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Gender and menopause influence the severity and development manner of nonalcoholic steatohepatitis (NASH). Male p62/Sqstm1 and nuclear factor E2-related factor-2 (p62 and Nrf2) double-knockout (DKO) mice exhibit severe steatohepatitis caused by hyperphagia-induced obesity, overload of lipopolysaccharide (LPS) into the liver, and potentiation of the inflammatory response in Kupffer cells. However, the pathogenetic phenotype of steatohepatitis in female DKO mice remains unknown. Phenotypic changes of steatohepatitis in DKO mice were compared in terms of gender differences. Compared with DKO male mice, DKO female mice exhibited later onset of steatohepatitis with obesity after 30 weeks of age, as well as milder severity of hepatic inflammation and fibrosis. Serum estradiol was higher in female than male mice, with levels increasing up to 30 weeks of age before decreasing until 50 weeks of age (corresponding to the post-menopausal period). Fecal and serum LPS were lower in female mice than male mice, and inflammatory signaling in the liver was attenuated in female compared with male mice. Correlating with LPS levels, the composition of intestinal microbiota in female mice was different from male mice. Gender differences were observed for the development of steatohepatitis in DKO mice. Low-grade inflammatory hit in the liver under in vivo conditions of high estradiol may be attributable to the milder pathological features of steatohepatitis in female mice.

Non-alcoholic fatty liver disease (NAFLD) constitutes a metabolic disorder with high worldwide prevalence and increasing incidence. The inflammatory progressive state, non-alcoholic steatohepatitis (NASH), leads to liver fibrosis and carcinogenesis. Here, we evaluated whether tyrosinase mutation underlies NASH pathophysiology. Tyrosinase point-mutated B6 (Cg)-Tyrc-2J/J mice (B6 albino) and C57BL/6J black mice (B6 black) were fed with high cholesterol diet (HCD) for 10 weeks. Normal diet-fed mice served as controls. HCD-fed B6 albino exhibited high NASH susceptibility compared to B6 black, a phenotype not previously reported. Liver injury occurred in approximately 50% of B6 albino from one post HCD feeding, with elevated serum alanine aminotransferase and aspartate aminotransferase levels. NASH was induced following 2 weeks in severe-phenotypic B6 albino (sB6), but B6 black exhibited no symptoms, even after 10 weeks. HCD-fed sB6 albino showed significantly higher mortality rate. Histological analysis of the liver revealed significant inflammatory cell and lipid infiltration and severe fibrosis. Serum lipoprotein analysis revealed significantly higher chylomicron and very low-density lipoprotein levels in sB6 albino. Moreover, significantly higher small intestinal lipid absorption and lower fecal lipid excretion occurred together with elevated intestinal NPC1L1 expression. As the tyrosinase point mutation represents the only genetic difference between B6 albino and B6 black, our work will facilitate the identification of susceptible genetic factors for NASH development and expand the understanding of NASH pathophysiology.

Microgravity induces skeletal muscle atrophy, particularly in the soleus muscle, which is predominantly composed of slow-twitch myofibre (type I) and is sensitive to disuse. Muscle atrophy is commonly known to be associated with increased production of reactive oxygen species. However, the role of NRF2, a master regulator of antioxidative response, in skeletal muscle plasticity during microgravity-induced atrophy, is not known. To investigate the role of NRF2 in skeletal muscle within a microgravity environment, wild-type and Nrf2-knockout (KO) mice were housed in the International Space Station for 31 days. Gene expression and histological analyses demonstrated that, under microgravity conditions, the transition of type I (oxidative) muscle fibres to type IIa (glycolytic) was accelerated in Nrf2-KO mice without affecting skeletal muscle mass. Therefore, our results suggest that NRF2 affects myofibre type transition during space flight., Hayashi et al. report on the effect of space flight on muscle mass, fibre size and type, composition and gene signalling of muscle in WT and Nrf2-KO mice. Their results demonstrate a key role of NRF2 in maintaining the slow-type fibres of soleus muscle during space flight and in microgravity environments.

