Efficacy of elobixibat as bowel preparation agent for colonoscopy: Prospective, randomized, multi-center study.

BACKGROUND AND AIM: Elobixibat is a novel ileal bile acid transporter inhibitor. This study aimed to compare the efficacy, tolerability, and safety of the combination of elobixibat and 1 L of polyethylene glycol formulation containing ascorbic acid (PEG-Asc) solution versus the combination of sodium picosulfate and 1-L PEG-Asc solution as bowel preparation for colonoscopy. METHODS: This multi-center, randomized, observer-blinded, non-inferiority study recruited 210 outpatients who were assigned to either the elobixibat plus 1-L PEG-Asc group (group A) or the sodium picosulfate plus 1-L PEG-Asc group (group B). The quality of the bowel cleansing level was assessed by the Boston Bowel Preparation Scale (BBPS) and compared the bowel cleansing level between the groups. Data regarding bowel preparation time, patients' tolerability, and adverse events were also analyzed. RESULTS: Data for 196 patients (99 in group A and 97 in group B) were analyzed finally. BBPS was comparable between group A and B (8.3 ± 0.9 vs. 8.3 ± 0.7; P = 0.88). Consequently, the adequate bowel preparation rate in groups A and B was 95.0% and 99.0%, respectively (-4.0%, 95% CI -9.3 to 1.5). Bowel preparation time in group A was similar to that in group B (348.2 ± 79.8 min vs. 330.8 ± 82.5 min; P = 0.13), whereas, sleep disturbance was significantly less frequent in group A than in group B (10.2% vs. 22.7%; P = 0.02). CONCLUSIONS: The combination of elobixibat and 1-L PEG-Asc can be considered an alternative bowel preparation for colonoscopy considering the equivalent bowel cleansing effect and less frequent sleep disturbance. The Japan Registry of Clinical Trials (jRCTs41180026).

A study on safe forceps grip force for the intestinal tract using haptic technology.

PURPOSE: The present study used haptic technology to determine the safe forceps grip force for preventing organ damage when handling the intestinal tract. MATERIAL AND METHODS: The small intestines of ten male beagle dogs (weighing 9.5-10 kg) were grasped with the entire forceps for one minute; the small intestines were then pulled out of the forceps and evaluated for damage. The force at which the shaft inside the forceps was pulled to close the tip of the forceps was defined as the grip force. Small intestine damage was classified into macroscopic (serosal defects, hemorrhage, hematomas, grip marks) and microscopic (damage layer to the mucosa, submucosa/muscularis mucosa, inner orbicularis muscle, external longitudinal muscle, serosa/subserosa). Grip marks and damage layer to the serosa/subserosa have been considered as acceptable safety margins when grasping the small intestines of beagle dogs. RESULTS: The macroscopic findings showed that the maximum grip force that produced a 0% incidence of hemorrhage and hematoma was 15 N. At the microscopic level, the maximum grip force that produced a 0% incidence of external longitudinal muscle injury was 15 N, respectively. CONCLUSIONS: A grip force of 15 N does not damage the small intestines of beagle dogs.

Lifestyle- and Comorbidity-Related Risk Factors Associated with Prescription of Gastric Acid Secretion Inhibitors to Japanese Patients Who Were Helicobacter pylori Negative and Had No Upper Gastrointestinal Lesions.

OBJECTIVE: The aim of this study was to determine the characteristics of patients without Helicobacter pylori infection who were prescribed antacid medications (potassium-competitive acid blockers, proton pump inhibitors, and/or H2 receptor antagonist) and had no upper gastrointestinal lesions detected by endoscopy. METHODS: This cross-sectional study included the patients who underwent upper gastrointestinal endoscopy in our institution between August 2017 and July 2018. They were aged from 55 to 89 years, had no upper gastrointestinal lesions detected by endoscopy, and no H. pylori infection. Exclusion criteria comprised low-dose aspirin and/or nonsteroidal anti-inflammatory drugs. The subjects were allocated to middle-aged (55-69 years) and older age groups (70-89 years). The relationships between antacid medications and patient lifestyle and comorbidities were evaluated by multivariate analyses. RESULTS: Of the 420 patients, 272 were in the middle-aged group and 148 patients in the older age group. Age was found to be a risk factor for antacid medications in both groups (p = 0.002, p = 0.007). No other lifestyle related factors were risk factors. As to comorbidities, hiatal hernia was positively associated with antacid medications in the middle-aged group (p = 0.002). Hypertension and Ca-blockers were positively associated with prescription of antacids in the older age group (p = 0.013); this association was not significant in the middle-aged group. CONCLUSIONS: Three lifestyle-related and/or comorbidity-associated factors known to exacerbate gastroesophageal reflux, namely, age, hiatus hernia, and Ca-blockers, were associated with prescription of antacid medications, even in patients without endoscopic reflux esophagitis.

