Publications by authors named "Antonio Vargas"

67 Publications

A Prospective Open-Label Observational Study of a Buffered Soluble 70 mg Alendronate Effervescent Tablet on Upper Gastrointestinal Safety and Medication Errors: The GastroPASS Study.

JBMR Plus 2021 Jul 17;5(7):e10510. Epub 2021 May 17.

Rheumatology Service Hospital del Mar, Passeig Marítim and IMIM (Hospital del Mar Medical Research Institute), Parc de Recerca Biomèdica de Barcelona Barcelona Spain.

Upper gastrointestinal (GI) side effects are a main reason for discontinuing bisphosphonate treatment, an important therapeutic option for osteoporosis patients. Consequently, the development of novel formulations with improved tolerability is warranted. In this multicenter prospective, observational, postauthorization safety study conducted in Italy and Spain, postmenopausal women (PMW) with osteoporosis (naïve to bisphosphonates) were treated weekly with a buffered soluble alendronate 70 mg effervescent (ALN-EFF) tablet (Binosto®) and followed for 12 ± 3 months. Information was collected on adverse events (AEs), medication errors, persistence, and compliance using the Morisky-Green questionnaire. Patients ( = 1028) aged 67 ± 9 years (mean ± SD) received ALN-EFF weekly. The cumulative incidence of upper GI AEs (oesophageal toxicity, gastritis, gastric ulcers, and duodenitis) related to ALN-EFF (primary endpoint) was 9.6% (95% confidence interval [CI] 7.9-11.6%), the vast majority being of mild intensity. The most frequently occurring upper GI AEs related to ALN-EFF were dyspepsia (2.7%), gastroesophageal reflux disease (2.4%), and nausea (2.2%). None of the relevant upper GI AEs listed in the primary endpoint and no serious AEs were reported. At least one medication error occurred in 29.9% (95% CI 27.1-32.8%) of patients. However, the majority of medication errors were associated with administration instructions applicable to any oral bisphosphonate and only seven medication errors were associated with the ALN-EFF formulation. ALN-EFF was discontinued in 209 of 1028 (20.3%) patients. The most frequent reasons for discontinuation were AEs related to ALN-EFF (46.9%) and patients' decision (42.6%). Compliance with ALN-EFF was high, reflected by a mean Morisky-Green score of 92.8 ± 18.6. PMW with osteoporosis treated with ALN-EFF in a real-world setting experienced few upper GI AEs. In addition, they had a low discontinuation and high compliance compared with other formulations, suggesting that ALN-EFF may increase patient satisfaction and therefore long-term adherence and efficacy. © 2021 The Authors. published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbm4.10510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260812PMC
July 2021

Analysis of Both Lipid Metabolism and Endocannabinoid Signaling Reveals a New Role for Hypothalamic Astrocytes in Maternal Caloric Restriction-Induced Perinatal Programming.

Int J Mol Sci 2021 Jun 11;22(12). Epub 2021 Jun 11.

Instituto de Investigación Biomédica de Málaga-IBIMA, 29010 Málaga, Spain.

Maternal malnutrition in critical periods of development increases the risk of developing short- and long-term diseases in the offspring. The alterations induced by this nutritional programming in the hypothalamus of the offspring are of special relevance due to its role in energy homeostasis, especially in the endocannabinoid system (ECS), which is involved in metabolic functions. Since astrocytes are essential for neuronal energy efficiency and are implicated in brain endocannabinoid signaling, here we have used a rat model to investigate whether a moderate caloric restriction (R) spanning from two weeks prior to the start of gestation to its end induced changes in offspring hypothalamic (a) ECS, (b) lipid metabolism (LM) and/or (c) hypothalamic astrocytes. Monitorization was performed by analyzing both the gene and protein expression of proteins involved in LM and ECS signaling. Offspring born from caloric-restricted mothers presented hypothalamic alterations in both the main enzymes involved in LM and endocannabinoids synthesis/degradation. Furthermore, most of these changes were similar to those observed in hypothalamic offspring astrocytes in culture. In conclusion, a maternal low caloric intake altered LM and ECS in both the hypothalamus and its astrocytes, pointing to these glial cells as responsible for a large part of the alterations seen in the total hypothalamus and suggesting a high degree of involvement of astrocytes in nutritional programming.
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http://dx.doi.org/10.3390/ijms22126292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230792PMC
June 2021

A Negative Energy Balance Is Associated with Metabolic Dysfunctions in the Hypothalamus of a Humanized Preclinical Model of Alzheimer's Disease, the 5XFAD Mouse.

Int J Mol Sci 2021 May 20;22(10). Epub 2021 May 20.

Instituto de investigación Biomédica de Málaga-IBIMA, 29010 Málaga, Spain.

Increasing evidence links metabolic disorders with neurodegenerative processes including Alzheimer's disease (AD). Late AD is associated with amyloid (Aβ) plaque accumulation, neuroinflammation, and central insulin resistance. Here, a humanized AD model, the 5xFAD mouse model, was used to further explore food intake, energy expenditure, neuroinflammation, and neuroendocrine signaling in the hypothalamus. Experiments were performed on 6-month-old male and female full transgenic (Tg), heterozygous (Tg), and non-transgenic (Non-Tg) littermates. Although histological analysis showed absence of Aβ plaques in the hypothalamus of 5xFAD mice, this brain region displayed increased protein levels of GFAP and IBA1 in both Tg and Tg mice and increased expression of IL-1β in Tg mice, suggesting neuroinflammation. This condition was accompanied by decreased body weight, food intake, and energy expenditure in both Tg and Tg mice. Negative energy balance was associated with altered circulating levels of insulin, GLP-1, GIP, ghrelin, and resistin; decreased insulin and leptin hypothalamic signaling; dysregulation in main metabolic sensors (phosphorylated IRS1, STAT5, AMPK, mTOR, ERK2); and neuropeptides controlling energy balance (NPY, AgRP, orexin, MCH). These results suggest that glial activation and metabolic dysfunctions in the hypothalamus of a mouse model of AD likely result in negative energy balance, which may contribute to AD pathogenesis development.
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http://dx.doi.org/10.3390/ijms22105365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161294PMC
May 2021

Recombinant IGF-1 Induces Sex-Specific Changes in Bone Composition and Remodeling in Adult Mice with Deficiency.

Int J Mol Sci 2021 Apr 14;22(8). Epub 2021 Apr 14.

Departamento de Anatomía Humana, Medicina Legal e Historia de la Ciencia, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, 29071 Málaga, Spain.

