Evaluation of bone health in terms of osteoporosis in adult patients with neuromuscular disease.

Background/aim: There are no current guidelines to help clinicians decide whether patients with adult neuromuscular disease (NMD) should be screened or treated for osteoporosis (OP). This study was undertaken to investigate the presence of OP in patients with various types of NMD and to examine the relationship between OP evaluation parameters and functional status, daily living activities, balance, and ambulation levels. Materials and methods: This cross-sectional study included 45 patients with NMDs. The patients were divided into 3 groups, depending on the affected component of the motor unit (neuronopathy group, neuropathy group, and myopathy group). The laboratory and demographic data were recorded from patient files. Functional level, pain, muscular strength, balance, and daily living activity scores were evaluated. The presence of OP was quantified using bone densitometry, fracture history, and biochemical parameters. Clinical findings were correlated with laboratory and dual-energy X-ray absorptiometry (DEXA) findings. Results: The mean hip T-score was -1.20, and the mean lumbar spine (L1-L4) T-score was -0.95 in all groups. Six patients with T-score values of -2.5 or below were detected. Vitamin D level was found to be low in all patient groups, especially in the myopathy group, but there was no significant difference (p > 0.05). There was a negative correlation between hip T-score and the frequency of falling (r = -0.604, p = 0.022), while a positive correlation was found between hip T-score and the age at which independent walking was no longer possible (r = 0.900, p = 0.037). Conclusion: OP is often overlooked in NMD patients with neurological problems and a high risk of falling. These patients should be screened for bone health and fragility.

Functional electrical stimulation cycling in patients with chronic spinal cord injury: a pilot study.

OBJECTIVE: To examine the therapeutic value of lower extremity functional electrical stimulation (FES) - evoked cycling on functional independence, health status, gait parameters, pulmonary functions, and biochemical values in patients with chronic complete/incomplete spinal cord injury (SCI). MATERIALS AND METHODS: Fifteen patients with SCI (duration of more than 6 months) who were able to stand up and walk with long leg braces or assistive devices and had stable neurological status and trunk balance undertook FES cycling for 6 weeks (three times per week). The main outcomes were: Functional Independence Measure (FIM), Nottingham Health Profile (NHP), 6-minute walk test (6MWT), and 20-meter walk test (20MWT). Secondary outcomes include measurements of pulmonary function tests and biochemical values. All parameters were evaluated at the beginning and end of the program. RESULTS: Improvements were seen in motor and total scores of FIM (p = 0.007), physical mobility subscale of NHP (p = 0.011), 6MWT (p = 0.001), and 20MWT (p = 0.011). In pulmonary functions, only forced vital capacity (FVC) levels demonstrated a significant increase compared with baseline (p = 0.011). Biochemical values reached no significant level. CONCLUSION: The results of this study showed that the FES cycling exercise program improves motor and total FIM scores, gait parameters, and FVC values of pulmonary functions in patients with chronic SCI experience. The FES cycle might be a valuable and well-tolerated intervention in clinical rehabilitation.

Genome-wide DNA methylation profiling using the methylation-dependent restriction enzyme LpnPI.

DNA methylation is a well-known epigenetic modification that plays a crucial role in gene regulation, but genome-wide analysis of DNA methylation remains technically challenging and costly. DNA methylation-dependent restriction enzymes can be used to restrict CpG methylation analysis to methylated regions of the genome only, which significantly reduces the required sequencing depth and simplifies subsequent bioinformatics analysis. Unfortunately, this approach has been hampered by complete digestion of DNA in CpG methylation-dense regions, resulting in fragments that are too small for accurate mapping. Here, we show that the activity of DNA methylation-dependent enzyme, LpnPI, is blocked by a fragment size smaller than 32 bp. This unique property prevents complete digestion of methylation-dense DNA and allows accurate genome-wide analysis of CpG methylation at single-nucleotide resolution. Methylated DNA sequencing (MeD-seq) of LpnPI digested fragments revealed highly reproducible genome-wide CpG methylation profiles for >50% of all potentially methylated CpGs, at a sequencing depth less than one-tenth required for whole-genome bisulfite sequencing (WGBS). MeD-seq identified a high number of patient and tissue-specific differential methylated regions (DMRs) and revealed that patient-specific DMRs observed in both blood and buccal samples predict DNA methylation in other tissues and organs. We also observed highly variable DNA methylation at gene promoters on the inactive X Chromosome, indicating tissue-specific and interpatient-specific escape of X Chromosome inactivation. These findings highlight the potential of MeD-seq for high-throughput epigenetic profiling.

