[Hematologic Diseases and Neurological Complications].

Many hematologic diseases can be complicated by neurological symptoms during the disease course. Hematologic diseases can contribute to strokes and neuropathies; thus, neurologists should be aware of them. Recent reports have increased of neurological side effects associated with new anticancer therapies such as immune checkpoint inhibitors and chimeric antigen receptor-T cell therapy. The relationship between hematologic diseases and neurological complications is expected to become more prevalent.

α-Pyrrolidinononanophenone derivatives induce differentiated SH-SY5Y neuroblastoma cell apoptosis via reduction of antioxidant capacity: Involvement of NO depletion and inactivation of Nrf2/HO1 signaling pathway.

α-Pyrrolidinononanophenone (α-PNP) derivatives are known to be one of the hazardous new psychoactive substances due to the most extended hydrocarbon chains of any pyrrolidinophenones on the illicit drug market. Our previous report showed that 4'-iodo-α-PNP (I-α-PNP) is the most potent cytotoxic compound among α-PNP derivatives and induces apoptosis due to mitochondrial dysfunction and suppression of nitric oxide (NO) production in differentiated human neuronal SH-SY5Y cells. In this study, to clarify the detailed action mechanisms by I-α-PNP, we investigated the mechanism of reactive oxygen species (ROS) -dependent apoptosis by I-α-PNP in differentiated SH-SY5Y with a focus on the antioxidant activities. Treatment with I-α-PNP elicits overproduction of ROS such as H2O2, hydroxyl radical, and 4-hydroxy-2-nonenal, and pretreatment with antioxidant N-acetyl-L-cysteine is attenuated the SH-SY5Y cells apoptosis by I-α-PNP. These results suggested that the overproduction of ROS is related to SH-SY5Y cell apoptosis by I-α-PNP. In addition, I-α-PNP markedly decreased antioxidant capacity in differentiated cells than in undifferentiated cells and inhibited the upregulation of hemeoxygenase 1 (HO1) and glutathione peroxidase 4 (GPX4) expression caused by induction of differentiation. Furthermore, the treatment with I-α-PNP increased the nuclear expression level of BTB Domain And CNC Homolog 1 (Bach1), a transcriptional repressor of Nrf2, only in differentiated cells, suggesting that the marked decrease in antioxidant capacity in differentiated cells was due to suppression of Nrf2/HO1 signaling by Bach1. Additionally, pretreatment with an NO donor suppresses the I-α-PNP-evoked ROS overproduction, HO1 down-regulation, increased nuclear Bach1 expression and reduced antioxidant activity in the differentiated cells. These findings suggest that the ROS-dependent apoptosis by I-α-PNP in differentiated cells is attributed to the inactivation of the Nrf2/HO1 signaling pathway triggered by NO depletion.

Palmitoyl ascorbic acid glucoside enhanced cell survival with post irradiation treatment.

Radiation exposure poses a significant threat to cellular integrity by inducing DNA damage through the generation of free radicals and reactive oxygen species. Ascorbic acid, particularly its derivative Palmitoyl Ascorbic Acid 2-Glucoside (PA2G), has demonstrated remarkable radioprotective properties. While previous research focused on its pre-irradiation application, this study explores the post-irradiation radiomitigation potential of PA2G. Our findings reveal that post-irradiation treatment with PA2G enhances cell survival and accelerates DNA repair processes, particularly the non-homologous end-joining (NHEJ) repair pathway. Notably, PA2G treatment reduces the frequency of lethal chromosomal aberrations and micronuclei formation, indicating its ability to enhance the repair of complex DNA lesions. Furthermore, PA2G is shown to play a role in potentially lethal damage repair (PLDR). These radioprotective effects are specific to NHEJ and ATM pathways, as cells deficient in these mechanisms do not benefit from PA2G treatment. This study highlights PA2G as a versatile radioprotector, both pre- and post-irradiation, with significant potential for applications in radiation therapy and protection, offering new insights into its mechanism of action. Further research is required to elucidate the precise molecular mechanisms underlying PA2G's radiomitigation effects and its potential clinical applications.

Alzheimer's Amyloid ß Peptide Induces Angiogenesis in an Alzheimer's Disease Model Mouse through Placental Growth Factor and Angiopoietin 2 Expressions.

