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The cytoplasmic regulatory protein p62 (Sequestosome 1/A170) is known to modulate various receptor-mediated intracellular signaling pathways.p62deficiency was shown to result in mature-onset obesity in mice, but the mechanisms underlying this abnormality remained unclear. Here we report that hyperphagia due to central leptin resistance is the cause of obesity inp62−/−mice. We found that these mice show hyperphagia. Restriction of food to the amount eaten by wild-type mice prevented excess body weight gain and fat accumulation, suggesting that overfeeding is the primary cause of obesity inp62−/−mice. Brain-specific p62 deficiency caused mature-onset obesity to the same extent as inp62−/−mice, further supporting a neuronal mechanism as the major cause of obesity in these mice. Immunohistochemical analysis revealed that p62 is highly expressed in hypothalamic neurons, including POMC neurons in the arcuate nucleus. Central leptin resistance was observed even in young preobesep62−/−mice. We found a defect in intracellular distribution of the transcription factor Stat3, which is essential for the action of leptin, inp62−/−mice. These results indicate that brain p62 plays an important role in bodyweight control by modulating the central leptin-signaling pathway and that lack of p62 in the brain causes leptin resistance, leading to hyperphagia. Thus, p62 could be a clinical target for treating obesity and metabolic syndrome.

Using a cue-dependent memory-based smooth-pursuit task previously applied to monkeys, we examined the effects of visual motion-memory on smooth-pursuit eye movements in normal human subjects and compared the results with those of the trained monkeys. These results were also compared with those during simple ramp-pursuit that did not require visual motion-memory. During memory-based pursuit, all subjects exhibited virtually no errors in either pursuit-direction or go/no-go selection. Tracking eye movements of humans and monkeys were similar in the two tasks, but tracking eye movements were different between the two tasks; latencies of the pursuit and corrective saccades were prolonged, initial pursuit eye velocity and acceleration were lower, peak velocities were lower, and time to reach peak velocities lengthened during memory-based pursuit. These characteristics were similar to anticipatory pursuit initiated by extra-retinal components during the initial extinction task of Barnes and Collins (J Neurophysiol 100:1135-1146, 2008b). We suggest that the differences between the two tasks reflect differences between the contribution of extra-retinal and retinal components. This interpretation is supported by two further studies: (1) during popping out of the correct spot to enhance retinal image-motion inputs during memory-based pursuit, pursuit eye velocities approached those during simple ramp-pursuit, and (2) during initial blanking of spot motion during memory-based pursuit, pursuit components appeared in the correct direction. Our results showed the importance of extra-retinal mechanisms for initial pursuit during memory-based pursuit, which include priming effects and extra-retinal drive components. Comparison with monkey studies on neuronal responses and model analysis suggested possible pathways for the extra-retinal mechanisms.

Polyglutamine (polyQ) diseases are inherited neurodegenerative disorders that are caused by the expansion of trinucleotide CAG repeats in the causative genes. Spinal and bulbar muscular atrophy (SBMA) is an inherited motor neuron disease that is caused by the expansion of a polyQ tract within the androgen receptor (AR). p62 is a ubiquitin- and light-chain 3-binding protein that is known to regulate the degradation of targeted proteins via autophagy and inclusion formation. In this study, we examined the effects of p62 depletion and overexpression on cultured cells and in a transgenic mouse model that overexpressed the mutant AR. Here, we demonstrate that depletion of p62 significantly exacerbated motor phenotypes and the neuropathological outcome, whereas overexpression of p62 protected against mutant AR toxicity in SBMA mice. Depletion of p62 significantly increased the levels of monomeric mutant AR and mutant AR protein complexes in an SBMA mouse model via the impairment of autophagic degradation. In addition, p62 overexpression improved SBMA mouse phenotypes by inducing cytoprotective inclusion formation. Our results demonstrate that p62 provides two different therapeutic targets in SBMA pathogenesis: (1) autophagy-dependent degradation and (2) benevolent inclusion formation of the mutant AR.

