NLRP3 inflammasome-driven IL-1ß and IL-18 contribute to lipopolysaccharide-induced septic cardiomyopathy.

Sepsis is a life-threatening syndrome, and its associated mortality is increased when cardiac dysfunction and damage (septic cardiomyopathy [SCM]) occur. Although inflammation is involved in the pathophysiology of SCM, the mechanism of how inflammation induces SCM in vivo has remained obscure. NLRP3 inflammasome is a critical component of the innate immune system that activates caspase-1 (Casp1) and causes the maturation of IL-1ß and IL-18 as well as the processing of gasdermin D (GSDMD). Here, we investigated the role of the NLRP3 inflammasome in a murine model of lipopolysaccharide (LPS)-induced SCM. LPS injection induced cardiac dysfunction, damage, and lethality, which was significantly prevented in NLRP3-/- mice, compared to wild-type (WT) mice. LPS injection upregulated mRNA levels of inflammatory cytokines (Il6, Tnfa, and Ifng) in the heart, liver, and spleen of WT mice, and this upregulation was prevented in NLRP3-/- mice. LPS injection increased plasma levels of inflammatory cytokines (IL-1ß, IL-18, and TNF-α) in WT mice, and this increase was markedly inhibited in NLRP3-/- mice. LPS-induced SCM was also prevented in Casp1/11-/- mice, but not in Casp11mt, IL-1ß-/-, IL-1α-/-, or GSDMD-/- mice. Notably, LPS-induced SCM was apparently prevented in IL-1ß-/- mice transduced with adeno-associated virus vector expressing IL-18 binding protein (IL-18BP). Furthermore, splenectomy, irradiation, or macrophage depletion alleviated LPS-induced SCM. Our findings demonstrate that the cross-regulation of NLRP3 inflammasome-driven IL-1ß and IL-18 contributes to the pathophysiology of SCM and provide new insights into the mechanism underlying the pathogenesis of SCM.

Caspase-11 deficiency attenuates neutrophil recruitment into the atherosclerotic lesion in apolipoprotein E-deficient mice.

Caspase-11 is an inflammatory caspase that triggers an inflammatory response by regulating non-canonical NLRP3 inflammasome activation. Although the deficiency of both caspase-11 and caspase-1, another inflammatory caspase that functions as an executor of the inflammasome, prevents the development of atherosclerosis, the effect of caspase-11 deficiency alone on the development of atherosclerosis has not been fully evaluated. In the present study, we found that caspase-11 deficiency prevented the formation of the necrotic core, whereas it did not affect the development of atherosclerosis in Apoe-deficient mice. Notably, the infiltration of neutrophils into atherosclerotic lesions was attenuated by caspase-11 deficiency. RNA-seq analysis of stage-dependent expression of atherosclerotic lesions revealed that both upregulations of caspase-11 and neutrophil migration are common features of advanced atherosclerotic lesions. Furthermore, similar expression profiles were observed in unstable human plaque. These data suggest that caspase-11 regulates neutrophil recruitment and plaque destabilization in advanced atherosclerotic lesions.

Effects of Repetitive Peripheral Magnetic Stimulation on Shoulder Subluxations Caused by Stroke: A Preliminary Study.

OBJECTIVES: Shoulder subluxation is a common problem after stroke. It causes shoulder pain that affects activities of daily living. This study aimed to investigate the effect of repetitive peripheral magnetic stimulation on shoulder subluxation after stroke. METHODS: We enrolled 12 consecutive patients who, as a result of stroke, suffered shoulder subluxations, measuring at half of a fingerbreadth or more. All subjects underwent conventional rehabilitation, as well as repetitive peripheral magnetic stimulation of their supraspinatus, posterior deltoid, and infraspinatus muscles. We assessed the following parameters: shoulder subluxation, evaluated as the acromio-humeral interval using measurements taken from X-rays; shoulder pain, evaluated using the Numerical Rating Scale; the active range of motion of shoulder abduction; and the motor impairment of the upper extremities, evaluated using the upper extremity of the Fugl-Meyer Assessment scale. RESULTS: The acromio-humeral interval before treatment was 22.8 ± 5.7 mm (mean ± SD). It significantly decreased to 19.6 ± 7.0 mm (p = 0.004) after treatment. Shoulder pain (p = 0.039), active range of motion of shoulder abduction (p = 0.016), and total (p = 0.005), subscale A (p = 0.005), and subscale C (p = 0.008) Fugl-Meyer Assessment scores also improved significantly after treatment. CONCLUSIONS: Repetitive peripheral magnetic stimulation effectively reduced shoulder subluxations and shoulder pain caused by stroke and improved voluntary upper-limb movements in stroke patients.

