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Previous studies have suggested that resistance training exercise under unstable conditions decreases the isometric force output, yet little is known about its influence on muscular outputs during dynamic movement. The objective of this study was to investigate the effect of an unstable condition on power, force, and velocity outputs during the bench press. Twenty male collegiate athletes (mean age, 21.3 +/- 1.5 years; mean height, 167.7 +/- 7.7 cm; mean weight, 75.9 +/- 17.5 kg) participated in this study. Each subject attempted 3 sets of single bench presses with 50% of 1 repetition maximum (1RM) under a stable condition with a flat bench and an unstable condition with a Swiss ball. Acceleration data were obtained with an accelerometer attached to the center of a barbell shaft, and peak outputs of power, force, and velocity were computed. Although significant loss of the peak outputs was found under the unstable condition (p < 0.017), their reduction rates remained relatively low, approximately 6% for force and 10% for power and velocity outputs, compared with previous findings. Such small reduction rates of muscular outputs may not compromise the training effect. Prospective studies are necessary to confirm whether the resistance training under an unstable condition permits the improvement of dynamic performance and trunk stability. [ABSTRACT FROM AUTHOR]

Objectives: To compare the pathogen identification rate and use of antibiotics before and after the implementation of multiplex polymerase chain reaction testing in children with respiratory infections in a PICU., Design: Single-center, pre-post study., Setting: PICU of Osaka Women's and Children's Hospital, Osaka, Japan., Patients: Consecutive children with respiratory infections who were admitted to the PICU between December 2017 and November 2018 (premultiplex polymerase chain reaction period) and between March 2019 and February 2020 (postmultiplex polymerase chain reaction period)., Interventions: Conventional rapid antigen tests and bacterial culture tests were performed throughout the study period. Multiplex polymerase chain reaction testing using the FilmArray respiratory panel (BioFire Diagnostics, Salt Lake City, UT) was conducted to detect 17 viruses and three bacterial pathogens. During the postmultiplex polymerase chain reaction period, we did not recommend prescribing antibiotics for stable children, depending on the virus species and laboratory test results., Measurements and Main Results: Ninety-six and 85 children were enrolled during the pre- and postmultiplex polymerase chain reaction periods, respectively. Rapid antigen tests identified pathogens in 22% of the children (n = 21) during the premultiplex polymerase chain reaction period, whereas rapid antigen tests and/or multiplex polymerase chain reaction testing identified pathogens in 67% of the children (n = 57) during the postmultiplex polymerase chain reaction period (p < 0.001). The most commonly identified pathogen using multiplex polymerase chain reaction testing was human rhino/enterovirus. Bacterial pathogens were identified in 50% of the children (n = 48) and 60% of the children (n = 51) during the pre- and postmultiplex polymerase chain reaction periods (p = 0.18). There were no differences in antibiotic use (84% vs 75%; p = 0.14), broad-spectrum antibiotic use (33% vs 34%; p = 0.91), or the duration of antibiotic use within 14 days of admission (6.0 vs 7.0 d; p = 0.45) between the pre- and postmultiplex polymerase chain reaction periods., Conclusions: Although the pathogen identification rate, especially for viral pathogens, increased using multiplex polymerase chain reaction testing, antibiotic use did not reduce in children with respiratory infections in the PICU. Definitive identification of bacterial pathogens and implementation of evidence-based antimicrobial stewardship programs employing multiplex polymerase chain reaction testing are warranted., Competing Interests: Drs. Yoshida and Hatachi received funding from a Sukoyaka Grant for Maternal and Child Health (2019); they disclosed that BioMerieux Japan Ltd. has temporarily provided the BioFire FilmArray Instrument for use in the research. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2021 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

