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1.  The Proximity between Hallucination and Delusion Dimensions: An Observational, Analytic, Cross-Sectional, Multicentre Study 
Frontiers in Psychology  2016;7:1642.
In psychiatric classifications, hallucinations (mainly auditory hallucinations) are one of the fundamental criteria for establishing a schizophrenia diagnosis or any of the related psychotic disorder's diagnoses. The conceptual proximity between delusions and hallucinations was maintained until the end of the XIX century, with several supporters during the XX century. Their limits were not yet definitely defined in terms of Descriptive Psychopathology, and much less so in terms of biochemical and anatomical models. In this article we aimed to analyse the dimensions of both hallucinations and delusions in a sample of patients with schizophrenia and schizoaffective disorder. We also intend to find the determinants of the main dimensions of hallucinations. One hundred patients with schizophrenia (80) or schizoaffective disorder (20), 64% males, mean age 39.75, from the outpatient and inpatient units of the Psychiatry Department of Hospital de Santa Maria and the Centro Hospitalar Psiquiátrico de Lisboa were assessed by means of the Psychotic Symptom Rating Scales (PSYRATS) and a structured interview. In this study we designed an empirical based model by means of bivariate Spearman's rank correlation coefficient, and multivariate statistics (linear regression and multiple multivariate linear regression), where the main dimensions of hallucinations are determined by the central dimensions of delusions.
PMCID: PMC5099164  PMID: 27877142
Psyrats; hallucinations; psychopathology; psychosis; delusions
2.  Acute Affective Responses and Frontal Electroencephalographic Asymmetry to Prescribed and Self-selected Exercise 
Our goal was to compare affective responses and frontal electroencephalographic alpha asymmetry induced by prescribed exercise (PE) and self-selected exercise (SS).
Twenty active participants underwent a submaximal exercise test to estimate maximal oxygen consumption (VO2max). Participants enrolled a cross-over randomized study where each participant completed three conditions: PE (50%PVO2max), SS and Control. The electroencephalography was performed before and after exercise. The feeling scale, felt arousal scale and heart rate were recorded before, during and after each condition. The ratings of perceived exertion were recorded during and after each condition.
The heart rate and ratings of perceived exertion showed higher values in the PE and SS conditions compared to controls, with no differences between the PE and SS conditions. For the feeling scale, the SS presented higher values compared to the PE and Control conditions. The felt arousal scale presented higher values in the PE and SS conditions compared to control. There was no interaction between condition and moment, or main effect for condition and moment for frontal alpha asymmetry (InF4-InF3).
The SS provided better affective responses compared to PE, thus can consider self-selected intensity as an appropriate option. In general, no frontal alpha asymmetry was seen due to an exercise intervention.
PMCID: PMC5095897  PMID: 27867416
Affective response; Frontal EEG asymmetry; Prescribed exercise; Self-selected exercise
3.  Insulin resistance uncoupled from dyslipidemia due to C-terminal PIK3R1 mutations 
JCI Insight  null;1(17):e88766.
Obesity-related insulin resistance is associated with fatty liver, dyslipidemia, and low plasma adiponectin. Insulin resistance due to insulin receptor (INSR) dysfunction is associated with none of these, but when due to dysfunction of the downstream kinase AKT2 phenocopies obesity-related insulin resistance. We report 5 patients with SHORT syndrome and C-terminal mutations in PIK3R1, encoding the p85α/p55α/p50α subunits of PI3K, which act between INSR and AKT in insulin signaling. Four of 5 patients had extreme insulin resistance without dyslipidemia or hepatic steatosis. In 3 of these 4, plasma adiponectin was preserved, as in insulin receptor dysfunction. The fourth patient and her healthy mother had low plasma adiponectin associated with a potentially novel mutation, p.Asp231Ala, in adiponectin itself. Cells studied from one patient with the p.Tyr657X PIK3R1 mutation expressed abundant truncated PIK3R1 products and showed severely reduced insulin-stimulated association of mutant but not WT p85α with IRS1, but normal downstream signaling. In 3T3-L1 preadipocytes, mutant p85α overexpression attenuated insulin-induced AKT phosphorylation and adipocyte differentiation. Thus, PIK3R1 C-terminal mutations impair insulin signaling only in some cellular contexts and produce a subphenotype of insulin resistance resembling INSR dysfunction but unlike AKT2 dysfunction, implicating PI3K in the pathogenesis of key components of the metabolic syndrome.
