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The V-shaped arrangement of hair bundles on cochlear hair cells is critical for auditory sensing. However, regulation of hair bundle arrangements has not been fully understood. Recently, defects in hair bundle arrangement were reported in postnatal Dishevelled-associating protein (ccdc88c, alias Daple)-deficient mice. In the present study, we found that adult Daple−/− mice exhibited hearing disturbances over a broad frequency range through auditory brainstem response testing. Consistently, distorted patterns of hair bundles were detected in almost all regions, more typically in the basal region of the cochlear duct. In adult Daple−/− mice, apical microtubules were irregularly aggregated, and the number of microtubules attached to plasma membranes was decreased. Similar phenotypes were manifested upon nocodazole treatment in a wild type cochlea culture without affecting the microtubule structure of the kinocilium. These results indicate critical role of Daple in hair bundle arrangement through the orchestration of apical microtubule distribution, and thereby in hearing, especially at high frequencies.

We herein report a case of a 75-year-old woman who presented with a low-grade fever, repeated cold-induced urticaria, and painful leg edemas with neutrocytosis. Because her mother also had cold-induced urticaria and her skin lesions histologically showed neutrophilic dermatitis, we suspected that she had familial cold autoinflammatory syndrome, a subtype of cryopyrin-associated periodic syndromes. Sequencing of the NLRP3 and MEFV genes revealed that she carried both the p.A439V missense mutation and p.E148Q homozygous mutation, which is commonly detected in familial Mediterranean fever patients. The administration of colchicine reduced the frequency and severity of her skin rash and leg edema.

The cochlear efferent feedback system plays important roles in auditory processing, including regulation of the dynamic range of hearing, and provides protection against acoustic trauma. These functions are performed through medial olivocochlear (MOC) neurons. However, the underlying cellular and molecular mechanisms are not fully understood. The serotonin type 3A (5-HT3A) receptor is widely expressed throughout the nervous system, which suggests important roles in various neural functions. However, involvement of the 5-HT3A receptor in the MOC system remains unclear. We used mice in this study and found that the 5-HT3A receptor was expressed in MOC neurons that innervated outer hair cells in the cochlea and was involved in the activation of MOC neurons by noise exposure. 5-HT3A receptor knockout impaired MOC functions, potentiated noise-induced hearing loss, and increased loss of ribbon synapses following noise exposure. Furthermore, 5-HT3 receptor agonist treatment alleviated the noise-induced hearing loss and loss of ribbon synapses, which enhanced cochlear protection provided by the MOC system. Our findings demonstrate that the 5-HT3A receptor plays fundamental roles in the MOC system and critically contributes to protection from noise-induced hearing impairment.

P2X2 receptors are ligand-gated cation channels activated by extracellular ATP that modulate neural transmission in various neuronal systems. Although the function and distribution of P2X2 receptors in the cochlea portion of the inner ear are well established, their physiological role in the vestibular portion is still not understood. Therefore, we investigated P2X2 receptor localization in the peripheral vestibular portion, and assessed their physiological function in vivo using P2X2 receptor knock out (P2X2-KO) mice. Histological analysis revealed that P2X2 receptors were localized on the epithelial surface of supporting and transitional cells of the vestibular end organs. To examine vestibular function in P2X2-KO mice, we conducted behavioral tests and tested the vestibulo-ocular reflex (VOR) during sinusoidal rotations. P2X2-KO mice exhibited significant motor balance impairment in the balance beam test. VOR gain in P2X2-KO mice was significantly reduced, with no decrease in the optokinetic response. In conclusion, we showed that P2X2 receptors are mainly localized in the supporting cells of the vestibular inner ear, and the loss of P2X2 receptors causes mild vestibular dysfunction. Taken together, our findings suggest that the P2X2 receptor plays a modulatory role in vestibular function.

We investigated fibroblast growth factor 12 (FGF12) as a transcript enriched in the inner ear by searching published cDNA library databases. FGF12 is a fibroblast growth factor homologous factor, a subset of the FGF superfamily. To date, its localisation and function in the inner ear have not been determined. Here, we show that FGF12 mRNA is localised in spiral ganglion neurons (SGNs) and the vestibular ganglion. We also show that FGF12 protein is localised in SGNs, the vestibular ganglion, and nerve fibres extending beneath hair cells. Moreover, we investigated FGF12 function in auditory and vestibular systems using Fgf12-knockout (FGF12-KO) mice generated with CRISPR/Cas9 technology. Our results show that the inner ear morphology of FGF12-KO mice is not significantly different compared with wild-type mice. However, FGF12-KO mice exhibited an increased hearing threshold, as measured by the auditory brainstem response, as well as deficits in rotarod and balance beam performance tests. These results suggest that FGF12 is necessary for normal auditory and equilibrium function.