Deficiency of pregnancy-associated plasma protein-A2 (PAPP-A2), an IGF-1 availability regulator, causes postnatal growth failure and dysregulation of bone size and density. The present study aimed to determine the effects of recombinant murine IGF-1 (rmIGF-1) on bone composition and remodeling in constitutive knock-out (ko/ko) mice. To address this challenge, X-ray diffraction (XRD), attenuated total reflection-fourier transform infra-red (ATR-FTIR) spectroscopy and gene expression analysis of members of the IGF-1 system and bone resorption/formation were performed. mice (both sexes) had reduced body and bone length. Male mice had specific alterations in bone composition (mineral-to-matrix ratio, carbonate substitution and mineral crystallinity), but not in bone remodeling. In contrast, decreases in collagen maturity and increases in , (resorption) and (formation) characterized the bone of females. A single rmIGF-1 administration (0.3 mg/kg) induced short-term changes in bone composition in mice (both sexes). rmIGF-1 treatment in females also increased collagen maturity, and , , and expression. In summary, acute IGF-1 treatment modifies bone composition and local IGF-1 response to bone remodeling in mice with deficiency. These effects depend on sex and provide important insights into potential IGF-1 therapy for growth failure and bone loss and repair.
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http://dx.doi.org/10.3390/ijms22084048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070906PMC
April 2021

Severe acute malnutrition morphological patterns in children under five.

Sci Rep 2021 Feb 19;11(1):4237. Epub 2021 Feb 19.

Laboratoire de Recherche en Nutrition et Alimentation Humaine (LARNAH), Département de Biologie Animale, Université Cheikh Anta Diop de Dakar, Dakar, Senegal.

Current methods for infant and child nutritional assessment rely on anthropometric measurements, whose implementation faces technical challenges in low- and middle-income countries. Anthropometry is also limited to linear measurements, ignoring important body shape information related to health. This work proposes the use of 2D geometric morphometric techniques applied to a sample of Senegalese participants aged 6-59 months with an optimal nutritional condition or with severe acute malnutrition to address morphometric variations due to nutritional status. Significant differences in shape and size body changes were described according to nutritional status, resulting age, sex and allometric effect crucial factors to establish nutritional morphological patterns. The constructed discriminant functions exhibited the best classification rates in the left arm. A landmark-based template registering body shape could be useful to both assess acute malnutrition and better understand the morphological patterns that nutritional status promotes in children during their first 5 years of growth and development.
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http://dx.doi.org/10.1038/s41598-021-82727-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895927PMC
February 2021

Impact of Different Levels of Supervision on the Recovery of Severely Malnourished Children Treated by Community Health Workers in Mali.

Nutrients 2021 Jan 26;13(2). Epub 2021 Jan 26.

Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, 1870 Copenhagen, Denmark.

(1) Background: The Ministry of Health in Mali included the treatment of severe acute malnutrition (SAM) into the package of activities of the integrated community case management (iCCM). This paper evaluates the most effective model of supervision for treating SAM using community health workers (CHWs). Methods (2): This study was a prospective non-randomized community intervention trial with two intervention groups and one control group with different levels of supervision. It was conducted in three districts in rural areas of the Kayes Region. In the high supervision group, CHWs received supportive supervision for the iCCM package and nutrition-specific supervision. In the light supervision group, CHWs received supportive supervision based on the iCCM package. The control group had no specific supervision. (3) Results: A total of 6112 children aged 6-59 months with SAM without medical complications were included in the study. The proportion of cured children was 81.4% in those treated by CHWs in the high supervision group, 86.2% in the light supervision group, and 66.9% in the control group. Children treated by the CHWs who received some supervision had better outcomes than those treated by unsupervised CHWs ( < 0.001). There was no difference between areas with light and high supervision, although those with high supervision performed better in most of the tasks analyzed. (4) Conclusions: Public policies in low-income countries should be adapted, and their model of supervision of CHWs for SAM treatment in the community should be evaluated.
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http://dx.doi.org/10.3390/nu13020367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911749PMC
January 2021

Sex-specific behavioral and neurogenic responses to cocaine in mice lacking and blocking dopamine D1 or dopamine D2 receptors.

J Comp Neurol 2021 Jun 22;529(8):1724-1742. Epub 2020 Oct 22.

UGC Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Regional de Málaga, Universidad de Málaga, Málaga, Spain.

Adult neurogenesis in rodents is modulated by dopaminergic signaling and inhibited by cocaine. However, the sex-specific role of dopamine D1 and D2 receptors (D1R, D2R) in the deleterious effect of cocaine on adult neurogenesis has not been described yet. Here, we explored sex differences in (a) cell proliferation (5'-bromo-2'-deoxyuridine [BrdU]), (b) neural precursor (nestin), (c) neuronal phenotype (BrdU/β3-tubulin), and (d) neuronal maturity (NeuN) in the subventricular zone (SVZ) of the lateral ventricles and striatum of mice with genetic deletion (D1 , D2 ) or pharmacological blockage (SCH23390: 0.1 mg/kg/day/5 days; Raclopride: 0.3 mg/kg/day/5 days) of D1R and D2R, and treated (10 mg/kg/day/5 days) and then challenged (5 mg/kg, 48 hr later) with cocaine. Results indicated that hyperactivity responses to cocaine were absent in D1 mice and reduced in SCH23390-treated mice. Activity responses to cocaine were reduced in D2 males, but absent in D2 females and increased in Raclopride-treated females. D1R deletion blocked the deleterious effect of cocaine on SVZ cell proliferation in males. Cocaine-exposed D1 males also had reduced neuronal phenotype of SVZ newborn cells and increased striatal neuronal maturity. D2 mice had lower proliferative and neural precursor responses. Cocaine in D2 females or coadministered with Raclopride in wild-type females improved SVZ cell proliferation, an effect that positively correlated with plasma brain-derived neurotrophic factor (BDNF) concentrations. In conclusion, the sex-specific D1R and D2R signaling on SVZ cell proliferation, neural progenitor and neuronal maturity is differentially perturbed by cocaine, and BDNF may be required to link D2R to neuroplasticity in cocaine addiction in females.
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http://dx.doi.org/10.1002/cne.25052DOI Listing
June 2021

Maternal hypercaloric diet affects factors involved in lipid metabolism and the endogenous cannabinoid systems in the hypothalamus of adult offspring: sex-specific response of astrocytes to palmitic acid and anandamide.

Nutr Neurosci 2020 Sep 21:1-14. Epub 2020 Sep 21.

Department of Endocrinology, Fundación Investigación Biomédica del Hospital Infantil Universitario Niño Jesús, Instituto de Investigación Biomédica la Princesa, Madrid, Spain.