Exercise ameliorates nonalcoholic fatty liver disease (NAFLD) by inducing phenotypic changes in Kupffer cells (KCs). p62/Sqstm1‐knockout (p62‐KO) mice develop NAFLD alongside hyperphagia‐induced obesity. We evaluated (1) the effects of long‐term exercise on the foreign‐body phagocytic capacity of KCs, their surface marker expression, and the production of steroid hormones in p62‐KO mice; and (2) whether long‐term exercise prevented the development of non‐alcoholic steatohepatitis (NASH) in p62‐KO mice fed a high‐fat diet (HFD). In experiment 1, 30‐week‐old male p62‐KO mice were allocated to resting (p62‐KO‐Rest) or exercise (p62‐KO‐Ex) groups, and the latter performed long‐term exercise over 4 weeks. Then, the phenotype of their KCs was compared to that of p62‐KO‐Rest and wild‐type (WT) mice. In experiment 2, 5‐week‐old male p62‐KO mice that were fed a HFD performed long‐term exercise over 12 weeks. In experiment 1, the phagocytic capacity of KCs and the proportion of CD68‐positive cells were lower in the p62‐KO‐Rest group than in the WT group, but they increased with long‐term exercise. The percentage of CD11b‐positive KCs was higher in the p62‐KO‐Rest group than in the WT group, but lower in the p62‐KO‐Ex group. The circulating dehydroepiandrosterone (DHEA) concentration was higher in p62‐KO‐Ex mice than in p62‐KO‐Rest mice. In experiment 2, the body mass and composition of the p62‐KO‐Rest and p62‐KO‐Ex groups were similar, but the hepatomegaly, hepatic inflammation, and fibrosis were less marked in p62‐KO‐Ex mice. The DHEA concentration was higher in p62‐KO‐Ex mice than in WT or p62‐KO‐Rest mice. Thus, long‐term exercise restores the impaired phagocytic capacity of KCs in NAFLD obese mice, potentially through greater DHEA production, and prevents the development of NASH by ameliorating hepatic inflammation and fibrogenesis. These results suggest a molecular mechanism for the beneficial effect of exercise in the management of patients with NAFLD., Long‐term running exercise by a high fat diet‐fed hyperphagic obese mice (p62‐KO mice) prevented the development of hepatic inflammation and fibrosis in non‐alcoholic steatohepatitis, via the restoration of foreign‐body phagocytic capacity and induction of phenotypic changes in the Kupffer cells.

The patient was a 74-year-old woman with rheumatoid arthritis who developed ataxia. MRI revealed T2-hyperintense lesions predominantly in the left middle cerebellar peduncle. Punctate or linear Gd enhancement was also observed on T1-weighted images. A brain biopsy was conducted and the pathology revealed a mild demyelinated lesion. Polymerase chain reaction (PCR) of biopsied brain tissues revealed the presence of JC virus (JCV) DNA, but JCV-infected oligodendroglia-like cells were not apparent on immunohistochemistry. Sensitive in-situ hybridization, however, detected three JCV-positive cells and the infiltration of CD4+ and CD8+ T cells and plasma cells was also observed. Immunosuppressants were tapered off and mirtazapine and mefloquine administered, resulting in a favorable outcome.

We report the case of a middle-aged woman who developed trigeminal neuralgia as a sequela of multiple sclerosis (MS). The trigeminal neuralgia was refractory to medications and persisted for two years. Eventually, it was resolved by a mandibular nerve block followed by natalizumab administration. The pain was controlled for 23 months, and additional nerve blocks were not required during this period. It has been previously reported that natalizumab therapy improves the Expanded Disability Status Scale (EDSS) scores and health-related quality of life in patients with MS. In the present case, natalizumab may have prolonged the effect of the mandibular nerve block and consequently improved the patient's quality of life.

The slowness in Parkinson's disease has been considered to be due to the impairment of movement initiation. Studies of gait in Parkinson's disease investigating EMG off/on latencies from a static posture to the initiation of movement have found unsynchronized off/on latencies in a homogeneous movement, which was correlated statistically with the slow gait speed of bradykinesia. Thus, the slowness was due to the difficulty in terminating the motor program controlling the primary posture. The previous studies concerning impairment of the sequential movements in Parkinson's disease have indicated that bradykinesia is involved in switching the sequence within on/on-latency interval of heterogeneous movements. These recent results elucidate that bradykinesia is involved in the impaired two sensory-motor functions. One is difficulty with the termination of the prior competitive motor program that had been activated in a past time within off/on-latency interval of homogeneous movement. The next is the difficulty in switching to the uncompetitive ongoing motor program sequentially within on/on-latency interval of heterogeneous movements.