Interleukin-4 receptor α (IL-4Rα) is highly expressed on the surface of various human solid tumors including head and neck squamous cell carcinoma (HNSCC). We designed a novel IL-4Rα-lytic hybrid peptide composed of a binding peptide to IL-4Rα and a cell-lytic peptide. In the present study, we evaluated the antitumor activity of the IL-4Rα-lytic hybrid peptide as a novel molecular-targeted therapy in HNSCC. Immunoblot analysis revealed that IL-4Rα was expressed in all tested HNSCC cell lines (HSC-2, HSC-3, HSC-4, Ca9-22 and OSC-19), but not in a human normal keratinocyte (HaCaT) cell line. Immunohistochemical expression levels of IL-4Rα in HNSCC tissues were higher compared to those in normal epithelial tissue. The IL-4Rα-lytic hybrid peptide showed cytotoxic activity in all five cancer cell lines with a concentration that killed 50% of all cells (IC50) as low as 10 µM. HaCaT cells were less sensitive to this peptide with an IC50 of >30 µM. In addition, intratumoral administration of IL-4Rα-lytic hybrid peptide significantly inhibited tumor growth in a xenograft model of human HNSCC in vivo. These results indicate that the IL-4Rα-lytic hybrid peptide may serve as a potent agent to provide a novel therapy for patients with HNSCC.

Processed Aconiti tuber (PAT) is used to treat pain associated with various disorders. Although it has been demonstrated that the κ opioid receptor (KOR) signaling pathway is a mediator of the analgesic effect of PAT, active components affecting opioid signaling have not yet been identified. In this study, we explored candidate components of PAT by pharmacokinetic analysis and identified ignavine, which is a different structure from aconitine alkaloids. A receptor binding assay of opioid receptors showed that ignavine specifically binds the μ opioid receptor (MOR), not the KOR. Receptor internalization assay in MOR-expressing cell lines revealed that ignavine augmented the responses produced by D-Ala(2)-N-Me-Phe(4)-Gly-ol(5)-enkephalin (DAMGO), a representative MOR agonist, at a low concentration and inhibited it at a higher concentration. Ignavine also exerted positive modulatory activity for DAMGO, endomorphin-1 and morphine in cAMP assay. Additionally, ignavine alone showed an analgesic effect in vivo. In silico simulation analysis suggested that ignavine would induce a unique structural change distinguished from those induced by a representative MOR agonist and antagonist. These data collectively suggest the possibility that ignavine could be a novel allosteric modulator of the MOR. The present results may open the way for the development of a novel pain management strategy.

A 16-year-old boy was admitted to our hospital, with a 4-day history of hyperthermia, vomiting, confusion, nuchal rigidity and dysbasia. Cerebrospinal fluid (CSF) examination showed: white cell count, 673/μL (69% polymorphonuclear cells); protein, 305 mg/dL; glucose ratio of CSF to serum, 0.35; and negative results for culture, antiviral antibodies, Epstein-Barr virus DNA and oligoclonal IgG bands (OB). Antibiotics and acyclovir were given intravenously under a tentative diagnosis of infectious meningitis. However, unconsciousness was prolonged. CSF myelin basic protein (MBP) and IgG index were abnormally elevated to 257 pg/mL (normal

Objective Peroxiredoxin (Prx) is a new family of antioxidative proteins. Prx I is ubiquitously expressed in various tissues and is important in the defense of tissues from increases in reactive oxygen species (ROS). The present study was designed to examine the expression of Prx subtypes in the mouse cochlea and to show the possible involvement of Prx I in protecting the cochlea against cisplatin ototoxicity. Methods Postnatal-day-3-to-5 wildtype mice and Prx I-deficient mice were used. Prx expression in the cochlea was assessed by real-time PCR assay. Prx I protein expression was examined by immunofluorescence staining. Cochlear explants were exposed to 2, 5, and 10-μM cisplatin for 48 h, and the cochlear hair cell losses of the wildtype and Prx I-deficient mice were compared. In addition, the histologic features of the cochlear lateral wall were examined after cisplatin incubation. Results mRNAs of all Prx subtypes were expressed in the mouse cochlea. Prx I was one of the abundant subtypes and was upregulated after 48-h exposure to 5-μM cisplatin. Immunofluorescence staining showed the ubiquitous expression of Prx I in the cochlea. No difference in cochlear hair cell loss induced by cisplatin was found between the wildtype mice and the Prx I-deficient mice. However, spiral ligament fibrocytes of Prx I-deficient mice were significantly sensitive to cisplatin at 20-μM or lower. Conclusion Prx I is important for protection of at least the spiral ligament fibrocytes of the cochlear lateral wall in cisplatin ototoxicity.