Oligo-DNA Stoichiometrically Binds ß-1,3-Glucan with the Best Fit Length.

Oligo-deoxyadenylic acid (dAX) forms a novel 1:2 triple-helix with ß-1,3-d-glucan schizophyllan (SPG). We found that dAX meticulously selects the most suitable length of SPG to bind; for example, dA30 only complexes with a short SPG chain having 30, 60, or 90 main-chain glucoses, and they can be easily isolated with each other. This study demonstrated such a novel stoichiometric complex formation by using gel permeation chromatography coupled with multi-angle light scattering and synchrotron small-angle X-ray scattering. These oligo-DNA/polysaccharide complexes can be used as a tool for delivering therapeutic oligonucleotides to immunocytes that express the ß-1,3-d-glucan receptors. The present study provides a robust platform technique to characterize them in terms of modern regulatory science of nanomedicines, which is requisite to transfer drug candidates into clinical trial. Our findings are important for characterizing these complexes as well as for providing a new insight into nucleotide and saccharide chemistry.

Correlation of Barrett's esophagus with colorectal polyps in Japanese patients: A retrospective chart review.

BACKGROUND AND AIM: Barrett's esophagus and colorectal polyps have several overlapping risk factors. Whereas several reports in Western countries have indicated a close relationship between Barrett's esophagus and colorectal polyps, the relationship between these two diseases remains unclear in Japan. This study was performed to determine whether the prevalence of Barrett's esophagus is related to that of colorectal polyps in Japanese patients. METHODS: The present retrospective chart review included 1582 Japanese patients who underwent both total colonoscopy and esophagogastroduodenoscopy from January 2010 to December 2016. The data on colorectal polyps and Barrett's esophagus were obtained from the endoscopic findings. The medical record of each patient was checked for age, sex, body mass index, smoking, alcohol drinking, use of acid suppression agents, and comorbidities including a history of diabetes, ischemic heart disease, gastroesophageal reflux disease, hiatal hernia, and Helicobacter pylori infection. RESULTS: Colorectal polyps were detected in 789 of the 1582 patients (49.9%). Barrett's esophagus was detected in 233 patients (14.7%), and most cases of Barrett's esophagus (n = 229) were classified as short-segment Barrett's esophagus. Colorectal polyps were more frequent in patients with than without Barrett's esophagus (odds ratio, 1.79; 95% confidence interval, 1.31-2.46; P < 0.001). In addition to Barrett's esophagus, the data indicated that old age, male sex, obesity, smoking, alcohol drinking, diabetes mellitus, and ischemic heart disease were independent risk factors for colorectal polyps. CONCLUSIONS: The present study revealed the correlation between the prevalence of Barrett's esophagus and colorectal polyps in Japanese patients.

Smoking and Drinking Did Not Increase the Failure of Therapeutic Helicobacter pylori Eradication by Vonoprazan, Clarithromycin, and Amoxicillin.

AIMS: The influence of lifestyle-related factors, including smoking and drinking, was evaluated for Helicobacter pylori eradication therapy with vonoprazan or proton pump inhibitors (PPIs). METHODS: Between 2012 and 2016, the medical records of 620 patients receiving H. pylori eradication therapy at Saiseikai Karatsu Hospital were evaluated. Patients had received vonoprazan (20 mg) or PPIs with 200 mg clarithromycin and 750 mg amoxicillin twice daily for 7 days. The influence of lifestyle-related factors on eradication failure was determined in the 2 groups. RESULTS: The eradication rates for vonoprazan and lansoprazole, rabeprazole, and esomeprazole were, respectively, 91.0, 73.8, 72.0, and 84.6%. The vonoprazan eradication rate was significantly higher than those for the PPIs (p < 0.01). Habitual smoking and drinking did not increase eradication failure, and smoking and drinking during the eradication period did not reduce the eradication rate. Metabolic syndrome-related factors including obesity, hypertension, and diabetes mellitus had no negative influence on the eradication rate. Eradication with vonoprazan was more effective compared with that achieved through the use of PPIs. CONCLUSION: Lifestyle-related factors including smoking and drinking did not exacerbate the H. pylori eradication failure, and vonoprazan was more effective than the PPIs.

