Effect of cyborg-type robot Hybrid Assistive Limb on patients with severe walking disability in acute stroke: A randomized controlled study.

OBJECTIVES: To investigate whether early gait training using Hybrid Assistive Limb (HAL) is feasible and improves walking and independency compared with conventional physical therapy (CPT) in patients with severe walking disability after stroke. METHODS: We conducted a single-center, randomized controlled study. Patients with first-ever stroke who had severe walking disability were included. All patients started gait training within 10 days post-stroke onset. Twenty-four patients were randomly assigned into HAL or CPT groups. Outcome measures were collected at three time points, at baseline, completion of 20 sessions of gait training (second assessment), and 3 months after the initiation of gait training. The primary outcomes were changes in motor sub-scores of the Functional Independence Measure or Functional Ambulation Category at the completion of the second assessment from baseline. RESULTS: Twenty-two patients (median age, 68 years; 12 patients in the HAL group and 10 patients in the CPT group) completed the study. There were no significant differences in primary outcomes. Apathy scale, one of the secondary outcomes, showed a decreasing trend in the HAL group (mean change of -3.8, 95% CI -8.14 to 0.475), and a slight increasing trend in the CPT group (mean change of 1.2, 95% CI -2.66 to 5.06) at the second assessment. Patients in the HAL group experienced no adverse events. CONCLUSIONS: Early gait training in patients with severe walking disability after stroke using HAL was feasible. Walking ability and independency were not improved at the completion of 20 sessions of gait training.

Determinants of Physical Activity at 90 Days After Acute Stroke or Transient Ischemic Attack in Patients With Home Discharge: A Pilot Study.

The aim was to identify the barriers to achieving premorbid physical activity in patients with home discharge after acute minor stroke or transient ischemic attack. Fifty-six patients (median age, 72 years) were analyzed. We assessed total physical activity in the premorbid condition and at 90 days after onset using the International Physical Activity Questionnaire. The patients were divided into two groups according to changes in total physical activity until 90 days after onset: decreased activity (n = 16) and nondecreased activity (n = 40) groups. Outcome measures were examined at discharge. The decreased activity group took significantly longer to perform the timed up and go test (median, 7.19 vs. 6.52 s) and contained more apathetic patients (44% vs. 15%). Apathy at discharge (relative risk 6.05, 95% confidence interval [1.33, 27.6]) was a significant determinant of decreased physical activity. Apathy is a barrier to the restoration of premorbid physical activity in stroke survivors.

Functional complementation of V-ATPase a subunit isoforms in osteoclasts.

In osteoclasts, the a3 isoform of the proton-pumping V-ATPase plays essential roles in anterograde trafficking of secretory lysosomes and extracellular acidification required for bone resorption. This study examined functional complementation of the a isoforms by exogenously expressing the a1, a2 and a3 isoforms in a3-knockout (KO) osteoclasts. The expression levels of a1 and a2 in a3KO osteoclasts were similar, but lower than that of a3. a1 significantly localized to lysosomes, whereas a2 slightly did. On the other hand, a2 interacted with Rab7, a regulator of secretory lysosome trafficking in osteoclasts, more efficiently than a1. a1 partly complemented the functions of a3 in secretory lysosome trafficking and calcium phosphate resorption, while a2 partly complemented the former but not the latter function.

Interleukin-19 as an Immunoregulatory Cytokine.

IL-19 is a type of anti-inflammatory cytokine. Since the receptor for IL-19 is common to IL-20 and IL-24, it is important to clarify the role of each of the three cytokines. If three different cytokines bind to the same receptor, these three may have been produced to complement the other two. However, perhaps it is unlikely. Recently, the existence of a novel receptor for IL-19 was suggested. The distinction between the roles of the three cytokines still makes sense. On the other hand, because T cells do not produce IL-19, their role in acquired immunity is limited or indirect. It has been reported that IL-19 causes inflammation in some diseases but does not have an anti-inflammatory effect. In this review, we introduce the current role of IL-19 in each disease. In addition, we will describe the molecular mechanism of IL-19 and its development for the prevention of diseases. IL-19 was previously considered an anti-inflammatory cytokine, but we would like to propose it as an immunoregulatory cytokine.