Upper Limb Motor Function Affects the Outcome after Treatment with Botulinum Toxin A.

BACKGROUND: Treatment with Botulinum toxin A (BoNT-A) is effective in decreasing upper limb spasticity. OBJECTIVE: This study aimed to determine the differences in the outcome based on the upper limb motor function before BoNT-A treatment. METHODS: The subjects were 61 patients who underwent BoNT-A treatment for upper limb spasticity. Limb function was evaluated using the Fugl-Meyer Assessment upper extremity (FMA-UE), modified Ashworth scale, passive range of motion and disability assessment scale before treatment as well as 2, 6, and 12 weeks after treatment. We divided the total and each subscale of FMA-UE before BoNT-A administration into beyond-the-mean-score group (higher score group) and below-the-mean-score group (lower score group). RESULTS: In both the higher and lower score groups of the FMA-UE total and modified Ashworth scale scores improved significantly after treatment. In FMA-UE, the higher score group of subscale A improved significantly, but subscale C decreased significantly at 2 and 6 weeks after the administration. The lower score group of total, subscale A, and B improved significantly. In the disability assessment scale, the self-dressing capability at 6 weeks and limb position at 2, 6 and 12 weeks after the administration improved significantly in the higher score group. In the lower score group, the hygiene capability at 2 weeks as well as the dressing capability and limb position improved significantly at 2, 6 and 12 weeks after administration. CONCLUSIONS: The time course after administration of BoNT-A differed based on upper limb motor function before injection. When administering BoNT-A into the finger flexor muscles of a patient, we should carefully judge the indications for administration.

Repetitive peripheral magnetic stimulation for preventing shoulder subluxation after stroke: a randomized controlled trial.

BACKGROUND: Shoulder subluxation caused by paralysis after stroke is a serious issue affecting shoulder pain and functional prognosis. However, its preventive treatment has not been fully investigated. AIM: To investigate the effects of repetitive peripheral magnetic stimulation (rPMS) on the prevention of shoulder subluxation. DESIGN: A single-center, parallel-group, prospective randomized, open-blinded, end-point study. SETTING: Convalescent rehabilitation ward. POPULATION: We included 50 inpatients in the convalescent rehabilitation ward with post-stroke, having upper limb paralysis, and the acromio-humeral interval (AHI) was within 1/2 finger-breadth. METHODS: A blinded computer-based allocation system was used to randomly assign patients into two groups: 1) conventional rehabilitation plus rPMS therapy (rPMS group, N=25); and 2) conventional rehabilitation alone (control group, N=25). Blinded assessors evaluated the patients before the intervention (T0), 6 weeks after (T1), and 12 weeks after (T2). The primary outcome was the change in AHIs from T0 to T1 between the groups. In contrast, the secondary outcomes were shoulder pain, spasticity, active range of motion, and Fugl-Meyer Assessment upper extremity (FMA-UE) score. RESULTS: Twenty-two patients in the rPMS group and 24 in the control group completed T1, whereas 16 in the rPMS group and 11 in the control group completed T2. The change in AHI was significantly lower in the rPMS group than in the control group ([95% CI, -5.15 to -0.390], P=0.023). Within-group analysis showed that AHI in the rPMS group did not change significantly, whereas it increased in the control group (P=0.004). There were no significant differences between T1 and T2 within or between the groups. Moreover, AHI did not show differences in patients with severe impairment but decreased in the rPMS group in patients with mild impairment (P=0.001). CONCLUSIONS: The rPMS may be a new modality for preventing shoulder subluxation. The association between motor impairment and the sustained effect needs to be further examined. CLINICAL REHABILITATION IMPACT: Applying rPMS to the muscles of the paralyzed shoulder after a stroke may prevent shoulder subluxation.

LONG-TERM REPEATED BOTULINUM TOXIN A TREATMENT OVER 12 YEARS GRADUALLY CHANGES GAIT CHARACTERISTICS: SINGLE-CASE STUDY.