Background: Life-threatening diseases should be promptly identified to provide appropriate medical care for emergency outpatients experiencing dizziness. However, dizziness is associated with various medical conditions; thus, a definitive diagnosis is challenging. To accurately diagnose vertigo in an emergency outpatient, we conducted a survey on the need to identify vertigo patients in the current outpatient departments., Materials and Methods: The participants included 509 patients who visited the outpatient department at our hospital from February 2014 to May 2017. Overall, 12 characteristics were retrospectively extracted from the patients' medical records: age, sex, visit method, medical history (diabetes, hypertension, cardiac, or cerebrovascular disease), dizziness history, vertigo characteristics, concomitant symptoms, systolic blood pressure, nystagmus, imaging history, diagnosis, and hospitalization department. Univariate and multivariate analyses were performed to identify factors related to central vertigo., Results: The diagnosis of central vertigo was confirmed when intracranial lesions were detected through imaging. In multivariate analysis, the presence/absence of a history of headache and cardiovascular disease were significantly correlated with central vertigo (P=0.002 and 0.006, respectively), with odds ratios of 5.18 and 4.38, respectively., Conclusions: To avoid missing central dizziness in a patient, diagnostic abilities should be improved by including careful interviews and confirmation of the presence/absence of accompanying symptoms. Furthermore, collaboration with neurology and neurosurgery departments is important for improving the diagnosis in suspected cases., Competing Interests: The authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: To evaluate blood pressure (BP)-lowering effects of Umezu polyphenols, polyphenols contained in Japanese plums, in a community-based sample by double-masked and placebo-controlled design., Methods: Seventy-two Japanese community-dwellers who were interested in prevention or control of their BP (preferably high-normal BP or grade I hypertension) but without antihypertensive medication were randomized into Umezu polyphenols or placebo groups. Each subject took 800 mg/day of Umezu polyphenols or placebo for 12 weeks, followed by a 2-week washout period. Their home and office BP were monitored for 14 weeks in a double-masked manner. We analyzed 56 subjects who met the inclusion criteria., Results: Home BP increased gradually in both the groups during the intervention period, while diastolic office BP insignificantly decreased in the intervention group. During the washout period, home systolic BP in the morning elevated only in the intervention group., Conclusions: The study failed to collect consistent evidence of a clear persistent hypotensive effect of Umezu polyphenols.

Several types of flap techniques have been developed to cover exposed bone after Draf procedures to reduce the possibility of re-stenosis. These techniques are relatively new and detailed measurements of the size of neo-Ostia during follow-up have not been reported. The authors aim to assess outcomes precisely by not only using endoscopic evaluation but also by measuring the diameter of the ostium and the thickness of the nasal beaks on pre- and postoperative computed tomography images. The authors reviewed 25 patients with 37 nasal cavities who have undergone a Draf surgery with a previously-reported superior lateral anterior pedicle flap technique. The anteroposterior (AP) distance of the frontal recess and the thickness of the nasal beaks were measured before, immediately after, and more than 6 months after surgery. Measured distances were statistically analyzed. The neo-ostium remained patent in long-term follow-up of all patients. The AP distance of the frontal recess and the thickness of the nasal beak were preserved during follow-up. Neither synechiae nor orbital injuries occurred. In conclusion, Draf type II and III procedures with superior lateral anterior pedicle flaps are safe and effective. Neo-Ostia remained patent throughout the follow-up period.

Objective: We sought to investigate the contextual effect of workplace bullying on subsequent individual psychological distress and intention to leave., Methods: A longitudinal study was conducted among 3142 Japanese employees in the public sector. Both the baseline and follow-up questionnaires inquired about demographic and occupational characteristics, workplace bullying, psychological distress, and intention to leave., Results: The results of three-level (individual-division-department) multilevel analyses revealed that division-level workplace bullying was associated with increased individual-level psychological distress after adjustment for individual experience of workplace bullying, while the association between individual experience of bullying and psychological distress was not statistically significant in the same model., Conclusion: The results of the current study suggest that the presence of bullying in the workplace can have a detrimental effect on employees' mental health even if they are not personally victimized.

Background and Purpose: Although subcortical vascular dementia, the major subtype of vascular dementia, is caused by a disruption in white matter integrity after cerebrovascular insufficiency, no therapy has been discovered that will restore cerebral perfusion or functional cerebral vessels. Because adrenomedullin (AM) has been shown to be angiogenic and vasoprotective, the purpose of the study was to investigate whether AM may be used as a putative treatment for subcortical vascular dementia., Methods: A model of subcortical vascular dementia was reproduced in mice by placing microcoils bilaterally on the common carotid arteries. Using mice overexpressing circulating AM, we assessed the effect of AM on cerebral perfusion, cerebral angioarchitecture, oxidative stress, white matter change, cognitive function, and brain levels of cAMP, vascular endothelial growth factor, and basic fibroblast growth factor., Results: After bilateral common carotid artery stenosis, mice overexpressing circulating AM showed significantly faster cerebral perfusion recovery due to substantial growth of the capillaries, the circle of Willis, and the leptomeningeal anastomoses and reduced oxidative damage in vascular endothelial cells compared with wild-type mice. Vascular changes were preceded by upregulation of cAMP, vascular endothelial growth factor, and basic fibroblast growth factor. White matter damage and working memory deficits induced by bilateral common carotid artery stenosis were subsequently restored in mice overexpressing circulating AM., Conclusions: These data indicate that AM promotes arteriogenesis and angiogenesis, inhibits oxidative stress, preserves white matter integrity, and prevents cognitive decline after chronic cerebral hypoperfusion. Thus, AM may serve as a strategy to tackle subcortical vascular dementia.