C-terminal mutations in human PIK3R1 are associated with severe insulin resistance in the absence of dyslipidemia or hepatic steatosis.
PMCID: PMC5070960  PMID: 27766312
4.  Mental Practice Combined with Motor Rehabilitation to Treat Upper Limb Hemiparesis of Post-Stroke Patients: Clinical and Experimental Evidence 
Stroke is one of the major causes of disability in the world. Due to the extended lifetime of the world's population, the number of people affected by stroke has increased substantially over the last years. Stroke may lead to sensorimotor deficits, usually causing hemiplegia or hemiparesia. In order to reduce motor deficits and accelerate functional recovery, MP combined with motor rehabilitation was introduced to the rehabilitation process of post-stroke patients. Evidence has shown that MP combining with motor rehabilitation based on activities of daily living was more effective than conventional motor rehabilitation used per se. This combination proved very useful and effective, with significant results in improvement of motor deficits in post-stroke patients. However, further studies must be conducted to determine specific parameters, such as type of imagery, frequency or duration.
PMCID: PMC4797678  PMID: 27346996
Hemiparesis; kinesthetic imagery; mental practice; stroke; visual imagery
5.  Acute knockdown of the insulin receptor or its substrates Irs1 and 2 in 3T3-L1 adipocytes suppresses adiponectin production 
Scientific Reports  2016;6:21105.
Loss of function of the insulin receptor (INSR) in humans produces severe insulin resistance. Unlike “common” insulin resistance, this is associated with elevated plasma levels of the insulin-sensitising, adipose-derived protein adiponectin. The underlying mechanism for this paradox is unclear, and it is at odds with the acute stimulation of adiponectin secretion reported on insulin treatment of cultured adipocytes. Given recent evidence for ligand-independent actions of the INSR, we used a lentiviral system to knock down Insr or its substrates Irs1 and Irs2 conditionally in 3T3-L1 murine preadipocytes/adipocytes to assess whether acute loss of their expression has different consequences to withdrawal of insulin. Efficient knockdown of either Insr or Irs1/2 was achieved by conditional shRNA expression, severely attenuating insulin-stimulated AKT phosphorylation and glucose uptake. Dual knockdown of Irs1 and Irs2 but not Insr in preadipocytes impaired differentiation to adipocytes. Acute knockdown of Insr or both Irs1 and Irs2 in adipocytes increased Adipoq mRNA expression but reduced adiponectin secretion, assessed by immunoassay. Knockdown sustained for 14 days also reduced immunoassay-detected adiponectin secretion, and moreover induced delipidation of the cells. These findings argue against a distinct effect of Insr deficiency to promote adiponectin secretion as the explanation for paradoxical insulin receptoropathy-related hyperadiponectinaemia.
PMCID: PMC4758029  PMID: 26888756
6.  Comparative Study of Subcortical Atrophy in Patients with Frontotemporal Dementia and Dementia with Extrapyramidal Signs 
Objectives : To investigate the severity of subcortical atrophy in frontotemporal dementia (FTD) without extrapyramidal symptoms (EPS) and dementia with EPS. In addition, we aim to verify if there is correlation between demographic and clinical characteristics and subcortical atrophy in the groups. Methodology : The sample was composed of 21 patients with dementia and EPS as well as 19 patients with FTD without EPS. A linear assessment was conducted in order to identify the degree of subcortical atrophy (i.e., bifrontal index - BFI) using MRI. Moreover, the Mini-Mental State Examination (MMSE), Pfeffer Functional Activities Questionnaire (FAQ) and the Clinical Dementia Rating (CDR) were used to investigate clinical aspects. Results : It was verified that patients with dementia and EPS was older than the patients with FTD (p=0.01). The severity of cognitive deficits was associated with BFI, as well as the dementia severity in the EPS group. Conclusion : FTD group presented mean BFI scores above the cutoff for normal elderly population, indicating the presence of subcortical atrophy in this group. Mean BFI was higher (although not statistically significant) in FTD group than in dementia with EPS, which can suggest at least that subcortical pathology in FTD may be as important as in the dementia with EPS group. Subcortical atrophy is a good biological marker for cognitive deterioration in FTD and in dementia with EPS.
