individuals in equatorial regions or in the southern hemisphere.

Conclusions

Season has a clinically significant association with cognition and its neurobiological correlates in older adults with and without AD pathology. There may be value in increasing dementia-related clinical resources in the winter and early spring, when symptoms are likely to be most pronounced. Moreover, the persistence of robust seasonal plasticity in cognition and its neurobiological correlates, even in the context of concomitant AD pathology, suggests that targeting environmental or behavioral drivers of seasonal cognitive plasticity, or the key transcription factors and genes identified in this study as potentially mediating these effects, may allow us to substantially improve cognition in adults with and without AD.

Calidad de vida en niños y adolescentes con TDAH, con y sin tratamiento farmacológico, y en controles

Children's and adolescents' perception of their quality of life in cases of attention deficit hyperactivity disorder with and without pharmacological treatment and in controls

Abstract

Health-related quality of life perceived by children and teenagers is important to assess the effects of therapeutic intervention.To analyze quality of life, comparing cases of attention deficit hyperactivity disorder (ADHD) treated with methylphenidate, untreated cases and controls.Sampling of 228 participants between 8 and 14 years-old. Consecutive sampling in ADHD according to DSM-IV criteria (ADHD Rating Scales IV) and random sampling of matched controls by sex and age. Evaluation of quality of life using KIDSCREEN-52 (children version). ANOVA with Bonferroni correction was used.There is a moderate significant correlation between greater intensity of ADHD symptoms and worse quality of life, except in the dimension of physical well-being. Cases of untreated ADHD have significantly worse quality of life than controls on psychic well-being, mood, autonomy school environment and social acceptance. Cases of treated ADHD present similar results, except in the school environment and psychological well-being. The cases of ADHD treated only differ significantly from ADHD not treated in having a better school environment.The cases of ADHD present dimensions of KIDSCREEN-52 with worse quality of life than controls and the cases of ADHD treated with methylphenidate only differ significantly from those not treated in presenting better results in the school environment.

La enfermedad de Parkinson podría detectarse en etapas tempranas gracias al aliento

Sensor Array for Detection of Early Stage Parkinson’s Disease before Medication

Abstract

Early diagnosis of Parkinson’s disease (PD) is important because it affects the choice of therapy and is subject to a relatively high degree of error. In addition, early detection of PD can potentially enable the start of neuroprotective therapy before extensive loss of dopaminergic neurons of the substantia nigra occurs. However, until now, studies for early detection of PD using volatile biomarkers sampled only treated and medicated patients. Therefore, there is a great need to evaluate untreated patients for establishing a real world screening and diagnostic technology. Here we describe for the first time a clinical trial to distinguish between de novo PD and control subjects using an electronic system for detection of volatile molecules in exhaled breath (sensor array). We further determine for the first time the association to other common tests for PD diagnostics as smell, ultrasound, and nonmotor symptoms. The test group consisted of 29 PD patients after initial diagnosis by an experienced neurologist, compared with 19 control subjects of similar age. The sensitivity, specificity, and accuracy values of the sensor array to detect PD from controls were 79%, 84%, and 81% respectively, in comparison with midbrain ultrasonography (93%, 90%, 92%) and smell detection (62%, 89%, 73%). The results confirm previous data showing the potential of sensor arrays to detect PD.

Keywords: 

Parkinson; ultrasonography; UPSIT; volatile organic compound; volatolomics

Un tipo de esclerosis múltiple sin lesiones en la sustancia blanca

Cortical neuronal densities and cerebral white matter demyelination in multiple sclerosis: a retrospective study

Background

Demyelination of cerebral white matter is thought to drive neuronal degeneration and permanent neurological disability in individuals with multiple sclerosis. Findings from brain MRI studies, however, support the possibility that demyelination and neuronal degeneration can occur independently. We aimed to establish whether post-mortem brains from patients with multiple sclerosis show pathological evidence of cortical neuronal loss that is independent of cerebral white-matter demyelination.

Methods

Brains and spinal cords were removed at autopsy from patients, who had died with multiple sclerosis, at the Cleveland Clinic in Cleveland, OH, USA. Visual examination of centimetre-thick slices of cerebral hemispheres was done to identify brains without areas of cerebral white-matter discoloration that were indicative of demyelinated lesions (referred to as myelocortical multiple sclerosis) and brains that had cerebral white-matter discolorations or demyelinated lesions (referred to as typical multiple sclerosis). These individuals with myelocortical multiple sclerosis were matched by age, sex, MRI protocol, multiple sclerosis disease subtype, disease duration, and Expanded Disability Status Scale, with individuals with typical multiple sclerosis. Demyelinated lesion area in tissue sections of cerebral white matter, spinal cord, and cerebral cortex from individuals classed as having myelocortical and typical multiple sclerosis were compared using myelin protein immunocytochemistry. Neuronal densities in cortical layers III, V, and VI from five cortical regions not directly connected to spinal cord (cingulate gyrus and inferior frontal cortex, superior temporal cortex, and superior insular cortex and inferior insular cortex) were also compared between the two groups and with aged-matched post-mortem brains from individuals without evidence of neurological disease.

