Cross-Sectional Study of Flood Damage Assumptions in Medical Facilities Using Geographic Information Systems.

Introduction Floods not only directly damage medical facilities but also hinder access to medical facilities, potentially disrupting local medical services. The scale of damage that medical facilities suffer from floods in Japan is unknown. In this study, we assessed the potential impact of floods on Japanese healthcare facilities by facility characteristics. Methods We conducted a cross-sectional study involving medical facilities registered in the Japan Medical Association Regional Medical Information System. Geographic data for the inundation area was obtained from open data of the Japanese government. Facilities that overlap with flooded areas were designated as affected facilities. The primary outcomes were the percentage of damaged facilities and beds. We calculated odds ratios (OR) and 95% confidence intervals (95%CI) using the Wald method to assess the impact of disaster base hospital designation on damage extent. Results We included 140,826 general clinics and 8,126 hospitals, which had 137,731 and 1,483,347 beds, respectively. The planned scale of flooding is estimated to affect 8.0% of general clinics and 10.8% of their beds. For hospitals, these figures were 8.8% and 7.8%, respectively. The maximum potential scale of flooding is estimated to affect 23.6% of general clinics and 23.9% of their beds. For hospitals, these figures were 22.5% and 20.6%, respectively. At the planned scale of flooding, there was no difference found in the rate of damaged facilities between disaster base hospitals and non-disaster base hospitals, and the rate of damaged beds was lower at non-disaster base hospitals (OR = 0.92, 95%CI = 0.71-1.18 for damaged facilities and OR = 0.79, 95%CI = 0.78-0.80 for damaged beds). At the maximum potential scale of flooding, there was no difference found in the expected damage between disaster base hospitals and non-disaster base hospitals (OR = 1.14, 95%CI = 0.95-1.38 for damaged facilities and OR = 0.99, 95%CI = 0.98-1.00 for damaged beds). Conclusion In Japan, floods can hinder nationwide medical functions, particularly in certain regions. Healthcare professionals should assess potential flood damage in advance and ensure that their workplace's business continuity plan includes appropriate countermeasures.

Progressive Supranuclear Palsy Diagnosed After a Severe Fall Trauma in a Patient Who Experienced Episodes of Easy Falling.

Progressive supranuclear palsy (PSP) is characterized by parkinsonism, downward gaze disorder, and a tendency to fall due to degeneration of the basal ganglia, the brain stem, and the cerebellum. We report a case of PSP that was diagnosed following a traumatic hemopneumothorax caused by a fall while descending stairs. A 79-year-old man experienced lightheadedness and frequent falls for two years. He fell on stairs at home and was transferred to our hospital due to mobility issues. He was hospitalized and treated for traumatic hemopneumothorax. Neurological examination revealed vertical ocular motility disorder, positive Myerson's sign, increased muscle stiffness, and increased limb tendon reflexes. Brain MRI showed a hummingbird sign. In this case, a midbrain area of 58.1 mm2 was consistent with PSP. He had no medication history that could have caused falls. He was diagnosed with PSP based on clinical and imaging findings, and treatment with levodopa was initiated. Two months later, walking showed limited improvement, and living at home became difficult. He was discharged to a care facility. PSP is a risk factor for frequent falls in the elderly. PSP usually requires three to four years for diagnosis, although falls appear earlier than in other forms of degenerative parkinsonism. Additionally, PSP often results in repeated dynamic falls due to a decreased perception of danger associated with reduced frontal lobe function. As a result, the severity of trauma from falls in PSP tends to be higher than in other neurodegenerative diseases. Therefore, early diagnosis of PSP may help improve patients' quality of life and prevent trauma. Despite frequent falls over two years, the cause was not thoroughly investigated until the patient experienced severe trauma. The lesson from this case is the importance of a thorough neurological examination and sagittal MRI for elderly patients experiencing repeated falls, to consider the possibility of PSP. Furthermore, quantitative evaluation of MRI enhances the diagnostic accuracy of PSP.

A Case of Acute Focal Bacterial Nephritis With Negative Pyuria and Urine Culture Test Results.

