The effects of experimentally-induced fatigue on gait parameters during obstacle crossing: A systematic review.

Striking an obstacle while walking can be dangerous, reflecting the higher risks of losing one's balance, tripping and falling. Particular situations during which internal resources are limited, such as in a fatigued state, may impair performance when crossing obstacles, enhancing the risks of falls or accidents. Our goal was thus to review the effects of experimentally-induced fatigue (EIF) on gait parameters during obstacle crossing by healthy individuals. We systematically searched PubMed and Web of Science databases using 'fatigue', 'obstacle crossing' and their equivalent terms to extract data from studies investigating this domain. Nine studies were found. First, EIF-related effects on kinetics, EMG and obstacle contacts have been poorly studied. Second, consistent and inconsistent results were found in the kinematic outcomes after EIF. Consistent results included reductions in stride duration and increased step width. Inconsistent results included gait velocity (no-effect vs increased), leading and trailing-foot vertical clearance (reduced vs increased) and horizontal distance from foot to the obstacle before obstacle avoidance (no-effect vs increased). These findings should be interpreted cautiously, however, due to the heterogeneity of the obstacle crossing and EIF protocols.

The lung immuno-oncology prognostic score (LIPS-3): a prognostic classification of patients receiving first-line pembrolizumab for PD-L1 ≥ 50% advanced non-small-cell lung cancer.

BACKGROUND: To stratify the prognosis of patients with programmed cell death-ligand 1 (PD-L1) ≥ 50% advanced non-small-cell lung cancer (aNSCLC) treated with first-line immunotherapy. METHODS: Baseline clinical prognostic factors, the neutrophil-to-lymphocyte ratio (NLR), PD-L1 tumour cell expression level, lactate dehydrogenase (LDH) and their combination were investigated by a retrospective analysis of 784 patients divided between statistically powered training (n = 201) and validation (n = 583) cohorts. Cut-offs were explored by receiver operating characteristic (ROC) curves and a risk model built with validated independent factors by multivariate analysis. RESULTS: NLR < 4 was a significant prognostic factor in both cohorts (P < 0.001). It represented 53% of patients in the validation cohort, with 1-year overall survival (OS) of 76.6% versus 44.8% with NLR > 4, in the validation series. The addition of PD-L1 ≥ 80% (21% of patients) or LDH < 252 U/l (25%) to NLR < 4 did not result in better 1-year OS (of 72.6% and 74.1%, respectively, in the validation cohort). Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2 [P < 0.001, hazard ratio (HR) 2.04], pretreatment steroids (P < 0.001, HR 1.67) and NLR < 4 (P < 0.001, HR 2.29) resulted in independent prognostic factors. A risk model with these three factors, namely, the lung immuno-oncology prognostic score (LIPS)-3, accurately stratified three OS risk-validated categories of patients: favourable (0 risk factors, 40%, 1-year OS of 78.2% in the whole series), intermediate (1 or 2 risk factors, 54%, 1-year OS 53.8%) and poor (>2 risk factors, 5%, 1-year OS 10.7%) prognosis. CONCLUSIONS: We advocate the use of LIPS-3 as an easy-to-assess and inexpensive adjuvant prognostic tool for patients with PD-L1 ≥ 50% aNSCLC.

Is dental general anaesthesia in children an outdated concept? A retrospective analysis.