Objective: To demonstrate the long-term efficacy of repeated botulinum toxin A injections into the same muscles for ameliorating lower limb spasticity and gait function. Design: Single-case study. Patient: A 36-year-old woman with right cerebral haemorrhage received her first botulinum toxin A injection 1,296 days after onset. The patient underwent 30 treatments over 12 years after the first injection to improve upper and lower limb spasticity and abnormal gait patterns. The mean duration between injections was 147 days. Methods: The Modified Ashworth Scale, passive range of motion, gait velocity, and degree of abnormal gait patterns during treadmill gait were evaluated pre-injection and at 2, 6, and 12 weeks after every injection. Results: The follow-up period showed no injection-related adverse events. Comfortable overground gait velocity gradually improved over 30 injections. The Modified Ashworth Scale and passive range of motion improved after each injection. Pre-injection values of the degree of pes varus, circumduction, hip hiking, and knee extensor thrust improved gradually. However, the degree of contralateral vaulting, excessive lateral shift of the trunk, and insufficient knee flexion did not improve after 30 injections. Conclusion: Repeated botulinum toxin A injections effectively improve abnormal gait patterns, even when a single injection cannot change these values.

Botulinum toxin A (BoNTA) is used to treat spasticity in the arms and legs of adult patients. We report a case of a woman who was treated with BoNTA 30 times over 12 years to improve limb spasticity and abnormal gait patterns. The range of motion improved after each injection, and some other features of her gait improved gradually. We did not observe any injection-related adverse events during the follow-up period. We conclude that repeated BoNTA injections can effectively improve some abnormal gait patterns and comfortable overground gait velocity, even when a single injection cannot change these values. Cumulative effects were also shown. The combination of BoNTA and rehabilitation may lead to better results.

Impact of intracerebral hemorrhage and cerebral infarction on ADL and outcome in stroke patients: A retrospective cohort study.

BACKGROUND: The impact of different stroke types on specific activities of daily living (ADL) is unclear. OBJECTIVE: To investigate how differences between intracerebral hemorrhage (ICH) and cerebral infarction (CI) affect improvement of ADL in patients with stroke within a hospital by focusing on the sub-items of the Functional Independence Measure (FIM). METHODS: Patients with first-stroke hemiplegia (n = 212) were divided into two groups: ICH (86 patients) and CI (126 patients). Primary assessments included 13 motor and 5 cognitive sub-items of the FIM assessed at admission and discharge. Between-group comparisons and multiple regression analyses were performed. RESULTS: Upon admission, the ICH group exhibited significantly lower FIM scores than those of the CI group across various activities, including grooming, dressing (upper body and lower body), toileting, bed/chair transfer, toilet transfer, walking/wheelchair, and stairs. Age and FIM motor scores at admission influenced both groups' total FIM motor scores at discharge, whereas the duration from onset affected only the CI group. CONCLUSION: Several individual FIM motor items were more adversely affected by ICH than by CI. Factors related to ADL at discharge may differ depending on stroke type. Recognizing these differences is vital for efficient rehabilitation practices and outcome prediction.

Acquisition Status of Basic Clinical Skills in Japanese Novice Rehabilitation Therapists: A Preliminary Single-Center Study.

The number of post-graduate rehabilitation therapists (novice therapists) is increasing due to the growing demand for rehabilitation services in Japan. This study investigated the acquisition status of Japanese novice therapists' basic clinical skills to clarify their quality and characteristics. Eleven participants' basic clinical skills (eight physical and three occupational therapists) were assessed using an Objective Structured Clinical Examination. Tasks included exercises of joint range of motion, muscle strengthening, getting up, standing up and sitting down, and transferring between wheelchair and bed. Assessment items were subdivided into categories: attitude, preparation, intervention, safety management, and feedback. One-way ANOVA and Friedman test were used for statistical analysis to compare the data between tasks and categories. The scores for each task's achievement rate were not statistically significant. However, the achievement rate of each category including tasks was 92.6% (SD 4.0%) for attitude, 81.4% (SD 11.1%) for preparation, 77.9% (SD 14.7%) for intervention, 87.6% (SD 17.3%) for safety management, and 64.0% (SD 14.2%) for feedback. There were significant differences between attitude and feedback (p < 0.001), and between safety management and feedback (p = 0.012). Post-graduate training programs should focus on improving the quality of clinical skills, especially in skills related to feedback.