The study of inner ear specific transcripts has revealed novel information about hereditary hearing loss and a mechanism of normal hearing. In this study, by analyzing a published cDNA library, we focused on Epiphycan (Epyc), a member of the small leucine-rich repeat proteoglycan family, whose transcript is enriched in the inner ear. Epyc mRNA was expressed abundantly and specifically in adult mice cochleae and was localized in supporting cells within the organ of Corti of both neonatal and adult mice. To examine the function of Epyc, we generated Epyc knockout (KO) mice using the CRISPR/Cas9 system. Epyc KO mice cochleae exhibited normal morphology. However, measurement of the auditory brain-stem response in Epyc KO mice revealed an elevated hearing threshold above 16 kHz frequency. This study suggests that Epyc is necessary for normal auditory function.

Objective This study was performed to determine whether endolymphatic sac surgery improves vestibular and cochlear endolymphatic hydrops 2 years after sac surgery and to elucidate the relationship between the degree of improvement of endolymphatic hydrops and the changes in vertigo symptoms, the hearing level, and the summating potential/action potential ratio (−SP/AP ratio) by electrocochleography (ECochG) in patients with Meniere’s disease (MD). Methods Twenty-one patients with unilateral MD who underwent sac surgery were included in this study. All patients underwent gadolinium-enhanced magnetic resonance imaging (Gd-MRI) before and 2 years after sac surgery. We evaluated the difference in vestibular and cochlear endolymphatic hydrops between before and after surgery in both ears and compared these findings with the frequency of vertigo attacks, hearing level, and ECochG findings. Results In affected ears, the presence of vestibular endolymphatic hydrops and the frequency of vertigo attacks significantly decreased after surgery. However, affected ears showed no significant improvement in the presence of cochlear endolymphatic hydrops or the −SP/AP ratio by ECochG; there was also no significant improvement or deterioration in the hearing level. Conclusion The present findings suggest that sac surgery reduces vestibular endolymphatic hydrops and prevents aggravation of cochlear endolymphatic hydrops, and these changes lead to a reduction of vertigo attacks and suppress the progression of hearing impairment associated with vertigo attacks.

Background Pseudoaneurysm of the internal carotid artery (ICA) is a very rare but potentially fatal complication of deep neck space infection. Methods This paper describes a very rare case of an ICA pseudoaneurysm rupture in the sphenoid sinus caused by a deep neck abscess. Results A 62-year-old male with a deep neck space infection underwent surgical drainage. On the postoperative 21st day, however, he suddenly had massive epistaxis. A transnasal endoscopic examination found massive bleeding out of the sphenoid sinus. Immediate intra-arterial angiography revealed two pseudoaneurysms of the left ICA at the cavernous segment (C4) and the clinoid segment (C5), which were embolized with coils. The patient made an uneventful recovery after the embolization. Conclusion We found no reports in the literature that pseudoaneurysms associated with a deep neck infection rupture in the sphenoid sinus. Prompt treatment along with accurate diagnosis is essential for successful management of such cases. J. Med. Invest. 66 : 188-189, February, 2019.