AIM: The aim of this retrospective study was to determine the prevalence of caries and treatment needs in the collective of patients ?16 years of age, who underwent scheduled dental general anaesthesia (DGA) at the University Clinic of Innsbruck from January 2015 to June 2019, with respect to demographic factors. MATERIALS AND METHODS: A retrospective analysis of children's diagnoses, demographics, and dental treatment under general anaesthesia in Innsbruck, Austria, from 2015 to 2019 was performed. Anonymised demographic data (age; gender; the presence or absence of general disease or disablement; parents' first language (German- (GS) or non-German-speaking (non-GS), reflecting ethnicity; and the number of teeth restored and extracted under DGA were collected from patients' files. Data was analysed by means of descriptive and comparative statistics. RESULTS: The main group consisted of 545 subjects at a median age of 5.3 (IQR 4.4-6.6) years, who had exclusively primary teeth and or first molars that received restorations or were extracted. Of the subjects, 84.4% were classified with uncooperativeness due to dental anxiety and 15.6% with systemic diseases or intellectual and or physical disablement. In this group, 47.9% were GS and 52.1% were non-GS or had GS or non- GS parents. In the total sample, 5 (IQR 3-7) primary teeth were restored and 4 (IQR 4-7) extracted. Subgroup analysis revealed statistically significant differences in the number of extracted primary teeth between children with and without systemic diseases or disablement - 3 (IQR 1-5) versus 4 (IQR 2-7) - and between children of GS and non-GS parents - 4 (IQR 2-6) versus 5 (IQR 3-7.8). Zero (IQR 0-0) first molars were filled and extracted. CONCLUSION: Within the study collective of children in poor oral health, the offspring of non-GS families were overrepresented (compared to their prevalence in the total population) and displayed a higher prevalence of deep caries than those of GS parents. By intensifying and special gearing of prophylactic measures to the non-GS population and promoting the parents' insight into the importance of oral hygiene and regular dental attendance, the demand for scheduled DGA might be greatly reduced. In the small share of children who suffer from severe diseases or disablement and are thus unable to cooperate with home care or dental treatment, DGA will remain the treatment of choice.

Optical coherence tomography (OCT) and OCT angiography allow early identification of sickle cell maculopathy in children and correlate it with systemic risk factors.

PURPOSE: To determine the presence of sickle cell retinopathy and maculopathy and to identify associations between markers of hemolysis and systemic and ocular manifestations in children affected by sickle cell disease. METHODS: Eighteen children with sickle cell disease, aged 5-16 years, underwent complete eye examination including best-corrected visual acuity, slit-lamp biomicroscopy, ophthalmoscopy after pharmacological mydriasis, spectral-domain optical coherence tomography (SD-OCT), and optical coherence tomography angiography (OCTA). Blood test results and clinical history information were collected for each child, including fetal hemoglobin (HbF), hemoglobin (Hb), hematocrit (Htc), mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration (MCHC), reticulocytes percentage (%ret), lactic dehydrogenase (LDH), total and direct bilirubin, glomerular filtration rate, number of painful crises, acute chest syndromes, and splenic sequestration. Therapeutic regimen and transfusion therapy were also evaluated. RESULTS: Sixteen of 36 eyes (44.4%) had non-proliferative sickle cell retinopathy on ophthalmoscopic evaluation. No patients had proliferative sickle cell retinopathy. In 13 of 36 eyes (36.1%), SD-OCT and OCTA detected signs of sickle cell maculopathy. Nine eyes (25%) presented sickle cell retinopathy and maculopathy, 7 eyes (19.4%) sickle cell retinopathy alone, and 4 eyes (11.1%) sickle cell maculopathy alone. A statistically significant association was found between sickle cell retinopathy; lower levels of HbF, Hb, and Htc; and higher MCV and percentage of reticulocytes. Sickle cell maculopathy was associated with lower values of H and Htc and higher levels of reticulocytes and total bilirubin. CONCLUSIONS: We identified early signs of sickle cell retinopathy and maculopathy in a pediatric population with SD-OCT and OCTA. These two retinal complications were more frequent in children with higher hemolytic rates.

Pyrethroid and organophosphate pesticide resistance in field populations of horn fly in Brazil.

Pesticides are used worldwide to control arthropod parasites in cattle herds. The indiscriminate and/or inappropriate use of pesticides without veterinary guidance is a reality in several countries of South America. Improper pesticide use increases the chances of contamination of food and the environment with chemical pesticides and their metabolites. Reduction of these contamination events is an increasing challenge for those involved in livestock production. The horn fly, Haematobia irritans (Linnaeus) (Diptera: Muscidae), is one of the most economically important parasites affecting cattle herds around the world. As such, horn fly control efforts are often required to promote the best productive performance of herds. Pesticide susceptibility bioassays revealed that pyrethroid resistance was widespread and reached high levels in horn fly populations in the Brazilian state of Rondônia. The knockdown resistance (kdr) sodium channel gene mutation was detected in all horn fly populations studied (n = 48), and the super kdr sodium channel gene mutation was found in all homozygous resistant kdr individuals (n = 204). Organophosphate resistance was not identified in any of the fly populations evaluated.