Objective: We demonstrated previously that mouse embryonic stem (ES) cell-derived vascular endothelial growth factor receptor-2 (VEGF-R2)-positive cells can differentiate into both vascular endothelial cells and mural cells. This time, we investigated kinetics of differentiation of human ES cells to vascular cells and examined their potential as a source for vascular regeneration., Methods and Results: Unlike mouse ES cells, undifferentiated human ES cells already expressed VEGF-R2, but after differentiation, a VEGF-R2-positive but tumor rejection antigen 1-60 (TRA1-60)-negative population emerged. These VEGF-R2-positive but tumor rejection antigen 1-60-negative cells were also positive for platelet-derived growth factor receptor alpha and beta chains and could be effectively differentiated into both VE-cadherin+ endothelial cell and alpha-smooth muscle actin+ mural cell. VE-cadherin+ cells, which were also CD34+ and VEGF-R2+ and thought to be endothelial cells in the early differentiation stage, could be expanded while maintaining their maturity. Their transplantation to the hindlimb ischemia model of immunodeficient mice contributed to the construction of new blood vessels and improved blood flow., Conclusions: We could identify the differentiation process from human ES cells to vascular cell components and demonstrate that expansion and transplantation of vascular cells at the appropriate differentiation stage may constitute a novel strategy for vascular regenerative medicine.

The ubiquitin-proteasome pathway is responsible for regulating cell cycle proteins, tumor-suppressor molecules, oncogenes, transcription factors, and pro- and anti-apoptotic proteins. The aim of this study is to evaluate the effects of proteasome inhibitors on human hepatocellular carcinoma (HCC) cells. HCC cells SK-Hep1, HLE and HepG2 were treated with the proteasome inhibitors MG132 and MG115. Our data showed that both inhibitors induce apoptosis in the three cell types tested in a dose-dependent manner. Moreover, subtoxic levels of MG132 and MG115 sensitized HCC cells to TRAIL-induced apoptosis. To investigate the mechanism of increased TRAIL sensitivity in HCC cells, we first examined surface expression of TRAIL and its receptors. MG132 upregulated TRAIL and its receptors (TRAIL-R1 and -R2) in SK-Hep1 and HLE, whereas MG115 upregulated them in SK-Hep1. MG132 downregulated expression of X-linked inhibitor of apoptosis protein (XIAP) in SK-Hep1 and HLE, and of survivin in all three cell-types. MG115 downregulated expression of XIAP in SK-Hep1, and survivin in SK-Hep1 and HepG2. Furthermore, MG132 downregulated phospho-AKT and its downstream target phospho-BAD, indicating that MG132 activated the mitochondrial apoptosis pathway by inhibiting phosphorylation of AKT and BAD. In conclusion, proteasome inhibitors induced apoptosis and augmented TRAIL sensitivity via both the IAP family and AKT pathways. Thus, combining proteasome inhibitors with a TRAIL agonist may provide a new therapeutic strategy for HCC.

Apoptosis and angiogenesis are critical biologic processes that are altered during carcinogenesis. Both apoptosis and angiogenesis may play an important role in pancreatic carcinogenesis. Despite numerous advances in the diagnosis and treatment of pancreatic cancer, its prognosis remains dismal and a new therapeutic approach is much needed. Recent research has revealed that apoptosis and angiogenesis are closely interrelated. Several reports show that a tumor suppresser gene that is expressed in pancreatic carcinoma and related to malignant potential can induce apoptosis and also inhibit angiogenesis. At present, it is generally accepted that tumor growth in cancers, including pancreatic cancer, depends on angiogenesis. We have identified 2 new angiogenesis inhibitors from a conditioned medium of human pancreatic carcinoma cell line (BxPC-3): antiangiogenic antithrombin III (aaAT-III) and vitamin D binding protein-macrophage activating factor (DBP-maf). These molecules were able to regress tumors in severe combined immunodeficiency disease (SCID) mice, demonstrating potent inhibition of endothelial cell proliferation. Moreover, the angiogenesis inhibitors induced tumor dormancy in the animal model. These results suggest that antiangiogenic therapy using angiogenesis inhibitors may become a new strategy for treatment of pancreatic cancer in the near future.