A 67-year-old man with elevated hepatobiliary enzymes was referred to our hospital for further examination. Computed tomography indicated hilar cholangiocarcinoma of Bismuth type Ⅳ and revealed invasion of the right hepatic artery and the left portal vein. We diagnosed locally advanced unresectable hilar cholangiocarcinoma, and performed 5 courses of chemotherapy with gemcitabine plus S-1. After chemotherapy, the tumor was significantly reduced in size and vascular invasions were alleviated, so we decided to perform surgical resection. An extended left hepatectomy with caudate lobe and extrahepatic bile duct resection was performed. Although the intraoperative pathological examination was positive for cancer at the hepatic margins, we did not perform further bile duct resection because of the difficulty. After the surgery, we administered adjuvant chemotherapy with gemcitabine for 5 courses. Another 8 courses of gemcitabine plus S-1 therapy were given because of elevation of CA19-9. The tumor marker levels normalized, and the patient is still alive without findings of recurrence 4 years after the first treatment. Multidisciplinary treatment with chemotherapy and surgery may suggest the possibility of increasing long term survival even for patients with locally advanced unresectable cholangiocarcinoma.

Acute ozone (O(3)) exposure causes oxidative stress leading inflammation in the lung. However, its precise mechanisms are not fully elucidated. Here, we examined the role of peroxiredoxin I (PrxI) in O(3)-induced pulmonary inflammation using PrxI null (PrxI(-/-)) and wild-type (WT) mice. PrxI is known as an antioxidant and also emerged as a potent proinflammatory factor that activates toll-like receptor 4/nuclear factor-kappa B signalling. Both mice were exposed to 2 ppm O(3) for 6 h and their responses to oxidative stress and acute inflammation in the lung were evaluated after 18 h. The O(3) inhalation activated the transcription factor nuclear factor-erythroid 2-related factor 2 and upregulated heme oxygenase-1 mRNA, the typical makers of oxidative stress, to similar extent in both lungs observed after 0 and 4 h, respectively. O(3) exposure induced significantly less pulmonary inflammation in PrxI(-/-) than in WT mice judging from the reduced infiltrations of neutrophils into the lung and the suppressed production of proinflammatory mediators, such as interleukin-6 and keratinocyte chemoattractant in the bronchoalveolar lavage fluids. Our results suggest that PrxI is not an effective protector against O(3)-induced oxidative damages reportedly caused by harmful lipid metabolites but plays a positive role in the initiation of lung inflammation following O(3) exposure.

Peroxiredoxins possess thioredoxin or glutathione peroxidase and chaperone-like activities and thereby protect cells from oxidative insults. Recent studies, however, reveal additional functions of peroxiredoxins in gene expression and inflammation-related biological reactions such as tissue repair, parasite infection and tumor progression. Notably, peroxiredoxin 1, the major mammalian peroxiredoxin family protein, directly interacts with transcription factors such as c-Myc and NF-κB in the nucleus. Additionally, peroxiredoxin 1 is secreted from some cells following stimulation with TGF-β and other cytokines and is thus present in plasma and body fluids. Peroxiredoxin 1 is now recognized as one of the pro-inflammatory factors interacting with toll-like receptor 4, which triggers NF-κB activation and other signaling pathways to evoke inflammatory reactions. Some cancer cells release peroxiredoxin 1 to stimulate toll-like receptor 4-mediated signaling for their progression. Interestingly, peroxiredoxins expressed in protozoa and helminth may modulate host immune responses partly through toll-like receptor 4 for their survival and progression in host. Extracellular peroxiredoxin 1 and peroxiredoxin 2 are known to enhance natural killer cell activity and suppress virus-replication in cells. Peroxiredoxin 1-deficient mice show reduced antioxidant activities but also exhibit restrained tissue inflammatory reactions under some patho-physiological conditions. Novel functions of peroxiredoxins in inflammation, cancer and innate immunity are the focus of this review.

We report a case of elderly-onset neuromyelitis optica (NMO) positive for the anti-aquaporin-4 (AQP-4) antibody; symptoms developed after the diagnosis of prostate adenocarcinoma and relapsed after a 23-valent pneumococcal polysaccharide vaccination. We suggest that activation of CD4-positive T cells and secretion of interferon-gamma induced by adenocarcinoma and complement activation induced by vaccination are responsible for the onset and relapse of NMO, even if a patient is positive for the anti-AQP-4 antibody. This case supports the previous experimental finding that the anti-AQP-4 antibody does not cause NMO-like lesions when injected alone, but does so after the induction of T cell-mediated experimental autoimmune encephalomyelitis or when co-injected with human complement.