We aimed to investigate whether maternal malnutrition during gestation/lactation induces long-lasting changes on inflammation, lipid metabolism and endocannabinoid signaling in the adult offspring hypothalamus and the role of hypothalamic astrocytes in these changes. We analyzed the effects of a free-choice hypercaloric palatable diet (P) during (pre)gestation, lactation and/or post-weaning on inflammation, lipid metabolism and endogenous cannabinoid signaling in the adult offspring hypothalamus. We also evaluated the response of primary hypothalamic astrocytes to palmitic acid and anandamide. Postnatal exposure to a P diet induced factors involved in hypothalamic inflammation ( and ) and gliosis ( and ) in adult offspring, being more significant in females. In contrast, maternal P diet reduced factors involved in astrogliosis (), fatty acid oxidation () and monounsaturated fatty acid synthesis (). These changes were accompanied by an increase in the expression of the genes for the cannabinoid receptor () and an enzyme involved in endocannabinoid synthesis, in females and a decrease in the endocannabinoid degradation enzyme in males. These changes suggest that the maternal P diet results in sex-specific alterations in hypothalamic endocannabinoid signaling and lipid metabolism. This hypothesis was tested in hypothalamic astrocyte cultures, where palmitic acid (PA) and the polyunsaturated fatty acid N-arachidonoylethanolamine (anandamide or AEA) were found to induce similar changes in the endocannabinoid system (ECS) and lipid metabolism. These results stress the importance of both maternal diet and sex in long term metabolic programming and suggest a possible role of hypothalamic astrocytes in this process.
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http://dx.doi.org/10.1080/1028415X.2020.1821519DOI Listing
September 2020

Abrupt cessation of reboxetine along alcohol deprivation results in alcohol intake escalation after reinstatement of drinking.

Addict Biol 2021 05 20;26(3):e12957. Epub 2020 Aug 20.

Departamento de Psicobiología y Metodología en Ciencias del Comportamiento, Facultad de Psicología, Universidad Complutense de Madrid, Madrid, Spain.

Major depression (MD) is a frequent comorbidity in alcohol use disorder (AUD) patients. Antidepressant prescription is often limited by poor clinical outcomes or unwanted side effects in comorbid AUD-MD patients. Recent studies suggest that abrupt cessation of selective serotonin reuptake inhibitors antidepressant treatment increases alcohol consumption after an alcohol deprivation period in rats. However, the appearance of this effect after the treatment with selective noradrenaline reuptake inhibitors (SNRIs) is not known. Here, we report that interruption of subchronic (14 days) treatment with the SNRIs reboxetine (15 mg/kg/day intraperitoneally) resulted in escalation of ethanol intake when the animals resume alcohol self-administration. This effect of reboxetine treatment cessation was associated with a profound deactivation of the endocannabinoid/acylethanolamide signaling system in the prefrontal cortex but not in the dorsal hippocampus, as reflected by the decrease in the protein expression of the cannabinoid CB receptor, the PPARα receptor, the 2-arachidonoylglycerol synthesizing enzymes DAGLα and DGALβ, and the endocanabinoid degrading enzyme MAGL. This was associated with dysregulation of the expression of glutamic acid receptors GluN1, GluA1, and mGlu5 in the medial prefrontal cortex and the dorsal hippocampus of the animals exposed to reboxetine. The present results further support the idea that abrupt cessation of antidepressant therapy along alcohol deprivation time can boost alcohol intake after relapse through mechanisms associated with endocannabinoid/glutamate signaling dysregulation. This finding might be relevant for patients suffering AUD/MD comorbidity where antidepressant therapy must be monitored with caution for avoiding unwanted side effects if adherence to the treatment is not fully achieved.
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http://dx.doi.org/10.1111/adb.12957DOI Listing
May 2021

Sex-Specific Anxiety and Prefrontal Cortex Glutamatergic Dysregulation Are Long-Term Consequences of Pre-and Postnatal Exposure to Hypercaloric Diet in a Rat Model.

Nutrients 2020 Jun 19;12(6). Epub 2020 Jun 19.

Hospital Regional Universitario de Málaga, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, 29010 Málaga, Spain.

Both maternal and early life malnutrition can cause long-term behavioral changes in the offspring, which depends on the caloric availability and the timing of the exposure. Here we investigated in a rat model whether a high-caloric palatable diet given to the mother and/or to the offspring during the perinatal and/or postnatal period might dysregulate emotional behavior and prefrontal cortex function in the offspring at adult age. To this end, we examined both anxiety responses and the mRNA/protein expression of glutamatergic, GABAergic and endocannabinoid signaling pathways in the prefrontal cortex of adult offspring. Male animals born from mothers fed the palatable diet, and who continued with this diet after weaning, exhibited anxiety associated with an overexpression of the mRNA of , and glutamate receptors in the prefrontal cortex. In addition, these animals had a reduced expression of the endocannabinoid system, the main inhibitory retrograde input to glutamate synapses, reflected in a decrease of the receptor and the enzyme. In conclusion, a hypercaloric maternal diet induces sex-dependent anxiety, associated with alterations in both glutamatergic and cannabinoid signaling in the prefrontal cortex, which are accentuated with the continuation of the palatable diet during the life of the offspring.
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http://dx.doi.org/10.3390/nu12061829DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7353464PMC
June 2020

Differential hepatoprotective role of the cannabinoid CB and CB receptors in paracetamol-induced liver injury.

Br J Pharmacol 2020 07 15;177(14):3309-3326. Epub 2020 Apr 15.

UGC Salud Mental, Hospital Regional Universitario de Málaga, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, Málaga, Spain.

Background And Purpose: Protective mechanisms of the endogenous cannabinoid system against drug-induced liver injury (DILI) are actively being investigated regarding the differential regulatory role of the cannabinoid CB and CB receptors in liver fibrogenesis and inflammation.

Experimental Approach: The 2-arachidonoylglycerol (2-AG)-related signalling receptors and enzymatic machinery, and inflammatory/fibrogenic factors were investigated in the liver of a mouse model of hepatotoxicity induced by acute and repeated overdoses (750 mg·kg ·day ) of paracetamol (acetaminophen), previously treated with selective CB (ACEA) and CB (JWH015) agonists (10 mg·kg ), or lacking CB and CB receptors.

Key Results: Acute paracetamol increased the expression of CB , ABHD6 and COX-2, while repeated paracetamol increased that of CB and COX-2 and decreased that of DAGLβ. Both acute paracetamol and repeated paracetamol decreased the liver content of acylglycerols (2-AG, 2-LG and 2-OG). Human liver samples from a patient suffering APAP hepatotoxicity confirmed CB and CB increments. Acute paracetamol-exposed CB KO mice had higher expression of the fibrogenic αSMA and the cytokine IL-6 and lower apoptotic cleaved caspase 3. CB deficiency enhanced the repeated APAP-induced increases in αSMA and cleaved caspase 3 and blocked those of CYP2E1, TNF-α, the chemokine CCL2 and the circulating γ-glutamyltransferase (γGT). Although JWH015 reduced the expression of αSMA and TNF-α in acute paracetamol, ACEA increased the expression of cleaved caspase 3 and CCL2 in repeated paracetamol.