Development of a simple mechanical measurement method to measure spasticity based on an analysis of a clinical maneuver and its concurrent validity with the modified Ashworth scale.

Background: Despite recent developments in the methodology for measuring spasticity, the discriminative capacity of clinically diagnosed spasticity has not been well established. This study aimed to develop a simple device for measuring velocity-dependent spasticity with improved discriminative capacity based on an analysis of clinical maneuver and to examine its reliability and validity. Methods: This study consisted of three experiments. First, to determine the appropriate motion of a mechanical device for the measurement of velocity-dependent spasticity, the movement pattern and the angular velocity used by clinicians to evaluate velocity-dependent spasticity were investigated. Analysis of the procedures performed by six physical therapists to evaluate spasticity were conducted using an electrogoniometer. Second, a device for measuring the resistance force against ankle dorsiflexion was developed based on the results of the first experiment. Additionally, preliminary testing of validity, as compared to that of the Modified Ashworth Scale (MAS), was conducted on 17 healthy participants and 10 patients who had stroke with spasticity. Third, the reliability of the measurement and the concurrent validity of mechanical measurement in the best ankle velocity setting were further tested in a larger sample comprising 24 healthy participants and 32 patients with stroke. Results: The average angular velocity used by physical therapists to assess spasticity was 268 ± 77°/s. A device that enabled the measurement of resistance force at velocities of 300°/s, 150°/s, 100°/s, and 5°/s was developed. In the measurement, an angular velocity of 300°/s was found to best distinguish patients with spasticity (MAS of 1+ and 2) from healthy individuals. A measurement of 300°/s in the larger sample differentiated the control group from the MAS 1, 1+, and 2 subgroups (p < 0.01), as well as the MAS 1 and 2 subgroups (p < 0.05). No fixed or proportional bias was observed in repeated measurements. Conclusion: A simple mechanical measurement methodology was developed based on the analysis of the clinical maneuver for measuring spasticity and was shown to be valid in differentiating the existence and extent of spasticity. This study suggest possible requirements to improve the quality of the mechanical measurement of spasticity.

Requirements for Eliciting a Spastic Response With Passive Joint Movements and the Influence of Velocity on Response Patterns: An Experimental Study of Velocity-Response Relationships in Mild Spasticity With Repeated-Measures Analysis.

Background: Spasticity is defined as a velocity-dependent increase in tonic stretch reflexes and is manually assessed in clinical practice. However, the best method for the clinical assessment of spasticity has not been objectively described. This study analyzed the clinical procedure to assess spasticity of the elbow joint using an electrogoniometer and investigated the appropriate velocity required to elicit a spastic response and the influence of velocity on the kinematic response pattern. Methods: This study included eight healthy individuals and 15 patients with spasticity who scored 1 or 1+ on the modified Ashworth Scale (MAS). Examiners were instructed to manually assess spasticity twice at two different velocities (slow and fast velocity conditions). During the assessment, velocity, deceleration value, and angle [described as the % range of motion (%ROM)] at the moment of resistance were measured using an electrogoniometer. Differences between the slow and fast conditions were evaluated. In addition, variations among the fast condition such as the responses against passive elbow extension at <200, 200-300, 300-400, 400°/s velocities were compared between the MAS 1+, MAS 1, and control groups. Results: Significant differences were observed in the angular deceleration value and %ROM in the fast velocity condition (417 ± 80°/s) between patients and healthy individuals, but there was no difference in the slow velocity condition (103 ± 29°/s). In addition, the deceleration values were significantly different between the MAS 1 and MAS 1+ groups in velocity conditions faster than 300°/s. In contrast, the value of %ROM plateaued when the velocity was faster than 200°/s. Conclusion: The velocity of the passive motion had a significant effect on the response pattern of the elbow joint. The velocity-response pattern differed between deceleration and the angle at which the catch occurred; the value of deceleration value for passive motion was highly dependent on the velocity, while the %ROM was relatively stable above a certain velocity threshold. These results provide clues for accurate assessment of spasticity in clinical practice.

Do therapists with fewer years of clinical experience encounter more accidents? The relationship between number of years of clinical experience and number of accidents in a year.