Deficiency of interleukin-19 exacerbates lipopolysaccharide/D-galactosamine-induced acute liver failure.

Interleukin (IL)-19 is a cytokine clustered in the IL-20 cytokine superfamily with both anti-inflammatory and pro-inflammatory aspects depending on the etiology of inflammatory disease. The function of IL-19 has been evaluated in cutaneous and inflammatory bowel diseases, but has not been studied in liver diseases. Here, we examined the effect of IL-19 on acute liver failure (ALF) using two mouse models of ALF: lipopolysaccharide and D-galactosamine (LPS/GalN)-induced model and concanavalin A (ConA)-induced model. In the LPS/GalN-induced ALF model, which is mainly caused by the innate immune response of liver macrophages, IL-19 knockout (KO) mice showed increased plasma level of liver deviation enzymes, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) compared with wild-type (WT) mice. In histopathology of liver sections, IL-19 KO mice exacerbated liver injury with marked hemorrhagic lesions and hepatocellular death in the liver compared with WT mice. In this model, mRNA expressions of pro-inflammatory chemokines, CCL2 and CCL5 were increased in liver tissue from IL-19 KO mice compared with WT mice. Moreover, the mRNA expressions of IL-19 and its receptor subunit were induced in liver tissue by LPS/GalN administration. However, there is no difference in liver injury between WT and IL-19KO in the ConA-induced ALF model induced by CD4+ T cell activation. These data suggest that IL-19 has a protective effect against inflammation-mediated liver injury, which is dependent on the etiology.

[Surgical Treatment for Primary Pulmonary Artery Sarcoma;Report of a Case].

Primary pulmonary artery sarcoma is a very rare tumor. The prognosis of primary pulmonary artery sarcoma is extremely poor and it is reported as 1.5 months without treatment. Here we report our experience of surgical treatment of primary pulmonary artery sarcoma. A 66-year-old woman with a diagnosis of pulmonary sarcoma by chest computed tomography( CT) scan was referred to our hospital because of a loss of consciousness. An emergecy surgery was planned to eliminate the risk of sudden death. To avoid circulatory collapse, we placed her on extracorporeal bypass before anesthesia induction. The tumor extending from right ventricle outflow tract to bilateral pulmonary artery was removed and resected without leaving residual mass, but the surgical margin was positive, and adjuvant chemoradiotherapy was performed after discharge. In conclusion, surgical resection was succesfully conducted to avoid sudden death.

Novel Trigone-Based Sizing Method for Mitral Ring Annuloplasty.

BACKGROUND: We devised a novel trigone-based sizing method, setting the trigones at one-quarter of the annular circumference, and used it for mitral annuloplasty in patients with mitral regurgitation (MR). METHODS: Between 1999 and 2017, 436 patients with degenerative (n = 192), nonischemic functional (n = 124), or ischemic (n = 120) MR underwent mitral valvuloplasty at our institution using an incomplete ring. The intertrigonal distance and prerepair and postrepair annular diameter were measured. Then the diameters predicted from body surface area, the intertrigonal distance, and the ratios of these diameters to observed data were computed. We investigated the influence of these measurements on MR recurrence, transmitral pressure gradient, and systolic anterior motion. RESULTS: Initial repair was successful in 433 patients (99%), but 3 patients with systolic anterior motion and MR required conversion to valve replacement. After 1, 5, and 10 years (mean follow-up, 6.3 years), the rate of freedom from grade 2 or higher recurrent MR was 96%, 92%, and 86% in the degenerative group, 99%, 97%, and 90% in the nonischemic functional group, and 95%, 90%, and 79%, respectively, in the ischemic group (P = .052). The observed/body surface area predicted diameter ratio was negatively correlated with the mean transmitral pressure gradient (mm Hg); 12.3 - 8.2 × (ratio) (R = -0.37, P < .001), despite a smaller ratio (<0.9) not being associated with less recurrence of MR. In the degenerative group, systolic anterior motion developed in 7 of 71 patients (10%) with an observed/intertrigonal distance predicted diameter ratio of less than 0.9 (P < .001). CONCLUSIONS: Our trigone-based sizing method achieved satisfactory control of MR, while avoiding functional mitral stenosis and systolic anterior motion.