A novel mechanism underlying the basic defensive response of macrophages against Mycobacterium infection.

Following inhalation of Mycobacterium tuberculosis, including bacillus Calmette-Guérin (BCG), pathogens enter and grow inside macrophages by taking advantage of their phagocytic mechanisms. Macrophages often fail to eliminate intracellular M. tuberculosis, leading to the induction of host macrophage death. Despite accumulating evidence, the molecular mechanisms underlying M. tuberculosis infection-induced cell death remain controversial. In this study, we show the involvement of two distinct pathways triggered by TLR2 and ß2 integrin in BCG infection-induced macrophage apoptosis. First, BCG infection induced activation of ERK1/2, which in turn caused phosphorylation/activation of the proapoptotic protein Bim in mouse macrophage-like Raw 264.7 cells. BCG-infected Raw cells treated with U0126, an MEK/ERK inhibitor, led to the suppression of Bim phosphorylation alongside a remarkable increase in the number of viable macrophages. Small interfering RNA-mediated knockdown of Bim rescued the macrophages from the apoptotic cell death induced by BCG infection. Stimulation with Pam3CSK, a TLR2 agonist, induced macrophage apoptosis with a concomitant increase in the phosphorylation/activation of MEK/ERK and Bim. These observations indicate the important role of the TLR2/MEK/ERK/Bim pathway in BCG infection-induced macrophage apoptosis. Second, we used the ß2 integrin agonists C3bi and fibronectin to show that the ß2 integrin-derived signal was involved in BCG infection-induced apoptosis, independent of MEK/ERK activation. Interestingly, latex beads coated with Pam3CSK and C3bi were able to induce apoptosis in macrophages to the same extent and specificity as that induced by BCG. Taken together, two distinct pattern-recognition membrane receptors, TLR2 and ß2 integrin, acted as triggers in BCG infection-induced macrophage apoptosis, in which MEK/ERK activation played a crucial role following the engagement of TLR2.

Tenascin-C-derived peptide TNIIIA2 highly enhances cell survival and platelet-derived growth factor (PDGF)-dependent cell proliferation through potentiated and sustained activation of integrin α5ß1.

Tenascin-C is an adhesion modulatory matrix protein that is highly expressed in tumors; however, its biochemical activity involved in tumorigenesis is not fully understood. On the other hand, increasing evidence indicates the importance of integrin α5ß1 in cancer development. We previously demonstrated that tenascin-C harbors a functional site that can be released as a proadhesive peptide such as TNIIIA2. Peptide TNIIIA2 is capable of inducing activation of ß1-integrins including α5ß1 via syndecan-4. In this study the proadhesive effect of TNIIIA2 was characterized by potentiated and sustained activation of integrin α5ß1. Based on this effect, TNIIIA2 rendered nontransformed fibroblasts (NIH3T3) resistant to serum deprivation-elicited anoikis through activation of the Akt/Bcl-2 pathway. Moreover, TNIIIA2 hyperstimulated PDGF-dependent proliferation of NIH3T3 by activating integrin α5ß1. Tenascin-C, a parental protein of TNIIIA2, also stimulated PDGF-dependent proliferation, which was blocked by a matrix metalloproteinase-2/9 inhibitor and an anti-TNIIIA2 function-blocking antibody, suggesting proteolytic exposure of the proadhesive effect of TNIIIA2. Mechanistic analyses revealed that TNIIIA2 induced a lateral association of PDGF receptor ß with the molecular complex of activated integrin α5ß1 and syndecan-4 in the membrane microdomains enriched with cholesterol/caveolin-1, resulting in prolonged activation of PDGF receptor ß and the subsequent Ras/mitogen-activated protein kinase pathway in a PDGF-dependent manner. Of note, TNIIIA2 induced continuous proliferation in NIH3T3 in an integrin α5ß1-dependent manner even after they formed a confluent monolayer. Thus, it was proposed that tenascin-C might be involved in deregulated cell growth through potentiated and sustained activation of integrin α5ß1 after exposure of the proadhesive effect of TNIIIA2.