OBJECTIVES: This study sought to determine whether therapists experience more accidents annually with increased clinical experience, and whether experiencing an accident in the first year of practice is associated with accidents in the second year of practice. METHODS: We categorized 642 therapists into five groups based on years of clinical experience (first, second, third, fourth, and 5-20 years; n=138, 112, 117, 58, and 217, respectively) and tallied the accidents they reported over an 8-year period. The difference between the five groups in the number of accidents per person per year was subjected to multiple comparisons testing using Kruskal-Wallis tests. RESULTS: Significant differences were revealed between the first year group and the 5-20 years group (p<0.01), between the second year group and the 5-20 years group (p<0.05), and between the third year group and the 5-20 years group (p<0.05). Specifically, participants in the 5-20 years group encountered fewer accidents than those in the other groups. Therapists who encountered an accident in their first year, compared with those who had not, had significantly more accidents in their second year. CONCLUSIONS: Therapists with 1-3 years of clinical experience are more likely to encounter an accident than therapists with >5 years of clinical experience. We conclude that young therapists who have experienced accidents are prone to future accidents. These findings inform the optimal allocation of educational resources to reduce the number of accidents encountered by therapists.

Calciprotein Particles Induce IL-1ß/α-Mediated Inflammation through NLRP3 Inflammasome-Dependent and -Independent Mechanisms.

Calciprotein particles (CPPs) are nanoparticles composed of calcium phosphate crystals and fetuin-A and have been implicated in diseases associated with inflammation. In the current study, we investigated the molecular mechanisms underlying CPP-induced inflammation in mice. CPPs predominantly upregulated IL-1ß and IL-1α and provided priming and activation signals for the NLRP3 inflammasome in murine macrophages. Pharmacological and genetic inhibition of the NLRP3 inflammasome revealed that CPPs induced the release of IL-1ß and IL-1α via NLRP3 inflammasome-dependent and -independent mechanisms, respectively. CPPs also induced necrotic cell death, but gasdermin D was dispensable for CPP-induced IL-1ß release and necrotic cell death. Although phagocytosis of CPPs was required for CPP-induced IL-1ß/α release and necrotic cell death, lysosomal dysfunction and K+ efflux were mainly involved in CPP-induced NLRP3 inflammasome activation and subsequent IL-1ß release but not in CPP-induced IL-1α release and necrotic cell death. In vivo experiments showed that CPP administration evoked acute inflammatory responses characterized by neutrophil accumulation via both IL-1ß and IL-1α. In particular, CPP-induced neutrophil inflammation was mediated predominantly through an IL-1α-induced CXCL1/CXCR2 signaling pathway. These results provide new insights into the mechanism underlying CPP-induced inflammation and suggest that targeting both IL-1ß and IL-1α is necessary to regulate the CPP-induced inflammatory response and to treat CPP-associated inflammatory disorders.

Quantitative assessment for flexed-elbow deformity during gait following botulinum toxin A treatment.

BACKGROUND: The effect of botulinum toxin A (BoNTA) injection on flexed-elbow deformity is usually evaluated using the Modified Ashworth Scale (MAS), but only with the muscle tone at rest. Some patients show the flexed-elbow deformity during gait despite low muscle tone at rest. OBJECTIVE: This study aimed to evaluate the effect of BoNTA injection on flexed-elbow deformity during gait using a three-dimensional motion analysis system. METHODS: Twenty stroke patients with spastic flexed-elbow deformity during gait received BoNTA injections into the upper limb muscles. The MAS score of the elbow flexors, passive elbow range of motion, comfortable overground gait velocity, and elbow flexion angle during treadmill gait were evaluated just before and 2, 6, and 12 weeks after the injection. Twenty-five healthy subjects were also recruited to provide a normal reference of the elbow flexion angle. RESULTS: The MAS scores at 2, 6 and 12 weeks after the injection were significantly lower than that before the injection. Some patients showed no spasticity at rest but an obviously flexed elbow during gait. The elbow flexion angles during gait at 2 and 6 weeks after the injection were significantly lower than that before the injection. CONCLUSIONS: BoNTA injections to the upper limb muscles reduced muscle tone at rest and flexed-elbow deformity during gait. However, the elbow flexion angle during gait returned to its pre-injection level sooner than the muscle tone at rest. We strongly recommend evaluating muscle tone during motion and at rest, preferably using three-dimensional motion analysis since it can objectively detect small changes.