Clinically most relevant psychometric properties of the Lower Extremity Functional Scale: a systematic review.

PURPOSE: To systematically review and summarize the literature on minimal detectable change (MDC) and minimal clinically important difference (MCID) values for the Lower Extremity Functional Scale (LEFS). METHODS: The databases that were searched included PubMed, Embase, Medline, and CINAHL, from database inception to August 2023. The inclusion criteria were studies that examined the MDC or MCID of the LEFS in various patient populations and languages. The data extracted included information regarding test-retest reliability, MDC, MCID, and the intervals between assessments. RESULTS: Twenty-four studies defined MDC and five studies MCID values for the LEFS. They review reported a wide range of MDC values, spanning 11 language versions and a variety of diagnoses, with testing intervals ranging from 1 day to 12 months. MCID values were defined with corresponding area under curve, specificity, and sensitivity metrics for three language versions and a variety of diagnoses across timeframes from 4 weeks to 12 months. CONCLUSIONS: The review defined MDC and MCID values that can be applied in clinical practice for the LEFS across a variety of timeframes, diagnoses, and languages. The findings of this study allow clinicians use the identified MDC and MCID values of the LEFS when interpreting clinical outcome data.

The systematic review identified 24 studies on the minimal detectable change (MDC) and five on the minimal clinically important difference (MCID) of the Lower Extremity Functional Scale (LEFS) across different timeframes, diagnoses, and language versions that can be applied in clinical practice.Clinicians can use the MDC and MCID values of the LEFS to make decisions regarding changes in patient scores over time.Clinicians should be cautious about interpreting the MDC and MCID values contextually, considering factors such as language, timeframe, and specific diagnoses.

Stability Analysis through a Stability Factor Metric for IQRF Mesh Sensor Networks Utilizing Merged Data Collection.

This paper introduces a novel stability metric specifically developed for IQRF wireless mesh sensor networks, emphasizing flooding routing and data collection methodologies, particularly IQRF's Fast Response Command (FRC) technique. A key feature of this metric is its ability to ensure network resilience against disruptions by effectively utilizing redundant paths in the network. This makes the metric an indispensable tool for field engineers in both the design and deployment of wireless sensor networks. Our findings provide valuable insights, demonstrating the metric's efficacy in achieving robust and reliable network operations, especially in data collection tasks. The inclusion of redundant paths as a factor in the stability metric significantly enhances its practicality and relevance. Furthermore, this research offers practical ideas for enhancing the design and management of wireless mesh sensor networks. The stability metric uniquely assesses the resilience of data collection activities within these networks, with a focus on the benefits of redundant paths, underscoring the significance of stability in network evaluation.

A Multicenter Cross-Sectional Study of the Swiss Cohort of LAMA2-Related Muscular Dystrophy.

Background: LAMA2-related muscular dystrophy (LAMA2-RD) is an autosomal-recessive disorder and one of the most common congenital muscular dystrophies. Due to promising therapies in preclinical development, there is an increasing effort to better define the epidemiology and natural history of this disease. Objective: The present study aimed to describe a well-characterized baseline cohort of patients with LAMA2-RD in Switzerland. Methods: The study used data collected by the Swiss Registry for Neuromuscular Disorders (Swiss-Reg-NMD). Diagnostic findings were derived from genetics, muscle biopsy, creatine kinase-level and electrophysiological testing, as well as from brain MRIs. Further clinical information included motor assessments (CHOP INTEND, MFM20/32), joint contractures, scoliosis, ophthalmoplegia, weight gain, feeding difficulties, respiratory function, cardiac investigations, EEG findings, IQ and schooling. Results: Eighteen patients with LAMA-RD were included in the Swiss-Reg-NMD as of May 2023 (age at inclusion into the registry: median age 8.7 years, range 1 month - 31 years F = 8, M = 10). Fourteen patients presented with the severe form of LAMA2-RD (were never able to walk; CMD), whereas four patients presented with the milder form (present or lost walking capability; LGMD). All patients classified as CMD had symptoms before 12 months of age and 11/14 before the age of six months. 15 carried homozygous or compound heterozygous pathogenic or likely pathogenic variants in LAMA2 and two were homozygous for a variant of unknown significance (one patient unknown). Brain MRI was available for 14 patients, 13 had white matter changes and 11 had additional structural abnormalities, including cobblestone malformations, pontine hypoplasia and an enlarged tegmento-vermial angle not reported before. Conclusion: This study describes the Swiss cohort of patients with LAMA2-RD and gives insights into measuring disease severity and disease progression, which is important for future clinical trials, as well as for a better clinical understanding and management of patients with LAMA2-RD.