Background The role of B cells in the pathogenesis of multiple sclerosis (MS) is a subject of much research. We report a case of a MS patient who presented with subacute diffuse lesions in the limbic system and short-term memory loss. Case presentation A male patient had experienced numbness in the left upper extremity at the age of 17 years, but this disappeared without treatment. At 19 years-of-age, he developed subacute short-term memory loss followed by paralysis and sensory disturbance in the left upper and lower extremities. Magnetic resonance brain fluid-attenuated/T2-weighted imaging showed diffuse high-intensity lesions in the medial parts of both temporal lobes, and spotty multiple lesions in the periventricular and subcortical white matter. Twenty days later, a new lesion was observed around the right putamen, and the temporal lesions had disappeared. A symptomatic cervical lesion with gadolinium enhancement was observed at C3. This lesion involved just one vertebral segment. Cerebrospinal fluid analysis showed no pleocytosis or elevated protein levels, but did show oligoclonal immunoglobulin G bands. No antibodies against aquaporin-4 or myelin oligodendrocyte glycoprotein were detected in the serum, and anti-N-methyl-D-aspartate receptor was not detected in the cerebrospinal fluid. We diagnosed the patient with MS despite the atypical diffuse lesions in the limbic system and the short-term memory loss. Corticosteroid medication effectively treated the symptoms in his extremities and his impaired memory. Conclusions The present case shows that cortical lesions can occur in MS patients and might be induced by B cell-mediated mechanisms.

Nonalcoholic steatohepatitis (NASH) is one of the leading causes of chronic liver disease worldwide. However, details of pathogenetic mechanisms remain unknown. Deletion of both p62/Sqstm1 and Nrf2 genes spontaneously led to the development of NASH in mice fed a normal chow and was associated with liver tumorigenesis. The pathogenetic mechanism (s) underlying the NASH development was investigated in p62:Nrf2 double-knockout (DKO) mice. DKO mice showed massive hepatomegaly and steatohepatitis with fat accumulation and had hyperphagia-induced obesity coupled with insulin resistance and adipokine imbalance. They also showed dysbiosis associated with an increased proportion of gram-negative bacteria species and an increased lipopolysaccharide (LPS) level in feces. Intestinal permeability was elevated in association with both epithelial damage and decreased expression levels of tight junction protein zona occludens-1, and thereby LPS levels were increased in serum. For Kupffer cells, the foreign body phagocytic capacity was decreased in magnetic resonance imaging, and the proportion of M1 cells was increased in DKO mice. In vitro experiments showed that the inflammatory response was accelerated in the p62:Nrf2 double-deficient Kupffer cells when challenged with a low dose of LPS. Diet restriction improved the hepatic conditions of NASH in association with improved dysbiosis and decreased LPS levels. The results suggest that in DKO mice, activation of innate immunity by excessive LPS flux from the intestines, occurring both within and outside the liver, is central to the development of hepatic damage in the form of NASH.

We treated a myelin oligodendrocyte glycoprotein (MOG) antibody disease patient who had been prescribed dimethyl fumarate because she was thought to have been suffering from multiple sclerosis (MS). Mild optic neuritis relapsed at one year and four months after the administration of dimethyl fumarate. Therefore, dimethyl fumarate was ineffective for preventing relapse of MOG antibody disease. However, dimethyl fumarate for MOG antibody disease was not harmful compared with when disease-modifying drugs (DMDs) of MS were used for anti-aquaporin-4 antibody-positive neuromyelitis optica. If MS patients repeat relapses even after the start of DMDs, a differential diagnosis including MOG antibody disease should be made.