PMCID: PMC4391205  PMID: 25870648
Bifrontal index; extrapyramidal signs; frontotemporal dementia; structural neuroimaging; subcortical atrophy.
7.  Physical Activity Interventions in Schools for Improving Lifestyle in European Countries 
Background : In the last decades, children’s and adolescents’ obesity and overweight have increased in European Countries. Unhealthy eating habits and sedentary lifestyle have been recognized to determine such an epidemic. Schools represent an ideal setting to modify harmful behaviors, and physical activity could be regarded as a potential way to avoid the metabolic risks related to obesity. Methods : A systematic review of the literature was carried out to summarize the evidence of school-based interventions aimed to promote, enhance and implement physical activity in European schools. Only randomized controlled trials were included, carried out in Europe from January 2000 to April 2014, universally delivered and targeting pupils aged between 3 and 18 years old. Results : Forty-seven studies were retrieved based either on multicomponent interventions or solely physical activity programs. Most aimed to prevent obesity and cardiovascular risks among youths. While few studies showed a decrease in BMI, positive results were achieved on other outcomes, such as metabolic parameters and physical fitness. Conclusion : Physical activity in schools should be regarded as a simple, non-expensive and enjoyable way to reach all the children and adolescents with adequate doses of moderate to vigorous physical activity.
PMCID: PMC4378026  PMID: 25834629
European countries; obesity prevention; physical activity; school-based intervention
8.  Hypogonadotropic Hypogonadism due to a Novel Missense Mutation in the First Extracellular Loop of the Neurokinin B Receptor 
The neurokinin B (NKB) receptor, encoded by TACR3, is widely expressed within the central nervous system, including hypothalamic nuclei involved in regulating GnRH release. We have recently reported two mutations in transmembrane segments of the receptor and a missense mutation in NKB in patients with normosmic isolated hypogonadotropic hypogonadism (nIHH).
Patients and Methods
We sequenced the TACR3 gene in a family in which three siblings had nIHH. The novel mutant receptor thus identified was studied in a heterologous expression system using calcium flux as the functional readout.
All affected siblings were homozygous for the His148Leu mutation, in the first extracellular loop of the NKB receptor. The His148Leu mutant receptor exhibited profoundly impaired signaling in response to NKB (EC50 = 3 ± 0.1 nm and >5 μm for wild-type and His148Leu, respectively). The location of the mutation in an extracellular part of the receptor led us also to test whether senktide, a synthetic NKB analog, may retain ability to stimulate the mutant receptor. However, the signaling activity of the His148Leu receptor in response to senktide was also severely impaired (EC50 = 1 ± 1 nm for wild-type and no significant response of His148Leu to 10 μm).
Homozygosity for the TACR3 His148Leu mutation leads to failure of sexual maturation in humans, whereas signaling by the mutant receptor in vitro in response to either NKB or senktide is severely impaired. These observations further strengthen the link between NKB, the NKB receptor, and regulation of human reproductive function.
PMCID: PMC4306717  PMID: 19755480
9.  Detrimental role of prolonged sleep deprivation on adult neurogenesis 
Adult mammalian brains continuously generate new neurons, a phenomenon called adult neurogenesis. Both environmental stimuli and endogenous factors are important regulators of adult neurogenesis. Sleep has an important role in normal brain physiology and its disturbance causes very stressful conditions, which disrupt normal brain physiology. Recently, an influence of sleep in adult neurogenesis has been established, mainly based on sleep deprivation studies. This review provides an overview on how rhythms and sleep cycles regulate hippocampal and subventricular zone neurogenesis, discussing some potential underlying mechanisms. In addition, our review highlights some interacting points between sleep and adult neurogenesis in brain function, such as learning, memory, and mood states, and provides some insights on the effects of antidepressants and hypnotic drugs on adult neurogenesis.
PMCID: PMC4396387  PMID: 25926773
sleep; adult neurogenesis; hypnotic drugs; antidepressants; circadian rhythms; hippocampus
10.  Hypomorphism in human NSMCE2 linked to primordial dwarfism and insulin resistance 
The Journal of Clinical Investigation  2014;124(9):4028-4038.