Metabolic enzyme IMPDH is also a transcription factor regulated by cellular state.

Cells need to coordinate gene expression and metabolic state. Inosine monophosphate dehydrogenase (IMPDH) controls the guanine nucleotide pool and, thereby, cell proliferation. We found that Drosophila IMPDH is also a DNA-binding transcriptional repressor. IMPDH attenuates expression of histone genes and E2f, a key driver of cell proliferation. Nuclear IMPDH accumulates during the G2 phase of the cell cycle or following replicative or oxidative stress. Thus, IMPDH can couple the expression of histones and E2F to cellular state. Genome-wide profiling and in vitro binding assays established that IMPDH binds sequence specifically to single-stranded, CT-rich DNA elements. Surprisingly, this DNA-binding function is conserved in E. coli IMPDH. The catalytic function of IMPDH is not required for DNA binding. Yet substitutions that correspond to human retinitis pigmentosa mutations disrupt IMPDH binding to CT-rich, single-stranded DNA elements. By doubling as nucleotide biosynthetic enzyme or transcription factor, IMPDH can either enable or restrict cell proliferation.

Allogeneic Mature Human Dendritic Cells Generate Superior Alloreactive Regulatory T Cells in the Presence of IL-15.

Expansion of Ag-specific naturally occurring regulatory T cells (nTregs) is required to obtain sufficient numbers of cells for cellular immunotherapy. In this study, different allogeneic stimuli were studied for their capacity to generate functional alloantigen-specific nTregs. A highly enriched nTreg fraction (CD4(+)CD25(bright)CD127(-) T cells) was alloantigen-specific expanded using HLA-mismatched immature, mature monocyte-derived dendritic cells (moDCs), or PBMCs. The allogeneic mature moDC-expanded nTregs were fully characterized by analysis of the demethylation status within the Treg-specific demethylation region of the FOXP3 gene and the expression of both protein and mRNA of FOXP3, HELIOS, CTLA4, and cytokines. In addition, the Ag-specific suppressive capacity of these expanded nTregs was tested. Allogeneic mature moDCs and skin-derived DCs were superior in inducing nTreg expansion compared with immature moDCs or PBMCs in an HLA-DR- and CD80/CD86-dependent way. Remarkably, the presence of exogenous IL-15 without IL-2 could facilitate optimal mature moDC-induced nTreg expansion. Allogeneic mature moDC-expanded nTregs were at low ratios (<1:320), potent suppressors of alloantigen-induced proliferation without significant suppression of completely HLA-mismatched, Ag-induced proliferation. Mature moDC-expanded nTregs were highly demethylated at the Treg-specific demethylation region within the FOXP3 gene and highly expressed of FOXP3, HELIOS, and CTLA4. A minority of the expanded nTregs produced IL-10, IL-2, IFN-γ, and TNF-α, but few IL-17-producing nTregs were found. Next-generation sequencing of mRNA of moDC-expanded nTregs revealed a strong induction of Treg-associated mRNAs. Human allogeneic mature moDCs are highly efficient stimulator cells, in the presence of exogenous IL-15, for expansion of stable alloantigen-specific nTregs with superior suppressive function.

Ultrasonographic Evaluation of the Radial Nerves in Patients with Unilateral Refractory Lateral Epicondylitis.

