Trilobatin contributes to the improvement of myopathy in a mouse model of Duchenne muscular dystrophy.

Duchenne muscular dystrophy (DMD) occurs due to genetic mutations that lead to a deficiency in dystrophin production and consequent progressive degeneration of skeletal muscle fibres, through oxidative stress and an exacerbated inflammatory process. The flavonoid trilobatin (TLB) demonstrates antioxidant and anti-inflammatory potential. Its high safety profile and effective action make it a potent therapy for the process of dystrophic muscle myonecrosis. Thus, we sought to investigate the action of TLB on damage in a DMD model, the mdx mouse. Eight-week-old male animals were treated with 160 mg/kg/day of trilobatin for 8 weeks. Control animals were treated with saline. Following treatment, muscle strength, serum creatine kinase (CK) levels, histopathology (necrotic myofibres, regenerated fibres/central nuclei, Feret's diameter and inflammatory area) and the levels of catalase and NF-κB (western blotting) of the quadriceps (QUA), diaphragm (DIA) and tibialis anterior (TA) muscles were measured. TLB was able to significantly increase muscle strength and reduce serum CK levels in dystrophic animals. The QUA of mdx mice showed a reduction in catalase and the number of fibres with a centralized nucleus after treatment with TLB. In the DIA of dystrophic animals, TLB reduced the necrotic myofibres, inflammatory area and NF-κB and increased the number of regenerated fibres and the total fibre diameter. In TA, TLB increased the number of regenerated fibres and reduced catalase levels in these animals. It is concluded that in the mdx experimental model, treatment with TLB was beneficial in the treatment of DMD.

Training volitional control of the theory of mind network with real-time fMRI neurofeedback.

Is there a way improve our ability to understand the minds of others? Towards addressing this question, here, we conducted a single-arm, proof-of-concept study to evaluate whether real-time fMRI neurofeedback (rtfMRI-NF) from the temporo-parietal junction (TPJ) leads to volitional control of the neural network subserving theory of mind (ToM; the process by which we attribute and reason about the mental states of others). As additional aims, we evaluated the strategies used to self-regulate the network and whether volitional control of the ToM network was moderated by participant characteristics and associated with improved performance on behavioral measures. Sixteen participants underwent fMRI while completing a task designed to individually-localize the TPJ, and then three separate rtfMRI-NF scans during which they completed multiple runs of a training task while receiving intermittent, activation-based feedback from the TPJ, and one run of a transfer task in which no neurofeedback was provided. Region-of-interest analyses demonstrated volitional control in most regions during the training tasks and during the transfer task, although the effects were smaller in magnitude and not observed in one of the neurofeedback targets for the transfer task. Text analysis demonstrated that volitional control was most strongly associated with thinking about prior social experiences when up-regulating the neural signal. Analysis of behavioral performance and brain-behavior associations largely did not reveal behavior changes except for a positive association between volitional control in RTPJ and changes in performance on one ToM task. Exploratory analysis suggested neurofeedback-related learning occurred, although some degree of volitional control appeared to be conferred with the initial self-regulation strategy provided to participants (i.e., without the neurofeedback signal). Critical study limitations include the lack of a control group and pre-rtfMRI transfer scan, which prevents a more direct assessment of neurofeedback-induced volitional control, and a small sample size, which may have led to an overestimate and/or unreliable estimate of study effects. Nonetheless, together, this study demonstrates the feasibility of training volitional control of a social cognitive brain network, which may have important clinical applications. Given the study's limitations, findings from this study should be replicated with more robust experimental designs.

High Prevalence of a c.5979dupA Variant in the Dysferlin Gene (DYSF) in Individuals from a Semiarid Region of Brazil.