Structural maintenance of chromosomes (SMC) complexes are essential for maintaining chromatin structure and regulating gene expression. Two the three known SMC complexes, cohesin and condensin, are important for sister chromatid cohesion and condensation, respectively; however, the function of the third complex, SMC5–6, which includes the E3 SUMO-ligase NSMCE2 (also widely known as MMS21) is less clear. Here, we characterized 2 patients with primordial dwarfism, extreme insulin resistance, and gonadal failure and identified compound heterozygous frameshift mutations in NSMCE2. Both mutations reduced NSMCE2 expression in patient cells. Primary cells from one patient showed increased micronucleus and nucleoplasmic bridge formation, delayed recovery of DNA synthesis, and reduced formation of foci containing Bloom syndrome helicase (BLM) after hydroxyurea-induced replication fork stalling. These nuclear abnormalities in patient dermal fibroblast were restored by expression of WT NSMCE2, but not a mutant form lacking SUMO-ligase activity. Furthermore, in zebrafish, knockdown of the NSMCE2 ortholog produced dwarfism, which was ameliorated by reexpression of WT, but not SUMO-ligase–deficient NSMCE. Collectively, these findings support a role for NSMCE2 in recovery from DNA damage and raise the possibility that loss of its function produces dwarfism through reduced tolerance of replicative stress.
PMCID: PMC4151221  PMID: 25105364
11.  Genetic Defects in Human Pericentrin Are Associated With Severe Insulin Resistance and Diabetes 
Diabetes  2011;60(3):925-935.
Genetic defects in human pericentrin (PCNT), encoding the centrosomal protein pericentrin, cause a form of osteodysplastic primordial dwarfism that is sometimes reported to be associated with diabetes. We thus set out to determine the prevalence of diabetes and insulin resistance among patients with PCNT defects and examined the effects of pericentrin depletion on insulin action using 3T3-L1 adipocytes as a model system.
A cross-sectional metabolic assessment of 21 patients with PCNT mutations was undertaken. Pericentrin expression in human tissues was profiled using quantitative real-time PCR. The effect of pericentrin knockdown on insulin action and adipogenesis in 3T3-L1 adipocytes was determined using Oil red O staining, gene-expression analysis, immunoblotting, and glucose uptake assays. Pericentrin expression and localization also was determined in skeletal muscle.
Of 21 patients with genetic defects in PCNT, 18 had insulin resistance, which was severe in the majority of subjects. Ten subjects had confirmed diabetes (mean age of onset 15 years [range 5–28]), and 13 had metabolic dyslipidemia. All patients without insulin resistance were younger than 4 years old. Knockdown of pericentrin in adipocytes had no effect on proximal insulin signaling but produced a twofold impairment in insulin-stimulated glucose uptake, approximately commensurate with an associated defect in cell proliferation and adipogenesis. Pericentrin was highly expressed in human skeletal muscle, where it showed a perinuclear distribution.
Severe insulin resistance and premature diabetes are common features of PCNT deficiency but are not congenital. Partial failure of adipocyte differentiation may contribute to this, but pericentrin deficiency does not impair proximal insulin action in adipocytes.
PMCID: PMC3046854  PMID: 21270239
12.  Cholesterol sensor ORP1L contacts the ER protein VAP to control Rab7–RILP–p150Glued and late endosome positioning 
The Journal of Cell Biology  2009;185(7):1209-1225.
Late endosomes (LEs) have characteristic intracellular distributions determined by their interactions with various motor proteins. Motor proteins associated to the dynactin subunit p150Glued bind to LEs via the Rab7 effector Rab7-interacting lysosomal protein (RILP) in association with the oxysterol-binding protein ORP1L. We found that cholesterol levels in LEs are sensed by ORP1L and are lower in peripheral vesicles. Under low cholesterol conditions, ORP1L conformation induces the formation of endoplasmic reticulum (ER)–LE membrane contact sites. At these sites, the ER protein VAP (VAMP [vesicle-associated membrane protein]-associated ER protein) can interact in trans with the Rab7–RILP complex to remove p150Glued and associated motors. LEs then move to the microtubule plus end. Under high cholesterol conditions, as in Niemann-Pick type C disease, this process is prevented, and LEs accumulate at the microtubule minus end as the result of dynein motor activity. These data explain how the ER and cholesterol control the association of LEs with motor proteins and their positioning in cells.