Conclusion And Implications: The differential role of CB versus CB receptors on inflammatory/fibrogenic factors related to paracetamol-induced hepatotoxicity should be considered for designing alternative therapies against DILI.
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http://dx.doi.org/10.1111/bph.15051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312315PMC
July 2020

Bringing severe acute malnutrition treatment close to households through community health workers can lead to early admissions and improved discharge outcomes.

PLoS One 2020 5;15(2):e0227939. Epub 2020 Feb 5.

Action Against Hunger, New York, New York, United States of America.

Severe acute malnutrition (SAM) affects over 16.6 million children worldwide. The integrated Community Case Management (iCCM) strategy seeks to improve essential health by means of nonmedical community health workers (CHWs) who treat the deadliest infectious diseases in remote rural areas where there is no nearby health center. The objective of this study was to assess whether SAM treatment delivered by CHWs close to families' locations may improve the early identification of cases compared to outpatient treatment at health facilities (HFs), with a decreased number complicated cases referred to stabilization centers, increased anthropometric measurements at admission (closer to the admission threshold) and similarity in clinical outcomes (cure, death, and default). The study included 930 children aged 6 to 59 months suffering from SAM in the Kita district of the Kayes Region in Mali; 552 children were treated by trained CHWs. Anthropometric measurements, the presence of edema, and other medical signs were recorded at admission, and the length of stay and clinical outcomes were recorded at discharge. The results showed fewer children with edema at admission in the CHW group than in the HF group (0.4% vs. 3.7%; OR = 10.585 [2.222-50.416], p = 0.003). Anthropometric measurements at admission were higher in the CHW group, with fewer children falling into the lowest quartiles of both weight-for-height z-scores (20.2% vs. 31.5%; p = 0.002) and mid-upper arm circumference (18.0% vs. 32.4%; p<0.001), than in the HF group. There was no difference in the length of stay. More children in the CHW group were cured (95.9% vs. 88.7%; RR = 3.311 [1.772-6.185]; p<0.001), and there were fewer defaulters (3.7% vs. 9.8%; RR = 3.345 [1.702-6.577]; p<0.001) than in the HF group. Regression analyses demonstrated that less severe anthropometric measurements at admission resulted in an increased probability of cure at discharge. The study results also showed that CHWs provided more integrated care, as they diagnosed and treated significantly more cases of infectious diseases than HFs (diarrhea: 36.0% vs. 18.3%, p<0.001; malaria: 41.7% vs. 19.8%, p<0.001; acute respiratory infection: 34.8% vs. 25.2%, p = 0.007). The addition of SAM treatment in the curative tasks that the CHWs provided to the families resulted in earlier admission and more integrated care for children than those associated with HFs. CHW treatment also achieved better discharge outcomes than standard community treatment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0227939PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001926PMC
April 2020

Impulse control symptoms in patients with Parkinson's disease: The influence of dopaminergic agonist.

Parkinsonism Relat Disord 2019 11 26;68:17-21. Epub 2019 Jun 26.

Universidade Federal de Minas Gerais, Unidade de Distúrbios Do Movimento, Departamento de Medicina Interna, Serviço de Neurologia, Belo Horizonte, MG, Brazil. Electronic address:

Background: Impulse control disorders and punding are common in Parkinson's disease patients. Cross-sectional studies suggest an association between dopamine replacement therapy, especially dopaminergic agonists, and impulse control and related disorders in Parkinson's disease. However, some surveys suggest that Parkinson's disease itself does not confer an altered risk for impulse control disorders and related behavior, although these disturbances are more frequently reported in Parkinsonian patients than in healthy controls.

Objective: To ascertain the frequency of impulse control disorders and punding symptoms in Parkinson's disease patients and healthy controls and to determine the influence of dopamine agonist treatment on the prevalence of these disturbances.

Methods: A case-control study was conducted on 207 Parkinson's disease patients (79 taking dopamine agonists) and 230 healthy controls. The outcome measures were the presence of current impulse control disorders and punding symptoms, based on clinical criteria after application of the Minnesota Impulsive Disorders Interview for screening.

Results: The frequency of impulse control disorders in Parkinson's disease patients vs. Healthy controls was 16.9% vs. 15.2% (p = 0.631). Punding was more frequent in Parkinson's disease patients (p = 0.028); however, impulse control disorders were more frequent in medicated Parkinson's disease patients taking dopamine agonists than in medicated patients not taking dopamine agonists (p = 0.001) and healthy controls (p = 0.014).

Conclusions: Parkinson's disease itself does not lead to the development of impulse control disorders. Dopaminergic agonist treatment may trigger the disorder in susceptible individuals. Punding may be more prevalent in Parkinson's disease patients.
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http://dx.doi.org/10.1016/j.parkreldis.2019.06.019DOI Listing
November 2019

LMNA-Related Muscular Dystrophy with Clinical Intrafamilial Variability.

J Mol Neurosci 2019 Dec 13;69(4):623-627. Epub 2019 Aug 13.

Human Genome and Stem Cells Research Center, Genetics and Evolutionary Biology Department, IBUSP, University of São Paulo, Rua do Matão, Travessa 13, no. 106, São Paulo, SP, 05508-090, Brazil.

The LMNA gene is associated to a huge broad of phenotypes, including congenital Emery-Dreifuss muscular dystrophy and late-onset LMNA-related muscular dystrophy. In these forms, muscle weakness, contractures, and cardiac impairment are common. In an autosomal dominant pedigree including 5 affected patients, NGS molecular analysis performed in 6 relatives identifies the heterozygous c.1129C>T p.Arg377Cys variant in the exon 6 of the LMNA gene in three of them. Clinical, laboratorial, imaging investigation of these affected patients showed a significant clinical variability: the father presented subclinical imaging muscular dystrophy masqueraded as radiculopathy. One of his sons presented cardiac arrhythmia, muscular weakness, elbow contractures, and intranuclear pseudoinclusions on muscle biopsy. A second son presented only decreased tendon reflexes. Two other brothers presenting myalgia and cramps were not carriers of the same mutation in the LMNA gene. Early diagnosis, considering these variable phenotype and genotype, is important for genetic counseling, as well as cardiac, and rehabilitation management.
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http://dx.doi.org/10.1007/s12031-019-01390-0DOI Listing
December 2019

Erratum to "Oleoylethanolamide restores alcohol-induced inhibition of neuronal proliferation and microglial activity in striatum" [Neuropharmacology 146 (2019) 184-197].

Neuropharmacology 2019 Dec 17;160:107708. Epub 2019 Jul 17.