Acute focal bacterial nephritis (AFBN) is a radiologically diagnosed acute localized kidney infection that appears in the continuum between a perinephric abscess and renal abscess. We report an unusual case of AFBN presenting without pyuria or positive urine cultures. A 42-year-old woman with chronic lower back pain who regularly used nonsteroidal anti-inflammatory drugs was admitted to our hospital with right-sided abdominal distention, fever, chills, and pain extending from the right lower abdomen to the back since two days. The physical examination revealed no abdominal or costovertebral angle tenderness. Urinalysis was negative. Abdominal ultrasound was notable for an indistinct nodular shadow (32 × 25 mm) on the upper pole of the right kidney. Abdominal contrast-enhanced computed tomography revealed a wedge-shaped area with a minimal uptake of the contrast in the right kidney. The patient was admitted to the hospital, and antimicrobial therapy was started for AFBN. Antibiotics were administered intravenously for one week and orally for two weeks. No relapse of symptoms was observed during the four-month follow-up period. This case report suggests the importance of considering AFBN as a differential diagnosis for cases of idiopathic fever and lateral pain or back pain, even when pyuria and urine culture test results are negative.

Rhynchophylline promotes stem cell autonomous metabolic homeostasis.

Rhynchophylline (Rhy) effectively obstructs the expansive signaling pathways of degenerative diseases, including Alzheimer disease, Parkinson disease, epilepsy and amyotrophic lateral sclerosis, and stimulates neurogenesis. Maintenance of stemness and cell proliferation requires sophisticated intracellular environments to achieve pluripotency via specific expression of genes and proteins. We examined whether Rhy promotes this regulation in bone marrow human mesenchymal stromal cells (BM-hMSCs). Results revealed (i) Rhy modulated biological activity by regulating the mitochondria, N-methyl-D-aspartate receptor subunit, and levels of FGFß (basic fibroblast growth factor), BDNF (brain-derived neurotrophic factor), OXTR (oxytocin receptor) and ATP (Adenosine triphosphate); (ii) Rhy altered expression level of BM-MSC proliferation/differentiation-related transcription genes; and (iii) interestingly, Rhy amplified the glycolytic flow ratio and lactate dehydrogenase activity while reducing pyruvate dehydrogenase activity, indicating a BM-hMSC metabolic shift of mitochondrial oxidative phosphorylation into aerobic glycolysis. Altogether, we demonstrated a novel mechanism of action for Rhy-induced BM-hMSC modification, which can enhance the cell transplantation approach by amplifying the metabolic activity of stem cells.

Empathy in stroke rats is modulated by social settings.

Rodents display "empathy" defined as perceived physical pain or psychological stress by cagemates when co-experiencing socially distinct traumatic events. The present study tested the hypothesis that empathy occurs in adult rats subjected to an experimental neurological disorder, by allowing co-experience of stroke with cagemates. Psychological stress was measured by general locomotor activity, Rat Grimace Scale (RGS), and plasma corticosterone. Physiological correlates were measured by Western blot analysis of advanced glycation endproducts (AGE)-related proteins in the thymus. General locomotor activity was impaired in stroke animals and in non-stroke rats housed with stroke rats suggesting transfer of behavioral manifestation of psychological stress from an injured animal to a non-injured animal leading to social inhibition. RGS was higher in stroke rats regardless of social settings. Plasma corticosterone levels at day 3 after stroke were significantly higher in stroke animals housed with stroke rats, but not with non-stroke rats, indicating that empathy upregulated physiological stress level. The expression of five proteins related to AGE in the thymus reflected the observed pattern of general locomotor activity, RGS, and plasma corticosterone levels. These results indicate that stroke-induced psychological stress manifested on both the behavioral and physiological levels and appeared to be affected by empathy-associated social settings.

Translating intracarotid artery transplantation of bone marrow-derived NCS-01 cells for ischemic stroke: Behavioral and histological readouts and mechanistic insights into stem cell therapy.