Exploring Splice-Site Mutations in LAMA2-Related Muscular Dystrophies: A Comprehensive Analysis of Genotypic and Phenotypic Patterns.

LAMA2-related muscular dystrophies (LAMA2-RDs) constitute the most prevalent subtype of congenital muscular dystrophies (CMDs). The clinical spectrum of LAMA2-RDs exhibits considerable diversity, particularly in motor development and disease progression. Phenotypic variability ranges from severe, early-onset presentation, known as merosin-deficient CMD type 1A, to milder, late-onset presentations, including limb-girdle muscular dystrophy-like phenotype. In this study, whole exome sequencing (WES) was applied to a family with a single proband affected by severe muscular dystrophy. The identified causative mutation was a biallelic splice-site mutation in intron 58 of the LAMA2 gene, leading to a premature termination codon in the critical G domain of laminin-α2 and resulting in a severe phenotype. Additionally, we summarized previously reported splice-site mutations to investigate the clinical and transcription consequences of these mutations. Our findings conclude that splice-site mutations predominantly lead to severe MDC1A, whether in a homozygous or heterozygous state, often associated with another loss-of-function mutation. Besides, splice-site mutations with available analysis of their transcriptional consequences were found to be responsible for exon skipping in most cases and the loss of the reading frame. These findings revealed the importance of WES in identifying disease-causing mutations, particularly in highly diversified pathologies like LAMA2-RDs. The results also underscore the importance of transcriptional analysis in determining the impact of splice-site mutations and the phenotype of LAMA2-RDs on patients.

lncRNA Biomarkers of Glioblastoma Multiforme.

Long noncoding RNAs (lncRNAs) are RNA molecules of 200 nucleotides or more in length that are not translated into proteins. Their expression is tissue-specific, with the vast majority involved in the regulation of cellular processes and functions. Many human diseases, including cancer, have been shown to be associated with deregulated lncRNAs, rendering them potential therapeutic targets and biomarkers for differential diagnosis. The expression of lncRNAs in the nervous system varies in different cell types, implicated in mechanisms of neurons and glia, with effects on the development and functioning of the brain. Reports have also shown a link between changes in lncRNA molecules and the etiopathogenesis of brain neoplasia, including glioblastoma multiforme (GBM). GBM is an aggressive variant of brain cancer with an unfavourable prognosis and a median survival of 14-16 months. It is considered a brain-specific disease with the highly invasive malignant cells spreading throughout the neural tissue, impeding the complete resection, and leading to post-surgery recurrences, which are the prime cause of mortality. The early diagnosis of GBM could improve the treatment and extend survival, with the lncRNA profiling of biological fluids promising the detection of neoplastic changes at their initial stages and more effective therapeutic interventions. This review presents a systematic overview of GBM-associated deregulation of lncRNAs with a focus on lncRNA fingerprints in patients' blood.

Prediction of deleterious non-synonymous SNPs of human MDC1 gene: an in silico approach.

MDC1 (Mediator of DNA damage Checkpoint protein 1) functions to facilitate the localization of numerous DNA damage response (DDR) components to DNA double-strand break sites. MDC1 is an integral component in preserving genomic stability and appropriate DDR regulation. There haven't been systematic investigations of MDC1 mutations that induce cancer and genomic instability. Variations in nsSNPs have the potential to modify the protein chemistry and their function. Describing functional SNPs in disease-associated genes presents a significant conundrum for investigators, it is possible to assess potential functional SNPs before conducting larger population examinations. Multiple sequences and structure-based bioinformatics strategies were implemented in the current in-silico investigation to discern potential nsSNPs of the MDC1 genes. The nsSNPs were identified with SIFT, SNAP2, Align GVGD, PolyPhen-2, and PANTHER, and their stability was determined with MUpro. The conservation, solvent accessibility, and structural effects of the mutations were identified with ConSurf, NetSurfP-2.0, and SAAFEC-SEQ respectively. Cancer-related analysis of the nsSNPs was conducted using cBioPortal and TCGA web servers. The present study appraised five nsSNPs (P1426T, P69S, P194R, P203L, and H131Y) as probably mutilating due to their existence in highly conserved regions and propensity to deplete protein stability. The nsSNPs P194R, P203L, and H131Y were concluded as deleterious and possibly damaging from the 5 prediction tools. The functional nsSNP P194R mutation is associated with skin cutaneous melanoma while no significant records were found for other nsSNPs. The present study concludes that the highly deleterious P194R mutations can potentially induce genomic instability and contribute to various cancers' pathogenesis. Developing drugs targeting these mutations can undoubtedly be advantageous in large population-based studies, particularly in the development of precision medicine.