Instituto de Investigación Biomédica de Málaga (IBIMA), UGC Salud Mental, Universidad de Málaga, Hospital Universitario Regional de Málaga, Málaga, Spain. Electronic address:

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http://dx.doi.org/10.1016/j.neuropharm.2019.107708DOI Listing
December 2019

Oleoylethanolamide Modulates BDNF-ERK Signaling and Neurogenesis in the Hippocampi of Rats Exposed to Δ-THC and Ethanol Binge Drinking During Adolescence.

Front Mol Neurosci 2019 24;12:96. Epub 2019 Apr 24.

Instituto de Investigación Biomédica de Málaga, U.G.C. de Salud Mental, Hospital Regional Universitario de Málaga, Málaga, Spain.

Oleoylethanolamide is an endogenous NAE that modulates ethanol-seeking behavior and ethanol-induced neuroinflammation. In the present study we further analyze the role of OEA in hippocampal neurogenesis, BDNF-ERK signaling, and spatial memory that are affected by alcohol. Additionally, we addressed the effects of OEA on the association of alcohol and cannabis, a frequent combination in human alcohol addicts, and whose long-term effects are far from being understood. To this end, OEA (10 mg/kg/day, i.p.) was pharmacologically administered for 5 days/week in a preclinical model of adolescent rats with binge-like consumption (1 day/week) of ethanol (3 g/kg, i.g.) combined or not with acute administrations of Δ-THC (5 mg/kg, i.p.) for 5 weeks. OEA restored ethanol/THC-related decreases in both short-term spatial memory (spontaneous alternation by Y-maze) and circulating levels of BDNF, reduced cell proliferation ( and IdU+ cells) and maturation (, ), and improved cell survival ( and BrdU+ cells) in the dorsal hippocampus. Interestingly, OEA alone or combined with THC also decreased the mRNA levels of neurotrophic factors (, ) and the NT3 receptor , but increased the BDNF receptor in the hippocampus of ethanol-exposed rats. These effects were likely associated with a OEA-specific phosphorylation of AKT and ERK1, key signaling regulators of cell proliferation and survival. These results suggest a regulatory role of OEA in short-term spatial memory and hippocampal neurogenesis through BDNF/AKT/ERK1 signaling in response to acute THC in an alcoholic context during adolescence.
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http://dx.doi.org/10.3389/fnmol.2019.00096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6491684PMC
April 2019

Bupropion, a possible antidepressant without negative effects on alcohol relapse.

Eur Neuropsychopharmacol 2019 06 4;29(6):756-765. Epub 2019 May 4.

Departamento de Psicobiología y Metodología en Ciencias del Comportamiento, Facultad de Psicología, Universidad Complutense de Madrid, 28224 Spain; Laboratorio de Medicina Regenerativa, Instituto de Investigación Biomédica de Málaga (IBIMA), UGC Salud Mental, Hospital Regional Universitario de Málaga, Av. Carlos Haya 82, sótano, Málaga 29010, Spain. Electronic address:

Rationale: the role that antidepressants play on alcohol consumption is not well understood. Previous studies have reported that treatment with a Selective Serotonin Reuptake Inhibitor (SSRIs) increases alcohol consumption in an animal model of relapse, however it is unknown whether this effect holds for other antidepressants such as the atypical dopamine/norepinephrine reuptake inhibitors (SNDRI).

Objectives: the main goal of the present study was to compare the effects of two classes of antidepressants drugs, bupropion (SNDRI) and fluoxetine (SSRI), on alcohol consumption during relapse. Since glutamatergic and endocannabinoid signaling systems plays an important role in alcohol abuse and relapse, we also evaluated the effects of both antidepressants onthe expression of the main important genes and proteins of both systems in the prefrontal cortex, a critical brain region in alcohol relapse.

Methods: rats were trained to self-administered alcohol. During abstinence, rats received a 14d-treatment with vehicle, fluoxetine (10 mg/kg) or bupropion (20 mg/kg), and we evaluated alcohol consumption during relapse for 3 weeks. Samples of prefrontal cortex were taken to evaluate the mRNA and protein expression of the different components of glutamatergic and endocannabinoid signaling systems.

Results: fluoxetine treatment induced a long-lasting increase in alcohol consumption during relapse, an effect that was not observed in the case of bupropion treatment. The observed increases in alcohol consumption were accompanied by distinct alterations in the glutamate and endocannabinoid systems.

Conclusions: our results suggest that SSRIs can negatively impact alcohol consumption in relapse while SNDRIs have no effects. The observed increase in alcohol consumption are accompanied by functional alterations in the glutamatergic and endocannabinoid systems. This finding could open new strategies for the treatment of depression in patients with alcohol use disorders.
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http://dx.doi.org/10.1016/j.euroneuro.2019.03.012DOI Listing
June 2019

Describing the children's body shape by means of Geometric Morphometric techniques.

Am J Phys Anthropol 2019 04 10;168(4):651-664. Epub 2019 Jan 10.

Grupo de investigación EPINUT, Facultad de Medicina, Departamento de Biodiversidad, Ecología y Evolución, Universidad Complutense de Madrid (UCM), Madrid, Spain.

Introduction: Large shape variations take place during the growth process of children, including quantitative mass and size increase plus qualitative changes in their body shape. The aim of the present study is to apply Geometric Morphometric techniques in order to visualize and quantify such body shape differences in healthy children aged 6-59 months with optimal nutritional status.

Materials And Methods: Anthropometrical measurements of weight, height, and middle-upper arm circumference were used to assess nutritional status on a sample of 258 Senegalese (n = 154) and Spanish (n = 104) children. A set of 36 anatomical and/or osteologically-based landmarks were identified on the body of the children along with 108 semi-landmarks used to capture curvature attributes on the frontal view of the body image. A specific method was developed to place and photograph children, as well as to locate landmarks, treat images and calculate semi-landmarks. Shape differences among children were analyzed in terms of age, sex, and population origin, taking into consideration allometry effects.

Results: Our results indicate significant differences in shape and size for all the three factors under study before removing size effect (p < .0001), and in shape after the size correction (p < .01). Only the ontogenetic effect persisted in the size of studied individuals after size-effects correction (p < .0001). Morphometric significant differences were described regarding age for PC1 and population origin in PC2 before removing size effect. Between-population morphometric differences were sorted along PC1 after size correction.

Discussion: Geometric Morphometric techniques are useful to study morphometric changes in the anterior whole-body view of children under 5 years old, allowing a precise description of shape changes observed when age and population origin are considered.
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http://dx.doi.org/10.1002/ajpa.23779DOI Listing
April 2019

Perinatal free-choice of a high-calorie low-protein diet affects leptin signaling through IRS1 and AMPK dephosphorylation in the hypothalami of female rat offspring in adulthood.

Acta Physiol (Oxf) 2019 06 21;226(2):e13244. Epub 2019 Jan 21.

Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, Spain.