Background: Dysferlinopathies represent a group of limb girdle or distal muscular dystrophies with an autosomal-recessive inheritance pattern resulting from the presence of pathogenic variants in the dysferlin gene (DYSF). Objective: In this work, we describe a population from a small city in Brazil carrying the c.5979dupA pathogenic variant of DYSF responsible for limb girdle muscular dystrophy type 2R and distal muscular dystrophy. Methods: Genotyping analyses were performed by qPCR using customized probe complementary to the region with the duplication under analysis in the DYSF. Results: A total of 104 individuals were examined. c.5979dupA was identified in 48 (46.15%) individuals. Twenty-three (22%) were homozygotes, among whom 13 (56.5%) were female. A total of 91.3% (21) of homozygous individuals had a positive family history, and seven (30.4%) reported consanguineous marriages. Twenty-five (24%) individuals were heterozygous (25.8±16 years) for the same variant, among whom 15 (60%) were female. The mean CK level was 697 IU for homozygotes, 140.5 IU for heterozygotes and 176 IU for wild-type homo-zygotes. The weakness distribution pattern showed 17.3% of individuals with a proximal pattern, 13% with a distal pattern and 69.6% with a mixed pattern. Fatigue was present in 15 homozygotes and one heterozygote. Conclusion: The high prevalence of this variant in individuals from this small community can be explained by a possible founder effect associated with historical, geographical and cultural aspects.

Stroke Hospital Admissions during the COVID-19 Outbreak in São Paulo, Brazil.

BACKGROUND: Globally, stroke remains an important cause of death and long-term disability, and the impact of coronavirus disease (COVID-19) on the health system may have impaired stroke care. Previous studies suggest significant reduction in hospital admissions for stroke after COVID-19 onset as patients may hesitate seeking medical help due to fear of exposure. METHODS: This cross-sectional study included cases of hospital admissions for stroke, identified from the Hospital Information System of the Unified Health System (Sistema Único de Saúde), which contains official and public data in Brazil. Data were collected in duplicate, then categorized according to the International Classification of Diseases, tenth revision (ICD-10), considering codes I60-I69. Linear regression was used to estimate the variation in hospital admissions for stroke in the city of São Paulo (SP) - the largest and most populous city in Brazil and Latin America, between January and June of each analyzed year (2017-2020). The percentage variation between June and January 2020 was also compared. The level of significance was set at 5%, and the statistical program used was Stata, version 14.0. RESULTS: In the city of SP, during the first wave of COVID-19, from January to June 2020, there were registered decreases in absolute numbers and mean monthly admissions for stroke. Compared to January 2020, data from June 2020 showed 17% reduction in hospitalizations for intracerebral hemorrhage, 32% for cerebral infarction, 26% for stroke unspecified, and 47% for other cerebrovascular diseases. CONCLUSION: We argue for policies aimed at improving stroke care and developing awareness campaigns regarding the importance of early diagnosis and treatment, as even in less severe presentations, stroke can trigger an increase in mortality, cost, and long-term disability.

Ixazomib, an oral proteasome inhibitor, exhibits potential effect in dystrophin-deficient mdx mice.

Dystrophin deficiency makes the sarcolemma fragile and susceptible to degeneration in Duchenne muscular dystrophy. The proteasome is a multimeric protease complex and is central to the regulation of cellular proteins. Previous studies have shown that proteasome inhibition improved pathological changes in mdx mice. Ixazomib is the first oral proteasome inhibitor used as a therapy in multiple myeloma. This study investigated the effects of ixazomib on the dystrophic muscle of mdx mice. MDX mice were treated with ixazomib (7.5 mg/kg/wk by gavage) or 0.2 mL of saline for 12 weeks. The Kondziela test was performed to measure muscle strength. The tibialis anterior (TA) and diaphragm (DIA) muscles were used for morphological analysis, and blood samples were collected for biochemical measurement. We observed maintenance of the muscle strength in the animals treated with ixazomib. Treatment with ixazomib had no toxic effect on the mdx mouse. The morphological analysis showed a reduction in the inflammatory area and fibres with central nuclei in the TA and DIA muscles and an increase in the number of fibres with a diameter of 20 µm2 in the DIA muscle after treatment with ixazomib. There was an increase in the expression of dystrophin and utrophin in the TA and DIA muscles and a reduction in the expression of osteopontin and TGF-ß in the DIA muscle of mdx mice treated with ixazomib. Ixazomib was thus shown to increase the expression of dystrophin and utrophin associated with improved pathological and functional changes in the dystrophic muscles of mdx mice.