Identification of plants' functional counterpart of the metazoan mediator of DNA Damage checkpoint 1.

Induction of DNA damage triggers rapid phosphorylation of the histone H2A.X (γH2A.X). In animals, mediator of DNA damage checkpoint 1 (MDC1) binds γH2A.X through a tandem BRCA1 carboxyl-terminal (tBRCT) domain and mediates recruitment of downstream effectors of DNA damage response (DDR). However, readers of this modification in plants have remained elusive. We show that from the Arabidopsis BRCT domain proteome, BCP1-4 proteins with tBRCT domains are involved in DDR. Through its tBRCT domain BCP4 binds γH2A.X in vitro and localizes to DNA damage-induced foci in an H2A.X-dependent manner. BCP4 also contains a domain that interacts directly with NBS1 and thus acts as a functional counterpart of MDC1. We also show that BCP1, that contains two tBRCT domains, co-localizes with γH2A.X but it does not bind γH2A.X suggesting functional similarity with human PAXIP1. A phylogenetic analysis supports that PAXIP1 and MDC1 in metazoa and their plant counterparts evolved independently from common ancestors with tBRCT domains. Collectively, our study reveals missing components and provides mechanistic and evolutionary insights into plant DDR.

Environmental chemicals change extracellular lipidome of mature human white adipocytes.

Certain environmental chemicals affect the body's energy balance and are known as metabolism disrupting chemicals (MDCs). MDCs have been implicated in the development of metabolic diseases, such as obesity and type 2 diabetes. In contrast to their well-known impact on developing adipocytes, MDC effects leading to altered energy balance and development of insulin resistance in mature white adipocytes, constituents of adult adipose tissue, are largely unclear. Here, we investigated the effects of six well-established environmental MDCs (bisphenol A (BPA), perfluorooctanoic acid (PFOA), triclosan (TCS), p,p-dichlorodiphenyl-dichloroethylene (ppDDE), tributyltin chloride (TBT) and triphenyl phosphate (TPP)) on mature human white adipocytes derived from mesenchymal stem cells in vitro. We aimed to identify biomarkers and sensitive endpoints of their metabolism disrupting effects. While most of the tested exposures had no effect on adipocyte glucose consumption, lipid storage and assessed gene expression endpoints, the highest concentration of triclosan affected the total lipid storage and adipocyte size, as well as glucose consumption and mRNA expression of the glucose transporter GLUT1, leptin and adiponectin. Additionally, an increased expression of adiponectin was observed with TPP and the positive control PPARγ agonist rosiglitazone. In contrast, the lipidomic analysis of the cell culture medium after a 3-day exposure was extremely sensitive and revealed concentration-dependent changes in the extracellular lipidome of adipocytes exposed to nearly all studied chemicals. While some of the extracellular lipidome changes were specific for the MDC used, some effects were found common to several tested chemicals and included increases in lysophosphatidylcholines, glycerophospholipids and ceramides and a decrease in fatty acids, with possible implications in inflammation, lipid and glucose uptake. This study points to early signs of metabolic disruption and likely systemic effects of mature adipocyte exposure to environmental chemicals, as well as to the need to include lipidomic endpoints in the assessment of adverse effects of MDCs.

KeepRunning: A MoCap-Based Rapid Test to Prevent Musculoskeletal Running Injuries.