Background and Purpose: We investigated the usefulness of central retinal artery (CRA) Doppler flowmetry in patients with cerebral small-vessel disease (SVD)., Methods: CRA Doppler flowmetry was performed in 103 SVD patients who underwent MRI. Sixty-four adjusted control subjects were also registered. We assessed average CRA flow parameter values for both eyes with the clinical and MRI findings., Results: Each Doppler flowmetry was performed within 5 minutes. Patients with SVD had significantly lower end-diastolic and mean velocities of the CRA than control subjects; they also had higher pulsatility and resistive indexes. Multivariate analysis showed that the number of small infarcts was an independent predictor of peak systolic and mean velocities. Grade of periventricular hyperintensities was an additional independent predictor of peak systolic and mean velocities, whereas the number of small infarcts was predictive of end-diastolic velocity., Conclusions: Flow parameters may be useful for the quantitative assessment of SVD severity.

Background: We demonstrated that vascular endothelial growth factor receptor 2 (VEGF-R2)-positive cells derived from mouse embryonic stem (ES) cells can differentiate into both endothelial cells and mural cells to suffice as vascular progenitor cells (VPCs). Here we examined whether VPCs occur in primate ES cells and investigated the differences in VPC differentiation kinetics between primate and mouse ES cells., Methods and Results: In contrast to mouse ES cells, undifferentiated monkey ES cells expressed VEGF-R2. By culturing these undifferentiated ES cells for 4 days on OP9 feeder layer, VEGF-R2 expression disappeared, and then reappeared after 8 days of differentiation. We then isolated these VEGF-R2-positive and vascular endothelial cadherin (VEcadherin)-negative cells by flow cytometry sorting. Additional 5-day reculture of these VEGF-R2+ VEcadherin- cells on OP9 feeder layer resulted in the appearance of platelet endothelial cell adhesion molecule-1 (PECAM1)-positive, VEcadherin-positive, endothelial nitric oxide synthase (eNOS)-positive endothelial cells. On a collagen IV-coated dish in the presence of serum, these cells differentiated into smooth muscle actin (SMA)-positive and calponin-positive mural cells (pericytes or vascular smooth muscle cells). Addition of 50 ng/mL VEGF to the culture on a collagen IV-coated dish resulted in the appearance of PECAM1+ cells surrounded by SMA+ cells. In addition, these differentiated VEGF-R2+ cells can form tube-like structures in a 3-dimensional culture., Conclusions: Our findings indicate that differentiation kinetics of VPCs derived from primate and mouse ES cells were different. Differentiated VEGF-R2+ VEcadherin- cells can act as VPCs in primates. To seek the clinical potential of VPCs for vascular regeneration, investigations of primate ES cells are indispensable.

A massive inflammatory reaction resulting from systemic cytokine release is the common pathway underlying sepsis or multiple organ dysfunction. The role of extra domain sequence A-containing fibronectin (EDA+FN) formation during the septic response is not known. The present study investigates the role of EDA+FN during the septic response under in vitro and in vivo conditions. The direct effects of interleukin-1, interleukin-6, and tumor necrosis factor-alpha on EDA+FN production were evaluated in primary cultured human hepatocytes and fibroblasts. Serial plasma EDA+FN levels were measured using an enzyme-linked immunosorbent assay in 24 patients who developed postoperative sepsis following general abdominal surgery of which there were 17 survivors and 7 non-survivors. EDA+FN secretion was significantly increased in cultured hepatocytes but not fibroblasts at 24 and 48 h following exposure to IL-1 compared to controls. In the clinical setting plasma EDA+FN levels in non-survivors were significantly higher than in survivors. Moreover, the EDA+FN levels were correlated closely with liver function tests. EDA+FN levels may represent a specific marker of vascular injury or systemic inflammatory response syndrome that is associated with an adverse clinical outcome.

The 14484 mutation in the ND6 gene of mitochondrial DNA (mtDNA) is a genetic mutation associated with Leber's hereditary optic neuropathy (LHON) in Caucasian patients who show a high incidence of visual recovery. We evaluated four Japanese patients with LHON associated with the 14484 mutation who were negative for eight proposed secondary mutations. There was no family history of optic atrophy in three of the four patients. All four patients were initially diagnosed as having optic neuritis, either anterior (Cases 1 and 3) or retrobulbar (Cases 2 and 4), based upon their fundus findings and clinical history. Molecular genetic testing of mtDNA confirmed the diagnosis of LHON in all four patients. The three patients who experienced recovery had their vision return to 20/50 or better in both eyes. The patient who did not was a heavy consumer of alcohol and tobacco. These findings indicate that Japanese patients with the 14484 mutation have a visual prognosis similar to that of Caucasians with this mutation.