Cognitive dysfunction and psychosis: expanding the phenotype of SPG7.

Spastic paraplegia type 7 (SPG7) is one of the most common forms of autosomal recessive hereditary spastic paraplegia, which can lead to a hybrid spastic-ataxic phenotype. Recently, novel complicated forms of SPG7, including cognitive and social impairment phenotypes, have been reported. We present a SPG7 case with two pathogenic variants in compound heterozygosity in the SPG7 gene, featuring a cerebellar cognitive affective syndrome with psychosis not yet described in the literature.

Social cognition or social class and culture? On the interpretation of differences in social cognitive performance.

BACKGROUND: The ability to understand others' mental states carries profound consequences for mental and physical health, making efforts at validly and reliably assessing mental state understanding (MSU) of utmost importance. However, the most widely used and current NIMH-recommended task for assessing MSU - the Reading the Mind in the Eyes Task (RMET) - suffers from potential assessment issues, including reliance on a participant's vocabulary/intelligence and the use of culturally biased stimuli. Here, we evaluate the impact of demographic and sociocultural factors (age, gender, education, ethnicity, race) on the RMET and other social and non-social cognitive tasks in an effort to determine the extent to which the RMET may be unduly influenced by participant characteristics. METHODS: In total, 40 248 international, native-/primarily English-speaking participants between the ages of 10 and 70 completed one of five measures on TestMyBrain.org: RMET, a shortened version of RMET, a multiracial emotion identification task, an emotion discrimination task, and a non-social/non-verbal processing speed task (digit symbol matching). RESULTS: Contrary to other tasks, performance on the RMET increased across the lifespan. Education, race, and ethnicity explained more variance in RMET performance than the other tasks, and differences between levels of education, race, and ethnicity were more pronounced for the RMET than the other tasks such that more highly educated, non-Hispanic, and White/Caucasian individuals performed best. CONCLUSIONS: These data suggest that the RMET may be unduly influenced by social class and culture, posing a serious challenge to assessing MSU in clinical populations given shared variance between social status and psychiatric illness.

Eye care and ocular findings at the Olympic and Paralympic Games Rio 2016.

OBJECTIVES: To describe the attendance and ocular profile of competitors and members of delegations who attended the Polyclinic Ophthalmology Division during the Olympic and Paralympic Games Rio 2016. METHODS: The eye clinic was allocated in the purpose-built polyclinic opened for competitors and members of delegations from 24 July to 18 September 2016. All individuals who attended the service received a comprehensive ocular examination including biomicroscopy, subjective refraction and fundus evaluation. A main clinical finding was assigned for each eye by the ophthalmologist. RESULTS: 5.6% of Olympic Games competitors and 8.9% of Paralympic Games competitors attended the Polyclinic Ophthalmology Division during the Rio Olympic and Paralympic Games. These rates compare with 2.6% and 6.5% at the London Olympic and Paralympic Games (2012). The main clinical finding was refractive error with 79.0% of the individuals receiving a glass prescription during the Olympic Games and 81.3% during the Paralympic Games. CONCLUSION: Our outcomes highlight the importance of the eye service at the polyclinic as it may represent the only opportunity for many individuals involved with the Olympic and Paralympic Games to receive ocular evaluation. Our description of clinic structure, delivery of service and clinical results will be useful in the organisation not only for the Olympic and Paralympic Games Tokyo 2020 but also for any other large sporting events that involves medical attention in a polyclinic format.

The use of aliskiren as an antifibrotic drug in experimental models: A systematic review.