Objective: To evaluate the possible radial nerve entrapment of patients with unilateral refractory lateral epicondylitis (LE) by using ultrasound (US) and electroneuromyography. Design: Cross-sectional study. Setting: Three physical medicine and rehabilitation departments. Subjects: Consecutive 44 patients (15 M, 29 F) with unilateral refractory LE. Methods: All patients underwent detailed clinical, electrophysiological and ultrasonographic evaluations. Ultrasound imaging was used to evaluate thickness and presence of abnormal findings of the common extensor tendon (CET) and cross-sectional area (CSA) of the radial nerve (at spiral groove and before bifurcation) bilaterally. Unaffected sides of the patients were taken as controls. Results: When compared with the unaffected sides, CET thickness and radial nerve CSAs (at both levels) were higher, and abnormal US findings regarding LE (47.7% vs. 6.8%) were more common on the affected sides than nonaffected sides (all P < 0.001). Grip strength values were lower on the affected sides ( P < 0.001). Electrophysiological studies were all normal, and similar between the two sides (all P > 0.05). When subgroup analyses were performed after taking into account the hand dominance, affected and dominant sides were found to be the same in 31 and different in 13 patients. In subgroups, CETs and radial nerve CSAs at both levels were higher on the affected sides (all P < 0.01). Conclusions: Radial nerves and the CETs seem to be swollen on the affected sides, independent from the hand dominance of the patients with refractory LE. These results morphologically support the previous literature that attributes some of the chronic complaints of these patients actually to radial nerve entrapment.

High-Voltage Electrical Stimulation Versus Ultrasound in the Treatment of Pressure Ulcers.

OBJECTIVE: The aim of this study was to assess and compare the efficacy of high-voltage electrical stimulation (HVES) with ultrasound (US) in treating Stage II through Stage IV pressure ulcers (PrUs)* of hospitalized patients. DESIGN: This study was designed as a prospective, controlled trial in which patients were randomly assigned to 2 groups. PARTICIPANTS AND SETTINGS: A total of 27 patients (22 male, 5 female) hospitalized for neurologic rehabilitation in the Clinic of Physical Medicine and Rehabilitation with Stage II through Stage IV PrUs were included in this study. The patients were randomly assigned to either HVES or US treatment group, and all patients underwent standard wound care. Over 4 to 12 weeks, HVES was applied for 60 minutes 3 times per week, and US was applied 3 times per week. MAIN OUTCOME MEASURES: Properties of the PrUs were noted during pre- and posttreatment. RESULTS: The PrUs of patients in the HVES and US groups healed at a mean rate of 43% and 63%, respectively. There was no statistically significant intergroup difference in healing found after treatment. Regression analysis was performed for the factors that could influence the wound surface areas, and significant effects were detected among the level of ambulation, pretreatment stage, and smoking. CONCLUSIONS: Both HVES and US are promising methods for wound healing, and both electrotherapy modalities have been demonstrated to support the healing of PrUs.

Shall We Inject Superficial or Deep to the Plantar Fascia? An Ultrasound Study of the Treatment of Chronic Plantar Fasciitis.

We compared the effectiveness of ultrasound (US)-guided corticosteroid, injected superficial or deep to the fascia, in patients with plantar fasciitis. Thirty patients (24 females [75%] and 6 males [25%]) with unilateral chronic plantar fasciitis were divided into 2 groups according to the corticosteroid injection site: superficial (n = 15) or deep (n = 15) to the plantar fascia. Patient heel pain was measured using a Likert pain scale and the Foot Ankle Outcome Scale (FAOS) for foot disability, evaluated at baseline and repeated in the first and sixth weeks. The plantar fascia and heel pad thicknesses were assessed on US scans at baseline and the sixth week. The groups were similar in age, gender, and body mass index (p > .05 for all). Compared with the baseline values, the Likert pain scale (p < .001 for all) and FAOS subscale (p < .01 for all) scores had improved at the first and sixth week follow-up visits in both groups. Although the plantar fascia thickness had decreased significantly in both groups at the sixth week (p < .001 for both), the heel pad thickness remained unchanged (p > .05 for both). The difference in the FAOS subscales (pain, p = .002; activities of daily living, p = .003; sports/recreational activities, p = .008; quality of life, p = .009) and plantar fascia thickness (p = .049) showed better improvement in the deep than in the superficial injection group. US-guided corticosteroid injections are safe and effective in the short-term therapeutic outcome of chronic plantar fasciitis. Additionally, injection of corticosteroid deep to the fascia might result in greater reduction in plantar fascia thickness, pain, and disability and improved foot-related quality of life.

Paroxysmal exercise-induced dystonia within the phenotypic spectrum of ECHS1 deficiency.