Prevalence of Autism Spectrum Disorder in a large Italian catchment area: a school-based population study within the ASDEU project.

AIMS: This study aims to estimate Autism Spectrum Disorders (ASD) prevalence in school-aged children in the province of Pisa (Italy) using the strategy of the ASD in the European Union (ASDEU) project. METHODS: A multistage approach was used to identify cases in a community sample (N = 10 138) of 7-9-year-old children attending elementary schools in Pisa - Italy. First, the number of children with a disability certificate was collected from the Local Health Authority and an ASD diagnosis was verified by the ASDEU team. Second, a Teacher Nomination form (TN) to identify children at risk for ASD was filled in by teachers who joined the study and the Social Communication Questionnaire (SCQ) was filled in by the parents of children identified as positive by the TN; a comprehensive assessment, which included the Autism Diagnostic Observation Schedule-Second Edition, was performed for children with positive TN and SCQ⩾9. RESULTS: A total of 81 children who had a disability certificate also had ASD (prevalence: 0.79%, i.e. 1/126). Specifically, 66 children (57 males and nine females; 62% with intellectual disability -ID-) were certified with ASD, whereas another 15 (11 males and four females; 80% with ID) were recognised as having ASD among those certified with another neurodevelopmental disorder. Considering the population of 4417 (children belonging to schools which agreed to participate in the TN/SCQ procedure) and using only the number of children certified with ASD, the prevalence (38 in 4417) was 0.86%, i.e. one in 116. As far as this population is concerned, the prevalence rises to 1% if we consider the eight new cases (six males and two females; no subject had ID) identified among children with no pre-existing diagnoses and to 1.15%, i.e., one in 87, if probabilistic estimation is used. CONCLUSIONS: This is the first population-based ASD prevalence study conducted in Italy so far and its results indicate a prevalence of ASD in children aged 7-9 years of about one in 87. This finding may help regional, national and international health planners to improve ASD policies for ASD children and their families in the public healthcare system.

Primary resistance to osimertinib due to SCLC transformation: Issue of T790M determination on liquid re-biopsy.

OBJECTIVES: EGFR T790M mutation is the most common mechanism of resistance to first-/second-generation EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC) and could be overcome by third-generation EGFR-TKIs, such as osimertinib. Liquid biopsy, a non-invasive technique used to test the presence of the resistant mutation, may help avoiding tissue re-biopsy. However, analysing only circulating-free DNA, information about other less frequent and coexisting resistance mechanisms may remain unrevealed. MATERIALS AND METHODS: All patients reported in this series participated in the ASTRIS trial, a real world treatment study testing the efficacy of osimertinib (80mg os die) in advanced T790M-positive NSCLC progressed to prior EGFR-TKI. Patients were considered eligible to osimertinib if T790M positive on tissue or plasma samples. In our patients, EGFR molecular testing on blood sample was conducted with digital droplet PCR (ddPCR). RESULTS: We report our experience of five patients treated with osimertinib after T790M detection on liquid biopsy that presented a disease progression at first tumor assessment mediated by SCLC transformation, as evidenced at tissue re-biopsies. All patients showed low ratio T790M/activating mutation in the blood before osimertinib (lower than 0.03). For three patients, EGFR mutational analysis was T790M-negative when re-assessed by using a less sensitive method (therascreen®) on the same liquid biopsy sample analysed by ddPCR before osimertinib therapy. CONCLUSION: Although liquid biopsy is a relevant tool to diagnose T790M presence in NSCLC patients resistant to EGFR-TKI, in case of a low ratio T790M/activating mutation, tissue biopsy should be considered to exclude the presence of SCLC transformation and/or other concomitant resistance mechanisms.