P2X

Aim of this work is to establish evaluation criteria for identifying endolymphatic hydrops in the vestibule and cochlea using a magnetic resonance imaging (MRI) scanner. This is a retrospective diagnostic study. We evaluated 70 ears of 35 unilateral Meniere’s disease patients. We performed 3-T MRI 4 h after intravenous gadolinium injection. Otologists manually traced the outline of vestibule, cochlea, and endolymphatic space of the vestibule and cochlea on two-dimensional fluid-attenuated inversion-recovery (2D-FLAIR) images. The traced area was measured, and rates of endolymphatic space to the vestibule and cochlea were calculated. The same otologists judged whether the low signal intensity area of the cochlea was at the edge of the cochlea. For measuring the rate of endolymphatic space to the vestibule, when the cut-off value was 30%, the presence of endolymphatic hydrops was determined with sensitivity of 87.1% and specificity of 94.3%. In contrast, the rate of endolymphatic space to the cochlea produced low accuracy. Therefore, when the presence of endolymphatic hydrops in the cochlea was judged by whether the low signal intensity area in the cochlea was at the edge of cochlea, endolymphatic hydrops could be detected with sensitivity of 91.4% and specificity of 94.3%. We were able to identify endolymphatic hydrops in the vestibule when the rate of endolymphatic space to the vestibule was greater than 30%, and could detect endolymphatic hydrops in the cochlea when a low signal intensity area was located at the edge of the cochlea in 2D-FLAIR images. Level of evidence 4.

A 38-year-old man underwent peritoneal dialysis (PD) in May 2011 due to chronic renal failure with chronic glomerulonephritis. In early February 2012, he underwent laparoscopy to salvage and correct a malpositioned PD catheter. The laparoscopic intra-abdominal findings revealed turbid ascites and multiple fibrin lumps, despite the patient's lack of history of peritonitis. Based on these findings, in addition to the presence of continuous inflammation and ascites, a diagnosis of pre-encapsulating peritoneal sclerosis was suspected, and the treatment was switched from PD to hemodialysis. The administration of prednisolone at a dose of 20 mg/day and peritoneal lavage resulted in a decrease in the ascites and fibrin lumps., Internal Medicine, 53(7), pp.767-770; 2014

Encapsulating peritoneal sclerosis (EPS) is a fatal complication that can occur in patients undergoing long-term peritoneal dialysis. It is characterized by bowel obstruction and marked sclerotic thickening of the peritoneal membrane. Although the mechanisms underlying the development of EPS are complex, angiogenesis, inflammation, and peritoneal fibrosis are known to be essential factors. Now, several animal models that exhibit EPS have pathophysiology similar to that of human EPS and have been proposed for use in research to provide insights into it. Recent histochemical methods also help us to understand the pathophysiology of EPS. Advances in basic research based on the findings in those animal models have enabled the development of several strategies for the prevention and treatment of EPS. We describe here interventional studies in some animal models for peritoneal fibrosis, one of the histological disorders findings characteristic to EPS, and we highlight the need for a sophisticated animal model that closely resembles human conditions.

We report herein on the case of a 71-year-old woman hospitalized for continued postauricular pain of unknown origin with tongue deviation. In view of the severe inflammatory reaction and multiple nodular shadows of the lungs, the existence of infectious disease was indicated. A contrast-enhanced CT scan of the neck revealed a thrombosis of the right internal jugular vein, osteomyelitis of right temporal-occipital bone and upper cervical spine, and cellulitis of the adjacent soft tissue. Multiple nodular shadows of the lungs were suspected to be the result of a metastatic septic embolism. Hence, she was diagnosed with Lemierre syndrome. Following treatment with long course of antimicrobial therapy including beta-lactams and clindamycin, complete recovery in this patient was achieved.

To establish a system of differential diagnosis for vertigo/dizziness at the Emergency Department (ED), careful history-taking of complications and examinations of nystagmus should be helpful and therefore prepared by ED staff.Vertigo/dizziness could come from various kinds of organs for equilibrium, sometimes resulting in an emergency due to the central origin. In the present study, we checked patients' background data at the ED in advance of a definitive diagnosis at the Department of Otolaryngology and examined the significance of the correlation between the data and the diagnosis.We studied a series of 120 patients with vertigo/dizziness, who visited the Departments of Emergency and Otolaryngology between April 2011 and March 2012. At the ED, we first checked patients' backgrounds and carried out neurologic and neuro-otologic examinations. At the Department of Otolaryngology, we finally diagnosed all the patients according to the criteria and classified the origins of vertigo/dizziness into central and non-central diseases.The ratio of patients with disease of central origin was 12.5% and that for non-central origin was 87.5%. The risk factors for cerebrovascular disease such as hypertension, heart disease, and diabetes were also the risk factors for central vertigo/dizziness by the chi-squared test. To predict a central origin for vertigo/dizziness, only gaze nystagmus was the significant factor by multivariate regression analysis.