BACKGROUND: ECHS1 encodes a mitochondrial enzyme involved in the degradation of essential amino acids and fatty acids. Recently, ECHS1 mutations were shown to cause a new severe metabolic disorder presenting as Leigh or Leigh-like syndromes. The objective of this study was to describe a family with 2 siblings affected by different dystonic disorders as a resulting phenotype of ECHS1 mutations. METHODS: Clinical evaluation, MRI imaging, genome-wide linkage, exome sequencing, urine metabolite profiling, and protein expression studies were performed. RESULTS: The first sibling is 17 years old and presents with generalized dystonia and severe bilateral pallidal MRI lesions after 1 episode of infantile subacute metabolic encephalopathy (Leigh-like syndrome). In contrast, the younger sibling (15 years old) only suffers from paroxysmal exercise-induced dystonia and has very mild pallidal MRI abnormalities. Both patients carry compound heterozygous ECHS1 mutations: c.232G>T (predicted protein effect: p.Glu78Ter) and c.518C>T (p.Ala173Val). Linkage analysis, exome sequencing, cosegregation, expression studies, and metabolite profiling support the pathogenicity of these mutations. Expression studies in patients' fibroblasts showed mitochondrial localization and severely reduced levels of ECHS1 protein. Increased urinary S-(2-carboxypropyl)cysteine and N-acetyl-S-(2-carboxypropyl)cysteine levels, proposed metabolic markers of this disorder, were documented in both siblings. Sequencing ECHS1 in 30 unrelated patients with paroxysmal dyskinesias revealed no further mutations. CONCLUSIONS: The phenotype associated with ECHS1 mutations might be milder than reported earlier, compatible with prolonged survival, and also includes isolated paroxysmal exercise-induced dystonia. ECHS1 screening should be considered in patients with otherwise unexplained paroxysmal exercise-induced dystonia, in addition to those with Leigh and Leigh-like syndromes. Diet regimens and detoxifying agents represent potential therapeutic strategies. © 2016 International Parkinson and Movement Disorder Society.

Histone chaperone NAP1 mediates sister chromatid resolution by counteracting protein phosphatase 2A.

Chromosome duplication and transmission into daughter cells requires the precisely orchestrated binding and release of cohesin. We found that the Drosophila histone chaperone NAP1 is required for cohesin release and sister chromatid resolution during mitosis. Genome-wide surveys revealed that NAP1 and cohesin co-localize at multiple genomic loci. Proteomic and biochemical analysis established that NAP1 associates with the full cohesin complex, but it also forms a separate complex with the cohesin subunit stromalin (SA). NAP1 binding to cohesin is cell-cycle regulated and increases during G2/M phase. This causes the dissociation of protein phosphatase 2A (PP2A) from cohesin, increased phosphorylation of SA and cohesin removal in early mitosis. PP2A depletion led to a loss of centromeric cohesion. The distinct mitotic phenotypes caused by the loss of either PP2A or NAP1, were both rescued by their concomitant depletion. We conclude that the balanced antagonism between NAP1 and PP2A controls cohesin dissociation during mitosis.

Hemiplegic shoulder pain: associated factors and rehabilitation outcomes of hemiplegic patients with and without shoulder pain.

OBJECTIVES: To analyze the incidence of and the factors associated with shoulder pain in people with hemiplegia and to understand the effect of rehabilitation programs on the parameters of motor function and activity limitations in patients with and without hemiplegic shoulder pain. METHODS: Patients in the initial 6-month period after stroke who were hospitalized in the physical medicine and rehabilitation clinic were included in the study. Patients were considered early rehabilitation entrants if they were admitted in the first 0 to 30 days after a stroke and late rehabilitation entrants if they were admitted 30 to 120 days after a stroke. Demographic and clinical features, complications, and medical histories of the patients were recorded. Upper extremity Fugl-Meyer Motor Assessment (FMA), Frenchay Arm Test (FAT), and Functional Independence Measure (FIM) were applied to the patients on admission, at discharge, and after 1 month of follow-up. RESULTS: Twenty-one (38%) patients did not have shoulder pain, and 34 (62%) patients had decreased shoulder pain. Immobilization, duration of disease, and late rehabilitation were shown to be effective treatments for shoulder pain. The major risk factors were disease duration and poor initial motor function. In both groups, the FMA, FAT, and FIM scores showed significant changes. This improvement did not differ between the 2 groups. CONCLUSION: Duration of disease and low motor functional capacities have the most important impact on shoulder pain. In patients with and without shoulder pain, a systematic rehabilitation program is beneficial with respect to motor function and daily living activities.