Iomazenil is a specific ligand for central-type benzodiazepine receptors (BZR). In order to determine the clinical significance of the findings of 123I-iomazenil single photon emission tomography (SPET) in cerebrovascular disease (CVD), we compared the cerebral uptake of 123I-iomazenil with oxygen metabolism measured by positron emission tomography (PET). Depending on the severity of the haemodynamic and/or metabolic impairment based on our institutional criteria [a reduction of < 30.6 ml 100g-1 min-1 in cerebral blood flow (CBF) and an increase of > 0.52 in the oxygen extraction fraction (OEF)], the cortical areas were classified into four groups as follows: Group I, normal CBF and OEF; Group II, normal CBF and increased OEF; Group III, reduced CBF and normal OEF; Group IV, reduced CBF and increased OEF. Seven patients (mean age 65 +/- 7 years) with CVD underwent both PET and 123I-iomazenil SPET within 8 days. The ratios of the mean counts in 14 regions of interest in the cerebral cortices to those in the cerebellar cortices (R/C ratios) were compared with the cerebral metabolic rate of oxygen (CMRO2). The R/C ratios of Group IV were lower than those of Group I (P < 0.005). The R/C ratios correlated with CMRO2 in Group III (r = 0.577, P < 0.01) and in Group IV (r = 0.707, P < 0.005), but not in Groups I or II. These results suggests that reduced uptake in 123I-iomazenil SPET reflects oxidative hypometabolism causing neuronal damage in haemodynamically and metabolically impaired areas in patients with CVD. This information may be valuable when deciding therapeutic approaches.

In the treatment and therapy of patients suffering a stroke, it is very important to predict whether viable neurones, even those of poor function, remain intact in the lesions of the brain. To determine whether viable neurones of low functional activity are represented in in vivo neuroreceptor imaging, we undertook experiments in gerbils with cerebral infarction, in which we examined histological changes and the results of dual-tracer in vivo autoradiography of glucose utilization with 14C-labelled deoxyglucose and benzodiazepine receptor binding with 123I-labelled Ro 16-0154. The unrelated findings of cerebral glucose metabolism and benzodiazepine receptor binding were observed in the primary infarct lesion and in remote areas, including the ipsilateral striatum and thalamus. Our experiments showed that when viable neurones with low functional activity remain intact, normal in vivo binding to benzodiazepine receptors is demonstrated as hypometabolism of glucose utilization. This functional, contrast-enhanced technique with 123I-labelled Ro 16-0154 may have an important role to play in the prediction of neuronal cell viability after recent brain infarction in experimental animals and humans using single photon emission tomography (SPET).

We investigated the induction of ischaemic tolerance in the hippocampal CA1 neurones to transient forebrain ischaemia following pretreatment with unilateral middle cerebral artery occlusion (MCAO) in gerbils. Histological evaluation was carried out after 5 min bilateral carotid artery occlusion (5BCO) in the gerbils with no MCAO pretreatment, MCAO pretreatment 3 days prior to 5BCO (MCAO-3d-5BCO), MCAO pretreatment 7 days prior to 5BCO and sham MCAO pretreatment 3 days prior to 5BCO. CA1 neurones were preserved at > 40% of normal controls only in the left hippocampus in the MCAO-3d-5BCO gerbils. CA1 neurones in the right side of MCAO-3d-5BCO gerbils as well as in both sides of animals in the other pretreatment groups almost completely disappeared after 5BCO. While the exact mechanism remains to be resolved, pretreatment with focal ischaemia seems to induce ischaemic tolerance in neurones outside of the primary ischaemic lesion.

In a modified version of the unilateral middle cerebral artery occlusion (MCAO) model in gerbils, both sides of hippocampus are spared from direct ischaemic insult. Using this newly employed left MCAO model in gerbils, we investigated the concentrations of extracellular amino acids in the left hippocampus by microdialysis and histological changes in both sides of hippocampus one month after ischaemia. The concentrations of glutamate and aspartate were significantly increased by more than 3.5 times basal levels after MCAO. Glutamate maintained this peak level for 40 to 120 min after the onset of ischaemia. However, hippocampal neurones were well preserved one month after MCAO. While the exact mechanism of the survival of hippocampal neurones remains to be elucidated, we suggest it may be crucial that the hippocampus be protected from ischaemic insult.