Corrigendum to "Energy analysis of gait in patients with down syndrome" [Heliyon 8 (11) (November 2022) Article e11702].

[This corrects the article DOI: 10.1016/j.heliyon.2022.e11702.].

Influence of Foot Morphology on the Center of Pressure Pattern in Patients with Down Syndrome.

BACKGROUND: The primary aim of this study was to assess how different conformations of the foot in individuals with Down syndrome affected the CoP during walking, and the secondary aim was to evaluate the effect of an excess of mass in young adults and children with Down syndrome and flat foot. The greater investigation of these aspects will allow for more targeted rehabilitation treatments to improve a patient's quality of life. METHODS: The tests were carried out on 217 subjects with Down syndrome, 65 children and 152 young adults, and on 30 healthy individuals, 19 children and 11 young adults. All subjects underwent gait analysis, and the group with Down syndrome was also assessed with baropodometric tests to evaluate foot morphology. RESULTS: The statistical analysis showed that within both the young adult and child groups, the CoP pattern in the anterior-posterior direction reflected a difficulty in proceeding in the walking direction compensated by a medio-lateral swing. The gait of children with Down syndrome was more impaired than that of young adults. In both young adults and children, a higher severity of impairment was found in overweight and obese female individuals. CONCLUSIONS: These results suggest that the sensory deficits and the development of hypotonic muscles and lax ligaments of the syndrome lead to morphological alterations of the foot that, combined with the physical characteristics of short stature and obesity, negatively impact the CoP pattern of people with Down syndrome during walking.

Effects of the whole-body vibration direction on the cognitive response of standing subjects.

This study aims to investigate the effect of whole-body vibration along different axes on the response time (RT) of standing subjects during a customised psychomotor vigilance task (PVT). Twenty-five subjects were exposed to harmonic vibration with amplitude of 0.7 m/s2 RMS and frequencies between 1.5 Hz and 12.5 Hz. ANOVA was used to assess if the difference of RT with and without vibration had a statistical relevance. Results showed that the RT was statistically affected by the vibration only at frequencies below 2 Hz. The vibration at higher frequencies had a minor effect on the RT. The RTs during the vibration exposure was, on average, 15% higher than the RT post exposure. Practitioner summary: This study investigates the effects of whole-body vibration (WBV) along different axes on the response time (RT). We measured the RTs to a psychomotor vigilance task of 25 standing subject exposed to WBV. The cognitive response was statistically affected by the WBV and, on average RT have increased of 15%.

Energy analysis of gait in patients with down syndrome.

Background: the primary aim of this study is to analyse the energy parameters of patients with Down syndrome compared to a control group and secondly to verify whether the sport activity leads to differences in energy expenditure. Methods: 3 groups of subjects were identified: 8 healthy subjects and 147 subjects with Down syndrome, of whom 14 played sports at least once a week. An energy index was calculated, given by the ratio between potential and kinetic energy. Next, kinetic ad potential energy parameters were extrapolated at 60% of the gait cycle (propulsion phase). Findings: Down syndrome group was compared with the control group and emerged that the energy index was higher in the first one. No changes were found between Down syndrome and Down syndrome Sport groups. The analysis of the energy parameters showed that all parameters, except the medio-lateral kinetic energy, were higher in the control than in the Down syndrome groups. The potential energy, medio-lateral kinetic energy, and vertical were higher in the Down syndrome Sport group than in the Down syndrome group. The kinetic energy and the mean velocity were higher in the control group than in Down syndrome Sport group while the medio-lateral kinetic energy was lower. Interpretation: sport modified the parameter of potential energy but not that of kinetic energy, which continued to be different compared to the healthy group and increased the oscillations in the medio-lateral plane, which were double compared to Down syndrome group. The increase in potential energy, found to be almost equal to that of control group, indicates an increase in vertical oscillations. This could be because subjects who practise sports have stronger muscles that allow a greater push-off ability, which therefore increases their potential energy.

Machine-Learning Based Determination of Gait Events from Foot-Mounted Inertial Units.

A promising but still scarcely explored strategy for the estimation of gait parameters based on inertial sensors involves the adoption of machine learning techniques. However, existing approaches are reliable only for specific conditions, inertial measurements unit (IMU) placement on the body, protocols, or when combined with additional devices. In this paper, we tested an alternative gait-events estimation approach which is fully data-driven and does not rely on a priori models or assumptions. High-frequency (512 Hz) data from a commercial inertial unit were recorded during 500 steps performed by 40 healthy participants. Sensors' readings were synchronized with a reference ground reaction force system to determine initial/terminal contacts. Then, we extracted a set of features from windowed data labeled according to the reference. Two gray-box approaches were evaluated: (1) classifiers (decision trees) returning the presence of a gait event in each time window and (2) a classifier discriminating between stance and swing phases. Both outputs were submitted to a deterministic algorithm correcting spurious clusters of predictions. The stance vs. swing approach estimated the stride time duration with an average error lower than 20 ms and confidence bounds between ±50 ms. These figures are suitable to detect clinically meaningful differences across different populations.