Intramuscular botulinum toxin-A in complex regional pain syndrome resistant to standard treatment: a case report.

OBJECTIVE: To present a patient with complex regional pain syndrome type 1 (CRPS-I) and improvement of contracture of hand muscles and grip strength after successful treatment with botulinum neurotoxin­A (BoNT-A). CASE: A 53-year-old woman with CRPS­I experienced severe allodynia, swelling and autonomic changes in the left hand after a distal radius fracture. Over the succeeding months, she developed contracture of the left hand muscles which was treated with injection of BoNT­A into the hand muscles (10 points). RESULTS: In the patient treatment with BoNT­A an improvement was seen in the hand range of motion (ROM) and grip strength. CONCLUSION: Successful results can be obtained with BoNT­A injection in treatment-resistant CRPS­I cases which may develop joint contracture.

Chronic IFN-γ production in mice induces anemia by reducing erythrocyte life span and inhibiting erythropoiesis through an IRF-1/PU.1 axis.

Anemia of chronic disease is a complication accompanying many inflammatory diseases. The proinflammatory cytokine IFN-γ has been implicated in this form of anemia, but the underlying mechanism remains unclear. Here we describe a novel mouse model for anemia of chronic disease, in which enhanced CD27-mediated costimulation strongly increases the formation of IFN-γ-producing effector T cells, leading to a progressive anemia. We demonstrate that the anemia in these mice is fully dependent on IFN-γ and that this cytokine reduces both the life span and the formation of red blood cells. Molecular analysis revealed that IFN-γ induces expression of the transcription factors of interferon regulatory factor-1 (IRF-1) and PU.1 in both murine and human erythroid precursors. We found that, on IFN-γ stimulation, IRF-1 binds to the promoter of SPI.1 (PU.1) and induces PU.1 expression, leading to inhibition of erythropoiesis. Notably, down-regulation of either IRF-1 or PU.1 expression is sufficient to overcome IFN-γ-induced inhibition of erythropoiesis. These findings reveal a molecular mechanism by which chronic exposure to IFN-γ induces anemia.

Three-year follow-up outcomes of adult patients with Guillain-Barré Syndrome after rehabilitation.

Background: Guillain-Barré syndrome (GBS), the most common cause of acute paralytic neuropathy, covers a number of recognizably different variants. We aimed to evaluate the clinical characteristics of the patients with GBS and the outcome results of the patients after rehabilitation. Methods: We enrolled 24 adult patients with GBS and evaluated their demographic characteristics, signs, complications, functional levels, and residual symptoms at admission, discharge, and during the 1st and 3rd-year follow-up visits. Functional Independence Scale (FIM), Functional Ambulation Scale (FAS), Hughes functional grading scale, Six-Minute Walking Test (6MWT), and Fatigue Severity Scale (FSS) were used for patient evaluation. Results: In this study, patients with a mean age of 47.29 ± 16.2 years (40% female) were hospitalized for an average of 28.91 ± 25.6 days. The predominant symptoms experienced by these patients were fatigue (100%), neuropathic pain (70.8%), joint pain (54.2%), and autonomic dysfunction (50%). Significant changes were observed in FIM, Hughes functional grading scale, FAS, 6MWT, and MRC score at admission, discharge, and 1st/3rd-year follow-ups (p=0.000, p=0.000, p=0.000, p=0.001, p=0.000, respectively). Fatigue and Hughes score increased significantly with age (p=0.019, r=0.475; p=0.041, r=0.419, respectively). Negative correlations were found between age and FAS, 6MWT, and MRC score at 1st-year follow-up (p=0.025, r=-0.456; p=0.027, r=-0.450; p=0.008, r=-0.528). FSS was above 4 before admission and in 53.1% at 3rd-year follow-up, correlating negatively with 6MWT and MRC sum score. GBS clinical types showed no significant differences. Conclusion: Rehabilitation improves functional improvement in GBS patients, with long-term benefits observed. However, residual symptoms such as fatigue and neuropathic pain may persist despite functional improvement. These findings highlight the importance of incorporating rehabilitation into the management of GBS and addressing residual symptoms to improve patient outcomes.