Increased angiogenesis, especially the pathological type, has been documented in Alzheimer's disease (AD) brains, and it is considered to be activated due to a vascular dysfunction-mediated hypoxic condition. To understand the role of the amyloid ß (Aß) peptide in angiogenesis, we analyzed its effects on the brains of young APP transgenic AD model mice. Immunostaining results revealed that Aß was mainly localized intracellularly, with very few immunopositive vessels, and there was no extracellular deposition at this age. Solanum tuberosum lectin staining demonstrated that compared to their wild-type littermates, the vessel number was only increased in the cortex of J20 mice. CD105 staining also showed an increased number of new vessels in the cortex, some of which were partially positive for collagen4. Real-time PCR results demonstrated that placental growth factor (PlGF) and angiopoietin 2 (AngII) mRNA were increased in both the cortex and hippocampus of J20 mice compared to their wild-type littermates. However, vascular endothelial growth factor (VEGF) mRNA did not change. Immunofluorescence staining confirmed the increased expression of PlGF and AngII in the cortex of the J20 mice. Neuronal cells were positive for PlGF and AngII. Treatment of a neural stem cell line (NMW7) with synthetic Aß1-42 directly increased the expression of PlGF and AngII, at mRNA levels, and AngII at protein levels. Thus, these pilot data indicate that pathological angiogenesis exists in AD brains due to the direct effects of early Aß accumulation, suggesting that the Aß peptide regulates angiogenesis through PlGF and AngII expression.

Practical Radiation Protection for Interventional Radiologist.

As per the International Commission on Radiological Protection 2010 recommendation, it was stated that "interventional radiologists performing difficult procedures with high workloads may be exposed to high doses" and that education and training of medical staffs in radiation exposure is "an urgent priority." There are many reports on the textbook aspects of radiation protection, but reports on the practical aspects of radiation protection have remained to be scarce. Various methods of reducing radiation exposure are described as "useful" or "can be reduced," but the priority of these methods and the "extent" to which they contribute to reducing radiation exposure are not clear. Thus, in this article, we will look into the protection of interventional radiologist from radiation exposure in a practical way, giving priority to clarity rather than academic accuracy.

Proteomic Analysis of Plasma-Derived Extracellular Vesicles From Mice With Echinococcus granulosus at Different Infection Stages and Their Immunomodulatory Functions.

The globally distributed cystic echinococcosis (CE) is caused by the larval stage of Echinococcus granulosus (E. granulosus), a cosmopolitan and zoonotic disease with potentially life-threatening complications in humans. The emerging roles for extracellular vesicles (EVs) in parasitic infection include transferring proteins and modifying host cell gene expression to modulate host immune responses. Few studies focused on the host-derived EVs and its protein profiles. We focused on the EVs from mouse infected with E. granulosus at different stages. ExoQuick kit was used for isolating EVs from mouse plasma and ExoEasy Maxi kit was used for isolating protoscolex culture supernatant (PCS) and hydatid cyst fluid (HCF). Firstly, EVs were characterized by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA) and immunoblot. Secondly, the proteins of plasma EVs were identified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The resulting LC-MS/MS data were processed using Maxquant search engine (v 1.5.2.8). Tandem mass spectra were researched against the mice and E. granulosus proteins database in the NCBI. The differentially expressed proteins are performed by proteomic label-free quantitative analysis and bioinformatics. Thirdly, in vitro experiment, the results of co-culture of plasma EVs and spleen mononuclear cells showed that 7W-EVs can increase the relative abundance of regulatory T (Treg) cells and IL-10. We further verified that EVs can be internalized by CD4+ and CD8+ T cells, B cells, and myeloid-derived suppressor cells (MDSC). These results implied host-derived EVs are multidirectional immune modulators. The findings can contribute to a better understanding of the role of host-derived EVs which are the optimal vehicle to transfer important cargo into host immune system. In addition, we have found several important proteins associated with E. granulosus and identified in infected mouse plasma at different stages. Furthermore, our study further highlighted the proteomics and immunological function of EVs from mouse infected with E. granulosus protoscoleces at different infection stages. We have laid a solid foundation for the role of EVs in cystic echinococcosis in the future research and supplemented a unique dataset for this E. granulosus.

Feasibility of magnetic resonance imaging-ultrasound guided high-dose-rate brachytherapy for localized prostate cancer: Preliminary results from a prospective study.