Inhibidores de puntos de control para tratar el melanoma que se ha extendido al cerebro

Combined Nivolumab and Ipilimumab in Melanoma Metastatic to the Brain

Abstract

BACKGROUND

Brain metastases are a common cause of disabling neurologic complications and death in patients with metastatic melanoma. Previous studies of nivolumab combined with ipilimumab in metastatic melanoma have excluded patients with untreated brain metastases. We evaluated the efficacy and safety of nivolumab plus ipilimumab in patients with melanoma who had untreated brain metastases.

METHODS

In this open-label, multicenter, phase 2 study, patients with metastatic melanoma and at least one measurable, nonirradiated brain metastasis (tumor diameter, 0.5 to 3 cm) and no neurologic symptoms received nivolumab (1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for up to four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks until progression or unacceptable toxic effects. The primary end point was the rate of intracranial clinical benefit, defined as the percentage of patients who had stable disease for at least 6 months, complete response, or partial response.

RESULTS

Among 94 patients with a median follow-up of 14.0 months, the rate of intracranial clinical benefit was 57% (95% confidence interval [CI], 47 to 68); the rate of complete response was 26%, the rate of partial response was 30%, and the rate of stable disease for at least 6 months was 2%. The rate of extracranial clinical benefit was 56% (95% CI, 46 to 67). Treatment-related grade 3 or 4 adverse events were reported in 55% of patients, including events involving the central nervous system in 7%. One patient died from immune-related myocarditis. The safety profile of the regimen was similar to that reported in patients with melanoma who do not have brain metastases.

CONCLUSIONS

Nivolumab combined with ipilimumab had clinically meaningful intracranial efficacy, concordant with extracranial activity, in patients with melanoma who had untreated brain metastases. (Funded by Bristol-Myers Squibb and the National Cancer Institute; CheckMate 204 ClinicalTrials.gov number, NCT02320058.)

Relacionan los productos fitosanitarios con una mayor incidencia de esclerosis lateral amiotrófica

Spatial Assessment of the Association between Long-Term Exposure to Environmental Factors and the Occurrence of Amyotrophic Lateral Sclerosis in Catalonia, Spain: A Population-Based Nested Case-Control Study

Abstract

Background: It is believed that an interaction between genetic and non-genetic factors may be involved in the development of amyotrophic lateral sclerosis (ALS). With the exception of exposure to agricultural chemicals like pesticides, evidence of an association between environmental risk factors and ALS is inconsistent. Our objective here was to investigate the association between long-term exposure to environmental factors and the occurrence of ALS in Catalonia, Spain, and to provide evidence that spatial clusters of ALS related to these environmental factors exist. Methods: We carried out a nested case-control study constructed from a retrospective population-based cohort, covering the entire region. Environmental variables were the explanatory variables of interest. We controlled for both observed and unobserved confounders. Results: We have found some spatial clusters of ALS. The results from the multivariate model suggest that these clusters could be related to some of the environmental variables, in particular agricultural chemicals. In addition, in high-risk clusters, besides corresponding to agricultural areas, key road infrastructures with a high density of traffic are also located. Conclusion: Our results indicate that some environmental factors, in particular those associated with exposure to pesticides and air pollutants as a result of urban traffic, could be associated with the occurrence of ALS.

Campos electromagnéticos en el ámbito laboral no se asocian claramente con un mayor riesgo de tumores cerebrales

Occupational exposure to high-frequency electromagnetic fields and brain tumor risk in the INTEROCC study: An individualized assessment approach

Abstract

Introduction

In 2011, the International Agency for Research on Cancer classified radiofrequency (RF) electromagnetic fields (EMF) as possibly carcinogenic to humans (group 2B), although the epidemiological evidence for the association between occupational exposure to RF-EMF and cancer was judged to be inadequate, due in part to limitations in exposure assessment. This study examines the relation between occupational RF and intermediate frequency (IF) EMF exposure and brain tumor (glioma and meningioma) risk in the INTEROCC multinational population-based case-control study (with nearly 4000 cases and over 5000 controls), using a novel exposure assessment approach.

Methods

Individual indices of cumulative exposure to RF and IF-EMF (overall and in specific exposure time windows) were assigned to study participants using a source-exposure matrix and detailed interview data on work with or nearby EMF sources. Conditional logistic regression was used to investigate associations with glioma and meningioma risk.

Results

Overall, around 10% of study participants were exposed to RF while only 1% were exposed to IF-EMF. There was no clear evidence for a positive association between RF or IF-EMF and the brain tumors studied, with most results showing either no association or odds ratios (ORs) below 1.0. The largest adjusted ORs were obtained for cumulative exposure to RF magnetic fields (as A/m-years) in the highest exposed category (≥90th percentile) for the most recent exposure time window (1–4 years before the diagnosis or reference date) for both glioma, OR = 1.62 (95% confidence interval (CI): 0.86, 3.01) and meningioma (OR = 1.52, 95% CI: 0.65, 3.55).

