Temporal changes in the expression of the translocator protein TSPO and the steroidogenic enzyme 5a-reductase in the dorsal spinal cord of animals with neuropathic pain: effects of progesterone administration

Neuropathic pain is a frequent complication of spinal cord injury (SCI), still refractory to conventional treatment. The presence and biological activity of steroidogenic regulatory proteins and enzymes in the spinal cord suggests that neurosteroids locally generated could modulate pain messages. In this study we explored temporal changes in the spinal expression of the 18kDa translocator protein TSPO, the steroidogenic acute regulatory protein (StAr) and the steroidogenic enzyme 5-reductase (5α-RI/II) in an experimental model of central chronic pain. Male Sprague-Dawley rats were subjected to a SCI and sacrificed at different time points (1, 14 or 28 days). The development of mechanical and cold allodynia was assessed. Injured animals showed an early increase in the mRNA levels of TSPO and 5α-RII, whereas in the chronic phase a significant decrease in the expression of 5α-RI and 5α-RII was observed, coinciding with the presence of allodynic behaviors. Furthermore, since we have shown that progesterone (PG) administration may offer a promising perspective in pain modulation, we also evaluated the expression of steroidogenic proteins and enzymes in injured animals receiving daily injections of the steroid. PG-treated did not develop allodynia and showed a marked increase in the mRNA levels of TSPO, StAR, 5α-RI and 5α-RII 28 days after injury. Our results suggest that in the acute phase after SCI, the increased expression of TSPO and 5α-RII may represent a protective endogenous response against tissue injury, which is not maintained in the chronic allodynic phase. PG may favor local steroidogenesis and the production of its reduced metabolites, which could contribute to the antiallodynic effects observed after PG treatment. Fil: Coronel, Maria Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Sánchez Granel, María Luz. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Raggio, María Celeste. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Adler, Natalia Sol. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: de Nicola, Alejandro Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Labombarda, Maria Florencia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; ArgentinaFil: Gonzalez, Susana Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentin

Where does purging disorder lie on the symptomatologic and personality continuum when compared to other eating disorder subtypes? Implications for the DSM

Objectives: To assess the clinical significance and distinctiveness of purging disorder (PD) from other eating disorder (ED) diagnoses. Method: Participants included 3127 women consecutively admitted to an ED treatment centre (246 PD, 465 anorexia nervosa restrictive [AN‐R], 327 AN‐binge purging [AN‐BP], 1436 bulimia nervosa [BN], 360 binge eating disorder [BED], 177 atypical AN and 116 unspecified feeding or eating disorder [UFED]) who were diagnosed according to DSM‐5 criteria. Additionally, 822 control participants were recruited from the community. All participants completed measures assessing ED symptoms (EDI‐2), general psychopathology (SCL‐90‐R) and personality (TCI‐R). Results: Patients with PD, when compared to controls, scored significantly higher on the EDI‐2 and SCL‐90‐R, and most TCI‐R dimensions. Most of the significant differences between PD and the other ED diagnoses emerged between PD and AN‐R, followed by Atypical‐AN, UFED, AN‐BP and BED, with patients with PD typically reporting higher scores on the EDI‐2 and SCL‐90‐R subscales. Significant differences between PD and BN were also present, but to a lesser extent. The findings for personality varied amongst the different ED diagnoses. Conclusions: PD is a clinically significant disorder, which seems to be more similar to BN than it is to AN and the other ED subtypes