Recent studies implicate the cerebellum in cognitive functions in addition to its well-established roles in motor control and learning. Using a memory-based smooth-pursuit task that separates visual working memory from motor preparation and execution, monkeys were trained to pursue (i.e., go) or not pursue (i.e., no-go), a cued direction, based on the working memory of visual motion-direction and a go/no-go instruction. Task-related neuronal activity was examined in cerebral and cerebellar major smooth-pursuit pathways. Different cerebral and cerebellar areas carried distinctly different signals during memory-based smooth-pursuit. In the cerebellum, prediction-related signals (visual working memory, pursuit selection and movement preparation) were represented in the vermal lobules VI-VII and caudal fastigial nucleus, whereas the floccular region (flocculus and ventral paraflocculus) contained predominantly execution-related signals. This task was applied to patients with cerebellar degeneration and idiopathic Parkinson's disease (PD). None of the PD patients tested exhibited impaired working memory of motion-direction and/or go/no-go selection, but they did show task-specific difficulty in generating an initial smooth-pursuit component, suggesting difficulty in smooth-pursuit preparation. In contrast, most cerebellar patients exhibited impaired visual working memory in addition to difficulty in preparing for and executing smooth-pursuit. These results suggest different roles for the basal ganglia and cerebellum in smooth-pursuit planning.

Using a memory-based smooth-pursuit task, macaque monkeys were trained to pursue (i.e., go) or not pursue (i.e., no-go), a cued direction, based on the memory of visual motion-direction and a go/no-go instruction. Task-related neuronal activity was examined in the supplementary eye fields, caudal frontal eye fields, cerebellar floccular region, dorsal vermis lobules VI-VII, and caudal fastigial nuclei. Different cerebral and cerebellar areas carried distinctly different signals during memory-based smooth pursuit. Chemical inactivation of these areas produced effects consistent with the differences in signals represented in each area. This task was applied to patients with idiopathic Parkinson's disease (PD), because impaired visual working memory has been reported during cognitive tasks in PD. None of the PD patients tested exhibited impaired working memory of motion-direction and/or go/no-go selection, but they had difficulty in preparing for and executing smooth-pursuit eye movements, suggesting a selective motor-related disturbance in Parkinson's disease.

Fluid shear stress plays a critical role in the regulation of vascular biology and its pathology, such as atherosclerosis, via modulation of redox balance. Both pro-atherogenic (either oscillatory or turbulent, nonunidirectional) shear stress and anti-atherogenic (either steady or pulsatile, unidirectional laminar) shear stress stimulate production of reactive oxygen species (ROS) and reactive nitrogen species (RNS) that are involved in signal transduction of gene expression. Nonunidirectional shear stress induces pro-atherogenic genes encoding adhesion molecules and chemokines in a manner dependent on production of both superoxide and nitric oxide. Steady or pulsatile laminar shear stress induces expression of genes encoding cytoprotective enzymes for glutathione biosynthesis and detoxification, which are regulated by the transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2). We show that pulsatile laminar shear stress (PLSS)-induced expression of adhesion molecules and chemokines was enhanced in human umbilical vein endothelial cells (HUVEC) treated with Nrf2 siRNA and arterial endothelial cells isolated from Nrf2 knockout mice. Hence, we propose the hypothesis that PLSS maintains the endothelium in an anti-atherogenic state via intracellular antioxidant levels increased as a result of Nrf2 activation, thereby preventing excess ROS/RNS production required for pro-atherogenic gene expression.

閉塞性大腸炎は大腸の閉塞病変の口側にびらんや潰瘍などが生じる非特異的炎症性疾患であるが，閉塞病変のために術前診断は困難とされる．今回われわれは，術前診断に難渋した閉塞性大腸炎合併S状結腸癌の1例を経験したので報告する．症例は64歳，男性．便秘・腹痛，高度貧血で前医入院中に，敗血症性ショックになり転院搬送，人工呼吸器管理となった．全身検索を行うもスコープが通過する程度の狭窄を伴うS状結腸癌以外には明らかな疾患はなかった．耐術可能となった緊急入院後60日目に手術を行った．術中所見で，横行結腸中央部の漿膜面まで閉塞性大腸炎を疑う所見があり，同部位まで切除範囲に含めて拡大結腸左半切除術を行った．病理結果は，SE，N1（1/58）で，H0，M0，P0，f Stage IIIaであった．癌の口側に広汎に閉塞性大腸炎を認め，その潰瘍部位に核内封入体を認めた．サイトメガロウイルス感染の合併が重症化の一因と考えられた．