Objectives Some patients with sudden sensorineural hearing loss (SSNHL) are frustrated by residual tinnitus even after accomplishment of the treatment for SSNHL. In the present prospective study, we examined patients’ backgrounds of sex, laterality and age together with changes in hearing level and the tinnitus score after the onset of SSHNL to determine the prognostic factors of residual tinnitus after the final day of medical treatment for SSNHL. Methods Forty-four patients with SSNHL were all treated with systemic administration of steroids for 2 weeks and oral intake of vasoactive drugs and vitamin B12 for 6 months before accomplishment of the treatment for SSNHL. The hearing improvement rate (HIR) was determined by comparing the hearing level before and 6 months after the start of treatment. Tinnitus was subjectively evaluated by the tinnitus scoring questionnaire before, 6 and 24 months after the start of treatment. The score of a five-step evaluation of subjective tinnitus feelings, “loudness”, “duration” and “annoyance”, was recorded. Results HIR was significantly correlated with tinnitus score improvement (TSI) in “duration” at 6 months after the start of treatment compared with before treatment. The tinnitus score of all 3 items was significantly improved 6 months after the start of treatment compared with that before treatment but it was not significantly changed between 6 and 24 months after the start of treatment. TSI in “duration” between 6 and 24 months was significantly correlated with the patients’ age and HIR using multiple regression analysis. Conclusion According to the tinnitus scoring questionnaire, “duration” is the most reliable item for subjective evaluation of tinnitus accompanied by SSNHL. Generally, subjective feelings for residual tinnitus 6 months after the start of treatment for SSNHL are supposed to be almost the same, even at the 24th post-treatment month. Especially, younger patients with better hearing improvement are predicted to achieve further improvement of tinnitus between 6 and 24 months after the start of treatment.

Aim Chronic kidney disease (CKD) is a known risk factor for cardiovascular disease (CVD). Cystatin C was recently reported to be an endogenous surrogate of kidney function, and a high level of cystatin C is reported to be a strong predictor of CVD; however, the association between cystatin C and arteriosclerosis in a non-CKD population is unclear. This study aimed to clarify the association between cystatin C and arteriosclerosis in a non-CKD population. Methods Of the 637 Japanese adults (264 men, 373 women) enrolled, we analyzed 446 participants with an estimated glomerular filtration rate (eGFR) >60 mL/min and no proteinuria (177 men, 269 women) without a history of CVD. Kidney function was evaluated according to serum cystatin C levels and eGFR. Arteriosclerosis was evaluated on the basis of the cardio-ankle vascular index (CAVI) and carotid intima-media thickness (CIMT). Results The mean age of our subjects was 67.0±10.0 years. No variables showed any significant differences according to gender. The results of multiple linear regression analysis showed a significant correlation between serum cystatin C and CAVI only in women, but not CIMT. Conclusion We observed a significant correlation between cystatin C and CAVI, which is a marker of early-stage arteriosclerosis, in women in a non-CKD population with no proteinuria and eGFR>60 mL/min.

A pathological nystagmus is an objective sign that a patient feels vertigo. However, there have been few opportunities to observe and record pathological nystagmus during a paroxysmal vertigo attack. Furthermore, it can be difficult to obtain cooperation in pediatric patients. We present two cases of paroxysmal vertigo in children in whom we successfully recorded and analyzed their pathological nystagmus during a vertigo attack.Of a total sample of 4349 patients seen at our hospital for dizziness in the last decade, a retrospective analysis revealed that 68 were children (15 years old; 1.6%). Of these 68 children, we successfully identified pathological nystagmus during paroxysmal vertigo in only two (2.9%).Case 1 was a 4-year-old girl. She felt vertigo the strongest when her left ear was down in the supine position. We observed and recorded her nystagmus during a vertigo attack with her mother's permission. Her positional nystagmus in the supine position was horizontal persistent apogeotropic nystagmus. Rightward nystagmus in the left-ear-down supine position was stronger than leftward nystagmus in the right-ear-down supine position. Therefore, the diagnosis was right lateral canal type of benign paroxysmal positional vertigo, of which the pathophysiology was cupulolithiasis. The other patient was an 11-year-old boy. He had a family history of migraines. His vertigo attacks occurred after onset of a severe migraine and lasted between 2 and 48 h. During an attack that we observed, he showed nystagmus, which was direction-fixed right torsional and rightward in darkness. His mother had noticed that his eyes moved abnormally and that his left eye did not shift to the left side when he looked leftward. He was old enough to clearly express his own symptoms. Other neurological examinations were normal. The diagnosis was vestibular migraine.We analyzed a pathological nystagmus during paroxysmal vertigo in two children. We conclude that children can be diagnosed with a combination of careful history taking and accurate examinations of a pathological nystagmus.