OBJECTIVE: This study aimed to investigate preliminary outcomes of a prospective trial of magnetic resonance imaging-ultrasound fusion-guided ultrafocal high-dose-rate brachytherapy in localized prostate cancer. METHODS: In our prospective study, data from patients who underwent this treatment between April 1, 2020 and March 31, 2021 were analyzed. In the procedure, the applicator needle was inserted through the perineum to target the lesion on the multiparametric magnetic resonance imaging, which was fused onto the transrectal ultrasound image. The prescription dose was set at a single fraction of 19 Gy. Data from patients who received whole-gland high-dose-rate brachytherapy were extracted and compared with data from patients who received ultrafocal high-dose-rate brachytherapy, to evaluate the frequency of acute adverse events. RESULTS: Eight patients underwent ultrafocal high-dose-rate brachytherapy with a median observation period of 7.75 months (range 5.96-15.36 months). No acute genitourinary or gastrointestinal adverse events were observed in this cohort. The planned procedure was completed in all patients, and no unexpected adverse events were observed; however, prostate-specific antigen failure was detected in one patient. In the 25 patients who underwent whole-gland high-dose-rate brachytherapy, acute genitourinary and gastrointestinal adverse events were observed in 88% and 20% of the patients, respectively. Ultrafocal high-dose-rate brachytherapy was a significant factor in avoiding acute adverse genitourinary events in univariate and multivariate analyses (P < 0.001 and P = 0.032, respectively). CONCLUSIONS: Magnetic resonance imaging-ultrasound fusion-guided ultrafocal high-dose-rate brachytherapy in localized prostate cancer is a safe and feasible treatment without acute genitourinary and gastrointestinal adverse events. Long-term observation and further investigation are warranted.

An in vitro system for experimentally induced cryptorchidism.

Cryptorchidism is one of the most common abnormalities of male sexual development, and is characterized by the failure of the testis to descend into the scrotum. Despite extensive studies of cryptorchidism over the past century, the mechanisms for temperature-induced germ-cell loss are not well understood. All of the main cell types in the testis are believed to be affected by the elevated testis temperature induced by cryptorchidism. The cooler temperature in the special environment of the scrotum is required for maintaining optional conditions for normal spermatogenesis. Many studies reported that experimentally induced cryptorchidism caused germ cell apoptosis and suppressed spermatogenesis. However, other factors including hormones must also be examined for cryptorchidism. To explore the mechanism for cryptorchidism, in vitro cultures of testes have been used, but complete spermatogenesis using in vitro methods was not accomplished until 2011. In 2011, Sato et al. (Nature, 471, 504-507) reported the in vitro production of functional sperm in cultured neonatal mouse testes. Using this in vitro system, for the first time, we report that spermatogenesis was abrogated at 37 °C, in accordance with in vivo surgery-mediated cryptorchidism, while spermatogenesis proceeded at 34 °C in cultured testes. This result clearly showed that temperature is the sole determinant of cryptorchidism. Moreover, we found that spermatogenesis was arrested before early spermatocytes at 37 °C. In conclusion, using our in vitro system, we have demonstrated that (1) temperature is the determining factor for cryptorchidism, and (2) higher temperature (37 °C) suppresses DNA synthesis in spermatogenesis.

Perillaldehyde inhibits bone metastasis and receptor activator of nuclear factor-κB ligand (RANKL) signaling-induced osteoclastogenesis in prostate cancer cell lines.

Perillaldehyde (PAH), one of the active ingredients of the traditional Chinese medicine (TCM) plant Perilla frutescens, is widely used and exerts crucial anti-cancer activities. The aim of current study is to illustrate the potential mechanisms of PAH-mediated regulation of bone metastasis and osteoclastogenesis in prostate cancer (PCa) cell lines. Effects of PAH on proliferation, invasion and migration of PC-3 cells were assessed with the Cell Counting Kit-8 (CCK-8) assay and Transwell assays, respectively. Effects of PAH on stem cell characteristics of PC-3 cells were evaluated by cell-matrix adhesion assay, colony formation assay, spheroid formation assay, as well as western blot . The anti-metastasis and anti-osteoclastogenesis activity of PAH in RAW264.7 cells was examined by osteoclast differentiation assay and western blot. The protein levels of CD133 and CD44 in PC-3 cells and the activity of nuclear factor kappa B (NF-κB) signaling pathway in RAW264.7 cells were measured by western blot. PAH suppressed proliferation, invasion and migration of PC-3 cells, prevented stem cell characteristics including cell-matrix adhesion, colony formation, spheroid formation as well as CD133 and CD44 expression. PAH inhibited bone metastasis and osteoclastogenesis via repressing the activation of NF-κB pathway as well as (RANKL) - and cancer cell-induced osteoclastogenesis in PCa cells. These findings suggested the potential therapeutic effects of PAH on the metastasis of patients with PCa.