The worldwide popularisation of running as a sport and recreational practice has led to a high rate of musculoskeletal injuries, usually caused by a lack of knowledge about the most suitable running technique for each runner. This running technique is determined by a runner's anthropometric body characteristics, dexterity and skill. Therefore, this study aims to develop a motion capture-based running analysis test on a treadmill called KeepRunning to obtain running patterns rapidly, which will aid coaches and clinicians in assessing changes in running technique considering changes in the study variables. Therefore, a review and proposal of the most representative events and variables of analysis in running was conducted to develop the KeepRunning test. Likewise, the minimal detectable change (MDC) in these variables was obtained using test-retest reliability to demonstrate the reproducibility and viability of the test, as well as the use of MDC as a threshold for future assessments. The test-retest consisted of 32 healthy volunteer athletes with a running training routine of at least 15 km per week repeating the test twice. In each test, clusters of markers were placed on the runners' body segments using elastic bands and the volunteers' movements were captured while running on a treadmill. In this study, reproducibility was defined by the intraclass correlation coefficient (ICC) and MDC, obtaining a mean value of ICC = 0.94 ± 0.05 for all variables and MDC = 2.73 ± 1.16° for the angular kinematic variables. The results obtained in the test-retest reveal that the reproducibility of the test was similar or better than that found in the literature. KeepRunning is a running analysis test that provides data from the involved body segments rapidly and easily interpretable. This data allows clinicians and coaches to objectively provide indications for runners to improve their running technique and avoid possible injury. The proposed test can be used in the future with inertial motion capture and other wearable technologies.

Absolute quantification of DNA damage response proteins.

BACKGROUND: DNA damage response (DDR) and repair are vital for safeguarding genetic information and ensuring the survival and accurate transmission of genetic material. DNA damage, such as DNA double-strand breaks (DSBs), triggers a response where sensor proteins recognize DSBs. Information is transmitted to kinases, initiating a sequence resulting in the activation of the DNA damage response and recruitment of other DDR and repair proteins to the DSB site in a highly orderly sequence. Research has traditionally focused on individual protein functions and their order, with limited quantitative analysis, prompting this study's attempt at absolute quantification of DNA damage response and repair proteins and capturing changes in protein chromatin affinity after DNA damage through biochemical fractionation methods. RESULTS: To assess the intracellular levels of proteins involved in DDR and repair, multiple proteins associated with different functions were quantified in EPC2-hTERT cells. H2AX had the highest intracellular abundance (1.93 × 106 molecules/cell). The components of the MRN complex were present at the comparable levels: 6.89 × 104 (MRE11), 2.17 × 104 (RAD50), and 2.35 × 104 (NBS1) molecules/cell. MDC1 was present at 1.27 × 104 molecules/cell. The intracellular levels of ATM and ATR kinases were relatively low: 555 and 4860 molecules/cell, respectively. The levels of cellular proteins involved in NHEJ (53BP1: 3.03 × 104; XRCC5: 2.62 × 104; XRCC6: 5.05 × 105 molecules/cell) were more than an order of magnitude higher than that involved in HR (RAD51: 2500 molecules/cell). Furthermore, we analyzed the dynamics of MDC1 and γH2AX proteins in response to DNA damage induced by the unstable agent neocarzinostatin (NCS). Using cell biochemical fractionation, cells were collected and analyzed at different time points after NCS exposure. Results showed that γH2AX in chromatin fraction peaked at 1 h post-exposure and gradually decreased, while MDC1 translocated from the isotonic to the hypertonic fraction, peaking at 1 hour as well. The study suggests increased MDC1 affinity for chromatin through binding to γH2AX induced by DNA damage. The γH2AX-bound MDC1 (in the hypertonic fraction) to γH2AX ratio at 1 h post-exposure was 1:56.4, with lower MDC1 levels which may attributed to competition with other proteins. CONCLUSIONS: The approach provided quantitative insights into protein dynamics in DNA damage response.

Macrophage-Derived Chemokine MDC/CCL22: An Ambiguous Finding in COVID-19.

Macrophage-derived chemokine (MDC/CCL22) is a chemokine of the C-C subfamily. It is involved in T-cellular maturation and migration. Our previous research shows that plasma CCL22/MDC tends to show a statistically significant depletion of concentrations in acute patients and convalescents when compared to healthy donors. In the current work, we investigate existing views on MDC/CCL22 dynamics in association with various pathologies, including respiratory diseases and, specifically, COVID-19. Additionally, we present our explanations for the observed decrease in MDC/CCL22 concentrations in COVID-19. The first hypothesis we provide implies that viral products bind to MDC/CCL22 and block its activity. Another explanation for this phenomenon is based on dendritic cells population and the inhibition of their function.