The patient was a 68-year-old woman who had experienced recurrent febrile episodes since 66 years of age. Despite various examinations and treatments, the etiology remained unclear. Further examinations following another referral failed to uncover the cause. Therefore, despite her age, it was presumed that she had familial Mediterranean fever. An analysis of the familial Mediterranean fever (MEFV) gene detected heterozygous L110P, E148Q, and R202Q mutations. No further febrile episodes occurred after colchicine treatment was initiated. Familial Mediterranean fever presenting in patients in their sixties is extremely rare., Internal Medicine, 51(18), pp.2649-2653; 2012

OBJECTIVE: To investigate the association with white blood cells (WBC) and atherosclerotic parameters including cardio-ankle vascular index (CAVI) and carotid intima-media thickness (CIMT) in the general population. METHODS: We investigated the relationship between WBC count and metabolic syndrome components, CAVI and CIMT in 3738 Japanese study participants. RESULTS: WBC count weakly correlated with CAVI in men (beta = 0.61, p = 0.043), but not in women (beta = 0.35, p = 0.17). On the other hand, WBC did not correlate with CIMT in either men or women (p = 0.41 and p = 0.71, respectively). CONCLUSION: WBC count was associated with lipids, blood pressure and body mass index, although the correlations with CAVI and CIMT were weak or absent., Biomarkers, 15(5), pp.454-460; 2010

BACKGROUND: The leptin:adiponectin ratio (L:A ratio) is an independent predictor of carotid intima-media thickness (CIMT). OBJECTIVE: To evaluate whether the leptin:high-molecular-weight adiponectin ratio (L:HA ratio) is associated with CIMT in the general population. METHODS: We investigated the relationship between the L:HA ratio and CIMT in 233 Japanese study participants (106 men and 127 women). RESULTS: After adjustment for confounding factors, CIMT was significantly correlated with the log L:HA ratio (beta = 0.11, p = 0.014) in men, whereas no correlation was observed in women (beta = 0.01, p = 0.50). Conclusion: The L:HA ratio is closely correlated with CIMT in men, but not in women., Biomarkers, 15(4), pp.340-344; 2010

To investigate the relationship between thyroid function and carotid intima-media thickness (CIMT) in a relatively large general population with euthyroid status we initially enrolled 1772 Japanese adults (421 men and 1351 women) who participated in a medical screening program for the general population over 40 years old. To evaluate only euthyroid subjects without vascular diseases and/or its major risk factors, 1129 were excluded and 643 participants (175 men and 468 women) were included for further analysis. Simple and multivariate linear regression analyses were performed to evaluate free thyroxine (fT4) and thyroid-stimulating hormone (TSH) levels and other existing parameters, including carotid intima-media thickness. By multivariate linear regression analysis adjusted for age and sex, free thyroxine was significantly correlated with triglycerides (beta=0.07, p=0.015), carotid intima-media thickness (beta=-0.091, p=0.049), and thyroid-stimulating hormone (beta=-0.091, p=0.003). Thyroid-stimulating hormone was significantly correlated with high-density lipoprotein cholesterol (HDL-C) (beta=-0.001, p=0.015), HbA(1c) (beta=0.038, p=0.045), carotid intima-media thickness (beta=0.27, p=0.001), and free thyroxine (beta=-0.15, p=0.003). When adjusted for confounding factors, free thyroxine was significantly correlated only with carotid intima-media thickness (beta=-0.13, p=0.043) and thyroid-stimulating hormone was significantly correlated with HDL-C (beta=-0.001, p, Atherosclerosis. 204(2), pp e77-e81