Conclusion

Despite the improved exposure assessment approach used in this study, no clear associations were identified. However, the results obtained for recent exposure to RF electric and magnetic fields are suggestive of a potential role in brain tumor promotion/progression and should be further investigated.

Un nuevo agente en los mecanismos de la adicción al alcohol y la ingesta: el núcleo incertus y el neuropéptido relaxina-3

A new agent in the mechanisms underlying addiction and ingestion of alcohol: the nucleus incertus and the neuropeptide relaxin-3

Abstract

Alcohol intake is facilitated by its relationship with eating behavior and both processes are highly influenced by situations of stress and anxiety. The dysregulation of these processes can reach pathological situations such as anorexia, bulimia or obesity. The neurobiological elements which underlie this control are not completely clarified. The nucleus incertus (NI) in the pontine tegmentum is a common element in the food intake and alcoholism. NI is characterized by using the neuropeptide relaxin-3 (RLN3) as transmitter and its receptor RXFP3. In the present review, we will analyze the participation of the NI-RLN3-RXFP3 system in these behaviors under conditions of anxiety or stress in animal models. The activation of NI has a positive effect on intake (orexigenic) and generates a wide response in the amygdala modulating anxiety states. The activity of RLN3-RXFP3 in the amygdala could affect alcohol addiction since the application of the RXFP3 antagonist in extended amygdala attenuates the relapse to alcohol induced by stress. The neuroanatomical data indicate that the NI-RLN3-RXFP3 system acts on the feeding behavior and alcohol intake by means of projections parallel to the canonical mesolimbic pathways. Thus, data in animal models indicate that the NI-RLN3-RXFP3 system should be taken into account as a target in the future treatment of disorders of eating and alcohol addictive behaviors.

El adelgazamiento de la retina podría ser una señal de advertencia temprana de enfermedad de Parkinson

Retinal thinning associates with nigral dopaminergic loss in de novo Parkinson disease

Abstract

Objective To analyze the relationship between retinal thinning and nigral dopaminergic loss in de novo Parkinson disease (PD).

Methods Forty-nine patients with PD and 54 age-matched controls were analyzed. Ophthalmologic examination and macula optical coherence tomography scans were performed with additional microperimetry, N-(3-[18F]fluoropropyl)-2-carbomethoxy-3-(4-iodophenyl) nortropane PET, and 3T MRI scans were done in patients with PD only. Retinal layer thickness and volume were measured in subfields of the 1-, 2.22-, and 3.45-mm Early Treatment of Diabetic Retinopathy Study circle and compared in patients with PD and controls. Correlation of inner retinal layer thinning with microperimetric response was examined in patients with PD, and the relationships between retinal layer thickness and dopamine transporter densities in the ipsilateral caudate, anterior and posterior putamen, and substantia nigra were analyzed.

Results Retinal layer thinning was observed in the temporal and inferior 2.22-mm sectors (false discovery rate–adjusted p < 0.05) of drug-naive patients with PD, particularly the inner plexiform and ganglion cell layers. The thickness of these layers in the inferior 2.22-mm sector showed a negative correlation with the Hoehn and Yahr stage (p = 0.032 and 0.014, respectively). There was positive correlation between macular sensitivity and retinal layer thickness in all 3.45-mm sectors, the superior 2.22-mm sector, and 1-mm circle (p < 0.05 for all). There was an association between retinal thinning and dopaminergic loss in the left substantia nigra (false discovery rate–adjusted p < 0.001).

Conclusion Retinal thinning is present in the early stages of PD, correlates with disease severity, and may be linked to nigral dopaminergic degeneration. Retinal imaging may be useful for detection of pathologic changes occurring in early PD.

CPEB4, una proteína clave en el desarrollo de los trastornos del espectro autista

Autism-like phenotype and risk gene mRNA deadenylation by CPEB4 mis-splicing

Abstract

Common genetic contributions to autism spectrum disorder (ASD) reside in risk gene variants that individually have minimal effect sizes. As environmental factors that perturb neurodevelopment also underlie idiopathic ASD, it is crucial to identify altered regulators that can orchestrate multiple ASD risk genes during neurodevelopment. Cytoplasmic polyadenylation element binding proteins 1–4 (CPEB1–4) regulate the translation of specific mRNAs by modulating their poly(A)-tails and thereby participate in embryonic development and synaptic plasticity. Here we find that CPEB4 binds transcripts of most high-confidence ASD risk genes. The brains of individuals with idiopathic ASD show imbalances in CPEB4 transcript isoforms that result from decreased inclusion of a neuron-specific microexon. In addition, 9% of the transcriptome shows reduced poly(A)-tail length. Notably, this percentage is much higher for high-confidence ASD risk genes, correlating with reduced expression of the protein products of ASD risk genes. An equivalent imbalance in CPEB4 transcript isoforms in mice mimics the changes in mRNA polyadenylation and protein expression of ASD risk genes and induces ASD-like neuroanatomical, electrophysiological and behavioural phenotypes. Together, these data identify CPEB4 as a regulator of ASD risk genes.