Aggregation of Cystatin C Changes Its Inhibitory Functions on Protease Activities and Amyloid ß Fibril Formation.

Cystatin C (CST3) is an endogenous cysteine protease inhibitor, which is implicated in cerebral amyloid angiopathy (CAA). In CAA, CST3 is found to be aggregated. The purpose of this study is to investigate whether this aggregation could alter the activity of the protein relevant to the molecular pathology of CAA. A system of CST3 protein aggregation was established, and the aggregated protein was characterized. The results showed that CST3 aggregated both at 80 °C without agitation, and at 37 °C with agitation in a time-dependent manner. However, the levels of aggregation were high and appeared earlier at 80 °C. Dot-blot immunoassay for oligomers revealed that CST3 could make oligomeric aggregates at the 37 °C condition. Electron microscopy showed that CST3 could make short fibrillary aggregates at 37 °C. Cathepsin B activity assay demonstrated that aggregated CST3 inhibited the enzyme activity less efficiently at pH 5.5. At 7.4 pH, it lost the inhibitory properties almost completely. In addition, aggregated CST3 did not inhibit Aß1-40 fibril formation, rather, it slightly increased it. CST3 immunocytochemistry showed that the protein was positive both in monomeric and aggregated CST3-treated neuronal culture. However, His6 immunocytochemistry revealed that the internalization of exogenous recombinant CST3 by an astrocytoma cell culture was higher when the protein was aggregated compared to its monomeric form. Finally, MTT cell viability assay showed that the aggregated form of CST3 was more toxic than the monomeric form. Thus, our results suggest that aggregation may result in a loss-of-function phenotype of CST3, which is toxic and responsible for cellular degeneration.

Case Report: Malignant Pheochromocytoma Without Hypertension Accompanied by Increment of Serum VEGF Level and Catecholamine Cardiomyopathy.

Introduction: Pheochromocytoma is a catecholamine-producing tumor in the adrenal medulla and is often accompanied by hypertension, hyperglycemia, hypermetabolism, headache, and hyperhidrosis, and it is classified as benign and malignant pheochromocytoma. In addition, persistent hypertension is often observed in subjects with malignant pheochromocytoma. Case Presentation: A 52-year-old Japanese male was referred and hospitalized in our institution. He had a health check every year and no abnormalities had been pointed out. In addition, he had no past history of hypertension. In endocrinology markers, noradrenaline level was as high as 7,693 pg/ml, whereas adrenaline level was within normal range. Abdominal contrast-enhanced computed tomography revealed a 50-mm hyper-vascularized tumor with calcification in the right adrenal gland and multiple hyper-vascularized tumors in the liver. In 131I MIBG scintigraphy, there was high accumulation in the right adrenal gland and multiple accumulation in the liver and bone. In echocardiography, left ventricular ejection fraction was as low as 14.3%. In coronary angiography, however, there was no significant stenosis in the coronary arteries. Based on these findings, we finally diagnosed him as malignant pheochromocytoma accompanied by multiple liver and bone metastases and catecholamine cardiomyopathy. However, blood pressure was continuously within normal range without any anti-hypertensive drugs. Right adrenal tumor resection was performed together with left hepatic lobectomy and cholecystectomy. Furthermore, serum levels of vascular endothelial growth factor (VEGF) and parathyroid (PTH)-related protein were very high before the operation but they were markedly reduced after the operation. Conclusions: This is the first report showing the time course of serum VEGF level in a subject with malignant pheochromocytoma, clearly showing that malignant pheochromocytoma actually secreted VEGF. In addition, this case report clearly shows that we should bear in mind once again that malignant pheochromocytoma is not necessarily accompanied by hypertension.

iTRAQ-based proteomic analysis after mesenchymal stem cell line transplantation for ischemic stroke.