Synthesis of Aluminum-Based Metal-Organic Framework (MOF)-Derived Carbon Nanomaterials and Their Water Adsorption Isotherm.

The characteristics of water vapor adsorption depend on the structure, porosity, and functional groups of the material. Metal-organic framework (MOF)-derived carbon (MDC) is a novel material that exhibits a high specific area and tunable pore sizes by exploiting the stable structure and porosity of pure MOF materials. Herein, two types of aluminum-based MOFs were used as precursors to synthesize hydrophobic microporous C-MDC and micro-mesoporous A-MDC via carbonization and activation depending on the type of ligands in the precursors. C-MDC and A-MDC have different pore characteristics and exhibit distinct water adsorption properties. C-MDC with hydrophobic properties and micropores exhibited negligible water adsorption (108.54 mgg-1) at relatively low pressures (P/P0~0.3) but showed a rapid increase in water adsorption ability (475.7 mgg-1) at relative pressures of about 0.6. A comparison with the isotherm model indicated that the results were consistent with the theories, which include site filling at low relative pressure and pore filling at high relative pressure. In particular, the Do-Do model specialized for type 5 showed excellent agreement.

Estimation of minimal detectable change in the 10-meter walking test for patients with stroke: a study stratified by gait speed.

Objective: This study aimed to classify and calculate the minimal detectable changes (MDC) in gait time and gait speed in a 10-meter walking test (10MWT) in patients with stroke classified according to their gait speed. Methods: The participants were 84 patients with stroke. Their gait times were measured twice each at their comfortable gait speed (CGS) and maximum gait speed (MGS) on a 10-meter straight track, and gait speed was calculated using gait time. Participants were assigned to three speed groups based on their CGS: low-speed (<0.4 m/s; n = 19); moderate-speed (0.4-0.8 m/s; n = 29); and high-speed (>0.8 m/s; n = 36). For each group, first and second retest reliability and MDC of CGS and MGS were calculated using gait time and gait speed in the 10MWT. Results: MDCs in the 10MWT at CGS were: low-speed group, gait time 5.25 s, gait speed 0.05 m/s; moderate-speed group, gait time 2.83 s, gait speed 0.11 m/s; and high-speed group, gait time 1.58 s, gait speed 0.21 m/s. MDCs in the 10MWT at MGS were: low-speed group, gait time 7.26 s, gait speed 0.04 m/s; moderate-speed group, gait time 2.48 s, gait speed 0.12 m/s; and high-speed group, gait time 1.28 s, gait speed 0.19 m/s. Conclusion: Since the MDC of gait speed and gait time differ depending on the participant's gait speed, it is necessary to interpret the results according to the participant's gait speed when judging the effectiveness of therapeutic interventions.

Merosin-deficient congenital muscular dystrophy type 1a: detection of LAMA2 variants in Vietnamese patients.

Background: Merosin-deficient congenital muscular dystrophy type 1A (MDC1A), also known as laminin-α2 chain-deficient congenital muscular dystrophy (LAMA2-MD), is an autosomal recessive disease caused by biallelic variants in the LAMA2 gene. In MDC1A, laminin- α2 chain expression is absent or significantly reduced, leading to some early-onset clinical symptoms including severe hypotonia, muscle weakness, skeletal deformity, non-ambulation, and respiratory insufficiency. Methods: Six patients from five unrelated Vietnamese families presenting with congenital muscular dystrophy were investigated. Targeted sequencing was performed in the five probands. Sanger sequencing was carried out in their families. Multiplex ligation-dependent probe amplification was performed in one family to examine an exon deletion. Results: Seven variants of the LAMA2 (NM_000426) gene were identified and classified as pathogenic/likely pathogenic variants using American College of Medical Genetics and Genomics criteria. Two of these variants were not reported in the literature, including c.7156-5_7157delinsT and c.8974_8975insTGAT. Sanger sequencing indicated their parents as carriers. The mothers of family 4 and family 5 were pregnant and a prenatal testing was performed. The results showed that the fetus of the family 4 only carries c.4717 + 5G>A in the heterozygous form, while the fetus of the family 5 carries compound heterozygous variants, including a deletion of exon 3 and c.4644C>A. Conclusion: Our findings not only identified the underlying genetic etiology for the patients, but also provided genetic counseling for the parents whenever they have an offspring.