患者は69歳，男性．2006年9月肝細胞癌に対し肝右葉切除術を施行した．2007年10月のCTにて残肝S2に結節影を認め，肝細胞癌の再発と考え手術予定とした．また，この時のCTで膵尾部の周囲に嚢胞状腫瘤を認めた．2007年12月突然心窩部痛が出現した．CTにて嚢胞状腫瘤の急激な増大を認めた．経皮的に腫瘍を穿刺したところ，内容物は血性であった．進行するDICも認めたため，急速に進行する膵原発の悪性腫瘍と考え，緊急で膵体尾部切除術を施行した．また，肝外側区域の結節に対し，肝部分切除術を施行した．膵尾部の腫瘍は病理組織所見にて退形成性膵管癌（多形細胞癌）と診断され，肝腫瘍は退形成膵管癌の転移と診断された．術後の経過は良好で退院したが，術後71日目再発を認めた．その後全身状態が急激に悪化し，術後92日目に死亡した．

This study evaluated the protective role of p38 mitogen-activated protein kinase (p38 MAPK) inhibitors and sequestosome 1 (Sqstm1/A170/p62), a stress-induced signal modulator, in acoustic injury of the cochlea in mice. Two weeks after the exposure of mice to acoustic stress, threshold shifts of the auditory brainstem response (ABR) from the pre-exposure level and hair cell loss were evaluated. The activation of p38 MAPK was observed in cochlea by immunostaining 4 h after acoustic stress. To examine the role of p38 MAPK in tissue injury, its inhibitors were i.p. injected into male wild-type C57BL mice before the acoustic overexposure. The inhibitors SB202190 and SB203580 but not the inactive analogue SB202474 dose-dependently decreased the auditory threshold shift and outer hair cell loss induced by acoustic overexposure, suggesting the involvement of p38 MAPK in ototoxicity. We found that acoustic overexposure induced the up-regulation of Sqstm1 mRNA expression in the cochlea of wild-type mice and that SQSTM1-deficient mice exhibited an enhanced ABR threshold shift and hair cell loss, suggesting a role of SQSTM1 in the protection of tissue from acoustic stress.

application/pdf, The anticancer agent cis-diamminedichloroplatinum (cisplatin) is a first-line chemotherapeutic agent for oral cancer. Cell exposure to cisplatin is associated with increased oxidative stress and post-translational changes in components of apoptosis pathways, including p38 Mitogen-activated protein kinase (MAPK), c-Jun-NH2-kinase (JNK), and extracellular signal-regulated kinase (ERK). Peroxiredoxin (Prx) I is an oxidative stress-inducible protein expressed in many tissues and important for reducing reactive oxygen species in vivo; however, whether Prx I helps protect cells from cisplatin injury is unknown. In this report, we examined the effects of Prx I on cell sensitivity to cisplatin-induced apoptosis. Mouse embryo fibroblasts (MEFs) derived from Prx I-deficient mice showed increased cisplatin-induced apoptosis compared with wild-type MEFs. Cisplatin treatment also led to increased activation of p38 MAPK and JNK, and reduced ERK phosphorylation in Prx I-deficient MEFs compared with wild-type MEFs. Furthermore, JNK- and ERK-specific inhibitors protected the Prx I-deficient MEFs from cisplatin-induced apoptosis, but Prx I-deficient MEFs remained more sensitive than wild-type MEFs when treated with a p38 MAPK-specific inhibitor. These findings indicate that Prx I modulates the cisplatin-evoked activation of MAPKs that lead to apoptosis, and Prx I may thus represent a useful target as a protective therapy against cisplatin cytotoxicity.