ALK-positive adenocarcinoma of the lung expressing neuroendocrine markers and presenting as a "pituitary adenoma".

We report an ALK-rearranged adenocarcinoma of the lung presenting as a pituitary metastasis, clinically simulating a pituitary adenoma. The patient, a 50 year-old, former-smoking woman was admitted with a Parinaud's syndrome characterized by progressive oculomotor impairment of visual verticality, bitemporal hemianopsia and nystagmus. Imaging studies showed a sellar tumor and the biopsy revealed a TTF-1 and napsin positive lung adenocarcinoma strongly expressing synaptophysin and CD56, also harboring ALK rearrangement. A subsequent CT scan disclosed the primary lung mass of the left upper lobe. The patient progressed after 4 cycles of cisplatin/pemetrexed as first line treatment, but showed a partial response and a significant clinical benefit from the combination of ceritinib and nivolumab in a phase Ib trial. Despite its central nervous system tropism, ALK-rearranged adenocarcinoma manifesting with pituitary gland involvement was never reported. Second generation ALK inhibitors seem the best therapeutic strategy.

Plantar pain is not always fasciitis.

The case is described of a patient with chronic plantar pain, diagnosed as fasciitis, which was not improved by conventional treatment. Magnetic resonance imaging revealed flexor hallucis longus tenosynovitis, which improved after local glucocorticoid injection.

Interleukin-8 is associated with acute and persistent dysfunction after optic neuritis.

BACKGROUND: Acute optic neuritis is often in association with multiple sclerosis (MS). Proinflammatory cytokines trigger neuronal damage in neuroinflammatory disorders but their role in optic neuritis is poorly investigated. OBJECTIVE: The objective of this work is to investigate the associations of intrathecal contents of proinflammatory cytokines with transient and persistent dysfunctions after optic neuritis. METHODS: In 50 MS patients followed for up to six months, cerebrospinal fluid (CSF) levels of IL-1ß, TNF and IL-8 were determined, along with clinical, neurophysiological and morphological measures of optic neuritis severity. RESULTS: Visual impairment, measured by high- and low-contrast visual acuity, and delayed visual-evoked potential (VEP) latencies were significantly correlated to IL-8 levels during optic neuritis. IL-8 at the time of optic neuritis was also associated with persistent demyelination and final axonal loss, inferred by VEP and optical coherence tomography measures, respectively. Contents of IL-8 were correlated to functional visual outcomes, being higher among patients with incomplete recovery. Multivariate analysis confirmed that IL-8 significantly predicted final visual acuity, at equal values of demographics and baseline visual scores. CONCLUSION: Our study points to IL-8 as the main inflammatory cytokine associated with demyelination and secondary neurodegeneration in the optic nerve after optic neuritis.

Effect of triceps surae and quadriceps muscle fatigue on the mechanics of landing in stepping down in ongoing gait.

The aim of this study was to evaluate the effects of muscle fatigue of triceps surae and quadriceps muscles in stepping down in ongoing gait. We expected that the subjects would compensate for muscle fatigue to prevent potential loss of balance in stepping down. A total of 10 young participants walked over a walkway at a self-selected velocity to step down a height difference of 10-cm halfway. Five trials were performed before and after a muscle fatigue protocol. Participants performed two fatigue protocols: one for ankle muscle fatigue and another for knee muscle fatigue. Kinematics of and ground reaction forces on the leading leg were recorded. Fatigue did not cause a change in the frequency of heel or toe landing. Our results indicate that in stepping down fatigue effects are compensated by redistributing work to unfatigued muscle groups and by gait changes aimed at enhancing balance control, which was however only partially successful.

Interleukin-1ß alters the sensitivity of cannabinoid CB1 receptors controlling glutamate transmission in the striatum.