This study in Parkinson's disease examined how spatiotemporal parameters in gait bradykinesia link to difficulty in terminating posture and initiating gait locomotion. 41 idiopathic Parkinson's disease patients and 15 age-matched healthy subjects participated in this study. After the patients fixated on a visual-fixation-target, gait was triggered by visual or vocal cue-stimulus. The LED instructed subjects to quickly achieve their own comfortable walking speed on a level floor. The posterior-anterior force of the y-axis vectors of sole relating to soleus and tibialis-anterior EMGs were examined. Step-gain was defined as the duration of the swing-phase relative that of the contralateral stance-phase. Dynamic-ratio was defined as the duration the fore-foot phase relative to that of the ipsilateral stance-phase as forward-oriented movement in each step. The pause in tonic soleus EMG was defined as the off-latency of posture (termination) and the onset of a tibialis-anterior EMG-burst as the on-latency of gait. In Parkinson's disease, soleus off-latencies were prolonged, whereas tibialis-anterior on-latencies were less prolonged. Unsynchronized off/on-latency differences correlated with spatiotemporal parameters of dynamic-ratios, step-gains, gait-initiation, and gait speed in gait bradykinesia. Delayed EMG off-latencies correlated with prolonged motor-latencies in gait bradykinesia as delayed initial backward body-shift. A delayed and deficient initial backward body-shift of y-axis vector was linked to each difficulty in terminating posture and initiating gait, changing to random gait akinesia. Gait bradykinesia in Parkinson's disease stemmed from unsynchronized off/on-latency EMG activities, linking to each difficulty in terminating posture and initiating gait synergic movement through an initial backward body-shift.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by a selective loss of motor neurons in the brain and spinal cord. Multiple toxicity pathways, such as oxidative stress, misfolded protein accumulation, and dysfunctional autophagy, are implicated in the pathogenesis of ALS. However, the molecular basis of the interplay between such multiple factors in vivo remains unclear. Here, we report that two independent ALS-linked autophagy-associated gene products; SQSTM1/p62 and ALS2/alsin, but not antioxidant-related factor; NFE2L2/Nrf2, are implicated in the pathogenesis in mutant SOD1 transgenic ALS models. We generated SOD1H46R mice either on a Nfe2l2-null, Sqstm1-null, or Sqstm1/Als2-double null background. Loss of SQSTM1 but not NFE2L2 exacerbated disease symptoms. A simultaneous inactivation of SQSTM1 and ALS2 further accelerated the onset of disease. Biochemical analyses revealed that loss of SQSTM1 increased the level of insoluble SOD1 at the intermediate stage of the disease, whereas no further elevation occurred at the end-stage. Notably, absence of SQSTM1 rather suppressed the mutant SOD1-dependent accumulation of insoluble polyubiquitinated proteins, while ALS2 loss enhanced it. Histopathological examinations demonstrated that loss of SQSTM1 accelerated motor neuron degeneration with accompanying the preferential accumulation of ubiquitin-positive aggregates in spinal neurons. Since SQSTM1 loss is more detrimental to SOD1H46R mice than lack of ALS2, the selective accumulation of such aggregates in neurons might be more insulting than the biochemically-detectable insoluble proteins. Collectively, two ALS-linked factors, SQSTM1 and ALS2, have distinct but additive protective roles against mutant SOD1-mediated toxicity by modulating neuronal proteostasis possibly through the autophagy-endolysosomal system.

We report two patients with chronic inflammatory demyelinating polyneuropathy complicated by idiopathic thrombocytopenic purpura. Both of the two diseases successfully responded to intravenous immunoglobulin infusion. A small number of similar patients have been previously reported. Because the immunological mechanism more evidently correlates to these patients than to the entire spectrum of chronic inflammatory demyelinating polyneuropathy, they might form a subgroup unusually responsive to immunomodulating therapy.

Open abdomen management is commonly used for the critically injured patients to avoid abdominal compartment syndrome. But it usually continues for days to weeks and finally results in abdominal wall defect that is too wide to close at once. This article presents an alternative approach to close the giant abdominal wall defect by using the combination of bipedicled flaps with the components separation technique and V.A.C.® system.

In Lewy body disease (LBD) such as dementia with LBs and Parkinson's disease, several lines of evidence show that disrupted proteolysis occurs. p62/SQSTM1 (p62) is highly involved with intracellular proteolysis and is a component of ubiquitin-positive inclusions in various neurodegenerative disorders. However, it is not clear whether p62 deficiency affects inclusion formation and abnormal protein accumulation. To answer this question, we used a mouse model of LBD that lacks p62, and found that LB-like inclusions were observed in transgenic mice that overexpressed α-synuclein (Tg mice) with or without the p62 protein. p62 deficiency enhanced α-synuclein pathology with regard to the number of inclusions and staining intensity compared with Tg mice that expressed p62. To further investigate the molecular mechanisms associated with the loss of p62 in Tg mice, we assessed the mRNA and protein levels of several molecules, and found that the neighbor of the brca1 gene (NBr1), which is functionally and structurally similar to p62, is increased in Tg mice without p62 compared with control Tg mice. These findings suggest that p62 and NBR1 affect the pathogenesis of neurodegenerative diseases through the cooperative modulation of α-synuclein aggregation.

