Variant STAT4 and Response to Ruxolitinib in an Autoinflammatory Syndrome.

BACKGROUND: Disabling pansclerotic morphea (DPM) is a rare systemic inflammatory disorder, characterized by poor wound healing, fibrosis, cytopenias, hypogammaglobulinemia, and squamous-cell carcinoma. The cause is unknown, and mortality is high. METHODS: We evaluated four patients from three unrelated families with an autosomal dominant pattern of inheritance of DPM. Genomic sequencing independently identified three heterozygous variants in a specific region of the gene that encodes signal transducer and activator of transcription 4 (STAT4). Primary skin fibroblast and cell-line assays were used to define the functional nature of the genetic defect. We also assayed gene expression using single-cell RNA sequencing of peripheral-blood mononuclear cells to identify inflammatory pathways that may be affected in DPM and that may respond to therapy. RESULTS: Genome sequencing revealed three novel heterozygous missense gain-of-function variants in STAT4. In vitro, primary skin fibroblasts showed enhanced interleukin-6 secretion, with impaired wound healing, contraction of the collagen matrix, and matrix secretion. Inhibition of Janus kinase (JAK)-STAT signaling with ruxolitinib led to improvement in the hyperinflammatory fibroblast phenotype in vitro and resolution of inflammatory markers and clinical symptoms in treated patients, without adverse effects. Single-cell RNA sequencing revealed expression patterns consistent with an immunodysregulatory phenotype that were appropriately modified through JAK inhibition. CONCLUSIONS: Gain-of-function variants in STAT4 caused DPM in the families that we studied. The JAK inhibitor ruxolitinib attenuated the dermatologic and inflammatory phenotype in vitro and in the affected family members. (Funded by the American Academy of Allergy, Asthma, and Immunology Foundation and others.).

Transcutaneous Auricular Vagus Nerve Stimulation (tAVNS) Delivered During Upper Limb Interactive Robotic Training Demonstrates Novel Antagonist Control for Reaching Movements Following Stroke.

Implanted vagus nerve stimulation (VNS) delivered concurrently with upper limb rehabilitation has been shown to improve arm function after stroke. Transcutaneous auricular VNS (taVNS) offers a non-invasive alternative to implanted VNS and may provide similar therapeutic benefit. There is much discussion about the optimal approach for combining VNS and physical therapy, as such we sought to determine whether taVNS administered during robotic training, specifically delivered during the premotor planning stage for arm extension movements, would confer additional motor improvement in patients with chronic stroke. Thirty-six patients with chronic, moderate-severe upper limb hemiparesis (>6 months; mean Upper Extremity Fugl-Meyer score = 25 ± 2, range 13-48), were randomized to receive 9 sessions (1 h in length, 3x/week for 3 weeks) of active (N = 18) or sham (N = 18) taVNS (500 ms bursts, frequency 30 Hz, pulse width 0.3 ms, max intensity 5 mA, ∼250 stimulated movements per session) delivered during robotic training. taVNS was triggered by the onset of a visual cue prior to center-out arm extension movements. Clinical assessments and surface electromyography (sEMG) measures of the biceps and triceps brachii were collected during separate test sessions. Significant motor improvements were measured for both the active and sham taVNS groups, and these improvements were robust at 3 month follow-up. Compared to the sham group, the active taVNS group showed a significant reduction in spasticity of the wrist and hand at discharge (Modified Tardieu Scale; taVNS = -8.94% vs. sham = + 2.97%, p < 0.05). The EMG results also demonstrated significantly increased variance for the bicep peak sEMG amplitude during extension for the active taVNS group compared to the sham group at discharge (active = 26.29% MVC ± 3.89, sham = 10.63% MVC ± 3.10, mean absolute change admission to discharge, p < 0.01), and at 3-month follow-up, the bicep peak sEMG amplitude was significantly reduced in the active taVNS group (P < 0.05). Thus, robot training improved the motor capacity of both groups, and taVNS, decreased spasticity. taVNS administered during premotor planning of movement may play a role in improving coordinated activation of the agonist-antagonist upper arm muscle groups by mitigating spasticity and increasing motor control following stroke. Clinical Trial Registration: www.ClinicalTrials.gov, identifier (NCT03592745).