The transcription factor Nrf2 is a key regulator for hepatic induction of detoxifying enzymes, antioxidative stress genes and Mrp efflux transporters. We aimed to investigate whether Nrf2 activation counteracts liver injury associated with cholestasis. The role of Nrf2 activation in counteracting cholestatic liver injury was studied using a bile duct-ligation (BDL) model of Keap1 gene-knockdown (Keap1-kd) mice that represent the sustained activation of Nrf2 in the liver. Upon Nrf2 activation, Keap1-kd mice showed large increases in Mrp efflux transporters, detoxifying enzymes and antioxidative stress genes in the livers. After BDL, the number of hepatic parenchymal necrosis and the reactive oxygen species content were significantly smaller in the livers of the Keap1-kd mice than in those of the WT mice. Moreover, the increase in serum bilirubin levels was attenuated in the Keap1-kd mice. In conclusion, the results suggest a hepatoprotective role of sustained Nrf2 activation against liver injury associated with cholestasis.

Peroxiredoxin (Prx) I, a ubiquitous antioxidant enzyme, is known to protect against inflammation; however, its role in the allergic inflammation remains unidentified. We determined whether intristic Prx I protects against allergic asthma traits using Prx-I knockout (-/-) mice. Prx I (-/-) and wild-type (WT) mice were immunized with ovalbumin (OVA) plus aluminum potassium sulfate (Alum: Th2 adjuvant) and subsequently challenged with OVA. Twenty-four hours after the last OVA challenge, leukocyte influx including eosinophils into bronchoalveolar lavage fluid was significantly greater in Prx I (-/-) mice compared to that in WT mice. On the other hand, when these mice were immunized with OVA+complete Freund's adjuvant (Th1 adjuvant), opposite phenomenon was observed. In the presence of OVA/Alum, peribronchial inflammatory leukocyte infiltration, cholinergic airway resistance, and the lung expression of interleukin (IL)-2 were significantly greater and that of interferon-gamma was significantly lesser in Prx I (-/-) than in WT mice. In vitro, OVA/Alum-sensitized Prx I (-/-) T cells proliferated more profoundly than WT T cells when they were cocultured with syngeneic bone marrow-generated dendritic cells. These results indicate that endogenous Prx I protects against allergen-related Th2-type airway inflammation and hyperresponsiveness, at least partly, via the suppression of the lung expression of IL-2 and regulation of the Th1/Th2 balance in addition to its antioxidative properties. Furthermore, Prx I can inhibit allergen-specific T-cell proliferation through immunological synapse. Our findings implicate an alternative therapeutic value of Prx I in the treatment of Th2-skewed allergic airway inflammatory diseases such as atopic asthma.

Deficiency in the signal adaptor protein sequestosome 1 (SQSTM1/A170/p62) in mice is associated with mature-onset obesity, accompanied by insulin and leptin resistance. We previously established that redox sensitive transcription factor Nrf2 up-regulates SQSTM1 expression in response to atherogenic stimuli or laminar shear stress in vascular cells, and here examine the role of SQSTM1 in neointimal hyperplasia and vascular remodelling in vivo following carotid artery ligation. Neointimal hyperplasia was markedly enhanced at ligation sites after 3 weeks in SQSTM1(-/-) compared with wild-type (WT) mice. The intimal area and stenotic ratio were, respectively, 2.1- and 1.7-fold higher in SQSTM1(-/-) mice, indicating enhanced proliferation of vascular smooth muscle cells (SMCs). When aortic SMCs were isolated from WT and SQSTM1(-/-) mice and cultured in vitro, we found that SQSTM1(-/-) SMCs proliferated more rapidly in response to foetal calf serum (FCS) and attained 2-3-fold higher cell densities compared to WT SMCs. Moreover, migration of SQSTM1(-/-) SMCs was enhanced compared to WT SMCs. Early and late phases of p38(MAPK) activation in response to FCS stimulation were also more enhanced in SQSTM1(-/-) SMCs, and inhibitors of p38 and ERK1/2 signalling pathways significantly attenuated SMC proliferation. In summary, SQSTM1(-/-) mice exhibit enhanced neointimal hyperplasia and vascular remodelling following arterial ligation in vivo. The enhanced proliferation of SQSTM1(-/-) aortic SMCs in vitro highlights a novel role for SQSTM1 in suppressing smooth muscle proliferation following vascular injury.