Background. Patients on long-term peritoneal dialysis develop progressive peritoneal fibrosis and loss of mesothelial layer. Regeneration of the mesothelium has been reported in the normal peritoneum but not the fibrotic peritoneum. Moreover, the origin of the regenerated mesothelial cells remains obscure. The aim of this study was to investigate mesothelial regeneration in fibrotic peritoneum induced by chlorhexidine gluconate. Methods. Peritoneal fibrosis was induced by injection of CG into the peritoneal cavity of Wistar rats. After injection, the abdomen was opened, and the parietal fibrotic peritoneum with mesothelial cells was stripped from the abdominal wall, and then the abdominal incision was closed. Rats were sacrificed, and peritoneal tissues were dissected out at 0, 1, 3, 5, or 7 days after the stripping procedure. Results. Spindle-shaped cells with microvilli appeared on the surface of stripped peritoneum at day 3 after denudation. Immunohistochemistry identified staining for vimentin, a marker of mesoderm cells, in the spindle-shaped cells at days 3, 5, and 7. Expression of α-SMA was observed in the same cells at days 3 and 5, but not 7. Expression of cytokeratin and HBME-1, markers for mesothelial cells, in these cells was delayed until day 7. Conclusions. Mesothelium can regenerate on the fibrotic peritoneum. The regenerated mesothelial cells seem to originate from vimentin-positive mesenchymal cells., This is an electronic version of an article published in Renal Failure, 30(1), pp.97-105; 2008. Renal Failure is available online at: http://www.informaworld.com/openurl?genre=article&id=doi:10.1080/08860220701741619., Renal Failure, 30(1), pp.97-105; 2008

Background: Osteopontin (OPN) plays a key role in the progression of T H l-immune-mediated disease in models of multiple sclerosis and rheumatoid arthritis. Aim: To determine whether plasma OPN levels in patients with inflammatory bowel disease are associated with disease activity. Methods: Plasma samples were obtained from patients with ulcerative colitis (UC, n = 30), Crohn's disease (CD, n = 30), and healthy volunteers (controls, n = 30) and enzyme immunoassay was performed. Results: Plasma OPN concentrations were significantly higher in patients with Crohn's disease than in controls (951.9 ± 538.5 ng/ mL and 659.0 ± 163.7ng/mL, respectively). OPN concentrations in patients with UC were also higher than in the controls (1149.6 ± 791.0 and 659.0 ± 163.7, respectively). There was a significant difference in plasma OPN level between active UC and inactive UC (2102.0 ± 552.8 and 649.4 ± 313.0, respectively). Moreover, a significant correlation was observed between plasma OPN concentration and disease activity, as determined by the clinical activity index in patients with UC. Conclusions: Our results indicate that the plasma concentrations of OPN are elevated in patients with UC and that OPN expression is correlated with clinical activity. These results provide insight into UC pathogenesis and suggest that OPN may be a useful tool for assessing disease activity.

A 52-year-old woman was admitted to our hospital for further examination of blurred vision, abnormal lung shadows and an elevated level of angiotensin-converting enzyme. Sarcoidosis was suspected, however, careful history taking revealed the existence of photosensitivity and polyarthralgia. Laboratory tests showed lymphocytopenia, liver dysfunction, hypergammaglobulinemia, and positive anti-nuclear, anti-double stranded DNA and anti-smooth muscle antibodies. Liver biopsy examination showed chronic active hepatitis. She was diagnosed with the triplex of sarcoidosis, systemic lupus erythematosus and autoimmune hepatitis. Marked improvement was noted after corticosteroid therapy., Internal Medicine, vol.46(19), pp.1657-1661; 2007

Transient receptor potential vanilloid (TRPV) 4 is a nonselective cation channel expressed in sensory neurons such as those in the dorsal root and trigeminal ganglia, kidney, and inner ear. TRPV4 is activated by mechanical stress, heat, low osmotic pressure, low pH, and phorbol derivatives such as 4α-phorbol 12,13-didecanoate (4α-PDD). We investigated the expression of TRPV4 in rat vestibular ganglion (VG) neurons. The TRPV4 gene was successfully amplified from VG neuron mRNA using reverse-transcription polymerase chain reaction. Furthermore, immunoblotting showed positive expression of TRPV4 protein in VG neurons. Immunohistochemistry indicated that TRPV4 was localized predominantly on the plasma membrane of VG neurons. Calcium (Ca2+) imaging of VG neurons showed that 4α-PDD and/or hypotonic stimuli caused an increase in intracellular Ca2+ concentration ([Ca2+]i) that was almost completely inhibited by ruthenium red, a selective antagonist of TRPV channels. Interestingly, a [Ca2+]i increase was evoked by both hypotonic stimuli and 4α-PDD in approximately 38% of VG neurons. These data indicate that TRPV4 is functionally expressed in VG neurons as an ion channel and that TRPV4 likely participates in VG neurons for vestibular neurotransmission as an osmoreceptor and/or mechanoreceptor.