Aim: We aimed to investigate whether a dysregulated maternal diet during gestation and lactation induces long-lasting changes in the hypothalamic control of feeding behavior in the offspring and whether this effect is sex specific.

Methods: The study included an analysis of appetite-regulating metabolic hormones and hypothalamic signaling in male and female offspring in adulthood after exposure to a free-choice high-calorie palatable low-protein (P) diet or standard chow (C) during (pre)gestation/lactation (maternal) and/or postweaning (offspring).

Results: Maternal exposure to the P diet resulted in decreased protein intake and body weight gain in dams and decreased body weight gain in offspring during lactation. The maternal P diet (PC) specifically increased feed efficacy and decreased body weight and cholesterol levels in the female offspring in adulthood, but no changes in adiposity or leptin levels were found. In contrast, P diet exposure after weaning (CP and PP) increased caloric intake, adiposity and circulating levels of leptin in the male and female offspring in adulthood. The hypothalami of the female offspring exposed to the maternal P diet (PC and PP) expressed high levels of the phospho-leptin receptor and low levels of SOCS3, phospho-IRS1 and phospho-AMPK, regardless of the postweaning diet. The hypothalami of the female rats in the PC group also showed increased levels of STAT3 and the orexigenic neuropeptide Agrp.

Conclusions: Maternal exposure to a free-choice high-calorie low-protein diet induces a long-term feed efficacy associated with changes in leptin signaling through IRS-1 and AMPK dephosphorylation in the hypothalami of female offspring in adulthood.
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http://dx.doi.org/10.1111/apha.13244DOI Listing
June 2019

Oleoylethanolamide restores alcohol-induced inhibition of neuronal proliferation and microglial activity in striatum.

Neuropharmacology 2019 03 26;146:184-197. Epub 2018 Nov 26.

Instituto de Investigación Biomédica de Málaga (IBIMA), UGC Salud Mental, Universidad de Málaga, Hospital Universitario Regional de Málaga, Málaga, Spain. Electronic address:

Previous findings demonstrate a homeostatic role for oleoylethanolamide (OEA) signaling in the ethanol-related neuroinflammation and behavior. However, extensive research is still required in order to unveil the effects of OEA on a number of neurobiological functions such as adult neurogenesis, cell survival and resident neuroimmunity that become notably altered by alcohol. Daily consumption of ethanol (10%) for 2 weeks (6.3 ± 1.1 g/kg/day during last 5 days) caused hypolocomotor activity in rats. This effect appears to rely on central signaling mechanisms given that alcohol increased the OEA levels, the gene expression of OEA-synthesizing enzyme Nape-pld and the number of PPARα-immunoreactive neurons in the striatum. Ethanol-related neurobiological alterations such as a reduction in the number of microglial cells expressing iNOS (a cytokine-inducible immune defense) and in adult neural stem/progenitor cell (NSPC) proliferation (phospho-H3 and BrdU) and maturation (BrdU/β3-tubulin), as well as an increase in damage cell activity (FosB) and apoptosis (cleaved caspase 3) were also observed in the rat striatum. Pharmacological administration of OEA (10 mg/kg) for 5 days during ethanol exposure exacerbated ethanol-induced hypolocomotion and cell apoptosis in the striatum. Interestingly, OEA abrogated the impaired effects of ethanol on PPARα-positive cell population and NSPC proliferation and maturation. OEA also decreased astrocyte-related vimentin immunoreactivity and increased microglial cell population (Iba-1, iNOS) in the striatum. These results suggest that OEA-PPARα signaling modulates glial activation, cell apoptosis and NSPC proliferation and maturation in response to striatal-specific neurobiological alterations induced by prolonged ethanol intake in rats.
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http://dx.doi.org/10.1016/j.neuropharm.2018.11.037DOI Listing
March 2019

Can community health workers manage uncomplicated severe acute malnutrition? A review of operational experiences in delivering severe acute malnutrition treatment through community health platforms.

Matern Child Nutr 2019 04 8;15(2):e12719. Epub 2018 Nov 8.

Action Against Hunger, New York, New York.

Community health workers (CHWs) play an important role in the detection and referral of children with severe acute malnutrition (SAM) in many countries. However, distance to health facilities remains a significant obstacle for caregivers to attend treatment services, resulting in SAM treatment coverage rates below 40% in most areas of intervention. The inclusion of SAM treatment into the current curative tasks of CHWs has been proposed as an approach to increase coverage. A literature review of operational experiences was conducted to identify opportunities and challenges associated with this model. A total of 18 studies providing evidence on coverage, clinical outcomes, quality of care, and/or cost-effectiveness were identified. The studies demonstrate that CHWs can identify and treat uncomplicated cases of SAM, achieving cure rates above the minimum standards and reducing default rates to less than 8%. Although the evidence is limited, these findings suggest that early detection and treatment in the community can increase coverage of SAM in a cost-effective manner. Adequate training and close supervision were found to be essential to ensure high-quality performance of CHWs. Motivation through financial compensation and other incentives, which improve their social recognition, was also found to be an important factor contributing to high-quality performance. Another common challenge affecting performance is insufficient stock of key commodities (i.e., ready-to-use therapeutic food). The review of the evidence ultimately demonstrates that the successful delivery of SAM treatment via CHWs will require adaptations in nutrition and health policy and practice.
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http://dx.doi.org/10.1111/mcn.12719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6587873PMC
April 2019

Alcohol-induced cognitive deficits are associated with decreased circulating levels of the neurotrophin BDNF in humans and rats.

Addict Biol 2019 09 12;24(5):1019-1033. Epub 2018 Sep 12.

Instituto de Investigación Biomédica de Málaga (IBIMA), UGC Salud Mental, Universidad de Málaga, Hospital Universitario Regional de Málaga, Spain.

Chronic alcohol consumption is associated with neurocognitive and memory deficits, dramatically affecting plasticity and connectivity, with maximal expression as dementia. Neurotrophic factors may contribute to alcohol-related cognitive decline. For further investigation, a cross-sectional study was performed to evaluate the association of cognitive impairment, by using frontal assessment battery, and memory loss, using memory failures everyday, with the circulating levels of the neurotrophin brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT-3) in abstinent subjects with alcohol use disorders (AUDs, N = 58, average of 17.9 years of problematic use and 4.3 months of abstinence) compared with healthy control subjects (N = 22). This association was also explored in a pre-clinical model of adolescent rats chronically exposed to alcohol up to adulthood (~77 days old) in a three-bottle free-choice (5-10-20 percent), repeated abstinence and relapse paradigm. AUD subjects had low educational level and cognitive impairment associated with teenage consumption and lower circulating levels of BDNF and NT-3. Only BDNF concentration showed a positive correlation with frontal assessment battery in AUD patients. In the ethanol-exposed rats, the plasma levels of BDNF and NT-3 were also decreased, and a negative correlation between hippocampal Bdnf mRNA levels and recognition memory was found. The ethanol-exposed rat hippocampus showed a decrease in the mRNA levels of neurotrophic (Bdnf and Ntf-3) and neurogenic (Mki67, Sox2, Dcx, Ncam1 and Calb1) factors, associated to a deactivation of the neurogenic regulator mitogen-activated protein kinase extracellular signal-regulated kinase. Results suggest a relevant role of BDNF/extracellular signal-regulated kinase 2 signaling in alcohol-induced cognitive impairment and suggest that early alcohol exposure-derived effects on cognition are associated with neurotrophin signaling deficits.
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http://dx.doi.org/10.1111/adb.12668DOI Listing
September 2019

Pharmacological blockade of fatty acid amide hydrolase (FAAH) by URB597 improves memory and changes the phenotype of hippocampal microglia despite ethanol exposure.