The present study used in vitro and in vivo stroke models to demonstrate the safety, efficacy, and mechanism of action of adult human bone marrow-derived NCS-01 cells. Coculture with NCS-01 cells protected primary rat cortical cells or human neural progenitor cells from oxygen glucose deprivation. Adult rats that were subjected to middle cerebral artery occlusion, transiently or permanently, and subsequently received intracarotid artery or intravenous transplants of NCS-01 cells displayed dose-dependent improvements in motor and neurological behaviors, and reductions in infarct area and peri-infarct cell loss, much better than intravenous administration. The optimal dose was 7.5 × 106 cells/mL when delivered via the intracarotid artery within 3 days poststroke, although therapeutic effects persisted even when administered at 1 week after stroke. Compared with other mesenchymal stem cells, NCS-01 cells ameliorated both the structural and functional deficits after stroke through a broad therapeutic window. NCS-01 cells secreted therapeutic molecules, such as basic fibroblast growth factor and interleukin-6, but equally importantly we observed for the first time the formation of filopodia by NCS-01 cells under stroke conditions, characterized by cadherin-positive processes extending from the stem cells toward the ischemic cells. Collectively, the present efficacy readouts and the novel filopodia-mediated mechanism of action provide solid lab-to-clinic evidence supporting the use of NCS-01 cells for treatment of stroke in the clinical setting.

Selective endovascular cooling for stroke entails brain-derived neurotrophic factor and splenic IL-10 modulation.

Stroke poses a serious health and economic burden, and the lack of treatment options necessitates a viable therapy. Hypothermia represents a promising stroke therapy, yet side effects of full-body cooling, such as pneumonia, limit its clinical application. Selective endovascular cooling (SEC), via infusion of cold saline through the intraarterial artery, represents an attractive alternative by locally cooling the brain while preserving body temperature. However, the mechanisms underlying SEC are poorly understood. Brain-derived neurotrophic factor (BDNF) is a widely recognized promotor of neuroplasticity and biomarker of stroke outcomes, as well as its association with inflammation, such as IL-10. Stroke-induced neuroinflammation exacerbates damage and stems from peripheral organs, namely the spleen. The spleen has emerged as a therapeutic target for stroke, yet the effect of SEC on the splenic inflammatory response is unknown. Here, we aimed to elucidate the local and peripheral mechanisms driving SEC as a neuroprotective stroke therapy by examining brain BDNF and splenic IL-10 expression. Animals that received SEC prior to stroke displayed elevated brain BDNF expression ipsilaterally and contralaterally across the cortex, striatum, and hippocampus. SEC also upregulated splenic IL-10, suggesting alteration of the peripheral inflammatory response. The oxygen-glucose deprivation in vitro model of stroke further demonstrated that "cold" rat splenocytes protected rat primary neurons by upregulating BDNF and IL-10. Altogether these data support BDNF- and IL-10-based mechanisms underlying the neuroprotective potential of SEC therapy for stroke, and further advance the concept of exploiting the pathological link between brain and spleen as therapeutic targets.

T-Regulatory Cells Confer Increased Myelination and Stem Cell Activity after Stroke-Induced White Matter Injury.

Stroke-induced hypoxia causes oligodendrocyte death due to inflammation, lack of oxygen and exacerbation of cell death. Bone marrow-derived stem cells (BMSCs) possess an endogenous population of T-regulatory cells (Tregs) which reduce secretion of pro-inflammatory cytokines that lead to secondary cell death. Here, we hypothesize that oligodendrocyte progenitor cells (OPCs) cultured with BMSCs containing their native Treg population show greater cell viability, less pro-inflammatory cytokine secretion and greater myelin production after exposure to oxygen-glucose deprivation and reoxygenation (OGD/R) than OPCs cultured without Tregs. OPCs were cultured and then exposed to OGD/R. BMSCs with or without Tregs were added to the co-culture immediately after ischemia. The Tregs were depleted by running the BMSCs through a column containing a magnetic substrate. Fibroblast growth factor beta (FGF-ß) and interleukin 6 (IL-6) ELISAs determined BMSC activity levels. Immunohistochemistry assessed OPC differentiation. OPCs cultured with BMSCs containing their endogenous Tregs showed increased myelin production compared to the BMSCs with depleted Tregs. IL-6 and FGF-ß were increased in the group cultured with Tregs. Collectively, these results suggest that BMSCs containing Tregs are more therapeutically active, and that Tregs have beneficial effects on OPCs subjected to ischemia. Tregs play an important role in stem cell therapy and can potentially treat white matter injury post-stroke.