Factors influencing the willingness to participate in rehabilitation in patients with subacute stroke.

OBJECTIVE: The aim of this study was to examine the parameters that may influence the willingness of patients to participate in post-stroke rehabilitation. METHODS: Patients in the subacute phase of stroke who underwent inpatient rehabilitation for one month were included in this study. The primary outcome measure was the level of rehabilitation participation as measured on the Pittsburgh Rehabilitation Participation Scale (PRPS). Other outcome measures evaluated were Mini-Mental State Examination (MMSE) for cognitive functions, Brunnstrom stage for motor recovery, modified Rankin Scale (mRS) for disability, Functional Independence Measure for functionality, Pittsburgh Sleep Quality Index for sleep quality, and Beck Depression Inventory for emotional state. RESULTS: A total of 38 patients with first-time stroke were studied. A negative correlation was found between the participation in rehabilitation and body mass index (BMI) (r: -0.398p = 0.012), myocardial infarction (MI) history (r: -0.387p = 0.015) and mRS (r: -0.351p = 0.031), while a positive correlation was determined with MMSE (r: 0.432P = 0.007). A 1-unit increase in BMI, MI history, and mRS resulted in a 0.176, 0.673, and 0.294-unit decrease in participation in rehabilitation, respectively. In addition, a 1-unit increase in MMSE provided an increase of 0.606-unit in participation. CONCLUSION: BMI within normal limits, prevention/treatment of cardiovascular diseases, and well-being of physical and cognitive functions might be the factors that positively influence participation in rehabilitation process. We consider that it would be appropriate to evaluate these parameters with particular emphasis in stroke patients in the subacute period to be rehabilitated.

Effectiveness of kinesiotape and sham kinesiotape application in children with cerebral palsy with dysphagia: A randomized controlled study.

Objectives: This study aimed to investigate the short- and long-term effects of kinesiotaping (KT) on dysphagia in children with cerebral palsy (CP). Patients and methods: One hundred one CP patients (59 males, 42 females; mean age: 49.3±18.8 years; range, 2 to 6 years) with dysphagia referred between October 2017 and January 2020 were enrolled in the randomized controlled study. Children who met the study criteria were randomly assigned to the kinesiotape group (n=54) or the sham group (n=47). Specific swallowing evaluations were performed on all patients before the therapy. The KT or sham application protocole combined with conventional rehabilitaion therapy was conducted for six weeks. Evaluation parameters were repeated at 6 and 18 weeks. The evaluated parameters were compared within and between groups. Results: Drooling, weak tongue movement, chewing difficulty, coughing/choking and retching/vomiting during/after feeding, functional oral intake score, and meal time were found to be significantly improved at six weeks in the kinesiotape group compared to the sham group, and the clinical improvements were present at 18 weeks (p<0.05). There was no statistically significant difference in any parameter in the sham group at 6 and 18 weeks compared to the pretreatment (p>0.05). Conclusion: The addition of KT to a home exercise program is an effective method for dysphagia in CP.

Comparison of Single Cell Transcriptome Sequencing Methods: Of Mice and Men.

Single cell RNAseq has been a big leap in many areas of biology. Rather than investigating gene expression on a whole organism level, this technology enables scientists to get a detailed look at rare single cells or within their cell population of interest. The field is growing, and many new methods appear each year. We compared methods utilized in our core facility: Smart-seq3, PlexWell, FLASH-seq, VASA-seq, SORT-seq, 10X, Evercode, and HIVE. We characterized the equipment requirements for each method. We evaluated the performances of these methods based on detected features, transcriptome diversity, mitochondrial RNA abundance and multiplets, among others and benchmarked them against bulk RNA sequencing. Here, we show that bulk transcriptome detects more unique transcripts than any single cell method. While most methods are comparable in many regards, FLASH-seq and VASA-seq yielded the best metrics, e.g., in number of features. If no equipment for automation is available or many cells are desired, then HIVE or 10X yield good results. In general, more recently developed methods perform better. This also leads to the conclusion that older methods should be phased out, and that the development of single cell RNAseq methods is still progressing considerably.