Biochem Pharmacol 2018 11 9;157:244-257. Epub 2018 Aug 9.

UGC Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga, Hospital Universitario Regional de Málaga, Málaga, Spain. Electronic address:

Changes in endogenous cannabinoid homeostasis are associated with both ethanol-related neuroinflammation and memory decline. Extensive research is still required to unveil the role of endocannabinoid signaling activation on hippocampal microglial cells after ethanol exposure. Either microglial morphology, phenotype and recruitment may become notably altered after chronic alcohol-related neurodegeneration. Here, we evaluated the pharmacological effects of fatty-acid amide-hydrolase (FAAH) inhibitor URB597 (0.3 mg/kg), oleoylethanolamide (OEA, 10 mg/kg), arachidonoylethanolamide (AEA, 10 mg/kg), the CB1 receptor agonist ACEA (3 mg/kg) and the CB2 receptor agonist JWH133 (0.2 mg/kg) administered for 5 days in a rat model of subchronic (2 weeks) ethanol diet (11% v/v) exposure. URB597 turned to be the most effective treatment. URB597 increased microglial (IBA-1+) cell population, and changed morphometric features (cell area and perimeter, roughness, fractal dimension, lacunarity) associated with activated microglia in the hippocampus of ethanol-exposed rats. Regarding innate immune activity, URB597 specifically increased mRNA levels of toll-like receptor 4 (TLR4), glial fibrillary acidic protein (Gfap) and the chemokine stromal cell-derived factor 1 (SDF-1α/CXCL12), and elevated the cell population expressing the chemokine receptors CX3CR1, CCR2 and CCR4 in the ethanol-exposed rat hippocampus. Contrary to ethanol effect, URB597 reduced mRNA levels of Iba-1, Tnfα, IL-6 and the monocyte chemoattractant protein-1 (MCP-1/CCL2), as well as cell population expressing iNOS. URB597 effects on hippocampal immune system were accompanied by changes in short and long-term visual recognition memory. These results suggest that FAAH inhibition may modulates hippocampal microglial recruitment and activation that can be associated with improved hippocampal-dependent memory despite ethanol exposure.
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http://dx.doi.org/10.1016/j.bcp.2018.08.005DOI Listing
November 2018

Impulse control and related disorders in Parkinson's disease.

Arq Neuropsiquiatr 2018 Jun;76(6):399-410

Universidade Federal de Minas Gerais, Unidade de Distúrbios do Movimento, Departamento de Clínica Médica, Serviço de Neurologia, Belo Horizonte MG, Brasil.

Neuropsychiatric disorders are common among patients with Parkinson's disease and may appear in any stage of the disease. However, these disorders often go undiagnosed and receive insufficient treatment. Observations in recent years have revealed that dopamine replacement therapy may lead to the development or worsening of conditions, such as gambling disorder, compulsive sexual behavior, compulsive buying and binge eating, in addition to punding and dopamine dysregulation syndrome. The pathophysiology of these disorders seems to be related to abnormal dopaminergic stimulation of the basal regions of the basal ganglia, especially via nigro-mesolimbic pathways. The aim of the present study was to perform a literature review on impulsivity, impulse control disorders and related conditions among patients with Parkinson's disease, with emphasis on their epidemiology, clinical characteristics and treatment.
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http://dx.doi.org/10.1590/0004-282X20180052DOI Listing
June 2018

The adiponectin promoter activator NP-1 induces high levels of circulating TNFα and weight loss in obese (fa/fa) Zucker rats.

Sci Rep 2018 06 29;8(1):9858. Epub 2018 Jun 29.

UGC Salud Mental, Instituto de Investigación Biomédica de Málaga (IBIMA), Universidad de Málaga-Hospital Universitario Regional de Málaga, Avda. Carlos Haya 82, Pabellón de Gobierno, 29010, Málaga, Spain.

Chronic NP-1 administration reduces body weight and hepatic steatosis despite induction of tolerance in adiponectin gene transcription with respect to the acute actions of this drug. This study explored the hypothesis that NP-1 could exert these effects through mechanisms independent of adiponectin. To this aim, we took advantage of the Zucker (fa/fa) rat model, which exhibits obesity, fatty liver and elevated leptin and adiponectin levels. Body weight and food intake were reduced after chronic NP-1 treatment. Plasma TNFα concentrations were elevated but no increase in adiponectin was found. Even so, NP-1 ameliorated fatty liver and corrected dyslipidemia by mechanisms probably associated with reduced feeding, transcription of Cpt1 and down-regulation of Hmgcr-CoA expression. In brown fat tissue NP-1 increased Dnmt1 (inhibitor of Adipoq) while it reduced Ucp1 expression and heat production, which excludes thermogenesis as a mechanism of the NP-1 slimming effect. The anti-obesity action of chronic NP-1 administration might be mediated by TNFα, which is known to have anorectic actions in the hypothalamus and to regulate both Dmnt1 and Ucp1 expression in adipose tissues. This finding opens up the possibility of using NP-1-mediated TNFα-induced weight loss as an innovative treatment of complicated obesity under strict pharmacologic control.
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http://dx.doi.org/10.1038/s41598-018-27871-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6026175PMC
June 2018

The relative frequency of common neuromuscular diagnoses in a reference center.

Arq Neuropsiquiatr 2017 Nov;75(11):789-795

Rede SARAH de Hospitais de Reabilitação, Departamento de Neurologia, Belo Horizonte MG, Brasil.

The diagnostic procedure in neuromuscular patients is complex. Knowledge of the relative frequency of neuromuscular diseases within the investigated population is important to allow the neurologist to perform the most appropriate diagnostic tests.

Objective: To report the relative frequency of common neuromuscular diagnoses in a reference center.

Methods: A 17-year chart review of patients with suspicion of myopathy.