Endothelial Progenitor Cells Modulate Inflammation-Associated Stroke Vasculome.

Stroke remains a major unmet clinical need that warrants novel therapies. Following an ischemic insult, the cerebral vasculature secretes inflammatory molecules, creating the stroke vasculome profile. The present study evaluated the therapeutic effects of endothelial cells on the inflammation-associated stroke vasculome. qRT-PCR analysis revealed that specific inflammation-related vasculome genes BRM, IκB, Foxf1, and ITIH-5 significantly upregulated by oxygen glucose deprivation (OGD. Interestingly, co-culture of human endothelial cells (HEN6) with human endothelial cells (EPCs) during OGD significantly blocked the elevations of BRM, IκB, and Foxf1, but not ITIH-5. Next, employing the knockdown/antisense technology, silencing the inflammation-associated stroke vasculome gene, IκB, as opposed to scrambled knockdown, blocked the EPC-mediated protection of HEN6 against OGD. In vivo, stroke animals transplanted with intracerebral human EPCs (300,000 cells) into the striatum and cortex 4 h post ischemic stroke displayed significant behavioral recovery up to 30 days post-transplantation compared to vehicle-treated stroke animals. At 7 days post-transplantation, quantification of the fluorescent staining intensity in the cortex and striatum revealed significant upregulation of the endothelial marker RECA1 and a downregulation of the stroke-associated vasculome BRM, IKB, Foxf1, ITIH-5 and PMCA2 in the ipsilateral side of cortex and striatum of EPC-transplanted stroke animals relative to vehicle-treated stroke animals. Altogether, these results demonstrate that EPCs exert therapeutic effects in experimental stroke possibly by modulating the inflammation-plagued vasculome.

Central and Peripheral Secondary Cell Death Processes after Transient Global Ischemia in Nonhuman Primate Cerebellum and Heart.

Cerebral ischemia and its pathological sequelae are responsible for severe neurological deficits generally attributed to the neural death within the infarcted tissue and adjacent regions. Distal brain regions, and even peripheral organs, may be subject to more subtle consequences of the primary ischemic event which can initiate parallel disease processes and promote comorbid symptomology. In order to characterize the susceptibility of cerebellar brain regions and the heart to transient global ischemia (TGI) in nonhuman primates (NHP), brain and heart tissues were harvested 6 months post-TGI injury. Immunostaining analysis with unbiased stereology revealed significant cell death in lobule III and IX of the TGI cerebellum when compared to sham cerebellum, coinciding with an increase in inflammatory and apoptotic markers. Cardiac tissue analysis showed similar increases in inflammatory and apoptotic cells within TGI hearts. A progressive inflammatory response and cell death within the cerebellum and heart of chronic TGI NHPs indicate secondary injury processes manifesting both centrally and peripherally. This understanding of distal disease processes of cerebral ischemia underscores the importance of the chronic aberrant inflammatory response and emphasizes the needs for therapeutic options tailored to target these pathways. Here, we discuss the protocols for characterizing the histopathological effects of transient global ischemia in nonhuman primate cerebellum and heart, with an emphasis on the inflammatory and apoptotic cell death processes.

Neuroprotective effects of human bone marrow mesenchymal stem cells against cerebral ischemia are mediated in part by an anti-apoptotic mechanism.

Transplantation of human bone marrow mesenchymal stem cells (hMSCs) stands as a potent stroke therapy, but its exact mechanism remains unknown. This study investigated the anti-apoptotic mechanisms by which hMSCs exert neuroprotective effects on cerebral ischemia. Primary mixed cultures of rat neurons and astrocytes were cultured and exposed to oxygen-glucose deprivation. A two-hour period of "reperfusion" in standard medium and normoxic conditions was allowed and immediately followed by hMSCs and/or Bcl-2 antibody treatment. Cell viability of primary rat neurons and astrocytes was determined by 3-(4,5-dimethylthianol-2-yl)-2,5 diphenyl tetrazolium bromide and trypan blue exclusion methods. hMSC survival and differentiation were characterized by immunocytochemistry, while the concentration of Bcl-2 in the supernatant was measured by enzyme-linked immunosorbent assay to reveal the secretory anti-apoptotic function of hMSCs. Cultured hMSCs expressed embryonic-like stem cell phenotypic markers CXCR4, Oct4, SSEA4, and Nanog, as well as immature neural phenotypic marker Nestin. Primary rat neurons and astrocytes were protected from oxygen-glucose deprivation by hMSCs, which was antagonized by the Bcl-2 antibody. However, Bcl-2 levels in the supernatants did not differ between hMSC- and non-treated cells exposed to oxygen-glucose deprivation. Neuroprotective effects of hMSCs against cerebral ischemia were partially mediated by the anti-apoptotic mechanisms. However, further studies are warranted to fully elucidate this pathway.