A case of catastrophic antiphospholipid syndrome, which presented an acute interstitial pneumonia-like image on chest CT scan.

We report the case of catastrophic antiphospholipid syndrome (CAPS) complicated with mixed connective tissue disease (MCTD). A female patient was diagnosed with acute interstitial pneumonia (AIP) with MCTD by chest CT scan. Corticosteroid therapy was refractory for lung involvement, and she died due to acute respiratory failure. The autopsy revealed that AIP was compatible with lung involvement of CAPS. We therefore suggest that chest CT might reveal AIP-like findings in CAPS patients whose condition is complicated with pulmonary manifestations.

Calmodulin antagonists induce cell cycle arrest and apoptosis in vitro and inhibit tumor growth in vivo in human multiple myeloma.

BACKGROUND: Human multiple myeloma (MM) is an incurable hematological malignancy for which novel therapeutic agents are needed. Calmodulin (CaM) antagonists have been reported to induce apoptosis and inhibit tumor cell invasion and metastasis in various tumor models. However, the antitumor effects of CaM antagonists on MM are poorly understood. In this study, we investigated the antitumor effects of naphthalenesulfonamide derivative selective CaM antagonists W-7 and W-13 on MM cell lines both in vitro and in vivo. METHODS: The proliferative ability was analyzed by the WST-8 assay. Cell cycle was evaluated by flow cytometry after staining of cells with PI. Apoptosis was quantified by flow cytometry after double-staining of cells by Annexin-V/PI. Molecular changes of cell cycle and apoptosis were determined by Western blot. Intracellular calcium levels and mitochondrial membrane potentials were determined using Fluo-4/AM dye and JC-10 dye, respectively. Moreover, we examined the in vivo anti-MM effects of CaM antagonists using a murine xenograft model of the human MM cell line. RESULTS: Treatment with W-7 and W-13 resulted in the dose-dependent inhibition of cell proliferation in various MM cell lines. W-7 and W-13 induced G1 phase cell cycle arrest by downregulating cyclins and upregulating p21cip1. In addition, W-7 and W-13 induced apoptosis via caspase activation; this occurred partly through the elevation of intracellular calcium levels and mitochondrial membrane potential depolarization and through inhibition of the STAT3 phosphorylation and subsequent downregulation of Mcl-1 protein. In tumor xenograft mouse models, tumor growth rates in CaM antagonist-treated groups were significantly reduced compared with those in the vehicle-treated groups. CONCLUSIONS: Our results demonstrate that CaM antagonists induce cell cycle arrest, induce apoptosis via caspase activation, and inhibit tumor growth in a murine MM model and raise the possibility that inhibition of CaM might be a useful therapeutic strategy for the treatment of MM.

Treatment of Catheter-Associated Internal Jugular Vein Thrombosis Using Apixaban for Less Than Three Months in Two Patients With Aggressive B-cell Lymphoma Undergoing Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisolone Therapy.

The selection of anticoagulant therapy and appropriate duration of treatment for central venous (CV) catheter-associated internal jugular vein thrombosis in patients with malignant lymphoma remain unclear. Two cases of aggressive B-cell lymphomas treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone), in which apixaban administered for less than three months was effective against CV catheter-associated internal jugular vein thrombosis, are reported. In one case, the right internal jugular vein thrombosis developed after eight courses of R-CHOP; when apixaban was orally administered for 37 days after the CV catheter was removed, the thrombus completely dissolved and did not recur for 27 months. In the other case, right internal jugular vein thrombosis developed after four courses of R-CHOP; two additional courses of the R-CHOP were administered alongside oral apixaban administration without catheter removal. After 66 days of oral apixaban, the thrombus completely dissolved, the CV catheter was removed, and no recurrence was observed for 8.5 months.

R723, a selective JAK2 inhibitor, effectively treats JAK2V617F-induced murine myeloproliferative neoplasm.