Robotic Kinematic measures of the arm in chronic Stroke: part 1 - Motor Recovery patterns from tDCS preceding intensive training.

BACKGROUND: Effectiveness of robotic therapy and transcranial direct current stimulation is conventionally assessed with clinical measures. Robotic metrics may be more objective and sensitive for measuring the efficacy of interventions on stroke survivor's motor recovery. This study investigated if robotic metrics detect a difference in outcomes, not seen in clinical measures, in a study of transcranial direct current stimulation (tDCS) preceding robotic therapy. Impact of impairment severity on intervention response was also analyzed to explore optimization of outcomes by targeting patient sub-groups. METHODS: This 2020 study analyzed data from a double-blind, sham-controlled, randomized multi-center trial conducted from 2012 to 2016, including a six-month follow-up. 82 volunteers with single chronic ischemic stroke and right hemiparesis received anodal tDCS or sham stimulation, prior to robotic therapy. Robotic therapy involved 1024 repetitions, alternating shoulder-elbow and wrist robots, for a total of 36 sessions. Shoulder-elbow and wrist kinematic and kinetic metrics were collected at admission, discharge, and follow-up. RESULTS: No difference was detected between the tDCS or sham stimulation groups in the analysis of robotic shoulder-elbow or wrist metrics. Significant improvements in all metrics were found for the combined group analysis. Novel wrist data showed smoothness significantly improved (P < ·001) while submovement number trended down, overlap increased, and interpeak interval decreased. Post-hoc analysis showed only patients with severe impairment demonstrated a significant difference in kinematics, greater for patients receiving sham stimulation. CONCLUSIONS: Robotic data confirmed results of clinical measures, showing intensive robotic therapy is beneficial, but no additional gain from tDCS. Patients with severe impairment did not benefit from the combined intervention. Wrist submovement characteristics showed a delayed pattern of motor recovery compared to the shoulder-elbow, relevant to intensive intervention-related recovery of upper extremity function in chronic stroke. TRIAL REGISTRATION: http://www.clinicaltrials.gov . Actual study start date September 2012. First registered on 15 November 2012. Retrospectively registered. Unique identifiers: NCT01726673 and NCT03562663 .

Robotic Kinematic measures of the arm in chronic Stroke: part 2 - strong correlation with clinical outcome measures.

BACKGROUND: A detailed sensorimotor evaluation is essential in planning effective, individualized therapy post-stroke. Robotic kinematic assay may offer better accuracy and resolution to understand stroke recovery. Here we investigate the added value of distal wrist measurement to a proximal robotic kinematic assay to improve its correlation with clinical upper extremity measures in chronic stroke. Secondly, we compare linear and nonlinear regression models. METHODS: Data was sourced from a multicenter randomized controlled trial conducted from 2012 to 2016, investigating the combined effect of robotic therapy and transcranial direct current stimulation (tDCS). 24 kinematic metrics were derived from 4 shoulder-elbow tasks and 35 metrics from 3 wrist and forearm evaluation tasks. A correlation-based feature selection was performed, keeping only features substantially correlated with the target attribute (R > 0.5.) Nonlinear models took the form of a multilayer perceptron neural network: one hidden layer and one linear output. RESULTS: Shoulder-elbow metrics showed a significant correlation with the Fugl Meyer Assessment (upper extremity, FMA-UE), with a R = 0.82 (P < 0.001) for the linear model and R = 0.88 (P < 0.001) for the nonlinear model. Similarly, a high correlation was found for wrist kinematics and the FMA-UE (R = 0.91 (P < 0.001) and R = 0.92 (P < 0.001) for the linear and nonlinear model respectively). The combined analysis produced a correlation of R = 0.91 (P < 0.001) for the linear model and R = 0.91 (P < 0.001) for the nonlinear model. CONCLUSIONS: Distal wrist kinematics were highly correlated to clinical outcomes, warranting future investigation to explore our nonlinear wrist model with acute or subacute stroke populations. TRIAL REGISTRATION: http://www.clinicaltrials.gov . Actual study start date September 2012. First registered on 15 November 2012. Retrospectively registered. Unique identifiers: NCT01726673 and NCT03562663 .