Transcriptional profiling of fibroblasts from patients with mutations in MCT8 and comparative analysis with the human brain transcriptome.

Thyroid hormone (TH) is crucial for normal brain development. TH transporters control TH homeostasis in brain as evidenced by the complex endocrine and neurological phenotype of patients with mutations in monocarboxylate transporter 8 (MCT8). We investigated the mechanisms of disease by analyzing gene expression profiles in fibroblasts from patients with MCT8 mutations. Studying MCT8 and its transcriptional context in different comprehensive spatial and temporal human brain transcriptome data sets revealed distinct region-specific MCT8 expression. Furthermore, MCT8 demonstrated a clear age-dependent decrease, suggesting its importance in early brain development. Performing comparative transcriptome analysis, we linked the genes differentially expressed (DE) in patient fibroblasts to the human brain transcriptome. DE genes in patient fibroblasts were strongly over-represented among genes highly correlated with MCT8 expression in brain. Furthermore, using the same approach we identified which genes in the classical TH signaling pathway are affected in patients. Finally, we provide evidence that the TRα2 receptor variant is closely connected to MCT8. The present study provides a molecular basis for understanding which pathways are likely affected in the brains of patients with mutations in MCT8. Our data regarding a functional relationship between MCT8 and TRα2 suggest an unanticipated role for TRα2 in the (patho)physiology of TH signaling in the brain. This study demonstrates how genome-wide expression data from patient-derived non-neuronal tissue related to the human brain transcriptome may be successfully employed to improve our understanding of neurological disease.

The effect of robotic rehabilitation on posture and trunk control in non-ambulatory cerebral palsy.

The purpose of this study was to investigate the effects of a combined robot-assisted gait training (RAGT) with standard physiotherapy (PT) on trunk control and posture in non-ambulatory children with cerebral palsy (CP). This nonrandomized, controlled study included 31 CP assigned into two groups. Study Group: RAGT (three times a week, 30 min/session, for 6 weeks) + PT. Control group: PT only. The patients were evaluated using gross motor function measure (GMFM)-88 (Section B, Sitting) and Trunk Impairment Scale (TIS), pre-treatment and 3rd month post-treatment. In the RAGT group, significant improvements were observed in the GMFM-B and TIS scores at the 3rd month post-treatment (p < 0.05). Comparison of the changes in GMFM-B and TIS scores from end to beginning of the study, the change in TIS static are significantly higher in the RAGT group than control group (p < 0.05). Addition of RAGT to standard physiotherapy seems to improve trunk control, sitting balance, and posture in non-ambulatory CP.

USP7 regulates the ncPRC1 Polycomb axis to stimulate genomic H2AK119ub1 deposition uncoupled from H3K27me3.

Ubiquitin-specific protease 7 (USP7) has been implicated in cancer progression and neurodevelopment. However, its molecular targets remain poorly characterized. We combined quantitative proteomics, transcriptomics, and epigenomics to define the core USP7 network. Our multi-omics analysis reveals USP7 as a control hub that links genome regulation, tumor suppression, and histone H2A ubiquitylation (H2AK119ub1) by noncanonical Polycomb-repressive complexes (ncPRC1s). USP7 strongly stabilizes ncPRC1.6 and, to a lesser extent, ncPRC1.1. Moreover, USP7 represses expression of AUTS2, which suppresses H2A ubiquitylation by ncPRC1.3/5. Collectively, these USP7 activities promote the genomic deposition of H2AK119ub1 by ncPRC1, especially at transcriptionally repressed loci. Notably, USP7-dependent changes in H2AK119ub1 levels are uncoupled from H3K27me3. Even complete loss of the PRC1 catalytic core and H2AK119ub1 has only a limited effect on H3K27me3. Besides defining the USP7 regulome, our results reveal that H2AK119ub1 dosage is largely disconnected from H3K27me3.