The activating mutations in JAK2 (including JAK2V617F) that have been described in patients with myeloproliferative neoplasms (MPNs) are linked directly to MPN pathogenesis. We developed R723, an orally bioavailable small molecule that inhibits JAK2 activity in vitro by 50% at a concentration of 2nM, while having minimal effects on JAK3, TYK2, and JAK1 activity. R723 inhibited cytokine-independent CFU-E growth and constitutive activation of STAT5 in primary hematopoietic cells expressing JAK2V617F. In an anemia mouse model induced by phenylhydrazine, R723 inhibited erythropoiesis. In a leukemia mouse model using Ba/F3 cells expressing JAK2V617F, R723 treatment prolonged survival and decreased tumor burden. In V617F-transgenic mice that closely mimic human primary myelofibrosis, R723 treatment improved survival, hepatosplenomegaly, leukocytosis, and thrombocytosis. R723 preferentially targeted the JAK2-dependent pathway rather than the JAK1- and JAK3-dependent pathways in vivo, and its effects on T and B lymphocytes were mild compared with its effects on myeloid cells. Our preclinical data indicate that R723 has a favorable safety profile and the potential to become an efficacious treatment for patients with JAK2V617F-positive MPNs.

Two Older Hematological Malignancy Patients for Whom Nutrition Rehabilitation Was Effective Against Global Leadership Initiative on Malnutrition-Defined Malnutrition and Sarcopenia.

The long-term survival rate of hematological malignancy patients with Global Leadership Initiative on Malnutrition (GLIM)-defined malnutrition and sarcopenia is poor, but nutritional rehabilitation effects in such patients are unknown. Here, two cases of older hematological malignancy patients in whom nutritional rehabilitation was effective against GLIM-defined malnutrition and sarcopenia are reported. By undergoing nutritional rehabilitation, the myeloma patient increased her six-meter walking speed and her maintained body mass index (BMI), appendicular skeletal muscle mass (ASM), and hand grip strength, whereas the Hodgkin lymphoma patient regained his hand grip strength and maintained his BMI, ASM, and six-meter walking speed.

Validation of a surgical drill with a haptic interface in spine surgery.

Real haptics is a technology that reproduces the sense of force and touch by transmitting contact information with real objects by converting human movements and the feel of the objects into data. In recent years, real haptics technology has been installed in several surgical devices. A custom-made surgical drill was used to drill into the posterior lamina to verify the time required for penetration detection and the distance the drill advanced after penetration. A surgeon operated with the drill and the same aspects were measured and verified. All experiments were performed on female miniature pigs at 9 months of age with a mean body weight of 23.6 kg (range 9-10 months and 22.5-25.8 kg, n = 12). There were statistically significant differences in the average reaction time and the distance travelled after penetration between a handheld drill and the drill with the penetration detection function (p < 0.001). The reaction time to detect penetration and the distance after penetration were both significantly improved when compared with those of the handheld surgical drill without the penetration detection function, with mean differences of 0.049 ± 0.019 s [95% CI 0.012, 0.086 s] and 2.511 ± 0.537 mm [95% CI 1.505, 3.516 mm]. In this study, we successfully conducted a performance evaluation test of a custom-made haptic interface surgical drill. A prototype high-speed drill with a haptic interface accurately detected the penetration of the porcine posterior lamina.

Efficacy and safety of vonoprazan-based regimen for Helicobacter pylori eradication therapy in Japanese adolescents: a prospective multicenter study.

BACKGROUND: Vonoprazan (VPZ)-based regimen for Helicobacter pylori (H. pylori) is safe and more efficacious than the proton pump inhibitor-based regimen mainly in adults. This study aimed to evaluate the efficacy and safety of a VPZ-based regimen for H. pylori eradication therapy in adolescents. METHODS: An H. pylori screening and treatment longitudinal project for third-year junior high school students in Saga Prefecture began in 2016. Students who tested positive for both urine and stool tests received a VPZ-based regimen. On the checklist, students were asked for diarrhea, fever, abdominal pain, nausea, vomiting, urticaria, dysgeusia, or bloody stool occurrence during the therapy. RESULTS: The longitudinal project for H. pylori screening and treatment among third-grade students in Saga Prefecture targeted 41,115 students from 2017 to 2021 and 836 as positive. Of the 645 students, 542 (84.0% in per protocol [PP] analysis and 73.6% in intention-to-treat [ITT] analysis) were successful in primary eradication therapy. The secondary eradication therapy was successful in 79 (96.3% in PP analysis and 76.7% in ITT analysis) of 82 students. In the primary eradication therapy, abdominal pain occurred in 164 (27.9%), diarrhea in 217 (36.9%), nausea or vomiting in 7 (1.2%), and urticaria in 13 (2.2%) students. In the secondary eradication therapy, abdominal pain occurred in 12 (19.4%) and diarrhea in 17 (27.4%) students. The eradication therapy of 5 students was interrupted due to adverse events only by primary eradication therapy. CONCLUSIONS: VPZ-based regimen for H. pylori was efficacious and safe for adolescents, as in adults, for both primary and secondary eradication therapies.