Clinical improvement with intensive robot-assisted arm training in chronic stroke is unchanged by supplementary tDCS.

BACKGROUND: Intensive robot-assisted arm training in the chronic phase of stroke recovery can lead to clinical improvement. Combinatorial therapeutic approaches are sought to further optimize stroke recovery. Transcranial direct current stimulation (tDCS) is one candidate to combine with robotic training, as transient increases in excitability and improvements in motor behavior have separately been reported. OBJECTIVE: To determine whether tDCS, delivered prior to robotic training, could augment clinical improvement. METHODS: We conducted a dual-site, randomized controlled trial in 82 chronic ischemic stroke patients (inclusion > 6 m post-injury, dominant hemisphere, first stroke; residual hemiparesis) who were split into two groups to receive tDCS (M1-SO montage, anode ipsilesional, 5×7 cm electrodes, 2 mA, 20 mins) or sham tDCS, prior to robotic upper-limb training (12 weeks; 36 sessions; shoulder-elbow robot or wrist robot on alternating sessions). The primary end-point was taken after 12 weeks of training, and assessed with the Upper Extremity Fugl-Meyer impairment scale (FM). Corticomotor conduction was assessed with transcranial magnetic stimulation (TMS). RESULTS: For the combined group (n = 82; post-training) robotic training increased the FM by 7.36 points compared to baseline (p < 0.0001). There was no difference in the FM increase between the tDCS and sham groups (6.97 and 7.73 respectively, p = 0.46). In both groups, clinically meaningful improvement (≥5 points) from baseline was evident in the majority of patients (56/77), was sustained six months later (54/72), and could be attained in severe, moderate and mild baseline hemiparesis. Clinical improvement was associated with increased excitability in the affected hemisphere as assessed by resting motor threshold (pre-post p = 0.029; pre-post 6 months p = 0.029), but not with threshold-adjusted assessment of MEP amplitude (pre-post p = 0.09; pre-post 6 months p = 0.15). Participants with motor evoked potentials were more likely to improve clinically than those without (17/18, 94%, versus 39/59, 66%, p = 0.018). CONCLUSIONS: Our study confirms the benefit of intensive robot-assisted training in stroke recovery, and indicates that conventional tDCS does not confer further advantage to robotic training. We also showed that corticospinal integrity, as assessed by TMS, is a predictor of clinically meaningful response to intensive arm therapy in chronic stroke.

Non-invasive treatment of patients with upper extremity spasticity following stroke using paired trans-spinal and peripheral direct current stimulation.

BACKGROUND: Muscle spasticity is a common impediment to motor recovery in patients with chronic stroke. Standard-of-care treatments such as botulinum toxin injections can temporarily relieve muscle stiffness and pain associated with spasticity, but often at the expense of increased muscle weakness. Recent preclinical investigations of a non-invasive treatment that pairs trans-spinal direct current stimulation and peripheral nerve direct current stimulation (tsDCS+pDCS) provided promising data for a novel approach based on bioelectronic medicine for the treatment of patients with post-stroke spasticity. METHODS: Twenty-six patients with upper limb hemiparesis and wrist spasticity at least 6 months after their initial stroke participated in this single-blind crossover design study to test whether tsDCS+pDCS reduces chronic upper-extremity spasticity. Subjects received five consecutive daily sessions (20 min of stimulation or sham) of anodal tsDCS+pDCS, separated by a one-week washout period. The sham condition always preceded the active condition. Clinical and objective measures of spasticity and motor function were collected before and after each condition, and for five weeks after the completion of the active intervention. RESULTS: Subjects treated with active tsDCS+pDCS demonstrated significant reductions in both Modified Tardieu Scale scores (summed across the upper limb, P < 0.05), and in objective torque measures (Nm) of the spastic catch response at the wrist flexor (P < 0.05), compared to the sham condition. Motor function also improved significantly (measured by the Fugl-Meyer and Wolf Motor Function Test; P < 0.05 for both tests) after active treatment. CONCLUSIONS: tsDCS+pDCS intervention alone significantly reduced upper limb spasticity in participants with stroke. Decreased spasticity was persistent for five weeks after treatment, and was accompanied by improved motor function even though patients were unsupervised and there was no prescribed activity or training during that interval. TRIAL REGISTRATION: NCT03080454, March 15, 2017.