Transplantation with mesenchymal stem cells (MSCs) has been reported to promote functional recovery in animal models of ischemic stroke. However, the molecular mechanisms underlying the therapeutic effects of MSC transplantation have been only partially elucidated. The purpose of this study was to comprehensively identify changes in brain proteins in rats treated with MSCs for ischemic stroke, and to explore the multi-target mechanisms of MSCs using a proteomics-based strategy. Twenty-eight proteins were found to be differentially expressed following B10 MSC transplantation in adult male Wistar rats, as assessed using isobaric tagging for relative and absolute protein quantification (iTRAQ). Subsequent bioinformatic analysis revealed that these proteins were mainly associated with energy metabolism, glutamate excitotoxicity, oxidative stress, and brain structural and functional plasticity. Immunohistochemical staining revealed decreased expression of EAAT1 in the phosphate-buffered saline group as opposed to normal levels in the B10 transplantation group. Furthermore, ATP levels were also significantly higher in the B10 transplantation group, thus supporting the iTRAQ results. Our results suggest that the therapeutic effects of B10 transplantation might arise from the modulation of the acute ischemic cascade via multiple molecular pathways. Thus, our findings provide valuable clues to elucidate the mechanisms underlying the therapeutic effects of MSC transplantation in ischemic stroke.

Myeloid-derived suppressor cells exert immunosuppressive function on the T helper 2 in mice infected with Echinococcus granulosus.

Cystic echinococcosis (CE) is a worldwide hazardous zoonotic parasitosis caused by Echinococcus granulosus. CE development involves complex immunological mechanisms, including participation of multiple immune cells and effector molecules. Myeloid-derived suppressor cells (MDSCs) are known to be involved in chronic and acute inflammatory conditions. In this study, we aimed to characterize the immune function of MDSCs in CE to improve the understanding, prevention and treatment of CE. Our results indicated that MDSCs overexpressing Ly6C and Ly6G inhibit the formation and activity of T helper 2 cells in a NO-dependent manner during E. granulosus infection.

Association between cystatin C gene polymorphism and the prevalence of white matter lesion in elderly healthy subjects.

Cystatin C (CST3) is a cysteine protease inhibitor abundant in the central nervous system, and demonstrated to have roles in several pathophysiological processes including vascular remodeling and inflammation. Previously, we showed a relation of CST3 gene polymorphisms with deep and subcortical white matter hyperintensity (DSWMH) in a small case-control study. In this study, we aimed to investigate the relation in a larger cross-sectional study. Participants of a brain health examination program were recruited (n = 1795) in the study, who underwent routine blood tests and cognitive function tests. Cerebral white matter changes were analyzed by MRI. Additionally, 7 single nucleotide polymorphisms (SNPs) (-82G/C, -78T/G, -5G/A, +4A/C, +87C/T, +148G/A and +213G/A) in the promoter and coding regions of CST3 gene were examined. Among them, carriers of the minor allele haplotype -82C/+4C/+148A were significantly associated with decreased CST3 concentration in the plasma. Unadjusted analysis did not show significant relation between carriers of the minor allele haplotype and periventricular hyperintensity (PVH), but DSWMH was marginally (p < 0.054) increased in this group. After adjusting the effects of other variables like age and kidney function, logistic regression analysis revealed that carriers of the minor allele haplotype were at a significantly increased risk of developing both PVH and DSWMH. Thus, our results suggest that carriers of the minor allele haplotype -82C/+4C/+148A of CST3 gene could be at an increased risk to develop cerebral white matter disturbance.

An Improved Assay for Quantitation of Cerebrospinal Fluid Cystatin C Using Liquid Chromatography Tandem Mass Spectrometry.

Cystatin C (CST3) is expressed ubiquitously and implicated in several neurological diseases. It can be posttranscriptionally modified. CST3 is usually quantified in a biological sample using antibody-based methods. Posttranscriptional modification can hamper antibody-based detection systems by altering antibody-binding epitope(s). To circumvent this problem, enzymatic digestion and liquid chromatography tandem mass spectrometry (LC-MS/MS) technique can be employed to identify and measure peptides of a target protein in a complex biological mixture. This chapter describes an LC-MS/MS-based method for accurate measurement of CST3 in cerebrospinal fluid (CSF). Here, CSF was directly subjected to trypsin digestion and digested peptides were extracted using a solid-phase extraction column. Extracted peptide samples were directly used for LC-MS/MS-based identification and quantification of CST3 peptides. Comparing the concentration in a set of samples measured by LC-MS/MS with that of immunoassay shows that it was significantly higher when measured by LC-MS/MS method, suggesting it a better quantification method. This approach is particularly well suited when posttranscriptional modification of CST3 is suspected and sample volume of CSF is small.