Functional Evaluation Using Inertial Measurement of Back School Therapy in Lower Back Pain.

Lower back pain is an extremely common health problem and globally causes more disability than any other condition. Among other rehabilitation approaches, back schools are interventions comprising both an educational component and exercises. Normally, the main outcome evaluated is pain reduction. The aim of this study was to evaluate not only the efficacy of back school therapy in reducing pain, but also the functional improvement. Patients with lower back pain were clinically and functionally evaluated; in particular, the timed "up and go" test with inertial movement sensor was studied before and after back school therapy. Forty-four patients completed the program, and the results showed not only a reduction of pain, but also an improvement in several parameters of the timed up and go test, especially in temporal parameters (namely duration and velocity). The application of the inertial sensor measurement in evaluating functional aspects seems to be useful and promising in assessing the aspects that are not strictly correlated to the specific pathology, as well as in rehabilitation management.

Whole-body vibration training in obese subjects: A systematic review.

OBJECTIVE: (i) to determine the outcomes of whole-body vibration training (WBVT) on obese individuals, and the intervention settings producing such effects; (ii) identify potential improper or harmful use of WBVT. DESIGN: Systematic review. DATA SOURCES: Medline, Scopus, Web of Science, PEDro and Scielo until July 2018. ELIGIBILITY CRITERIA: Full papers evaluating the effect of WBVT on body composition, cardiovascular status and functional performance in obese adults. Papers with PEDro score<4 were excluded. STUDY APPRAISAL AND SYNTHESIS: Risk of bias and quality of WBVT reporting were assessed with PEDro scale (randomized controlled trials) or TREND checklist (non-randomized studies) and a 14-items checklist, respectively. Weighted acceleration, daily exposure and Hedges' adjusted g were computed. RESULTS: We included 18 papers published 2010-2017. Typical interventions consisted in three sessions/week of exercises (squats, calf-raises) performed on platforms vibrating at 25-40 Hz (amplitude: 1-2 mm); according to ISO 2631-1:1997, daily exposure was "unsafe" in 7/18 studies. Interventions lasting ≥6 weeks improved cardiac autonomic function and reduced central/peripheral arterial stiffness in obese women; 10 weeks of WBVT produced significant weight/fat mass reduction, leg strength improvements as resistance training, and enhanced glucose regulation when added to hypocaloric diet. No paper evidenced losses of lean mass. Isolated cases of adverse effects were reported. SUMMARY: To date, WBVT is a promising adjuvant intervention therapy for obese women; long-term studies involving larger cohorts and male participants are required to demonstrate the associated safety and health benefits. The therapeutic use of WBVT in the management of obese patients is still not standardised and should be supported by an extensive knowledge on the causality between vibration parameters and outcomes.

Metallothionein 1G acts as an oncosupressor in papillary thyroid carcinoma.

The molecular pathogenesis of tumors arising from the thyroid follicular epithelial cells, including papillary (PTC) and follicular thyroid carcinoma (FTC), is only partially understood, and the role of tumor suppressor genes has not yet been assessed. The metallothionein (MT) gene family encodes a class of metal-binding proteins involved in several cellular processes, and their expression is often deregulated in human tumors. Recently, downregulation of MT gene expression in PTC has been reported, suggesting a possible oncosuppressor role of this gene family in the pathogenesis of thyroid tumors. To further explore this possibility, we performed expression and functional studies. Analysis of microarray data of thyroid tumors of different histologic types showed that several MT genes were downregulated with respect to normal tissue. The microarray data were corroborated by quantitative PCR experiments, showing downregulation of MTs in PTC and FTC, but to a greater extent in papillary carcinoma. The expression of MTs was also investigated at the protein level by immunohistochemistry; the results were consistent with the microarray data, showing general downregulation in tumor samples, which was more evident in PTC. The functional consequence of MT downregulation was addressed employing an experimental model made of the PTC-derived K1 cell line in which MT1G expression is repressed by promoter methylation. Restoration of MT1G expression by cDNA transfection affected growth rate and in vivo tumorigenicity of K1 cells, indicating an oncosuppressor role for MT1G in thyroid papillary tumorigenesis.