Essential role of protein kinase C zeta in transducing a motility signal induced by superoxide and a chemotactic peptide, fMLP.

Under various pathological conditions, including infection, malignancy, and autoimmune diseases, tissues are incessantly exposed to reactive oxygen species produced by infiltrating inflammatory cells. We show augmentation of motility associated with morphological changes of human squamous carcinoma SASH1 cells, human peripheral monocytes (hPMs), and murine macrophage-like cell line J774.1 by superoxide stimulation. We also disclose that motility of hPMs and J774.1 induced by a chemotactic peptide (N-formyl-methionyl-leucyl-phenylalanine [fMLP]) was inhibited by superoxide dismutase or N-acetylcystein, indicating stimulation of motility by superoxide generated by fMLP stimulation. In these cells, protein kinase C (PKC) zeta was activated to phosphorylate RhoGDI-1, which liberated RhoGTPases, leading to their activation. These events were inhibited by dominant-negative PKCzeta in SASH1 cells, myristoylated PKCzeta peptides in hPMs and J774.1, or a specific inhibitor of RhoGTPase in SASH1, hPMs, and J774.1. These results suggest a new approach for manipulation of inflammation as well as tumor cell invasion by targeting this novel signaling pathway.

Potentiated activation of VLA-4 and VLA-5 accelerates proplatelet-like formation.

Fibronectin (FN) plays important roles in the proliferation, differentiation, and maintenance of megakaryocytic-lineage cells through FN receptors. However, substantial role of FN receptors and their functional assignment in proplatelet-like formation (PPF) of megakaryocytes are not yet fully understood. Herein, we investigated the effects of FN receptors on PPF using the CHRF-288 human megakaryoblastic cell line, which expresses VLA-4 and VLA-5 as FN receptors. FN and phorbol 12-myristate 13-acetate (PMA) were essential for inducing PPF in CHRF-288 cells. Blocking experiments using anti-ß1-integrin monoclonal antibodies indicated that the adhesive interaction with FN via VLA-4 and VLA-5 were required for PPF. PPF induced by FN plus PMA was accelerated when CHRF-288 cells were enforced adhering to FN by TNIIIA2, a peptide derived from tenascin-C, which we recently found to induce ß1-integrin activation. Adhesion to FN enhanced PMA-stimulated activation of extracellular signal-regulated protein kinase 1 (ERK1)/2 and enforced adhesion to FN via VLA-4 and VLA-5 by TNIIIA2-accelerated activation of ERK1/2 with FN plus PMA. However, c-Jun amino-terminal kinase 1 (JNK1), p38, and phosphoinositide-3 kinase (PI3K)/Akt were not stimulated by FN plus PMA, even with TNIIIA2. Thus, the enhanced activation of ERK1/2 by FN, PMA plus TNIIIA2 was responsible for acceleration of PPF with FN plus PMA.

Intravenous administration of auto serum-expanded autologous mesenchymal stem cells in stroke.