The role of angiotensin I-converting enzyme gene polymorphism and global DNA methylation in the negative associations between urine di-(2-ethylhexyl) phthalate metabolites and serum adiponectin in a young Taiwanese population.

BACKGROUND: Adiponectin is a key protein produced in adipose tissue, with crucial involvement in multiple metabolic processes. Di-(2-ethylhexyl) phthalate (DEHP), one of the phthalate compounds used as a plasticizer, has been shown to decrease adiponectin levels in vitro and in vivo studies. However, the role of angiotensin I-converting enzyme (ACE) gene polymorphism and epigenetic changes in the relationship between DEHP exposure and adiponectin levels is not well understood. METHODS: This study examined the correlation between urine levels of DEHP metabolite, epigenetic marker 5mdC/dG, ACE gene phenotypes, and adiponectin levels in a sample of 699 individuals aged 12-30 from Taiwan. RESULTS: Results showed a positive relationship between mono-2-ethylhexyl phthalate (MEHP) and 5mdC/dG, and a negative association between both MEHP and 5mdC/dG with adiponectin. The study found that the inverse relationship between MEHP and adiponectin was stronger when levels of 5mdC/dG were above the median. This was supported by differential unstandardized regression coefficients (- 0.095 vs. - 0.049, P value for interaction = 0.038)). Subgroup analysis also showed a negative correlation between MEHP and adiponectin in individuals with the I/I ACE genotype, but not in those with other genotypes, although the P value for interaction was borderline significant (0.06). The structural equation model analysis indicated that MEHP has a direct inverse effect on adiponectin and an indirect effect via 5mdC/dG. CONCLUSIONS: In this young Taiwanese population, our findings suggest that urine MEHP levels are negatively correlated with serum adiponectin levels, and epigenetic modifications may play a role in this association. Further study is needed to validate these results and determine causality.

Interrater, Test-retest Reliability of the Y Balance Test: A Reliability Study Including 51 Healthy Participants.

The aim was to determine the relative and absolute interrater, test-retest reliability of the Y-Balance Test (YBT) in a sample of healthy and active adults aged 18 to 50 years. The sample consisted of 51 healthy and active participants, 30 men and 21 women with a mean age of 28 ± 7 years. The YBT was performed on the right leg in the three test directions. Test and retest of the YBT were performed with a median interval of 15 days. The method for data collection was in line with the Y Balance Test Lower Quarter Protocol (YBT-LQ). The test was conducted by raters previously inexperienced in the use of the YBT. The relative reliability was reported as Intraclass Correlation Coefficient (ICC(2,1)). The absolute reliability was reported as Standard Error of Measurement (SEM) and Minimal Detectable Change (MDC). The ICC ranged from 0.79-0.86. SEM ranged from 2%-4%, indicating the measurement error at group level and MDC ranged from 5%-11%, indicating the measurement error at individual level. The YBT showed good relative and absolute reliability. The YBT is therefore considered suitable at both group and individual level in physically active populations.

Vemurafenib improves muscle histopathology in a mouse model of LAMA2-related congenital muscular dystrophy.

Laminin-α2-related congenital muscular dystrophy (LAMA2-CMD) is a neuromuscular disease affecting around 1-9 in 1,000,000 children. LAMA2-CMD is caused by mutations in the LAMA2 gene resulting in the loss of laminin-211/221 heterotrimers in skeletal muscle. LAMA2-CMD patients exhibit severe hypotonia and progressive muscle weakness. Currently, there is no effective treatment for LAMA2-CMD and patients die prematurely. The loss of laminin-α2 results in muscle degeneration, defective muscle repair and dysregulation of multiple signaling pathways. Signaling pathways that regulate muscle metabolism, survival and fibrosis have been shown to be dysregulated in LAMA2-CMD. As vemurafenib is a US Food and Drug Administration (FDA)-approved serine/threonine kinase inhibitor, we investigated whether vemurafenib could restore some of the serine/threonine kinase-related signaling pathways and prevent disease progression in the dyW-/- mouse model of LAMA2-CMD. Our results show that vemurafenib reduced muscle fibrosis, increased myofiber size and reduced the percentage of fibers with centrally located nuclei in dyW-/- mouse hindlimbs. These studies show that treatment with vemurafenib restored the TGF-ß/SMAD3 and mTORC1/p70S6K signaling pathways in skeletal muscle. Together, our results indicate that vemurafenib partially improves histopathology but does not improve muscle function in a mouse model of LAMA2-CMD.