Robotic Arm Rehabilitation in Chronic Stroke Patients With Aphasia May Promote Speech and Language Recovery (but Effect Is Not Enhanced by Supplementary tDCS).

Objective: This study aimed to determine the extent to which robotic arm rehabilitation for chronic stroke may promote recovery of speech and language function in individuals with aphasia. Methods: We prospectively enrolled 17 individuals from a hemiparesis rehabilitation study pairing intensive robot assisted therapy with sham or active tDCS and evaluated their speech (N = 17) and language (N = 9) performance before and after a 12-week (36 session) treatment regimen. Performance changes were evaluated with paired t-tests comparing pre- and post-test measures. There was no speech therapy included in the treatment protocol. Results: Overall, the individuals significantly improved on measures of motor speech production from pre-test to post-test. Of the subset who performed language testing (N = 9), overall aphasia severity on a standardized aphasia battery improved from pre-test baseline to post-test. Active tDCS was not associated with greater gains than sham tDCS. Conclusions: This work indicates the importance of considering approaches to stroke rehabilitation across different domains of impairment, and warrants additional exploration of the possibility that robotic arm motor treatment may enhance rehabilitation for speech and language outcomes. Further investigation into the role of tDCS in the relationship of limb and speech/language rehabilitation is required, as active tDCS did not increase improvements over sham tDCS.

Educación emocional. Abordaje del proceso de la muerte en la escuela / Emotional education. Approach to the process of death at schooll

El tema de la muerte es raramente abordado en las escuelas, existiendo una negación a la misma, propia de valores y arraigos presentes en la sociedad occidental actual. La educación socio-emocional en las escuelas, es un área emergente con escasos programas rigurosos y bien diseñados en relación a la muerte y el duelo; educar hacia el proceso de pérdida y lo que esta genera en las personas, debería incluirse como contenido curricular. Realizar un análisis sistemático sobre las diferentes propuestas metodológicas orientadas a la educación para la muerte(AU)

The issue of death is rarely addressed in schools, there is a denial of it, typical of values and roots present in today's Western society. Social-emotional education in schools is an emerging area with few rigorous and well-designed programs in relation to death and grief; educate towards the process of loss and what it generates in people, should be included as curricular content. Carry out a systematic analysis on the different methodological proposals aimed at education for death(AU)

Intensive seated robotic training of the ankle in patients with chronic stroke differentially improves gait.

BACKGROUND: Robotic driven treatment plans targeting isolated joints of the upper limb have improved the sensorimotor condition of patients with stroke. Similar intensive efforts to allay lower limb gait impairment have not been so successful. In patients with stroke, targeted robot assisted training of the ankle joint, in a seated position, has demonstrated significant alterations in ankle stiffness and foot-ankle orientation at foot strike which may provide a new treatment option for gait impairment. OBJECTIVE: To determine if isolated robot-assisted training of the ankle joint improves chronic hemiparetic gait in patients with stroke who are categorized according to baseline gait impairment. METHODS: Patients with chronic stroke (>6mo) and hemiparetic gait (N = 29) received 18 sessions of isolated robot-assisted motor training of the ankle (3×/week for 6 weeks). All participants had stable clinical baseline scores across three admission measures, and no participant was receiving simultaneous outpatient rehabilitation. Baseline gait speed determined three impairment groups: high, >0.8 m/s; medium, 0.4-0.8 m/s; low, <0.4 m/s. Outcome measures included the Berg Balance Scale, the 6 Minute Walk Test, and the 10 Meter Walk Test, and were recorded upon admission, discharge, and 3 months following intervention. RESULTS: Three distinct and significant between-group patterns of recovery emerged for gait speed. The within-group analysis showed that the medium and high group exhibited significant improvements in gait speed and endurance upon discharge, that were maintained at 3-months. Gait speed improvements were clinically significant (>0.16 m/s) for the high function group across all gait speed and endurance measures at discharge and at 3 months. The moderate group also exhibited clinically significant improvements at follow-up on the 10 Meter Walk Test, fast pace (0.16 m/sec), and approached clinical significance for the 10 Meter Walk comfortable pace (0.12 m/sec). The low group had small but significant improvements, at discharge on two of the three gait measures, and these improvements were maintained at 3 months. For balance measures, the low and moderate impairment groups had significant improvements at discharge that were robust on follow-up measure. The high function group demonstrated no significant change in balance. CONCLUSIONS: Joint-specific robotic training of the paretic ankle provided the most benefit to individuals with moderate or mild gait speed impairments after stroke. Baseline gait speed function (low, moderate, high) was associated with three distinct recovery profiles. This suggests that severity-specific intervention may be critical to improving efficiency of stroke recovery.