[Recent progress in the pathophysiological role of interleukin-19].

Cytokine signal is essential for the biological function including development, maintenance of homeostasis and progression of disease. There are growing evidences that signaling via pro-inflammatory cytokines underlie a variety of immunological diseases such as psoriasis, atopic dermatitis, inflammatory bowel disease, and metabolic syndromes, in which cytokine signals are known as a potential therapeutic target of antibody drugs. In contrast, anti-inflammatory cytokines, which is represented by IL-10, largely contribute to suppression of inflammation and restoration of injured tissues. IL-19 is a member of IL-10 cytokine family, which comprises IL-20 cytokine subfamily with IL-20, IL-22, IL-24, and IL-26. IL-19 is produced by myeloid and epithelial cells with stimulation of bacterial components and cytokines. Although IL-19 has been originally recognized as a potential Th2-related cytokine, in recent researches, it has been reported that this cytokine upregulates Th17 response to reflect and promote progression of Th17-related disease including psoriasis. On the other hand, IL-19 has anti-inflammatory effects on inflammatory diseases such as infectious skin disease, inflammatory bowel disease, and cardiovascular disease. Therefore, IL-19 may exert pleiotropic effects dependent on the pathological mechanism of inflammatory diseases. In this review, we summarize recent studies about IL-19 and introduce the pathophysiological and therapeutic role of IL-19 in inflammatory diseases.

[Giant Right Coronary Artery Aneurysm Causing Acute Myocardial Infarction;Report of a Case].

We report a case of giant right coronary artery aneurysm causing acute myocardial infarction. A 59-year-old man presented with syncope and referred to our hospital in ambulance. Electrocardiogram showed acute myocardial infarction of the right coronary artery, and emergent coronary angiography was performed. Angiography confirmed a giant coronary artery aneurysm in the mid-portion of the right coronary artery. He underwent aneurysmectomy and coronary artery bypass grafting to the posterior descending artery. Spontaneous rupture of a giant coronary artery aneurysm is rare, but critical condition such as acute myocardial infarction or fistula to heart chamber can occur. Surgical intervention is indicated for a giant coronary artery aneurysm to prevent possible life-threatening consequences in the future.

Acute stroke rehabilitation for gait training with cyborg type robot Hybrid Assistive Limb: A pilot study.

Robot-assisted gait training following acute stroke could allow patients with severe disability to receive a high dosage and intensity of gait training compared with conventional physical therapy (CP). However, given the limited data on gauging the efficacy of Hybrid Assistive Limb (HAL) on gait training in patients with acute stroke, we aimed to evaluate several outcome measures following gait training with HAL. Patients with first-ever stroke, who required a walking aid and were able to start gait training within 1 week of stroke onset were included in the current study. Patients were assigned to either the CP or HAL group. Outcome measures were collected at baseline, and at the 2nd (at 2-6 weeks), and 3rd (at 3-5 months) assessments. All patients underwent physical therapy until the 3rd assessment; patients in the HAL group underwent gait training using HAL until the 2nd assessment. Thirty-seven patients (19 from CP and 18 from HAL, median age = 69 years) completed the study. At the 2nd assessment, the total Functional Independence Measure (FIM) score was higher in the HAL group than in the CP group (90.1 vs. 79.0, p = 0.042). In conclusion, the FIM scale could be used to identify responsiveness to acute stroke rehabilitation using HAL.

Ibudilast attenuates doxorubicin-induced cytotoxicity by suppressing formation of TRPC3 channel and NADPH oxidase 2 protein complexes.