Intra-abdominal desmoid tumor mimicking local recurrence of renal cell carcinoma after laparoscopic partial nephrectomy.

A 64-year-old man had an intra-abdominal mass that was detected in a follow-up examination after laparoscopic partial nephrectomy for renal cell carcinoma (RCC). CT showed an enhanced mass of 2.5-cm diameter near the right kidney, where partial nephrectomy had been performed. Local recurrence of RCC with duodenum invasion was suspected, and excision was performed. The final pathological diagnosis of desmoid tumor differed from the preoperative diagnosis. Therefore, we report this case as a rare example of intra-abdominal desmoid tumor mimicking local recurrence of RCC. To our knowledge, this is the first report of intra-abdominal desmoid tumor after laparoscopic partial nephrectomy.

Multidimensional analysis of clinicopathological characteristics of false-negative clinically significant prostate cancers on multiparametric MRI of the prostate in Japanese men.

PURPOSE: To clarify clinicopathological features of false-negative clinically significant prostate cancer (csPC) at multiparametric prostate MRI (mpMRI). METHODS: 95 patients with 139 csPC undergoing 3T mpMRI before radical prostatectomy were included. Two radiologists were independently evaluated mpMR images using PI-RADS v2. Clinicopathological findings were compared between (a) detectable and undetectable lesions using overall mpMRI criteria (o-mpMRI criteria) and (b) lesions with early enhancement effect (EEE) and lesions without EEE at DCE-MRI. RESULTS: The detection rate of csPS using cutoff value of category 3 or more in PI-RADS v2 for positive lesion was 72.1% (98/136 lesions). In 38 false-negative lesions with less than PI-RADS v2 category 3, the DCE-MRI detected 14 lesions. 17 undetectable lesions on o-mpMR criteria had lower PSA and D'amico risk classification, and higher tumor apparent diffusion coefficient (ADC) than those of 118 detectable lesions (p ≤ 0.048). 89 lesions with EEE showed higher PSA, tumor size, prostatectomy GS grade, frequency of lesions with GS ≥ 4 + 3 and lower tumor ADC than those in 38 lesions without EEE (p ≤ 0.046). CONCLUSION: Tumor detectability of csPC with PI-RADS v2 was limited compared with o-mpMRI criteria in Japanese men. Moreover, false-negative lesions on o-mpMRI criteria were characterized as small in size, low risk and low cellularity.

A Mesenchymal stem cell line (B10) increases angiogenesis in a rat MCAO model.

A human mesenchymal stem cell line (B10) transplantation has been shown to improve ischemia-induced neurological deficits in animal stroke models. To understand the underlying mechanism, we have investigated the effects of B10 transplantation on cerebral angiogenesis in a rat middle cerebral artery occlusion (MCAO) model. B10 cells were transplanted intravenously 24 h after MCAO. Immunofluorescence staining results showed that compared to PBS-groups, vWF positive vessel and endoglin positive new vessels were increased in B10-transplanted MCAO groups in the lesion areas. The mRNA of angiogenesis factors including placental growth factor and hypoxia inducible factor (HIF)-1α were increased 3 days after MCAO in the core and IBZ areas of B10-transplanted group. Angiopoetin1 mRNA was increased only in the IBZ. Western blotting results showed that HIF-1α and vascular endothelial growth factor (VEGF) proteins were increased in B10-transplanted group. Both HIF-1α and VEGF were expressed in macrophage/microglia in the core area. In the IBZ, however, HIF-1α was expressed both in astrocytes and macrophage/microglia, while VEGF was expressed only in macrophage/microglia. Moreover, TGFß protein levels were found to be increased in B10-transplanted group in the core and IBZ regions. Cell culture experiments using a human microglia cell line (HMO6) and B10 showed that IL-1ß induced VEGF mRNA expression in both cell types. IL-1ß was found to be highly expressed in B10 cells, and its co-culture with HMO6 further increased that in B10. Co-culture increased VEGF mRNA in both B10 and HMO6. In the rat brains, IL-1ß was expressed in macrophage/microglia and transplanted-B10 cells in the core. IL-1ß positive cell number was increased slightly, but significantly in B10-transplanted rats. To explore further, IL-1ß expression was silenced in B10 cells by transfecting mRNA specific siRNA, and then transplanted in MCAO rats. Immunostaining result showed that endoglin positive area was decreased in IL-1ß-silenced B10 transplanted groups compared to nonsilenced-B10 transplanted groups. Interestingly, vessel-like structure appeared as early as 3 days after MCAO in IL-1ß-silenced B10-transplanted group. Thus our results demonstrated that B10 cells increased angiogenesis in MCAO rat model, through the regulation of HIF-1α and VEGF expression, where IL-1ß might play a role.