Long-term peritoneal dialysis therapy causes inflammation and histological changes in the peritoneal membrane. Inflammation generally activates fibroblasts and results in fibroblast-myofibroblast differentiation. Heat-shock protein 47 (HSP 47), a collagen-specific molecular chaperone, is localized in myofibroblasts and is involved in the progression of peritoneal fibrosis. Daikenchuto (DKT), a Kampo medicine, is used to prevent postoperative colon adhesion. It inhibits inflammation and HSP 47 expression in the gastrointestinal tract. We examined the effect of DKT on chlorhexidine gluconate (CG)-induced peritoneal fibrosis in mice injected with 0.1% CG dissolved in 15% ethanol. DKT was dissolved in the drinking water. Histological changes were assessed using Masson trichrome staining. Cells expressing α-smooth muscle actin (α-SMA), HSP 47, phospho-Smad 2/3, F4/80, and monocyte chemotactic protein-1 were examined immunohistochemically. Compared with the control group, the peritoneal tissues of the CG group were markedly thickened, and the number of cells expressing α-SMA, HSP 47, phospho-Smad 2/3, F4/80, and monocyte chemotactic protein-1 was significantly increased. However, these changes were inhibited in the DKT-treated group. These results indicate that DKT can prevent peritoneal fibrosis by inhibiting inflammation and HSP 47 expression.

We describe here two sisters with nephronophthisis, which was not detected until the development of endstage renal failure. Twenty- and 15-year-old female siblings were admitted to our hospital for further examination of renal dysfunction. No urinalysis abnormalities had been found in yearly health checks in either patient. The serum creatinine level was 7.2 mg/dl in case 1 (the 20-year-old) and 6.4 mg/dl in case 2. Medical history, physical findings, and laboratory tests showed no evidence of urinary tract infection, use of any drugs, arthritis, or skin eruptions. To identify the cause of the renal failure, open left renal biopsies were performed in both patients. Histopathological findings were very similar in the two patients and included marked tubular and interstitial changes (tubular dilatation, focal tubular atrophy, interstitial fibrosis, and infiltration of mononuclear cells). The glomeruli were devoid of mesangial proliferation, mesangial expansion, and adhesion of Bowman's capsule. Based on the clinical and pathological findings, the final diagnosis was nephronophthisis in both patients. It is important to remember that some progressive renal diseases, including nephronophthisis, cannot be detected even by annual urinary screening tests, which are widely performed in Japan.

Background: The renin-angiotensin II system (RAS) has been implicated in the development of glomerulonephritis. The aims of this study were to determine (1) the expression of RAS components, angiotensin (Ang II)-forming enzymes [angiotensin-I-converting enzyme (ACE) and chymase], and Ang II receptors, and (2) the correlation between RAS expression and severity of tissue injury in IgA nephropathy (IgAN). Methods: The expression levels of ACE, chymase, and Ang II type 1 and type 2 receptor (AT1R and AT2R) mRNAs were determined by in situ hybridization in renal specimens from 18 patients with IgAN, 5 patients with non-IgA mesangial proliferative glomerulonephritis (non-IgAN) and 10 patients with nonmesangial proliferative glomerulonephritis (minimal change nephrotic syndrome, n = 5, and membranous nephropathy, n = 5). Normal portions of surgically resected kidney served as control. Results: In normal kidney, a few mesangial cells and glomerular and tubular epithelial cells weakly expressed ACE, chymase and AT1R mRNAs. In IgAN and non-IgAN samples, ACE, chymase, AT1R and AT2R mRNAs were expressed in resident glomerular cells, including mesangial cells, glomerular epithelial cells and cells of Bowman’s capsule. The glomerular expressions in IgAN were stronger than in minimal change nephrotic syndrome and membranous nephropathy. In IgAN, the expressions in glomeruli correlated with the degree of mesangial hypercellularity, whereas the expression levels were weaker at the area of mesangial expansion. IgAN with severe tubulointerstitial injury showed expression of ACE, chymase, AT1R and AT2R mRNAs in atrophic tubules and infiltrating cells and such expression correlated with the degree of tubulointerstitial damage. Conclusion: Our results suggest that renal cells can produce RAS components and that locally synthesized Ang II may be involved in tissue injury in IgAN through Ang II receptors in the kidney.