Induction of a proinflammatory program in normal human thyrocytes by the RET/PTC1 oncogene.

Rearrangements of the RET receptor tyrosine kinase gene generating RET/PTC oncogenes are specific to papillary thyroid carcinoma (PTC), the most frequent thyroid tumor. Here, we show that the RET/PTC1 oncogene, when exogenously expressed in primary normal human thyrocytes, induces the expression of a large set of genes involved in inflammation and tumor invasion, including those encoding chemokines (CCL2, CCL20, CXCL8, and CXCL12), chemokine receptors (CXCR4), cytokines (IL1B, CSF-1, GM-CSF, and G-CSF), matrix-degrading enzymes (metalloproteases and urokinase-type plasminogen activator and its receptor), and adhesion molecules (L-selectin). This effect is strictly dependent on the presence of the RET/PTC1 Tyr-451 (corresponding to RET Tyr-1062 multidocking site). Selected relevant genes (CCL20, CCL2, CXCL8, CXCR4, L-selectin, GM-CSF, IL1B, MMP9, UPA, and SPP1/OPN) were found up-regulated also in clinical samples of PTC, particularly those characterized by RET/PTC activation, local extrathyroid spread, and lymph node metastases, when compared with normal thyroid tissue or follicular thyroid carcinoma. These results, demonstrating that the RET/PTC1 oncogene activates a proinflammatory program, provide a direct link between a transforming human oncogene, inflammation, and malignant behavior.

Gene expression profiling of advanced ovarian cancer: characterization of a molecular signature involving fibroblast growth factor 2.

Epithelial ovarian cancer (EOC) is the gynecological disease with the highest death rate. We applied an automatic class discovery procedure based on gene expression profiling to stages III-IV tumors to search for molecular signatures associated with the biological properties and progression of EOC. Using a complementary DNA microarray containing 4451 cancer-related, sequence-verified features, we identified a subset of EOC characterized by the expression of numerous genes related to the extracellular matrix (ECM) and its remodeling, along with elements of the fibroblast growth factor 2 (FGF2) signaling pathway. A total of 10 genes were validated by quantitative real-time polymerase chain reaction, and coexpression of FGF2 and fibroblast growth factor receptor 4 in tumor cells was revealed by immunohistochemistry, confirming the reliability of gene expression by cDNA microarray. Since the functional relationships among these genes clearly suggested involvement of the identified molecular signature in processes related to epithelial-stromal interactions and/or epithelial-mesenchymal cellular plasticity, we applied supervised learning analysis on ovarian-derived cell lines showing distinct cellular phenotypes in culture. This procedure enabled construction of a gene classifier able to discriminate mesenchymal-like from epithelial-like cells. Genes overexpressed in mesenchymal-like cells proved to match the FGF2 signaling and ECM molecular signature, as identified by unsupervised class discovery on advanced tumor samples. In vitro functional analysis of the cell plasticity classifier was carried out using two isogenic and immortalized cell lines derived from ovarian surface epithelium and displaying mesenchymal and epithelial morphology, respectively. The results indicated the autocrine, but not intracrine stimulation of mesenchymal conversion and cohort/scatter migration of cells by FGF2, suggesting a central role for FGF2 signaling in the maintenance of cellular plasticity of ovary-derived cells throughout the carcinogenesis process. These findings raise mechanistic hypotheses on EOC pathogenesis and progression that might provide a rational underpinning for new therapeutic modalities.

Differential requirement of Tyr1062 multidocking site by RET isoforms to promote neural cell scattering and epithelial cell branching.

The receptor tyrosine kinase RET is alternatively spliced to yield two main isoforms, RET9 and RET51, which differ in their carboxyl terminal. Activated RET induces different biological responses such as morphological transformation, neurite outgrowth, proliferation, cell migration and branching. The two isoforms have been suggested to have separate intracellular signaling pathways and different roles in mouse development. Here we show that both isoforms are able to induce cell scattering of SK-N-MC neuroepithelioma cell line and branching tubule formation in MDCK cell line. However, the Y1062F mutation, which abrogates the transforming activity of both activated RET isoforms in NIH3T3 cells, does not abolish scattering and branching morphogenesis of RET51, whereas impairs these biological effects of RET9. The GDNF-induced biological effects of RET51 are inhibited by the simultaneous abrogation of both Tyr1062 and Tyr1096 docking sites. Thus, Tyr1096 may substitute the functions of Tyr1062. GRB2 is the only known adaptor protein binding to Tyr1096. Dominant-negative GRB2 expressed in MDCK cells together with RET9 or RET51 significantly reduces branching. Therefore, GRB2 is necessary for RET-mediated branching of MDCK cells.