Transplantation of a bone marrow mesenchymal stem cell line increases neuronal progenitor cell migration in a cerebral ischemia animal model.

Mesenchymal stem cell (MSC) transplantation is demonstrated to improve functional and pathological recovery in cerebral ischemia. To understand the underlying mechanism, we transplanted a MSC line (B10) in a rat middle cerebral artery occlusion (MCAO) model and checked the proliferation and migration of neuronal progenitor cells (NPCs). B10 transplantation increased NPCs in the subventricular zone and their migration towards the lesion area at an earlier time. Fourteen days after MCAO, some NPCs were differentiated to neurons and astrocytes. Although B10 transplantation increased total number of both astrocytes and neurons, it only increased the differentiation of NPC to astrocyte. The mRNA of polysialylation enzyme ST8SiaIV and a chemokine SDF-1 were persistently increased in B10-transplanted groups. SDF-1-positive cell number was increased in the core and penumbra area, which was expressed in macrophage/microglia and transplanted B10 cells at 3 days after MCAO. Furthermore, SDF-1 mRNA expression in cell culture was high in B10 compared to a microglia (HMO) or a neuronal (A1) cell line. B10 culture supernatant increased in vitro A1 cell migration, which was significantly inhibited by siRNA-mediated SDF-1 silencing in B10. Thus, our results suggested that MSC transplantation increased endogenous NPC migration in cerebral ischemic condition by increasing chemokine and polysialylation enzyme expression, which could be helpful for the restorative management of cerebral ischemia.

COPD uncovered: a cross-sectional study to assess the socioeconomic burden of COPD in Japan.

Background: COPD remains a major health problem in Japan. Patients with COPD experience a reduced quality of life (QoL) and have a higher chance of work impairment and productivity loss. However, there is a lack of data on the impact of COPD in terms of QoL and work activity impairment in Japan. This study assessed the socioeconomic burden of COPD in Japan and the impact it may have on the working age population. Patients and methods: This was a 2-year retrospective chart review in COPD patients aged ≥40 years, with at least one health care visit to clinic or hospital in the previous 12 months. Patients were required to have available medical charts for at least the previous 24 months. Symptoms were assessed using COPD assessment test score; EuroQoL Group 5 Dimension (EQ-5D-5L) and work productivity and activity impairment general health questionnaires were used to evaluate health-related QoL and work productivity, and health care resource utilization data were obtained from clinical charts. Results: In total, 71 patients aged <65 years, and 151 patients aged ≥65 years were included; the majority of patients had moderate or severe airflow limitation. Exacerbations (moderate or severe) were reported by ~35% of patients in both age groups; 52.1% and 62.9% of patients in the <65-year and ≥65-year age groups had COPD assessment test scores ≥10. EQ-5D-5L index scores in the <65-year and ≥65-year age groups were 0.79 and 0.77, respectively. Work productivity and activity impairment scores were higher in <65-year age group. Annual costs of health care resource use per patient in the <65-year and ≥65-year age groups were ¥438,975 (US$4,389) and ¥467,871 (US$4,678), respectively. Costs due to productivity loss were estimated to be ¥5,287,024 (US$52,870) in the <65-year age group and ¥3,018,974 (US$30,187) in the ≥65-year age group. Conclusion: COPD represents a significant socioeconomic burden in Japan. Patients with COPD report significant use of health care resources. Higher impact on work impairment and productivity loss was observed frequently in the working age population.