BACKGROUND AND PURPOSE: Doxorubicin is a highly effective anticancer agent but eventually induces cardiotoxicity associated with increased production of ROS. We previously reported that a pathological protein interaction between TRPC3 channels and NADPH oxidase 2 (Nox2) contributed to doxorubicin-induced cardiac atrophy in mice. Here we have investigated the effects of ibudilast, a drug already approved for clinical use and known to block doxorubicin-induced cytotoxicity, on the TRPC3-Nox2 complex. We specifically sought evidence that this drug attenuated doxorubicin-induced systemic tissue wasting in mice. EXPERIMENTAL APPROACH: We used the RAW264.7 macrophage cell line to screen 1,271 clinically approved chemical compounds, evaluating functional interactions between TRPC3 channels and Nox2, by measuring Nox2 protein stability and ROS production, with and without exposure to doxorubicin. In male C57BL/6 mice, samples of cardiac and gastrocnemius muscle were taken and analysed with morphometric, immunohistochemical, RT-PCR and western blot methods. In the passive smoking model, cells were exposed to DMEM containing cigarette sidestream smoke. KEY RESULTS: Ibudilast, an anti-asthmatic drug, attenuated ROS-mediated muscle toxicity induced by doxorubicin treatment or passive smoking, by inhibiting the functional interactions between TRPC3 channels and Nox2, without reducing TRPC3 channel activity. CONCLUSIONS AND IMPLICATIONS: These results indicate a common mechanism underlying induction of systemic tissue wasting by doxorubicin. They also suggest that ibudilast could be repurposed to prevent muscle toxicity caused by anticancer drugs or passive smoking.

The clarified role of interleukin-19 in the inflammatory bowel disease and hypersensitivity: Insights from animal models and humans.

The cytokine interleukin-19 (IL-19) is a member of the IL-10 family that includes IL-20, IL-22, IL-24, and IL-26. Previous studies indicated that IL-19 is produced by keratinocytes, epithelial cells, macrophages, and B-cells. Especially, the number of IL-4-producing T cells increased, whereas the number of IFN-γ-producing T cells decreased when naive T cells from healthy people were cultured in the presence of IL-19. There is an increasing body of data demonstrating that IL-19 is associated with the development of type 1 helper T cell-responses, although IL-19 was originally associated with the development of type 2 helper T cell-responses. In this review, we will attempt to discuss current knowledge about the role of IL-19 on several T cell response-mediated inflammatory diseases including inflammatory bowel disease and hypersensitivity.

Correlation between toll-like receptor 4 and nucleotide-binding oligomerization domain 2 (NOD2) and pathological severity in dogs with chronic gastrointestinal diseases.

Toll-like receptor 4 (TLR4), nucleotide-binding oligomerization domain 2 (NOD2), and TNF-α play important roles in human inflammatory bowel diseases. The aim of this study was to elucidate the relationship between Toll-like receptor 4, NOD2, and TNF-α and the severity of chronic gastrointestinal diseases in dogs. We examined the expression levels of TLR4, NOD2, and TNF-α in the stomach, duodenum, ileum, colon, and rectum obtained from 21 dogs with chronic gastrointestinal disease, including inflammatory bowel disease, high-grade lymphoma, food responsive enteropathy, chronic pancreatitis, low-grade lymphoma, inflammatory colorectal polyp, and chronic colitis. Next, we demonstrated whether there is good correlation between the expression levels of TLR4, NOD2, and TNF-α and the histopathological analysis of each sample. We found that the level of TLR4 expression in the ileum of dogs with chronic gastrointestinal disease was positively associated with the histopathological severity. We also found that the level of NOD2 expression in the duodenum, stomach, and rectum was positively associated with the histopathological severity. However, there was no correlation between TNF-α expression in the 5 regions tested in this study and the histopathological severity. These findings indicate that TLR4 and NOD2 are remarkably associated with the severity of chronic gastrointestinal disease in dogs.

[Giant Aneurysm of the Left Sinus of Valsalva Accompanied by Left Main Coronary Artery Compression, Myocardial Ischemia, Pericardial Tamponade].