PMCID: PMC2712958  PMID: 19564404
13.  A Genome-Wide Association Study Reveals Variants in ARL15 that Influence Adiponectin Levels 
PLoS Genetics  2009;5(12):e1000768.
The adipocyte-derived protein adiponectin is highly heritable and inversely associated with risk of type 2 diabetes mellitus (T2D) and coronary heart disease (CHD). We meta-analyzed 3 genome-wide association studies for circulating adiponectin levels (n = 8,531) and sought validation of the lead single nucleotide polymorphisms (SNPs) in 5 additional cohorts (n = 6,202). Five SNPs were genome-wide significant in their relationship with adiponectin (P≤5×10−8). We then tested whether these 5 SNPs were associated with risk of T2D and CHD using a Bonferroni-corrected threshold of P≤0.011 to declare statistical significance for these disease associations. SNPs at the adiponectin-encoding ADIPOQ locus demonstrated the strongest associations with adiponectin levels (P-combined = 9.2×10−19 for lead SNP, rs266717, n = 14,733). A novel variant in the ARL15 (ADP-ribosylation factor-like 15) gene was associated with lower circulating levels of adiponectin (rs4311394-G, P-combined = 2.9×10−8, n = 14,733). This same risk allele at ARL15 was also associated with a higher risk of CHD (odds ratio [OR] = 1.12, P = 8.5×10−6, n = 22,421) more nominally, an increased risk of T2D (OR = 1.11, P = 3.2×10−3, n = 10,128), and several metabolic traits. Expression studies in humans indicated that ARL15 is well-expressed in skeletal muscle. These findings identify a novel protein, ARL15, which influences circulating adiponectin levels and may impact upon CHD risk.
Author Summary
Through a meta-analysis of genome-wide association studies of 14,733 individuals, we identified common base-pair variants in the genome which influence circulating adiponectin levels. Since adiponectin is an adipocyte-derived circulating protein which has been inversely associated with risk of obesity-related diseases such as type 2 diabetes (T2D) and coronary heart disease (CHD), we next sought to understand if the identified variants influencing adiponectin levels also influence risk of T2D, CHD, and several metabolic traits. In addition to confirming that variation at the ADIPOQ locus influences adiponectin levels, our analyses point to a variant in the ARL15 (ADP-ribosylation factor-like 15) locus which decreases adiponectin levels and increases risk of CHD and T2D. Further, this same variant was associated with increased fasting insulin levels and glycated hemoglobin. While the function of ARL15 is not known, we provide insight into the tissue specificity of ARL15 expression. These results thus provide novel insights into the physiology of the adiponectin pathway and obesity-related diseases.
PMCID: PMC2781107  PMID: 20011104
14.  Activation of endosomal dynein motors by stepwise assembly of Rab7–RILP–p150Glued, ORP1L, and the receptor βlll spectrin 
The Journal of Cell Biology  2007;176(4):459-471.
The small GTPase Rab7 controls late endocytic transport by the minus end–directed motor protein complex dynein–dynactin, but how it does this is unclear. Rab7-interacting lysosomal protein (RILP) and oxysterol-binding protein–related protein 1L (ORP1L) are two effectors of Rab7. We show that GTP-bound Rab7 simultaneously binds RILP and ORP1L to form a RILP–Rab7–ORP1L complex. RILP interacts directly with the C-terminal 25-kD region of the dynactin projecting arm p150Glued, which is required for dynein motor recruitment to late endocytic compartments (LEs). Still, p150Glued recruitment by Rab7–RILP does not suffice to induce dynein-driven minus-end transport of LEs. ORP1L, as well as βIII spectrin, which is the general receptor for dynactin on vesicles, are essential for dynein motor activity. Our results illustrate that the assembly of microtubule motors on endosomes involves a cascade of linked events. First, Rab7 recruits two effectors, RILP and ORP1L, to form a tripartite complex. Next, RILP directly binds to the p150Glued dynactin subunit to recruit the dynein motor. Finally, the specific dynein motor receptor Rab7–RILP is transferred by ORP1L to βIII spectrin. Dynein will initiate translocation of late endosomes to microtubule minus ends only after interacting with βIII spectrin, which requires the activities of Rab7–RILP and ORP1L.
PMCID: PMC2063981  PMID: 17283181

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