Idiopathic plasmacytic lymphadenopathy (IPL) with polyclonal hypergammaglobulinemia has been proposed as a new disease entity resembling the plasma cell type of multicentric Castleman's disease. Here, we report a case of IPL accompanied by renal failure and skin involvement. A 35-year-old man was admitted for advanced renal failure, anemia, systemic lymphadenopathy and skin rashes. Laboratory examinations indicated polyclonal hypergammaglobulinemia and elevated serum interleukin-6 (IL-6). Biopsy of a cervical lymph node revealed follicular hyperplasia with normal germinal centers, sheets of polyclonal proliferating plasma cells and the absence of marked proliferation of blood vessels in the interfollicular area. Lesions of the kidney and skin also had pathological characteristics of IPL. Following a diagnosis of IPL, corticosteroid therapy successfully improved the anemia and hypergammaglobulinemia, and serum IL-6 levels decreased to a normal range. This case may give suggestions about diagnosing and preventing the progression of complications from this disease entity.

Although it has been generally believed that parturients have delayed gastric emptying during anesthesia, the most recent reports suggest that gastric emptying is not delayed during pregnancy except during labor. Electrical slow waves in the stomach determine the frequency and the peristaltic nature of gastric contractions. In this study we performed electrogastrography during and after elective cesarean section (CS) in an attempt to evaluate gastric motility.Sixteen American Society of Anesthesiologists physical status I or II term parturients undergoing elective CS were enrolled. Combined spinal-epidural anesthesia was initiated with 10 mg of bupivacaine plus 10 microg of fentanyl. Four-channel electrogastrography was obtained for 10 min prior to venous catheter insertion (baseline), 10 min following spinal injection of bupivacaine and fentanyl (Sp-1), 10 to 20 min following spinal injection (Sp-2), 10 min prior to the end of operation (end), and finally 10 min on the seventh postoperative day (POD 7).The mean +/- SD values for dominant frequency of electrogastrography (DF) were determined as: 1.57 +/- 0.36 cpm (baseline), 1.81 +/- 0.32 cpm (Sp-1), 2.08 +/- 0.36 cpm (Sp-2), 1.96 +/- 0.36 cpm (end), and 3.02 +/- 0.28 cpm (POD 7). The DF of Sp-1, Sp-2, and end were significantly higher than that of baseline (P0.05). The DF of POD 7 was significantly higher than that of baseline, Sp-1, Sp-2, and end (P0.01).Electrogastrography analysis suggests that the frequency of gastric contractions during CS was less than that in the postpartum period.

背景·目的: 病院輸血部門は血液センターと輸血使用現場を中継する位置にあり，危機的出血発生時には迅速な対応が要求される．今回，病院輸血部門の体制をアンケート調査し，危機的出血発生時の対応における問題点を明らかにした． 対象·方法: 病床数500床以上の麻酔科認定病院385施設を対象とし，2007年11月に調査を実施した． 成績: 輸血管理体制はほぼ整備されていたが，緊急輸血や大量輸血時への対応マニュアルの記載内容は不十分であった．危機的出血への対応ガイドライン（危機的出血GL）は認識されていたが，院内周知は不足していた．異型適合血使用を阻む要因が多々あった．輸血検査の所要時間，緊急出庫要請から使用可能になるまでの時間は，時間外で延長していた．血液センターからの緊急搬送時間は，時間内·時間外で変わらなかった．過去1年間に未交差同型血の使用実績がある施設は時間内，時間外とも43%，異型適合血に関しては時間内24%，時間外28%であった． 結論: 危機的出血GLなどを参考に危機的出血発生時の院内手順を定め，異型適合血使用に対する啓発活動を行う必要がある．危機的出血発生時には，状況を迅速に判断し，未交差同型血や異型適合血の使用を躊躇しないことが必要である．

The protective action of ursodeoxycholic acid (UDCA) in cholestatic liver diseases may be mediated by choleresis, detoxification, and cytoprotection against oxidative stress. Nrf2, one transcription factor, serves as a cellular stress sensor and is a key regulator for hepatic induction of detoxifying enzymes, antioxidative stress genes, and numerous Mrp family members. We aimed to investigate whether UDCA induces hepatic Mrp expression along with that of detoxifying enzymes and antioxidative stress genes via the Nrf2 transcriptional pathway. The protein level, subcellular localization, and mRNA level of Mrp family members were assessed in livers of Keap1 gene-knockdown ( Keap1-kd) mice and those of UDCA-fed wild-type (WT) and Nrf2 gene-null ( Nrf2-null) mice. Nuclear levels of Nrf2 in livers of Keap1-kd mice markedly increased, resulting in constitutive activation of Nrf2. Keap1-kd mice have high-level expression of hepatic Mrp2, Mrp3, and Mrp4 relative to WT mice. UDCA potently increased nuclear Nrf2 expression level in livers of WT mice, and the treatment showed maximal hepatic induction of Mrp2, Mrp3, and Mrp4 in association with enhanced membranous localizations in an Nrf2-dependent manner. UDCA similarly increased nuclear Nrf2 expression level in rat hepatocytes. Chromatin immunoprecipitation assays using mouse hepatocytes revealed the binding of Nrf2 to antioxidant response elements in the promoter regions of Mrp2, Mrp3, and Mrp4. These findings demonstrate an important role of Nrf2 in the induction of Mrp family members in livers and suggest that a therapeutic mechanism of UDCA action is, via Nrf2 activation, a stimulation of detoxification and antioxidative stress systems, along with Mrp-mediated efflux transport.