Regulatory T-cells within bone marrow-derived stem cells actively confer immunomodulatory and neuroprotective effects against stroke.

Regulatory T-cells (Tregs) may exert a neuroprotective effect on ischemic stroke by inhibiting both inflammation and effector T-cell activation. Transplantation of human bone marrow-derived stem cells (BMSCs) in ischemic stroke affords neuroprotection that results in part from the cells' anti-inflammatory property. However, the relationship between Tregs and BMSCs in treatment of ischemic stroke has not been fully elucidated. Here, we tested the hypothesis that Tregs within the BMSCs represent active mediators of immunomodulation and neuroprotection in experimental stroke. Primary rat neuronal cells were subjected to an oxygen-glucose deprivation and reperfusion (OGD/R) condition. The cells were re-perfused and co-cultured with Tregs and/or BMSCs. We detected a minority population of Tregs within BMSCs with both immunocytochemistry (ICC) and flow cytometry identifying cells expressing phenotypic markers of CD4, CD25, and FoxP3 protein. BMSCs with the native population of Tregs conferred maximal neuroprotection compared to the treatment conditions containing 0%, 10%, and 100% relative ratio Tregs. Increasing the Treg population resulted in increased IL6 secretion and decreased FGF-ß secretion by BMSCs. This study shows that a minority population of Tregs exists within the therapeutic BMSC population, which serves as robust mediators of the immunomodulatory and neuroprotective effect provided by BMSC transplantation.

Histopathological and Behavioral Assessments of Aging Effects on Stem Cell Transplants in an Experimental Traumatic Brain Injury.

Traumatic brain injury (TBI) displays cognitive and motor symptoms following the initial injury which can be exacerbated by secondary cell death. Aging contributes significantly to the morbidity of TBI, with higher rates of negative neurological and behaviors outcomes. In the recent study, young and aged animals were injected intravenously with human adipose-derived mesenchymal stem cells (hADSCs) (Tx), conditioned media (CM), or vehicle (unconditioned media) following TBI. The beneficial effects of hADSCs were analyzed using various molecular and behavioral techniques. More specially, DiR-labeled hADSCs were used to observe the biodistribution of the transplanted cells. In addition, a battery of behavior tests was conducted to evaluate the neuromotor function for each treatment group and various regions of the brain were analyzed utilizing Nissl, hematoxylin and eosin (H&E), and human nuclei (HuNu) staining. Finally, flow cytometry was also performed to determine the levels of various proteins in the spleen. Here, we discuss the protocols for characterizing the histopathological and behavioral effects of transplanted stem cells in an animal model of TBI, with an emphasis on the role of aging in the therapeutic outcomes.

Human stem cells transplanted into the rat stroke brain migrate to the spleen via lymphatic and inflammation pathways.

Despite mounting evidence of a massive peripheral inflammatory response accompanying stroke, the ability of intracerebrally transplanted cells to migrate to the periphery and sequester systemic inflammation remains unexamined. Here, we tested the hypothesis that human bone marrow mesenchymal stromal cells intracerebrally transplanted in the brain of adult rats subjected to experimental stroke can migrate to the spleen, a vital organ that confers peripheral inflammation after stroke. Sham or experimental stroke was induced in adult Sprague-Dawley rats by a 1 hour middle cerebral artery occlusion model. One hour after surgery, rats were intracerebrally injected with human bone marrow mesenchymal stromal cells (3×105/9 µL), then euthanized on day 1, 3, or 7 for immunohistochemical assays. Cell migration assays were performed for human bone marrow mesenchymal stromal cells using Boyden chambers with the bottom plate consisting of microglia, lymphatic endothelial cells, or both, and treated with different doses of tumor necrosis factor-α. Plates were processed in a fluorescence reader at different time points. Immunofluorescence microscopy on different days after the stroke revealed that stem cells engrafted in the stroke brain but, interestingly, homed to the spleen via lymphatic vessels, and were propelled by inflammatory signals. Experiments using human bone marrow mesenchymal stromal cells co-cultured with lymphatic endothelial cells or microglia, and treated with tumor necrosis factor-α, further indicated the key roles of the lymphatic system and inflammation in directing stem cell migration. This study is the first to demonstrate brain-to-periphery migration of stem cells, advancing the novel concept of harnessing the lymphatic system in mobilizing stem cells to sequester peripheral inflammation as a brain repair strategy.