Left sinus of Valsalva aneurysm(SVAn)is a very rare clinical entity. We present a 68-year-old female with left SVAn, 5 cm in diameter, compressing the left main coronary artery and causing antero-septal asynergy. She also had massive pericardial effusion, moderate to severe(grade Ⅲ)aortic regurgitation, and mitral regurgitation. One month after pericardial drainage, the patient successfully underwent composite graft replacement of the aortic root, reimplantation of the right coronary artery and suture closure of thin friable left main trunk(LMT)orifice, as well as double coronary artery bypass grafting with bilateral internal mammary arteries to the left anterior descending artery and the diagonal branch. Mitral valve repair was also performed. She recovered uneventfully and remains asymptomatic at 2 years after surgery. To our knowledge, only 13 cases undergoing open heart surgery for left SVAn have been reported in Japan.

Chronic kidney disease after 5/6 nephrectomy disturbs the intestinal microbiota and alters intestinal motility.

Organ-organ crosstalk is involved in homeostasis. Gastrointestinal symptoms are common in patients with renal failure. The aim of this study was to elucidate the relationship between gastrointestinal motility and gastrointestinal symptoms in chronic kidney disease. We performed studies in C57BL/6 mice with chronic kidney disease after 5/6 nephrectomy. Gastrointestinal motility was evaluated by assessing the ex vivo responses of ileum and distal colon strips to electrical field stimulation. Feces were collected from mice, and the composition of the gut microbiota was analyzed using 16S ribosomal RNA sequencing. Mice with chronic kidney disease after 5/6 nephrectomy showed a decreased amount of stool, and this constipation was correlated with a suppressed contraction response in ileum motility and decreased relaxation response in distal colon motility. Spermine, one of the uremic toxins, inhibited the contraction response in ileum motility, but four types of uremic toxins showed no effect on the relaxation response in distal colon motility. The 5/6 nephrectomy procedure disturbed the balance of the gut microbiota in the mice. The motility dysregulation and constipation were resolved by antibiotic treatments. The expression levels of interleukin 6, tumor necrosis factor-α, and iNOS in 5/6 nephrectomy mice were increased in the distal colon but not in the ileum. In addition, macrophage infiltration in 5/6 nephrectomy mice was increased in the distal colon but not in the ileum. We found that 5/6 nephrectomy altered gastrointestinal motility and caused constipation by changing the gut microbiota and causing colonic inflammation. These findings indicate that renal failure was remarkably associated with gastrointestinal dysregulation.

[Valve Repair for Mitral Regurgitation with Absent Right Superior Vena Cava and Persistent Left Superior Vena Cava;Report of a Case].

A 73-year-old male was suffering from severe mitral regurgitation due to P3 torn chorda and moderate tricuspid regurgitation with absent right superior vena cava (RSVC) and persistent left superior vena cava (PLSVC). The patient successfully underwent mitral valve repair with 2 artificial chords (Gore-Tex CV3)and Cosgrove band 32 mm, tricuspid annuloplasty with Cosgrove band 34 mm, and maze procedure. Cardiopulmonary bypass was established with aortic and double caval cannulation. The PLSVC was directly cannulated with an L-shaped cannula at the left of the main pulmonary artery. We believe that it should be advantageous, because it would neither impinge on operative view nor cause damage to sinus node tissue around the coronary sinus. To our knowledge, there have been only 8 cases of open heart surgery with such systemic venous drainage anomaly so far in Japan.

[Surgery for Left Main Coronary Artery Aneurysm with Severe Triple Vessel Disease;Report of a Case].

Coronary artery aneurysm is a rare disease and its surgical indication is still controversial. We present a 63-year-old male having left main coronary artery aneurysm with 6 mm in diameter and symptomatic severe triple vessel disease. It was saccular and expanding into the myocardium. The patient successfully underwent off-pump quadruple coronary artery bypass and suture ligation of the aneurysmal neck. We believe that this technique is effective and less invasive to manage small or medium-sized coronary artery aneurysm in case aneurysmal shape, size, and location should be fitting for it.