Transplantation of human mesenchymal stem cells has been shown to reduce infarct size and improve functional outcome in animal models of stroke. Here, we report a study designed to assess feasibility and safety of transplantation of autologous human mesenchymal stem cells expanded in autologous human serum in stroke patients. We report an unblinded study on 12 patients with ischaemic grey matter, white matter and mixed lesions, in contrast to a prior study on autologous mesenchymal stem cells expanded in foetal calf serum that focused on grey matter lesions. Cells cultured in human serum expanded more rapidly than in foetal calf serum, reducing cell preparation time and risk of transmissible disorders such as bovine spongiform encephalomyelitis. Autologous mesenchymal stem cells were delivered intravenously 36-133 days post-stroke. All patients had magnetic resonance angiography to identify vascular lesions, and magnetic resonance imaging prior to cell infusion and at intervals up to 1 year after. Magnetic resonance perfusion-imaging and 3D-tractography were carried out in some patients. Neurological status was scored using the National Institutes of Health Stroke Scale and modified Rankin scores. We did not observe any central nervous system tumours, abnormal cell growths or neurological deterioration, and there was no evidence for venous thromboembolism, systemic malignancy or systemic infection in any of the patients following stem cell infusion. The median daily rate of National Institutes of Health Stroke Scale change was 0.36 during the first week post-infusion, compared with a median daily rate of change of 0.04 from the first day of testing to immediately before infusion. Daily rates of change in National Institutes of Health Stroke Scale scores during longer post-infusion intervals that more closely matched the interval between initial scoring and cell infusion also showed an increase following cell infusion. Mean lesion volume as assessed by magnetic resonance imaging was reduced by >20% at 1 week post-cell infusion. While we would emphasize that the current study was unblinded, did not assess overall function or relative functional importance of different types of deficits, and does not exclude placebo effects or a contribution of recovery as a result of the natural history of stroke, our observations provide evidence supporting the feasibility and safety of delivery of a relatively large dose of autologous mesenchymal human stem cells, cultured in autologous human serum, into human subjects with stroke and support the need for additional blinded, placebo-controlled studies on autologous mesenchymal human stem cell infusion in stroke.

Limitations of the L3 skeletal muscle index and the Asian Working Group for Sarcopenia 2019 consensus diagnostic criteria for sarcopenia evaluation in a case of diffuse large B-cell lymphoma.

Sarcopenia is an adverse prognostic factor for diffuse large B-cell lymphoma. A case of diffuse large B-cell lymphoma whose diagnosis, severity, and therapeutic effect of sarcopenia were difficult to determine owing to lymphoma cell infiltration into the psoas major and femoral bone marrow is reported. At presentation, the cross-sectional area of left psoas major at L3 was enlarged owing to lymphoma cell infiltration; thus, sarcopenia evaluation was impossible by L3 skeletal muscle index. The patient was bedridden; thus, sarcopenia evaluation was impossible by the Asian Working Group for Sarcopenia 2019 consensus diagnostic criteria at presentation. At the terminal stage, she could not walk due to bilateral anterior thigh pain caused by lymphoma infiltration into femoral marrow; thus, sarcopenia evaluation was impossible by the Asian Working Group for Sarcopenia 2019 consensus diagnostic criteria. Although the L3 skeletal muscle index and the Asian Working Group for Sarcopenia 2019 consensus diagnostic criteria are representative sarcopenia evaluation systems, they cannot be used to evaluate sarcopenia in some diffuse large B-cell lymphoma patients.

Apoptotic death of hematopoietic tumor cells through potentiated and sustained adhesion to fibronectin via VLA-4.

It has been postulated that inactivated beta1-integrins are involved in the disordered growth of hematopoietic tumor cells. We recently found that TNIIIA2, a peptide derived from tenascin-C, strongly activates beta1-integrins through binding with syndecan-4. We show here that Ramos Burkitt's lymphoma cells can survive and grow in suspension but undergo apoptosis when kept adhering to fibronectin by stimulation with TNIIIA2. Other integrin activators, Mg(2+) and TS2/16 (an integrin-activating antibody), were also capable of inducing apoptosis. The inactivation of ERK1/2 and Akt and the subsequent activation of Bad were involved in the apoptosis. The results using other hematopoietic tumor cell lines expressing different levels of fibronectin receptors (VLA-4 and VLA-5) showed that potentiated and sustained adhesion to fibronectin via VLA-4 causally induces apoptosis also in various types of hematopoietic tumor cells in addition to Ramos cells. Because TNIIIA2 requires syndecan-4 as a membrane receptor for activation of beta1-integrins, it induced apoptosis preferentially in hematopoietic tumor cells, which expressed both VLA-4 and syndecan-4 as membrane receptors mediating the effects of fibronectin and TNIIIA2, respectively. Therefore, normal peripheral blood cells, such as neutrophils, monocytes, and lymphocytes, which poorly expressed syndecan-4, were almost insusceptible to TNIIIA2-induced apoptosis. The TNIIIA2-related matricryptic site of TN-C could contribute, once exposed, to preventing prolonged survival of hematopoietic malignant progenitors through potentiated and sustained activation of VLA-4.