The failure of Kupffer cells (KCs) to remove endotoxin is an important factor in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). In this study, the effects of exercise training on KC function were studied in terms of in vivo endotoxin clearance and inflammatory responses. Mice were allocated into rest and exercise groups. KC bead phagocytic capacity and plasma steroid hormone levels were determined following exercise training. Endotoxin and inflammatory cytokine levels in plasma were determined over time following endotoxin injection. KC bead phagocytic capacity was potentiated and clearance of exogenously-injected endotoxin was increased in the exercise group. Inflammatory cytokine (TNF-α and IL-6) levels were lower in the exercise group. We found that only DHEA was increased in the plasma of the exercise group. In an in vitro experiment, the addition of DHEA to RAW264.7 cells increased bead phagocytic capacity and attenuated endotoxin-induced inflammatory responses. These results suggest that exercise training modulates in vivo endotoxin clearance and inflammatory responses in association with increased DHEA production. These exercise-induced changes in KC capacity may contribute to a slowing of disease progression in NAFLD patients.

This study examined how gait bradykinesia is changed by the motor programming in Parkinson’s disease. Thirty-five idiopathic Parkinson’s disease patients and nine age-matched healthy subjects participated in this study. After the patients fixated on a visual-fixation target (conditioning-stimulus), the voluntary-gait was triggered by a visual on-stimulus. While the subject walked on a level floor, soleus, tibialis anterior EMG latencies, and the y-axis-vector of the sole-floor reaction force were examined. Three paradigms were used to distinguish between the off-/on-latencies. The gap-task: the visual-fixation target was turned off; 200 ms before the on-stimulus was engaged (resulting in a 200 ms-gap). EMG latency was not influenced by the visual-fixation target. The overlap-task: the on-stimulus was turned on during the visual-fixation target presentation (200 ms-overlap). The no-gap-task: the fixation target was turned off and the on-stimulus was turned on simultaneously. The onset of EMG pause following the tonic soleus EMG was defined as the off-latency of posture (termination). The onset of the tibialis anterior EMG burst was defined as the on-latency of gait (initiation). In the gap-task, the on-latency was unchanged in all of the subjects. In Parkinson’s disease, the visual-fixation target prolonged both the off-/on-latencies in the overlap-task. In all tasks, the off-latency was prolonged and the off-/on-latencies were unsynchronized, which changed the synergic movement to a slow, short-step-gait. The synergy of gait was regulated by two independent sensory-motor programs of the off- and on-latency levels. In Parkinson’s disease, the delayed gait initiation was due to the difficulty in terminating the sensory-motor program which controls the subject’s fixation. The dynamic gait bradykinesia was involved in the difficulty (long off-latency) in terminating the motor program of the prior posture/movement.

A man aged 42 years presented with progressive muscle weakness and fasciculation in his legs. He was diagnosed with sporadic amyotrophic lateral sclerosis (ALS) based on clinical and electrophysiological upper and lower motor neuron dysfunction. He presented no obvious cognitive or behavioural impairment indicative of frontotemporal dementia (FTD), although detailed cognitive tests were not performed. When he was 43 years old, he presented with tetraplegia and respiratory failure without extraocular muscle impairment and received a tracheostomy with invasive ventilation (TIV). His first brain MRI at age 43 years showed signs of upper motor neuronal degeneration and global discrete cortical atrophy (figure 1). During the ensuing years, he communicated with others using extraocular movements and did not exhibit any symptoms of obvious dementia. When he was 46 years old, his extraocular muscles became non-functional. He lost his voluntary motor function and communication ability entirely, falling into the so-called ‘totally locked-in state (TLS)’.1 A brain MRI at age 47 years, …

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.

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.

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.

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.

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.

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．

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.

According to studies using animal models of multiple sclerosis (MS), the pathogenesis of Interleukin-1 (IL-1) and the effects of the IL-1 inhibition therapy for MS have been clarified. In both MS and neuromyelitis optica, systemic IL-1 inhibition will be a therapeutic target. However, studies to clarify whether maintenance therapy for MS with IL-1 inhibitor will prevent the next relapse will be needed, because IL-1ra gene therapy after disease onset was not effective in the animal study.

We report two cases of neuromyelitis optica patients with progressive cerebral atrophy. The patients exhibited characteristic clinical features, including elderly onset, secondary progressive tetraparesis and cognitive impairment, abnormally elevated CSF protein and myelin basic protein levels, and extremely highly elevated serum anti-AQP-4 antibody titer. Because neuromyelitis optica pathology cannot switch from an inflammatory phase to the degenerative phase until the terminal phase, neuromyelitis optica rarely appears as a secondary progressive clinical course caused by axonal degeneration. However, severe intrathecal inflammation and massive destruction of neuroglia could cause a secondary progressive clinical course associated with cerebral atrophy in neuromyelitis optica patients.