During off-pump coronary artery bypass (OPCAB), the displacement of the heart causes mitral regurgitation. We hypothesized that patients with impaired left ventricle (LV) function would be more prone to develop mitral regurgitation, due to further LV end-diastolic pressure elevation and mitral annulus distortion. Therefore, in this study, we examined the relationship between LV function and the severity of mitral regurgitation.We studied 41 patients undergoing elective OPCAB. LV function was evaluated by LV ejection fraction (LVEF), serum brain natriuretic peptide (BNP) levels, the Tei index (myocardial performance index) and mitral inflow propagation velocity (Vp).Among all of the anastomoses performed mitral regurgitation was most severe during anastomosis of the left circumflex artery (LCX) territory (P0.001). Twenty-five patients (61%) had no to mild mitral regurgitation during anastomosis of the LCX territory (M-MR group) and 16 patients (39%) had moderate to severe mitral regurgitation during anastomosis of the LCX territory (S-MR group). There were significant differences between these groups in preoperative serum BNP levels (median, 26 pg.ml(-1) interquartile range [IQR, 14 to 75 pg.ml(-1)] versus median, 173 pg.ml(-1) [IQR, 91 to 296 pg.ml(-1)]; P0.001), Tei index values (median, 0.35; [IQR, 0.27 to 0.41] versus median, 0.53 [IQR, 0.47 to 0.57]; P0.001), and Vp (median, 63 cm.s(-1); [IQR, 57 to 72 cm.s(-1)] versus median, 47 cm.s(-1); [IQR, 40 to 57 cm.c(-1)]; P = 0.008), while there was no significant difference in LVEF between the patients in the M-MR group and those in the S-MR group.Preoperative LV dysfunction is a predictor of severe mitral regurgitation during OPCAB. When poor LV function is suggested, it is necessary to be prepared for further hemodynamic deterioration caused by mitral regurgitation.

Heme oxygenase-1 (HO-1) is markedly upregulated by sodium arsenite and previous studies implicated the transcriptional enhancers Nrf2 and AP-1 in arsenite-induced ho-1 gene expression in murine cells. To further evaluate the role of Nrf2 and its signalling pathway in the induction of HO-1 in response to low levels of arsenite, this paper studied wild-type and Nrf2-deficient murine embryonic fibroblasts. It was found that Nrf2 plays a crucial role in the early activation of ho-1 transcription and that increased Nrf2 levels returned to basal levels within 24 h. In Nrf2(-/-) cells, HO-1 gene activation increased gradually and HO-1 protein levels were approximately half of those attained in Nrf2(+/+) cells. The tyrosine kinase inhibitor genistein and JNK inhibitor SP600125 significantly attenuated arsenite induced increases in ho-1 mRNA levels in Nrf2 deficient cells but had negligible effects on Nrf2 activation, suggesting tyrosine kinase/JNK/c-Jun plays a key role in the HO-1 upregulation via AP-1.

先天性横隔膜ヘルニア (CDH) 合併児では, 啼泣やマスク換気による胸腔内消化管への空気の流入や, 意識下挿管のストレスによる肺血管抵抗の増大を避けるため, 当院では無呼吸状態で娩出後, ただちに気管挿管し, 高頻度振動換気下に一酸化窒素吸入療法を行っている. レミフェンタニルは胎盤通過性が高く, 胎児麻酔において有利な可能性がある. CDHを合併する予定帝王切開術9症例をプロポフォールとレミフェンタニルによる全静脈麻酔で行った. レミフェンタニルは子宮漿膜切開時より胎児娩出時まで増量した. この麻酔では, 娩出後の啼泣・呼吸がなく, 娩出児の気管挿管も容易で, 有用な方法と思われた.