Alternative mutations of BRAF, RET and NTRK1 are associated with similar but distinct gene expression patterns in papillary thyroid cancer.

Papillary thyroid carcinoma (PTC) is associated with RET and NTRK1 rearrangements and BRAF mutations. A series of 60 PTCs collected in a single center from Italian patients were histologically re-examined and subclassified as well differentiated or tall cell variant. The sample collection was analysed for the presence of all the reported PTC-associated genetic alterations through DNA or cDNA amplification, followed by automated sequencing. The analysis of exons 11 and 15 of BRAF gene revealed the T1796A (V599E) mutation in 32% of cases, and this alteration is significantly associated with PTC tall cell variant. Oncogenic rearrangements of RET and NTRK1 receptors were found in 33 and 5% of cases, respectively. No Ras mutations were detected. Overall, genetic alterations were detected in two-thirds of samples, and in no single case more than one mutational event was found simultaneously. Gene expression profiling of a subset of 31 tumors performed using cDNA microarray chips showed no strong differences in global gene expression among the different cases. However, a supervised analysis of the obtained data identified a subset of genes differentially expressed in tumors carrying BRAF mutation or RTK rearrangement.

DNA damage-induced cell-cycle phase regulation of p53 and p21waf1 in normal and ATM-defective cells.

The ATM-dependent accumulation of p53 and induction of p21waf1 are key events for G1 cell-cycle checkpoint arrest following DNA damage. In ATM-null AT cells, even though the p53 and p21waf1 responses are kinetically delayed and quantitatively reduced, the G1 checkpoint is virtually disrupted, suggesting that these proteins arrive too late in G1 to enforce the arrest. As the precise mechanism remains unclear, we examined the response to DNA double-strand breaks generated by gamma-radiation (IR), to determine if ATM deficiency affects the cell-cycle phase regulation of these molecules. We find that, after irradiation, whereas normal LCL-N cells markedly increase their levels of p53 in all phases of the cell cycle, AT cells fail to show any p53 increase in the G1 phase. In addition, whereas in LCL-N p21waf1 is induced in G1 and G2-M, in AT cells this induction is partly seen in G2-M, but not in G1, indicating a different cell-cycle phase regulation of p53 and p21waf1 as a result of ATM deficiency. The levels and catalytic activity of the p53-targeting kinases ATR and DNA-PK in LCL-N and AT cells are very similar throughout the cell cycle, both before and after IR, thus excluding a phase-specific activity for these kinases. Collectively, our findings demonstrate that, in ATM-deficient cells, the p53-dependent p21waf1 response to DNA damage is not only quantitatively reduced, but also specifically suppressed in the G1 phase, thus providing a mechanistic explanation for the severe disruption of the G1 checkpoint in AT cells.

Cavernous sinus exenteration for invasive cranial base tumors.

OBJECTIVE: Invasive tumors involving the cavernous sinus, such as recurrent benign meningiomas or sarcomas, raise therapeutic problems that may be resolved by cavernous sinus exenteration (CSE). METHODS: Our series comprises 18 patients (9 women and 9 men ranging in age from 14 to 64 yr) who underwent CSE during the past 8 years. The tumors in these patients included 12 meningiomas, 3 chondrosarcomas, 1 rhabdomyosarcoma, 1 lipomyosarcoma, and 1 epidermoid carcinoma. Preoperative occlusion of the internal carotid artery was confirmed in 15 cases by a balloon occlusion test. Three patients had a negative balloon occlusion test, and their internal carotid arteries were preserved (n = 1) or revascularized (n = 2) through an external carotid artery-to-middle cerebral artery bypass. RESULTS: CSE was performed as a primary treatment in 5 patients and after one to five recurrences in 13 patients. In all patients, CSE included the internal carotid artery and Cranial Nerves III, IV, and VI and one to three branches of Cranial Nerve V. Orbital exenteration was performed in eight patients, and partial hypophysectomy was performed in five patients. Ten patients had received radiotherapy before CSE, and five patients underwent irradiation after CSE. The operative mortality includes two patients. Cerebrospinal fluid leakage was the main complication in four patients, with three patients having meningitis. Follow-up ranged from 6 months to 5 years, with three deaths from new recurrences at 2, 3, and 4 years after CSE. As compared with their clinical courses before CSE, all patients except the two who died postoperatively benefited from CSE. CONCLUSION: CSE has useful indications in invasive and rapidly growing tumors, including apparently benign meningiomas. A better understanding of the biological behavior of these tumors is necessary for appropriate selection of patients for CSE.