Fetal sex modulates developmental response to maternal malnutrition

The incidence of obesity and metabolic diseases is dramatically high in rapidly developing countries. Causes have been related to intrinsic ethnic features with development of a thrifty genotype for adapting to food scarcity, prenatal programming by undernutrition, and postnatal exposure to obesogenic lifestyle. Observational studies in humans and experimental studies in animal models evidence that the adaptive responses of the offspring may be modulated by their sex. In the contemporary context of world globalization, the new question arising is the existence and extent of sex-related differences in developmental and metabolic traits in case of mixed-race. Hence, in the current study, using a swine model, we compared male and female fetuses that were crossbred from mothers with thrifty genotype and fathers without thrifty genotype. Female conceptuses evidence stronger protective strategies for their adequate growth and postnatal survival. In brief, both male and female fetuses developed a brain-sparing effect but female fetuses were still able to maintain the development of other viscerae than the brain (mainly liver, intestine and kidneys) at the expense of carcass development. Furthermore, these morphometric differences were reinforced by differences in nutrient availability (glucose and cholesterol) favoring female fetuses with severe developmental predicament. These findings set the basis for further studies aiming to increase the knowledge on the interaction between genetic and environmental factors in the determination of adult phenotype

Long-Term Effectiveness of a Smartphone App and a Smart Band on Arterial Stiffness and Central Hemodynamic Parameters in a Population with Overweight and Obesity (Evident 3 Study): Randomised Controlled Trial

Background: mHealth technologies could help to improve cardiovascular health; however, their effect on arterial stiffness and hemodynamic parameters has not been explored to date. Objective: To evaluate the effect of a mHealth intervention, at 3 and 12 months, on arterial stiffness and central hemodynamic parameters in a sedentary population with overweight and obesity. Methods: Randomised controlled clinical trial (Evident 3 study). 253 subjects were included: 127 in the intervention group (IG) and 126 in the control group (CG). The IG subjects were briefed on the use of the Evident 3 app and a smart band (Mi Band 2, Xiaomi) for 3 months to promote healthy lifestyles. All measurements were recorded in the baseline visit and at 3 and 12 months. The carotid-femoral pulse wave velocity (cfPWV) and the central hemodynamic parameters were measured using a SphigmoCor System® device, whereas the brachial-ankle pulse wave velocity (baPWV) and the Cardio Ankle Vascular Index (CAVI) were measured using a VaSera VS-2000® device. Results: Of the 253 subjects who attended the initial visit, 237 (93.7%) completed the visit at 3 months of the intervention, and 217 (85.3%) completed the visit at 12 months of the intervention. At 12 months, IG showed a decrease in peripheral augmentation index (PAIx) (−3.60; 95% CI −7.22 to −0.00) and ejection duration (ED) (−0.82; 95% CI −1.36 to −0.27), and an increase in subendocardial viability ratio (SEVR) (5.31; 95% CI 1.18 to 9.44). In CG, cfPWV decreased at 3 months (−0.28 m/s; 95% CI −0.54 to −0.02) and at 12 months (−0.30 m/s, 95% CI −0.54 to −0.05), central diastolic pressure (cDBP) decreased at 12 months (−1.64 mm/Hg; 95% CI −3.19 to −0.10). When comparing the groups we found no differences between any variables analyzed. Conclusions: In sedentary adults with overweight or obesity, the multicomponent intervention (Smartphone app and an activity-tracking band) for 3 months did not modify arterial stiffness or the central hemodynamic parameters, with respect to the control group. However, at 12 months, CG presented a decrease of cfPWV and cDBP, whereas IG showed a decrease of PAIx and ED and an increase of SEVR

Behavioural intervention to reduce disruptive behaviours in adult day care centres users: A randomizsed clinical trial (PROCENDIAS study)