Aliskiren is an oral antihypertensive medication that acts by directly inhibiting renin. High levels of circulating renin and prorenin activate the pathological signaling pathway of fibrosis. This drug also reduces oxidative stress. Thus, the aim of this systematic review is to analyze experimental studies that show the actions of aliskiren on fibrosis. PubMed and LILACS databases were consulted using the keywords aliskiren and fibrosis within the period between 2005 and 2017. Fifty-three articles were analyzed. In the heart, aliskiren attenuated remodeling, hypertrophy, inflammatory cytokines, collagen deposition, and oxidative stress. In the kidneys, there was a reduction in interstitial fibrosis, the infiltration of inflammatory cells, apoptosis, proteinuria, and in the recruitment of macrophages. In diabetic models, an improvement in the albumin/creatinine relationship and in the insulin pathway in skeletal muscles was observed; aliskiren was beneficial to pancreatic function and glucose tolerance. In the liver, aliskiren reduced fibrosis, steatosis, inflammatory cytokines, and collagen deposition. In the lung and peritoneal tissues, there was a reduction in fibrosis. Many studies have reported on the beneficial effects of aliskiren on endothelial function and arterial rigidity. A reduction in fibrosis in different organs is cited by many authors, which complies with the results found in this review. However, studies diverge on the use of the drug in diabetic patients. Aliskiren has antifibrotic potential in several experimental models, interfering with the levels of fibrogenic cytokines and oxidative stress. Therefore, its use in diseases in which fibrosis plays an important pathophysiological role is suggested.

The effects of transcutaneous low-level laser therapy on the skin healing process: an experimental model.

We aim to evaluate the action of transcutaneous laser in the initial wound healing process. The use of low-level laser therapy (LLLT) has proven to be effective on inflammatory modulation and wound healing. The trial was performed on five groups of rats, through a dorsal incision. All groups received treatment on auricular artery. Groups 1 and 3 were treated with transcutaneous LLLT over a period of 15 min. Groups 2 and 4 received one and two inactive laser applications (placebo), respectively. Group 5 was the control one. Blood samples were collected 2 h after the last application of LLLT so that cytokine levels could be measured by ELISA. Tissue fragments were harvested for morphometric, histomorphometric, and RT-qPCR analyses. The morphometric analysis revealed a greater decrease in the wounded area in G1 when compared with G2, whereas in G3, the improvement in the area was greater when compared with G4. Finally, the histomorphometric analysis showed that G1 was the group closer to G5 in terms of collagen fiber count. G2 and G4 had higher amounts of collagen fibers than G5 while G3 had a lower quantity. The use of the transcutaneous LLLT in the current study influenced the wound healing process.

Detecting Topological Transitions in Two Dimensions by Hamiltonian Evolution.

We show that the evolution of two-component particles governed by a two-dimensional spin-orbit lattice Hamiltonian can reveal transitions between topological phases. A kink in the mean width of the particle distribution signals the closing of the band gap, a prerequisite for a quantum phase transition between topological phases. Furthermore, for realistic and experimentally motivated Hamiltonians, the density profile in topologically nontrivial phases displays characteristic rings in the vicinity of the origin that are absent in trivial phases. The results are expected to have an immediate application to systems of ultracold atoms and photonic lattices.

Language processing in the occipital cortex of congenitally blind adults.

Humans are thought to have evolved brain regions in the left frontal and temporal cortex that are uniquely capable of language processing. However, congenitally blind individuals also activate the visual cortex in some verbal tasks. We provide evidence that this visual cortex activity in fact reflects language processing. We find that in congenitally blind individuals, the left visual cortex behaves similarly to classic language regions: (i) BOLD signal is higher during sentence comprehension than during linguistically degraded control conditions that are more difficult; (ii) BOLD signal is modulated by phonological information, lexical semantic information, and sentence-level combinatorial structure; and (iii) functional connectivity with language regions in the left prefrontal cortex and thalamus are increased relative to sighted individuals. We conclude that brain regions that are thought to have evolved for vision can take on language processing as a result of early experience. Innate microcircuit properties are not necessary for a brain region to become involved in language processing.

Cytotoxic, hematologic and histologic effects of niobium pentoxide in Swiss mice.