The Role of Interleukin-19 in Contact Hypersensitivity.

Interleukin (IL)-19 is a member of the IL-10 family of interleukins and is an immuno-modulatory cytokine produced by the main macrophages. The gastrointestinal tissues of IL-19 knockout mice show exacerbated experimental colitis mediated by the innate immune system and T cells. There is an increasing focus on the interaction and relationship of IL-19 with the function of T cells. Contact hypersensitivity (CHS) is T cell-mediated cutaneous inflammation. Therefore, we asked whether IL-19 causes CHS. We investigated the immunological role of IL-19 in CHS induced by 1-fluoro-2,4-dinitrofluorobenzene as a hapten. IL-19 was highly expressed in skin exposed to the hapten, and ear swelling was increased in IL-19 knockout mice. The exacerbation of the CHS response in IL-19 knockout mice correlated with increased levels of IL-17 and IL-6, but no alterations were noted in the production of interferon (IFN)γ and IL-4 in the T cells of the lymph nodes. In addition to the effect on T cell response, IL-19 knockout mice increased production of inflammatory cytokines. These results show that IL-19 suppressed hapten-dependent skin inflammation in the elicitation phase of CHS.

Fatty acid transport protein 1 enhances the macrophage inflammatory response by coupling with ceramide and c-Jun N-terminal kinase signaling.

Macrophages are important cells that need to be controlled at the site of inflammation. Several factors are involved in chronic inflammation and its timely resolution. Free fatty acids drive the inflammatory response in macrophages and contribute to the vicious cycle of the inflammatory response. However, the identity of the uptake pathways of fatty acids is not fully clear in macrophages and how the inflammatory responses are regulated by the uptake of fatty acids remain poorly understood. We investigated the relationship between fatty acid transport protein (FATP) and the inflammatory response signaling pathway in macrophages as the first report. The FATP family has composed six isoforms, FATP1-6. We found that FATP1 is the most highly expressed isoform in macrophages. Forced expression of FATP1 enhanced production of inflammatory cytokines, such as TNFα and IL-6 concomitant with the increased uptake of fatty acids, increased level of ceramide, and increased phosphorylation of c-Jun N-terminal kinase (JNK). The enhancement by FATP1 was abolished by treatment with a JNK inhibitor, NF-κB inhibitor, or ceramide synthesis inhibitor. siRNA-mediated knockdown of FATP1 strongly inhibited the production of TNFα and IL-6. Similarly, an inhibitor of FATP1 inhibited the production of TNFα and IL-6. Finally, an inhibitor of FATP1 attenuated the production of inflammatory cytokines in bronchoalveolar lavage fluid in an LPS-induced acute lung injury in vivo mouse model. In summary, we propose that FATP1 is an important regulator of inflammatory response signaling in macrophages. Our findings suggest that ceramide-JNK signaling is important to terminate or sustain inflammation.

Aggressive Crosstalk Between Fatty Acids and Inflammation in Macrophages and Their Influence on Metabolic Homeostasis.

From the immunological point of view, macrophages are required to maintain metabolic homeostasis. Recently, there has been an increased focus on the influence of macrophage phenotypes in adipose tissue on the maintenance of metabolic homeostasis in healthy conditions because dysregulated metabolic homeostasis causes metabolic syndrome. This review notes several types of inflammatory and anti-inflammatory mediators in metabolic homeostasis. M1 macrophage polarization mediates inflammation, whereas M2 macrophage polarization mediates anti-inflammation. Fatty acids and their related factors mediate both inflammatory and anti-inflammatory responses. Saturated fatty acids and polyunsaturated fatty acids mediate inflammation, whereas marine-derived n-3 fatty acids, such as eicosapentaenoic acid and docosahexaenoic acid, mediate anti-inflammation. In this review, we discuss the current understanding of the crosstalk between fatty acids and inflammation in macrophages and their influence on metabolic homeostasis.