[ENG]Aim: This study assesses the effect of an intervention to reduce the disruptive behaviours (DB) presented by care recipient users of adult day care centres (ADCC), thereby reducing caregiver overload. While ADCC offer beneficial respite for family caregivers, the DB that many care recipients show promote resistance to attending these centres, which can be a great burden on their family caregivers. Design: Randomized controlled clinical trial. Methods: The study was carried out with 130 family caregivers of people attending seven ADCC in the municipality of Salamanca (Spain), randomly distributed into intervention and control groups. The intervention was applied across eight sessions, one per week, in groups of 8–10 people where caregivers were trained in the Antecedent- Behavior-Consequence (ABC) model of functional behaviour analysis. The primary outcome was the reduction of DB measured with the Revised Memory and Behavior Problems Checklist (RMBPC). Results: An average reduction in the RMBPC of 4.34 points was obtained in the intervention group after applying the intervention (p < 0.01 (U de Mann–Whitney); Cohen d = 1.00); furthermore, differences were found in the Center for Epidemiologic Studies Depression Scale (CES-D) (U = −2.67; p = 0.008; Cohen d = 0.50) and in the Short Zarit Burden Interview (Short ZBI) (t = −4.10; p < 0.01; Cohen d = 0.98). Conclusion: The results obtained suggest that the implementation of this intervention could reduce both the frequency of DB occurrence and the reaction of the caregiver to their appearance. Improvement was also noted in the results regarding overload and emotional state of the family caregiver. Impact: To our knowledge, this is the first randomized clinical trial to show that an intervention based on the ABC model could reduce the frequency and reaction of DB of care recipients in ADCC increasing their quality of life, and improving the mental health and overload of their family caregivers

Ontogeny of sex-related differences in foetal developmental features, lipid availability and fatty acid composition

Sex-related differences in lipid availability and fatty acid composition during swine foetal development were investigated. Plasma cholesterol and triglyceride concentrations in the mother were strongly related to the adequacy or inadequacy of foetal development and concomitant activation of protective growth in some organs (brain, heart, liver and spleen). Cholesterol and triglyceride availability was similar in male and female offspring, but female foetuses showed evidence of higher placental transfer of essential fatty acids and synthesis of non-essential fatty acids in muscle and liver. These sex-related differences affected primarily the neutral lipid fraction (triglycerides), which may lead to sex-related postnatal differences in energy partitioning. These results illustrate the strong influence of the maternal lipid profile on foetal development and homeorhesis, and they confirm and extend previous reports that female offspring show better adaptive responses to maternal malnutrition than male offspring. These findings may help guide dietary interventions to ensure adequate fatty acid availability for postnatal development

Cerebral Amyloid Angiopathy in Down Syndrome and Sporadic and Autosomal-Dominant Alzheimer\u27s Disease

Introduction—We aimed to investigate if cerebral amyloid angiopathy (CAA) is more frequent in genetically determined than in sporadic early-onset forms of Alzheimer\u27s disease (AD) (early-onset AD [EOAD]). Methods—Neuroimaging features of CAA, APOE, and cerebrospinal fluid-Aβ40 levels were studied in subjects with Down syndrome (DS, n = 117), autosomal-dominant AD (ADAD, n = 29), sporadic EOAD (n = 42), and healthy controls (n = 68). Results—CAA was present in 31%, 38%, and 12% of cognitively impaired DS, symptomatic ADAD, and sporadic EOAD subjects and in 13% and 4% of cognitively unimpaired DS individuals and healthy controls, respectively. APOE-ε4 genotype was borderline significantly associated with CAA in sporadic EOAD (p = .06) but not with DS or ADAD. There were no differences in Aβ040 levels between groups or between subjects with and without CAA. Discussion—CAA is more frequently found in genetically determined AD than in sporadic EOAD. Cerebrospinal fluid-Aβ40 levels are not a useful biomarker for CAA in AD

Differences in Emotion Regulation Considering Gender, Age, and Gambling Preferences in a Sample of Gambling Disorder Patients