May the force be with you: Transfer of healthy mitochondria from stem cells to stroke cells.

Stroke is a major cause of death and disability in the United States and around the world with limited therapeutic option. Here, we discuss the critical role of mitochondria in stem cell-mediated rescue of stroke brain by highlighting the concept that deleting the mitochondria from stem cells abolishes the cells' regenerative potency. The application of innovative approaches entailing generation of mitochondria-voided stem cells as well as pharmacological inhibition of mitochondrial function may elucidate the mechanism underlying transfer of healthy mitochondria to ischemic cells, thereby providing key insights in the pathology and treatment of stroke and other brain disorders plagued with mitochondrial dysfunctions.

ß-Eudesmol, an Oxygenized Sesquiterpene, Reduces the Increase in Saliva 3-Methoxy-4-Hydroxyphenylglycol After the "Trier Social Stress Test" in Healthy Humans: A Randomized, Double-Blind, Placebo-Controlled Cross-Over Study.

Hops, the immature inflorescences of the female hop plant (Humulus lupulus L.) are one of the main components of beer and provides flavor and bitterness. ß-Eudesmol, an oxygenated sesquiterpene, is reported to accumulate in a particular hop cultivar. Recently, we revealed that ß-Eudesmol ingestion affected autonomic nerve activity in an animal model. The effect on humans has not been elucidated, therefore, we investigated the effects of ß-Eudesmol on reducing objective and subjective markers related to sympathetic nerve activity after the application of mental stress in healthy participants. Fifty participants (male and female aged 20 to 50 years) were randomly assigned to two groups. Five minutes before taking the Trier Social Stress Test (TSST) as a mental stressor, participants in each group ingested a beverage containing ß-Eudesmol, the active beverage, or a placebo beverage that did not contain ß-Eudesmol. Saliva 3-methoxy-4-hydroxyphenylglycol (MHPG), a major product of noradrenaline breakdown and a representative marker of sympathetic nerve activity, was significantly lower just after the TSST in the active group compared with the placebo group. Saliva cortisol, a marker of the endocrine stress response system, was not significantly different between the two groups. No adverse events related to test beverage ingestion were observed. This is the first experimental evidence of ß-Eudesmol effect for mental stress in human.

Pituitary Adenylate Cyclase Activating Polypeptide Elicits Neuroprotection Against Acute Ischemic Neuronal Cell Death Associated with NMDA Receptors.

BACKGROUND/AIMS: The endogenous neurotrophic peptides pituitary adenylate cyclase-activating polypeptides (PACAP-27/38) protect against stroke, but the molecular mechanism remains unknown. METHODS: Primary rat neural cells were exposed to PACAP-27 or PACAP-38 before induction of experimental acute ischemic stroke via oxygen-glucose deprivation-reperfusion (OGD/R) injury. To reveal PACAP's role in neuroprotection, we employed fluorescent live/dead cell viability and caspase 3 assays, optical densitometry of mitochondrial dehydrogenase and cell growth, glutathione disulfide luciferase activity, ELISA for high mobility group box1 extracellular concentration, ATP bioluminescence, Western blot analysis of PACAP, NMDA subunits, apoptosis regulator Bcl-2, social interaction hormone oxytocin, and trophic factor BDNF, and immunocytochemical analysis of PACAP. RESULTS: Both PACAP-27 and PACAP-38 (PACAP-27/38) increased cell viability, decreased oxidative stress-induced cell damage, maintained mitochondrial activity, prevented the release of high mobility group box1, and reduced cytochrome c/caspase 3-induced apoptosis. PACAP-27/38 increased the protein expression levels of BDNF, Bcl-2, oxytocin, and precursor PACAP. N-methyl-D-aspartate receptor (NMDAR)-induced excitotoxicity contributes to the cell death associated with stroke. PACAP-27/38 modulated the protein expression levels of NMDAR subunits. PACAP-27/38 increased the protein expression levels of the GluN1 subunit, and decreased that of the GluN2B and GluN2D subunits. PACAP-27, but not PACAP-38, increased the expression level of the GluN2C subunit. CONCLUSION: This study provides evidence that PACAP regulated NMDAR subunits, affording neuroprotection after OGD/R injury.