The use of metal devices in medical application is increasing but it remains incompletely understood the physiological effects of component degradation. Niobium (Nb) alloys have already been investigated in the 1980's and recent studies demonstrated the potential of Nb as an implant material. The purpose of this study was to determine cytotoxic, hematologic and histologic effects of niobium in Swiss mice. Animals were treated with a single dose of 3 % niobium oxide (Nb2O5) diluted in PBS, i.p. Cytotoxic assay, hematologic and histologic evaluation were done 3, 7 and 12 days after niobium treatment. Data have shown increased number of cells after niobium treatment, but there was no difference in cell viability. Furthermore, it was not observed hematological modification 3, 7 or 12 days after niobium treatment. Despite the fact that animals treated with niobium for 3 and 7 days showed mild degeneration in hepatocytes, mice kept alive for 12 days showed liver cells regeneration. Our results suggested that niobium cytotoxicity was not progressive because 12 days after treatment there was an evident liver regeneration. Data obtained indicated that niobium may be promising alternatives to biomedical applications.

Endothelial, renal and hepatic variables in Wistar rats treated with Vancomycin.

Vancomycin (VCM) is indicated in combat against Gram-positive infections, but it is not considered a first-choice drug because of its adverse effects. It is believed that oxidative stress is the primary mechanism of endothelial injury and the consequent VCM toxicity, which varies from phlebitis to nephrotoxicity. Moreover, dose recommendations, dilution, rates and types of infusion are still controversial. The aim of this study was to determine the effect of different VCM dilutions in endothelial, liver and kidney injuries by biochemical parameters and histopathological analysis. Wistar rats were randomly divided into six groups and subjected to femoral vein cannulation for drug administration. Control groups received 0.9 ml of saline and the others received VCM (10mg/Kg/day) at dilutions of 5.0 and 10.0 mg/mL for 3 and 7 days. Homocysteine, hs-CRP, AST, ALT, GGT, urea, creatinine, lycopene, alpha-tocopherol, beta-carotene and retinol were analyzed. Kidney, liver and cannulated femoral vein fragments were collected.This study showed alterations in ALT which featured hepatotoxicity. However, drug dilutions were not able to show changes in other biochemical parameters. In contrast, kidney and endothelium pathological changes were observed. More studies are needed to characterize VCM induced kidney and endothelium toxicity and biochemical markers able to show such morphological modifications.

Social victimization, default mode network connectivity, and psychotic-like experiences in adolescents.

Social victimization (SV) and altered neural connectivity have been associated with each other and psychotic-like experiences (PLE). However, research has not directly examined the associations between these variables, which may speak to mechanisms of psychosis-risk. Here, we utilized two-year follow-up data from the Adolescent Brain Cognitive Development study to test whether SV increases PLE through two neural networks mediating socio-affective processes: the default mode (DMN) and salience networks (SAN). We find that a latent SV factor was significantly associated with PLE outcomes. Simultaneous mediation analyses indicated that the DMN partially mediated the SV-PLE association while the SAN did not. Further, multigroup testing found that while Black and Hispanic adolescents experienced SV differently than their White peers, the DMN similarly partially mediated the effect of SV on PLE for these racial groups. These cross-sectional results highlight the importance of SV and its potential impact on social cognitive neural networks for psychosis risk.

Decision-making under risk and its correlates in schizophrenia.

Schizophrenia spectrum disorders (SSD) are associated with pervasive cognitive impairments, including deficits in decision-making under risk. However, there is inconclusive evidence regarding specific mechanisms underlying altered decision-making patterns. In this study, participants (33 SSD and 28 non-SSD) completed the Columbia Card Task, an explicit risk-taking task, to better understand risk preference and adjustment in dynamic decision-making. We found that while there is no group difference in overall risk-taking, risk preference, or optimal decision-making, risk adjustment to contextual factors (e.g., loss probability) is blunted in SSD. We also found associations between risk-taking/suboptimal decision-making and disorganized symptoms, excited symptoms, and role functioning, but no associations between decision-making and working memory. These results suggest that during a complex, dynamic risk-taking task, individuals with SSD exhibit less adaption to changing information about risk, which may reflect risk imperception.

Atypical brain activation patterns during a face-to-face joint attention game in adults with autism spectrum disorder.