70歳, 女性。45歳時に左小指爪下の悪性黒色腫に対して, 指切断術を行った (Stage IA)。 術後10年間の経過観察中に局所再発や転移は認められなかった。術後24年目に左乳房に出現した腫瘤を, 当院外科で摘出したところ悪性黒色腫であった。当科へ転科して全身検索を行った結果, 左腋窩リンパ節, 両鼠径リンパ節, 全身の皮下脂肪織, 肺, 肝への転移を認めた。治療はDAC-Tam療法を3コース行った。各リンパ節転移, 皮下脂肪織転移巣および肺転移巣は縮小あるいは消失した。肝転移に対しては, TAEおよびCDDPとIFN-βの肝動注を行ったが, 不変であった。その後の経過中に脳への多発転移が出現し, 不幸な転帰をとった。

A 59-year-old Japanese woman was referred to our hospital due to upper abdominal pain. At the age of 44, she was diagnosed with a congenital choledochal cyst, Todani's type Ic. She then underwent bypass operation with end-to-side choledochojejunostomy with Roux-en-Y technique as well as cholecystectomy. Magnetic resonance cholangiopancreatography revealed an ‘oval’ shaped cystic lesion with a maximal diameter of 25 mm, which had been ‘spindle’ shaped with a maximal diameter of 18 mm, 15 years ago. It also showed an anomalous pancreaticobiliary ductal union. In addition, a complete absence of the dorsal primordia of pancreas was revealed by magnetic resonance image and computed tomography scan. The patient underwent the surgical exploration for the resection of the ‘oval’ shaped cystic lesion. Haematoxylin and eosin staining of the thin section of the resected cyst showed a compact spindle cell pattern which was compatible with schwannoma, Antoni type A, which was confirmed by immunocytochemical technique. We present a very interesting case showing choledochal cyst, anomalous pancreaticobiliary ductal union, total agenesis of the dorsal pancreas and late-development of bile duct schwannoma in the remnant choledochal cyst.

Huntington's disease (HD) is a dominantly inherited genetic disease caused by mutant huntingtin (htt) protein with expanded polyglutamine (polyQ) tracts. A neuropathological hallmark of HD is the presence of neuronal inclusions of mutant htt. p62 is an important regulatory protein in selective autophagy, a process by which aggregated proteins are degraded, and it is associated with several neurodegenerative disorders including HD. Here, we investigated the effect of p62 depletion in three HD model mice: R6/2, HD190QG and HD120QG mice. We found that loss of p62 in these models led to longer life spans and reduced nuclear inclusions, although cytoplasmic inclusions increased with polyQ length. In mouse embryonic fibroblasts (MEFs) with or without p62, mutant htt with a nuclear localization signal (NLS) showed no difference in nuclear inclusion between the two MEF types. In the case of mutant htt without NLS, however, p62 depletion increased cytoplasmic inclusions. Furthermore, to examine the effect of impaired autophagy in HD model mice, we crossed R6/2 mice with Atg5 conditional knockout mice. These mice also showed decreased nuclear inclusions and increased cytoplasmic inclusions, similar to HD mice lacking p62. These data suggest that the genetic ablation of p62 in HD model mice enhances cytoplasmic inclusion formation by interrupting autophagic clearance of polyQ inclusions. This reduces polyQ nuclear influx and paradoxically ameliorates disease phenotypes by decreasing toxic nuclear inclusions.

Idiopathic hypereosinophilic syndrome (IHES) is characterised by persistent eosinophilia and organ damage after ruling out other causes. IHES is clinically and pathologically heterogeneous, and several disease mechanisms have been described. Although neurological involvement with IHES is extremely rare, we report the first cases of acute myelitis with IHES, which are confirmed using MRI, fulfil the diagnostic criteria of IHES and pathologically reveal eosinophilic tissue infiltration in the liver and skin. Patient 1 had longitudinally extensive transverse myelitis, which developed in the absence of steroid therapy. Patient 2 developed acute myelitis with two short lesions during a 3 mg/day corticosteroid treatment. Both cases had eosinophilia (1500/mm(3)) at the onset of myelitis. These findings suggest that earlier treatment and a sufficient dose of corticosteroids may prevent the lesional expansion in acute myelitis. Steroid therapy should be initiated early before organ involvement, because permanent neuronal damage with a larger lesion becomes more critical.