The relationship between the effect of matured hop extract and physical activity on reducing body fat: re-analysis of data from a randomized, double-blind, placebo-controlled parallel group study.

BACKGROUND: We recently reported that successive ingestion of matured hop extract (MHE), produced by oxidation of hops, results in a reduction of body fat in healthy overweight participants. A combined effect of MHE and physical activity on body fat has not been investigated. Thus, we re-analyzed data from the previous study to explore the relationship between the effect of MHE and walking as an index of physical activity. METHODS: This analysis uses existing data from a randomized, double-blind, placebo-controlled parallel group study in which MHE (active) or placebo was given for 12 w to 200 healthy overweight Japanese, from May to December 2014. Correlation between the change in abdominal fat areas at 12 w and the number of steps taken per day was tested by Spearman's correlation coefficient test. The subjects were stratified using the average number of steps per day of Japanese into walking less and walking more subgroups (WL and WM, respectively) as follows: placebo (WL, n = 43; WM, n = 44) and active (WL, n = 49; WM, n = 42). Reductions in total, visceral, and subcutaneous fat area (TFA, VFA and SFA, respectively) were evaluated. The interaction effect between ingestion (active/placebo) and walking (WL/WM) was analyzed using two-way analysis of variance (ANOVA). RESULTS: There was a significant negative correlation between the change in VFA and daily steps taken in the active group (r = - 0.208, P = 0.048). No significant correlation in TFA or SFA. Although the interaction effect in TFA was not significant, the main effect of ingestion was significant (P = 0.045). In contrast, the interaction effect in VFA was suggested to be synergistic (P = 0.055). CONCLUSION: The results suggested that MHE ingestion combined with light intensity exercise would induce a greater reduction in VFA which would be beneficial for obese or overweight individuals in reducing obesity and obesity-related diseases. TRIAL REGISTRATION: UMIN-CTR UMIN000014185 registered 6 June 2014.

Extracellular HMGB1 Modulates Glutamate Metabolism Associated with Kainic Acid-Induced Epilepsy-Like Hyperactivity in Primary Rat Neural Cells.

BACKGROUND/AIMS: Neuroinflammatory processes have been implicated in the pathophysiology of seizure/epilepsy. High mobility group box 1 (HMGB1), a non-histone DNA binding protein, behaves like an inflammatory cytokine in response to epileptogenic insults. Kainic acid (KA) is an excitotoxic reagent commonly used to induce epilepsy in rodents. However, the molecular mechanism by which KA-induced HMGB1 affords the initiation of epilepsy, especially the role of extracellular HMGB1 in neurotransmitter expression, remains to be elucidated. METHODS: Experimental early stage of epilepsy-related hyperexcitability was induced in primary rat neural cells (PRNCs) by KA administration. We measured the localization of HMGB1, cell viability, mitochondrial activity, and expression level of glutamate metabolism-associated enzymes. RESULTS: KA induced the translocation of HMGB1 from nucleus to cytosol, and its release from the neural cells. The translocation is associated with post-translational modifications. An increase in extracellular HMGB1 decreased PRNC cell viability and mitochondrial activity, downregulated expression of glutamate decarboxylase67 (GAD67) and glutamate dehydrogenase (GLUD1/2), and increased intracellular glutamate concentration and major histocompatibility complex II (MHC II) level. CONCLUSIONS: That a surge in extracellular HMGB1 approximated seizure initiation suggests a key pathophysiological contribution of HMGB1 to the onset of epilepsy-related hyperexcitability.