Joint attention behaviors include initiating one's own and responding to another's bid for joint attention to an object, person, or topic. Joint attention abilities in autism are pervasively atypical, correlate with development of language and social abilities, and discriminate children with autism from other developmental disorders. Despite the importance of these behaviors, the neural correlates of joint attention in individuals with autism remain unclear. This paucity of data is likely due to the inherent challenge of acquiring data during a real-time social interaction. We used a novel experimental set-up in which participants engaged with an experimenter in an interactive face-to-face joint attention game during fMRI data acquisition. Both initiating and responding to joint attention behaviors were examined as well as a solo attention (SA) control condition. Participants included adults with autism spectrum disorder (ASD) (n = 13), a mean age- and sex-matched neurotypical group (n = 14), and a separate group of neurotypical adults (n = 22). Significant differences were found between groups within social-cognitive brain regions, including dorsal medial prefrontal cortex (dMPFC) and right posterior superior temporal sulcus (pSTS), during the RJA as compared to SA conditions. Region-of-interest analyses revealed a lack of signal differentiation between joint attention and control conditions within left pSTS and dMPFC in individuals with ASD. Within the pSTS, this lack of differentiation was characterized by reduced activation during joint attention and relative hyper-activation during SA. These findings suggest a possible failure of developmental neural specialization within the STS and dMPFC to joint attention in ASD.

The role of vitamin D in pathophysiology and treatment of fibromyalgia.

Recent studies showed that most cells have receptors and enzymes responsible for metabolism of vitamin D. Several diseases have been linked to vitamin D deficiency, such as hypertension, diabetes, depression, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and chronic pain syndromes such as fibromyalgia. The association between fibromyalgia and vitamin D deficiency is very controversial in the literature with conflicting studies and methodological problems, which leads to more questions than answers. The purpose of this article is to raise questions about the association of hypovitaminosis D with fibromyalgia considering causal relationships, treatment, and pathophysiological explanations.

Hematological and hepatic effects of vascular epidermal growth factor (VEGF) used to stimulate hair growth in an animal model.

BACKGROUND: Alopecia areata is the hair loss usually reversible, in sharply defined areas. The treatment of alopecia using growth factors shows interesting activity in promoting hair growth. In this concept, VEGF (vascular endothelial growth factor) is a marker of angiogenesis, stimulating hair growth by facilitating the supply of nutrients to the hair follicle, increasing follicular diameter. The aim of this study was the evaluation of a topical gel enriched with VEGF liposomes on the hair growth stimulation and its toxicological aspects. METHODS: Mesocricetus auratus were randomly divided into three groups. Control group was treated with Aristoflex® gel, 1% group with the same gel but added 1% VEGF and 3% group with 3% VEGF. Biochemical, hematological and histological analyses were done. RESULTS: At the end of the experiment (15th day of VEGF treatment) efficacy was determined macroscopically by hair density dermatoscopy analysis, and microscopically by hair diameter analysis. They both demonstrated that hair of the VEGF group increased faster and thicker than control. On the other hand, biochemical and hematological results had shown that VEGF was not 100% inert. CONCLUSIONS: VEGF increased hair follicle area, but more studies are necessary to confirm its toxicity.

Standardization of a method to study angiogenesis in a mouse model.

In the adult organism, angiogenesis is restricted to a few physiological conditions. On the other hand, uncontrolled angiogenesis have often been associated to angiogenesis-dependent pathologies. A variety of animal models have been described to provide more quantitative analysis of in vivo angiogenesis and to characterize pro- and antiangiogenic molecules. However, it is still necessary to establish a quantitative, reproducible and specific method for studies of angiogenesis factors and inhibitors. This work aimed to standardize a method for the study of angiogenesis and to investigate the effects of thalidomide on angiogenesis. Sponges of 0.5 x 0.5 x 0.5 cm were implanted in the back of mice groups, control and experimental (thalidomide 200 mg/K/day by gavage). After seven days, the sponges were removed. The dosage of hemoglobin in sponge and in circulation was performed and the ratio between the values was tested using nonparametric Mann-Whitney test. Results have shown that sponge-induced angiogenesis quantitated by ratio between hemoglobin content in serum and in sponge is a helpful model for in vivo studies on angiogenesis. Moreover, it was observed that sponge-induced angiogenesis can be suppressed by thalidomide, corroborating to the validity of the standardized method.