Results: Among 3,412 examinations, 1,603 (46.98%) yielded confirmatory results: 782 (48.78%) underwent molecular studies, and 821 (51.21%) had muscle biopsies. The most frequent diagnoses were: dystrophinopathy 460 (28.70%), mitochondriopathy 330 (20.59%), spinal muscular atrophy 158 (9.86%), limb girdle muscular dystrophy 157 (9.79%), Steinert myotonic dystrophy 138 (8.61%), facioscapulohumeral muscular dystrophy 99 (6.17%), and other diagnoses 261 (16.28%).

Conclusion: Using the presently-available diagnostic techniques in this service, a specific limb girdle muscular dystrophy subtype diagnosis was reached in 61% of the patients. A neuromuscular-appropriate diagnosis is important for genetic counseling, rehabilitation orientation, and early treatment of respiratory and cardiac complications.
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http://dx.doi.org/10.1590/0004-282X20170151DOI Listing
November 2017

Acetaminophen-Induced Liver Injury Alters the Acyl Ethanolamine-Based Anti-Inflammatory Signaling System in Liver.

Front Pharmacol 2017 6;8:705. Epub 2017 Oct 6.

Unidad de Gestión Clínica de Salud Mental, Instituto de Investigación Biomédica de Málaga, Hospital Regional Universitario de Málaga, Universidad de Málaga, Málaga, Spain.

Protective mechanisms against drug-induced liver injury are actively being searched to identify new therapeutic targets. Among them, the anti-inflammatory -acyl ethanolamide (NAE)-peroxisome proliferators activated receptor alpha (PPARα) system has gained much interest after the identification of its protective role in steatohepatitis and liver fibrosis. An overdose of paracetamol (APAP), a commonly used analgesic/antipyretic drug, causes hepatotoxicity, and it is being used as a liver model. In the present study, we have analyzed the impact of APAP on the liver NAE-PPARα system. A dose-response (0.5-5-10-20 mM) and time-course (2-6-24 h) study in human HepG2 cells showed a biphasic response, with a decreased α expression after 6-h APAP incubation followed by a generalized increase of NAE-PPARα system-related components (α, , and ), including the NAEs oleoyl ethanolamide (OEA) and docosahexaenoyl ethanolamide, after a 24-h exposure to APAP. These results were partially confirmed in a time-course study of mice exposed to an acute dose of APAP (750 mg/kg). The gene expression levels of α and were decreased after 6 h of treatment and, after 24 h, the gene expression levels of and , as well as the liver levels of OEA and palmitoyl ethanolamide, were increased. Repeated APAP administration (750 mg/kg/day) up to 4 days also decreased the expression levels of PPARα and FAAH, and increased the liver levels of NAEs. A resting period of 15 days completely restored these impairments. Liver immunohistochemistry in a well-characterized human case of APAP hepatotoxicity confirmed PPARα and FAAH decrements. Histopathological and hepatic damage (, αα, and )-related alterations observed after repeated APAP administration were aggravated in the liver of α-deficient mice. Our results demonstrate that the anti-inflammatory NAE-PPARα signaling system is implicated in liver toxicity after exposure to APAP overdose, and may contribute to its recovery through a long-term time-dependent response.
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http://dx.doi.org/10.3389/fphar.2017.00705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5635604PMC
October 2017

Phenotypic Variability of Dystrophinopathy Symptomatic Female Carriers.

Can J Neurol Sci 2017 May 9;44(3):304-310. Epub 2017 Feb 9.

5Department of Neurology,SARAH Network of Rehabilitation Hospitals,Belo Horizonte,Minas Gerais,Brazil.

Background: Dystrophinopathies are X-linked muscular dystrophies characterized by pathogenic mutations in the dystrophin gene. Symptomatic dystrophinopathy female carriers may present with limb-girdle weakness. The diagnosis may be challenging in the absence of affected male relatives. We aimed to describe the phenotypic variability in a series of molecular-confirmed female dystrophinopathy patients.

Methods: This is a retrospective analysis of medical records from 1997 to 2015.

Results: Ten female dystrophinopathy patients were selected, two with unusual phenotypes: one with early joint contractures muscular dystrophy and the other with very late onset myopathy. Muscle imaging studies demonstrated predominant asymmetric fat replacement. Muscle biopsy immunohistochemistry demonstrated clear mosaic pattern in two cases and only subtle reduction of dystrophin intensity in three.

Conclusions: Adequate diagnosis is fundamental for genetic counseling and cardiologic follow-up. Female patients with dystrophinopathy may present unusual phenotypes such as early contractures and very late onset myopathy.
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http://dx.doi.org/10.1017/cjn.2016.448DOI Listing
May 2017

HIV-1 Variants and Drug Resistance in Pregnant Women from Bata (Equatorial Guinea): 2012-2013.

PLoS One 2016 31;11(10):e0165333. Epub 2016 Oct 31.

HIV-1 Molecular Epidemiology Laboratory, Microbiology and Parasitology Department, Hospital Universitario Ramón y Cajal, IRYCIS and CIBERESP, Madrid, Spain.

Objectives: This is the first study describing drug resistance mutations (DRM) and HIV-1 variants among infected pregnant women in Equatorial Guinea (GQ), a country with high (6.2%) and increasing HIV prevalence.

Methods: Dried blood spots (DBS) were collected from November 2012 to December 2013 from 69 HIV-1 infected women participating in a prevention of mother-to-child transmission program in the Hospital Regional of Bata and Primary Health Care Centre María Rafols, Bata, GQ. The transmitted (TDR) or acquired (ADR) antiretroviral drug resistance mutations at partial pol sequence among naive or antiretroviral therapy (ART)-exposed women were defined following WHO or IAS USA 2015 lists, respectively. HIV-1 variants were identified by phylogenetic analyses.

Results: A total of 38 of 69 HIV-1 specimens were successfully amplified and sequenced. Thirty (79%) belonged to ART-experienced women: 15 exposed to nucleoside reverse transcriptase inhibitors (NRTI) monotherapy, and 15 to combined ART (cART) as first regimen including two NRTI and one non-NRTI (NNRTI) or one protease inhibitor (PI). The TDR rate was only found for PI (3.4%). The ADR rate was 37.5% for NNRTI, 8.7% for NRTI and absent for PI or NRTI+NNRTI. HIV-1 group M non-B variants caused most (97.4%) infections, mainly (78.9%) recombinants: CRF02_AG (55.2%), CRF22_A101 (10.5%), subtype C (10.5%), unique recombinants (5.3%), and A3, D, F2, G, CRF06_cpx and CRF11_cpx (2.6% each).

Conclusions: The high rate of ADR to retrotranscriptase inhibitors (mainly to NNRTIs) observed among pretreated pregnant women reinforces the importance of systematic DRM monitoring in GQ to reduce HIV-1 resistance transmission and to optimize first and second-line ART regimens when DRM are present.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0165333PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5087953PMC
June 2017
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