Recurrent fevers and failure to thrive in an infant.

We describe a 2-year old boy with consanguineous parents who recently emigrated from India and presented with oral ulcers and lymphadenopathy. He also had a history of recurrent fevers, polyarticular arthritis, chronic diarrhea, failure to thrive, and developmental delay. Infectious workup revealed herpes simplex virus 1 viremia and radiological evaluation revealed osteopenia and erosions involving multiple joints. We describe the immunologic and genetic evaluation of this patient and discuss the diagnostic and therapeutic approach to an infant with recurrent fevers.

Pilot study of a robotic protocol to treat shoulder subluxation in patients with chronic stroke.

BACKGROUND: Shoulder subluxation is a frequent complication of motor impairment after stroke, leading to soft tissue damage, stretching of the joint capsule, rotator cuff injury, and in some cases pain, thus limiting use of the affected extremity beyond weakness. In this pilot study, we determined whether robotic treatment of chronic shoulder subluxation can lead to functional improvement and whether any improvement was robust. METHODS: 18 patients with chronic stroke (3.9 ± 2.9 years from acute stroke), completed 6 weeks of robotic training using the linear shoulder robot. Training was performed 3 times per week on alternate days. Each session consisted of 3 sets of 320 repetitions of the affected arm, and the robotic protocol alternated between training vertical arm movements, shoulder flexion and extension, in an anti-gravity plane, and training horizontal arm movements, scapular protraction and retraction, in a gravity eliminated plane. RESULTS: Training with the linear robot improved shoulder stability, motor power, and resulted in improved functional outcomes that were robust 3 months after training. CONCLUSION: In this uncontrolled pilot study, the robotic protocol effectively treated shoulder subluxation in chronic stroke patients. Treatment of subluxation can lead to improved functional use of the affected arm, likely by increasing motor power in the trained muscles.

Nuclear scintigraphy findings for Askin tumor with In111-pentetreotide, Tc99m-MIBI and F18-FDG.

Askin tumor is a rare disease which had previously been reported as being thallium-201 and gallium-67 avid. Varying data regarding 18F- fluorodeoxyglucose metabolism has been described with Ewing family of soft tissue tumors. In this case, we present a patient found to have an Askin tumor of the left chest wall which demonstrated indium-111 pentetreotide and technetium-99m MIBI avidity. The lesion did not show 18F- fluorodeoxyglucose hypermetabolism in this case despite the aggressiveness of the tumor. The patient was treated with surgical excision of the tumor and chemotherapy. Subsequently, contrast enhanced CT, indium-111 pentetreotide and technetium 99m-MIBI showed that the lesion had regressed. These findings suggest that Askin tumor can demonstrate Indium-111 pentetreotide and technetium 99m-MIBI uptake and need not be hypermetabolic on 18F-fluorodeoxyglucose exam.

Bilateral hilar foci on 18F-FDG PET scan in patients without lung cancer: variables associated with benign and malignant etiology.