Proinflammatory cytokines such as tumor necrosis factor-α and interleukin-1ß (IL1ß) regulate both excitatory and inhibitory synaptic transmission in the central nervous system. The interaction between IL1ß and endocannabinoid system (ECS) is also emerging, based on the evidence that IL1ß effects on striatal spontaneous excitatory and inhibitory postsynaptic currents are regulated by transient receptor potential vanilloid 1 (TRPV1) channels, members of the ECS. Furthermore, IL1ß has also been shown to control the sensitivity of cannabinoid CB1 receptors controlling GABA transmission (CB1Rs(GABA)) in the striatum. To better detail the synaptic action of IL1ß, and to clarify its complex interaction with the ECS, here we investigated the possible interplay between IL1ß and CB1Rs controlling glutamate transmission (CB1Rs(glu)), other critical elements of the ECS. Our results show that the sensitivity of CB1Rs(glu) is fully blocked in the presence of IL1ß in corticostriatal brain slices, and that the protein kinase C/TRPV1 pathway is involved in this effect. IL1ß failed to modulate the sensitivity of glutamate synapses to the stimulation of GABAB receptors. We also provided evidence that IL1ß-CB1Rs(GABA) but not IL1ß-CB1Rs(glu) interaction is under the control of the brain-derived neurotrophic factor (BDNF)/trkB signaling and of lipid raft composition, because BDNF gene partial deletion, pharmacological blockade of trkB and membrane cholesterol removal with methyl-ß-cyclodextrin all blocked IL1ß-mediated inhibition of CB1Rs(GABA) but left unaltered the sensitivity of CB1Rs(glu) to this cytokine. Our results provide further evidence that synaptic transmission and the ECS are regulated by IL1ß in the striatum.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy from the pediatric perspective.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) is a rare autosomal recessive disease caused by mutations of the AutoImmune REgulator gene. The clinical spectrum of the disease encompasses several autoimmune endocrine and non-endocrine manifestations, which may lead to acute metabolic alterations and eventually life-threatening events. The clinical diagnosis is defined by the presence of at least two components of the classic triad including chronic mucocoutaneous candidiasis (CMC), chronic hypoparathyroidism (CH), Addison's disease (AD). Other common features of the disease are hypergonadotropic hypogonadism, alopecia, vitiligo, autoimmune hepatitis, Type 1 diabetes, gastrointestinal dysfunction. APECED usually begins in childhood. CMC is the first manifestation to appear, usually before the age of 5 yr, followed by CH and then by AD. The clinical phenotype may evolve over several years and many components of the disease may not appear until the 4th or 5th decade of life. The phenotypical expression of the syndrome shows a wide variability even between siblings with the same genotype. In view of this heterogeneity, an early diagnosis of APECED can be very challenging often leading to a considerable diagnostic delay. Therefore, clinicians should be aware that the presence of even a minor component of APECED in children should prompt a careful investigation for other signs and symptoms of the disease, thus allowing an early diagnosis and prevention of severe and life-threatening events. Aim of this review is to focus on clinical presentation, diagnosis and management of the major components of APECED in children particularly focusing on endocrine features of the disease.

Systemic treatment with adipose-derived mesenchymal stem cells ameliorates clinical and pathological features in the amyotrophic lateral sclerosis murine model.

Therapeutic strategies for the fatal neurodegenerative disease amyotrophic lateral sclerosis (ALS) are actually minimally effective on patients' survival and quality of life. Although stem cell therapy has raised great expectations, information on the involved molecular mechanisms is still limited. Here we assessed the efficacy of the systemic administration of adipose-derived mesenchymal stem cells (ASC), a previously untested stem cell population, in superoxide-dismutase 1 (SOD1)-mutant transgenic mice, the animal model of familial ALS. The administration of ASC to SOD1-mutant mice at the clinical onset significantly delayed motor deterioration for 4-6 weeks, as shown by clinical and neurophysiological tests. Neuropathological examination of ASC-treated SOD1-mutant mice at day 100 (i.e. the time of their best motor performance) revealed a higher number of lumbar motorneurons than in phosphate-buffered saline-treated SOD1-mutant mice and a restricted number of undifferentiated green fluorescent protein-labeled ASC in the spinal cord. By examining the spinal cord tissue factors that may prolong neuronal survival, we found a significant up-regulation in levels of glial-derived neurotrophic factor (GDNF) and basic fibroblast growth factor (bFGF) after ASC treatment. Considering that ASC produce bFGF but not GDNF, these findings indicate that ASC may promote neuroprotection either directly and/or by modulating the secretome of local glial cells toward a neuroprotective phenotype. Such neuroprotection resulted in a strong and long-lasting effect on motor performance and encourages the use of ASC in human pathologies, in which current therapies are not able to maintain a satisfying neurological functional status.