Impairments in emotion regulation are understood to be a transdiagnostic risk factor of suffering from compulsive and addictive behaviors. The aim of this study was to investigate the role of emotion regulation deficits in gambling disorder and to analyze these differences taking gender, age, and gambling activity preferences into account. Methods: The sample included n = 484 patients seeking treatment for gambling disorder at a specialized outpatient service. Main outcomes were sociodemographic variables, emotion regulation, and gambling severity. Results: Differences between sexes were found in non-acceptance of emotions. Older patients obtained higher levels in non-acceptance of emotions, lack of emotion regulation strategies, emotional clarity, and global emotion regulation scores. No differences were found in emotion scores considering gambling preferences (non-strategic versus strategic). Path analysis showed that emotion regulation scores and age had a direct effect on gambling disorder severity, while emotion regulation and gambling preference were not mediational variables in the relationships of gender and age with gambling severity. Conclusions: Emotion regulation impairments differ in patients seeking treatment for gambling problems. Early prevention and intervention programs should incorporate the different dimensions of this process, taking into account clinical phenotypes

Molecular profiling of long-term responders to immune checkpoint inhibitors in advanced non-small cell lung cancer

Altres ajuts: This work was supported by the Fundacion Cientifica Asociación Española Contra el Cancer-AECC [grant number GCB14142170 to LMM, MS-C, and EF].Immunotherapy has transformed advanced non-small cell lung cancer (NSCLC) treatment strategies and has led to unprecedented long-lasting responses in some patients. However, the molecular determinants driving these long-term responses remain elusive. To address this issue, we performed an integrative analysis of genomic and transcriptomic features of long-term immune checkpoint inhibitors (ICIs)-associated responders. We assembled a cohort of 47 patients with NSCLC receiving ICIs that was enriched in long-term responders [>18 months of progression-free survival (PFS)]. We performed whole-exome sequencing from tumor samples, estimated the tumor mutational burden (TMB), and inferred the somatic copy number alterations (SCNAs). We also obtained gene transcription data for a subset of patients using Nanostring, which we used to assess the tumor immune infiltration status and PD-L1 expression. Our results indicate that there is an association between TMB and benefit to ICIs, which is driven by those patients with long-term response. Additionally, high SCNAs burden is associated with poor response and negatively correlates with the presence of several immune cell types (B cells, natural killers, regulatory T cells or effector CD8 T cells). Also, CD274 (PD-L1) expression is increased in patients with benefit, mainly in those with long-term response. In our cohort, combined assessment of TMB and SCNAs burden enabled identification of long-term responders (considering PFS and overall survival). Notably, the association between TMB, SCNAs burden, and PD-L1 expression with the outcomes of ICIs treatment was validated in two public datasets of ICI-treated patients with NSCLC. Thus, our data indicate that TMB is associated with long-term benefit following ICIs treatment in NSCLC and that TMB, SCNAs burden, and PD-L1 are complementary determinants of response to ICIs

Tocilizumab in visual involvement of giant cell arteritis: a multicenter study of 471 patients

Background: Visual involvement is the most feared complication of giant cell arteritis (GCA). Information on the efficacy of tocilizumab (TCZ) for this complication is scarce and controversial. Objective: We assessed a wide series of GCA treated with TCZ, to evaluate its role in the prevention of new visual complications and its efficacy when this manifestation was already present before the initiation of TCZ. Design: This is an observational multicenter study of patients with GCA treated with TCZ. Methods: Patients were divided into two subgroups according to the presence or absence of visual involvement before TCZ onset. Visual manifestations were classified into the following categories: transient visual loss (TVL), permanent visual loss (PVL), diplopia, and blurred vision. Results: Four hundred seventy-one GCA patients (mean age, 74 +/- 9 years) were treated with TCZ. Visual manifestations were observed in 122 cases (26%), of which 81 were present at TCZ onset: PVL (n = 60; unilateral/bilateral: 48/12), TVL (n = 17; unilateral/bilateral: 11/6), diplopia (n = 2), and blurred vision (n = 2). None of the patients without previous visual involvement or with TVL had new episodes after initiation of TCZ, while only 11 out of 60 (18%) patients with PVL experienced some improvement. The two patients with diplopia and one of the two patients with blurred vision improved. Conclusion: TCZ may have a protective effect against the development of visual complications or new episodes of TVL in GCA. However, once PVL was established, only a few patients improved