UNLABELLED: Bilateral hilar (18)F-FDG-avid foci are often noted on PET studies of patients without lung cancer. This finding may lead to diagnostic uncertainty about the presence of metastatic disease. Our objective was to evaluate features of these foci associated with benign or malignant etiology. METHODS: We performed a retrospective study of patients with cancer with bilateral hilar foci on 1 or 2 sequential (18)F-FDG PET studies between 2002 and 2006. Patients with lung cancer, sarcoidosis, or anthracosis/silicosis were excluded. Variables evaluated were maximum standard uptake values (SUV max), purity (absence of (18)F-FDG-avid foci in nonhilar mediastinal nodes), symmetry (difference between left and right side SUV max), the primary tumor, node size determined by CT, and, in those who participated in 2 studies, stability of uptake over time. The gold standard was histologic diagnosis or long-term clinical follow-up (range, 19-41 mo; mean, 25 mo). RESULTS: Fifty-one patients with the finding of bilateral hilar (18)F-FDG-avid foci underwent a staging-only PET study; 52 scans from an additional set of patients demonstrated this abnormality on at least 1 of 2 sequential studies, the first of which was performed for staging. On univariate analysis, variables associated with malignancy were SUV max (6.6+/-4.1 vs. 3.5+/-1.0 for benign, P<0.001; t test); impurity (P<0.001; chi(2) test), with 79% of impure scans versus 18% of pure scans being malignant; node size determined by CT (P=0.027); and change in uptake between scans 1 and 2 (change in SUV=2.7+/-2.1 vs. 0.73+/-1.1 for benign, P < 0.01; t test). Variables associated with benign etiology were: symmetry (difference between left and right sides=0.57+/-0.54 for benign vs. 1.8+/-1.7 for malignant, P<0.01), purity, and colorectal primary (75% of colorectal were benign vs. 34% of breast, 49% of lymphoma, and 37% of other, P=0.030; chi(2) test). After multivariate analysis, SUV max and purity were found to be independent predictors, with the odds of malignancy increasing by 1.54 (95% confidence interval, 1.16-2.05) for each unit increase in SUV and decreasing by 0.08 (95% confidence interval, 0.03-0.22) if pure. CONCLUSION: In patients with nonlung cancer, in particular colorectal, foci of symmetric and mild uptake limited to the hilar regions that are stable on 2 sequential PET studies despite intervening anticancer therapy are likely related to a benign etiology.

Structure of the 1,4-bis(2'-deoxyadenosin-N6-yl)-2R,3R-butanediol cross-link arising from alkylation of the human N-ras codon 61 by butadiene diepoxide.

The solution structure of the 1,4-bis(2'-deoxyadenosin-N(6)-yl)-2R,3R-butanediol cross-link arising from N(6)-dA alkylation of nearest-neighbor adenines by butadiene diepoxide (BDO(2)) was determined in the oligodeoxynucleotide 5'-d(CGGACXYGAAG)-3'.5'-d(CTTCTTGTCCG)-3'. This oligodeoxynucleotide contained codon 61 (underlined) of the human N-ras protooncogene. The cross-link was accommodated in the major groove of duplex DNA. At the 5'-side of the cross-link there was a break in Watson-Crick base pairing at base pair X(6).T(17), whereas at the 3'-side of the cross-link at base pair Y(7).T(16), base pairing was intact. Molecular dynamics calculations carried out using a simulated annealing protocol, and restrained by a combination of 338 interproton distance restraints obtained from (1)H NOESY data and 151 torsion angle restraints obtained from (1)H and (31)P COSY data, yielded ensembles of structures with good convergence. Helicoidal analysis indicated an increase in base pair opening at base pair X(6).T(17), accompanied by a shift in the phosphodiester backbone torsion angle beta P5'-O5'-C5'-C4' at nucleotide X(6). The rMD calculations predicted that the DNA helix was not significantly bent by the presence of the four-carbon cross-link. This was corroborated by gel mobility assays of multimers containing nonhydroxylated four-carbon N(6),N(6)-dA cross-links, which did not predict DNA bending. The rMD calculations suggested the presence of hydrogen bonding between the hydroxyl group located on the beta-carbon of the four-carbon cross-link and T(17) O(4), which perhaps stabilized the base pair opening at X(6).T(17) and protected the T(17) imino proton from solvent exchange. The opening of base pair X(6).T(17) altered base stacking patterns at the cross-link site and induced slight unwinding of the DNA duplex. The structural data are interpreted in terms of biochemical data suggesting that this cross-link is bypassed by a variety of DNA polymerases, yet is significantly mutagenic [Kanuri, M., Nechev, L. V., Tamura, P. J., Harris, C. M., Harris, T. M., and Lloyd, R. S. (2002) Chem. Res. Toxicol. 15, 1572-1580].