Nerve pathology is prevented by linker proteins in mouse models for LAMA2-related muscular dystrophy.

LAMA2-related muscular dystrophy (LAMA2 MD or MDC1A) is a devastating congenital muscular dystrophy that is caused by mutations in the LAMA2 gene encoding laminin-α2, the long chain of several heterotrimeric laminins. Laminins are essential components of the extracellular matrix that interface with underlying cells. The pathology of LAMA2 MD patients is dominated by an early-onset, severe muscular dystrophy that ultimately leads to death by respiratory insufficiency. However, pathology in nonmuscle tissues has been described. Prior work in the dyW /dyW mouse model for LAMA2 MD has shown that two linker proteins, mini-agrin and αLNNd, when expressed in skeletal muscle fibers, greatly increase survival from a few months up to more than 2 years. However, the restoration of skeletal muscle function accentuates the pathology in nonmuscle tissue in dyW /dyW mice, first and foremost in the peripheral nerve resulting in paralysis of the hind limbs. We now show that the expression of the two linker proteins in all tissues ameliorates the muscular dystrophy and prevents the appearance of the hind limb paralysis. Importantly, the same ameliorating effect of the linker proteins was seen in dy3K /dy3K mice, which represent the most severe mouse model of LAMA2 MD. In summary, these data show that the two linker proteins can compensate the loss of laminin-α2 in muscle and peripheral nerve, which are the two organs most affected in LAMA2 MD. These results are of key importance for designing appropriate expression constructs for mini-agrin and αLNNd to develop a gene therapy for LAMA2 MD patients.

Novel compound heterozygous mutations of LAMA2-limb-girdle muscular dystrophy: A case report and literature review.

The laminin α2 (LAMA2) gene pathogenic variants can lead to limb-girdle muscular dystrophy (known as LGMDR23), which is rarely reported and characterized by proximal weakness in the limbs. We present the case of a 52-year-old woman who gradually developed weakness in both lower extremities since the age of 32 years. Magnetic resonance imaging (MRI) brain showed symmetrical sphenoid wings-like white matter demyelination in bilateral lateral ventricles. Electromyography showed quadriceps muscle damage on the bilateral lower extremity. Next-generation sequencing (NGS) found two loci variations in the LAMA2 gene, i.e., c.2749 + 2dup and c.8689C>T. This case highlights the importance of considering LGMDR23 in patients presenting with weakness and white matter demyelination on MRI brain and further expands the gene variants spectrum of LGMDR23.

Validity and reliability of upper extremity star excursion balance test in adolescent swimmers.

Background: Upper limb balance is one of the important physical fitness parameters for all populations, especially overhead athletes like swimmers. Upper extremity star excursion balance test (UESEBT) is a comprehensive dynamic balance assessment, this study aims to explore the reliability and validity of UESEBT among adolescent swimmers. Methods: This cross-sectional study recruited 70 adolescent swimmers. All participants were required to complete UESEBT, upper quarter Y-balance test (UQYBT), maximal isometric strength (MIS) tests in upper limb, closed kinetic chain upper extremity stability test (CKCUEST), trunk flexor endurance test (TFET) and lateral trunk endurance test (LTET). The intra- and inter-operator reliability and the correlation of UESEBT with other physical performances were conducted. Results: For reliability, the intra- and inter-operator reliability of all directions and composite score were high-to-excellent (ICC = 0.706-1.000) among all participants. For validity, the UESEBT has a moderate-to-strong correlation with UQYBT (r = 0.42-0.72, p < 0.001), and a weak-to moderate one with CKCUEST (r = 0.25-0.42, p < 0.05). Furthermore, the UESEBT performance showed weak-to-moderate correlations with MIS (r = 0.24-0.44, p < 0.05). UESEBT was correlated to LTET (r = 0.24-0.33, p < 0.05) whereas no relationship was found with TFET. Conclusions: UESEBT was a reliable and valid tool to screen upper extremity dynamic balance among adolescent swimmers. UESEBT provides more detailed information in eight directions to assess the upper limb sport performance. Further study should explore the prediction ability of UESEBT for injury.