Anomalous colour in Neotropical mammals: a review with new records for Didelphis sp. (Didelphidae, Didelphimorphia) and Arctocephalus australis (Otariidae, Carnivora).

Anomalous colourations occur in many tropical vertebrates. However, they are considered rare in wild populations, with very few records for the majority of animal taxa. We report two new cases of anomalous colouration in mammals. Additionally, we compiled all published cases about anomalous pigmentation registered in Neotropical mammals, throughout a comprehensive review of peer reviewed articles between 1950 and 2010. Every record was classified as albinism, leucism, piebaldism or eventually as undetermined pigmentation. As results, we report the new record of a leucistic specimen of opossum (Didelphis sp.) in southern Brazil, as well as a specimen of South American fur seal (Arctocephalus australis) with piebaldism in Uruguay. We also found 31 scientific articles resulting in 23 records of albinism, 12 of leucism, 71 of piebaldism and 92 records classified as undetermined pigmentation. Anomalous colouration is apparently rare in small terrestrial mammals, but it is much more common in cetaceans and michrochiropterans. Out of these 198 records, 149 occurred in cetaceans and 30 in bats. The results related to cetaceans suggest that males and females with anomolous pigmentation are reproductively successful and as a consequence their frequencies are becoming higher in natural populations. In bats, this result can be related to the fact these animals orient themselves primarily through echolocation, and their refuges provide protection against light and predation. It is possible that anomalous colouration occurs more frequently in other Neotropical mammal orders, which were not formally reported. Therefore, we encourage researchers to publish these events in order to better understand this phenomenon that has a significant influence on animal survival.

Differential role of EGF and BFGF in human GBM-TIC proliferation: relationship to EGFR-tyrosine kinase inhibitor sensibility.

Glioblastoma multiforme (GBM) is among the most devastating human tumors being rapidly fatal despite aggressive surgery, radiation and chemotherapies. It is characterized by extensive dissemination of tumor cells within the brain that hinders complete surgical resection. GBM tumor initiating-cells (TICs) are a rare subpopulation of cells responsible for tumor development, growth, invasiveness and recurrence after chemotherapy. TICs from human GBM can be selected in vitro using the same conditions permissive for the growth of normal neural cells, of which share some features including marker expression, self-renewal capacity, long-term proliferation, and ability to differentiate into neuronal and glial cells. EGFR overexpression and its constitutive activation is one of the most important signaling alteration identified in GBM, and its pharmacological targeting represents an attractive therapeutic goal. We previously demonstrated that human GBM TICs have different sensitivity to the EGFR kinase inhibitors erlotinib and gefitinib, depending on the differential modulation of downstream signaling cascades. In this work we investigated the mechanisms of resistance to erlotinib in two human GBM TIC cultures, analyzing EGF and bFGF individual contribution to proliferation, clonogenicity, and migration. We demonstrated the presence of a small cell subpopulation whose proliferation is supported by EGF and a larger one mainly dependent on bFGF. Thus, insensitivity to EGFR kinase inhibitors as far as TIC proliferation results from a predominant FGFR activation that hides the inhibitory effects induced on EGFR signaling. Conversely, EGF and bFGF induced cell migration with similar efficacy. In addition, unlike neural stem/progenitors cells, the removal of chondroitin sulphate proteoglycans from cell surface was unable to discern EGF- and bFGF-dependent subpopulations in GBM TICs.