わが国での透析患者は年々増加し, また高齢化の一途をたどっており, 多数の合併症を有する患者が増えていることが予想される. 透析患者が腹痛を訴えた場合, 消化器疾患が原因であることが多いが, 中には腎自然破裂や大動脈解離の場合もあり, 早急な判断が必要となることがある. 今回, 大腸憩室炎の経過中に腎自然破裂を合併し, 腹痛と腹部腫瘤の鑑別に苦慮した症例を経験した. 症例は64歳男性. 透析歴12年. 2002年大腸憩室炎の既往あり. 2003年2月7日血液透析後に下血が出現. 貧血の進行と黒褐色便, 腹痛を認めたため大腸憩室炎など消化管病変が疑われた. その後腹痛の増強と, 新たに左側腹部に圧痛を伴う腫瘤を触知するようになり, 貧血もさらに進行しショック状態となったため当院入院となった. 腹部CT検査と左腎動脈造影検査の結果, 左腎破裂との診断にて左腎動脈塞栓術を施行し, 輸血を行ったところ次第に全身状態は改善した. また入院時便潜血反応陽性であり, 消化管出血の精査を行ったところ, 腸管内に多発する憩室と凝血塊を認め, 経過から大腸憩室炎による消化管出血が疑われた. 絶食・安静にて消化管出血と腹痛は改善している. 透析患者が腹痛を訴えた場合, 頻度的には虚血性腸炎や大腸憩室炎など消化管疾患であることが多いが, このほか, 大動脈解離や腎破裂など消化管以外の疾患の鑑別もすることが重要である.

TNP-470, an angiogenesis inhibitor, suppresses the progression of peritoneal fibrosis in mouse experimental model. Background In patients on long-term peritoneal dialysis (PD), angiogenesis and vasculopathy are observed in the peritoneum, and the degree of vascularization correlates with the area of fibrotic tissue, suggesting the involvement of angiogenesis in the progression of peritoneal fibrosis. The aim of the present study was to evaluate the effect of TNP-470, an anti-angiogenic compound, on the development of peritoneal fibrosis induced by chlorhexidine gluconate (CG). Methods Peritoneal fibrosis was induced by injection of CG into peritoneal cavity of Institute for Cancer Research (ICR) mice. TNP-470 was injected subcutaneously with CG. Mice were sacrificed, and peritoneal tissues were dissected out at days eight and 16 after CG and TNP-470 injection. The expression patterns of CD31 (as a marker of endothelial cells), vascular endothelial cell growth factor (VEGF), α-smooth muscle actin (as a marker of myofibroblasts), heat shock protein 47 (HSP47), type III collagen, F4/80 (as a marker of mice macrophages), proliferating cell nuclear antigen (PCNA), and cyclin-dependent kinase 2 (Cdk2) were examined by immunohistochemistry. Results CG-injected mice showed thickening of the submesothelial zone and increased number of vessels, myofibroblasts, and infiltrating macrophages. The expression levels of VEGF, type III collagen, and HSP47 were increased, and a large number of PCNA-positive cells and Cdk2-expressing cells were observed in the thickened submesothelial area. Treatment with TNP-470 suppressed the submesothelial zone thickening and reduced collagen III expression as well as angiogenesis. TNP-470 also decreased the number of VEGF-expressing cells, myofibroblasts, macrophages, PCNA-positive cells, and Cdk2-expressing cells. Conclusion Our results indicate the involvement of angiogenesis in the progression of peritoneal fibrosis, and suggest that TNP-470 may be potentially useful for the prevention of peritoneal fibrosis through inhibition of angiogenesis and suppression of myofibroblast proliferation.

Background: The transcription factor nuclear factor-κB (NF-κB) is involved in inflammatory and immune responses through induction of various cytokines and growth factors. The aim of this study is to examine the correlation between NF-κB expression and severity of tissue injury in immunoglobulin A (IgA) nephropathy and the mechanism of such correlation. Methods: The study included 43 renal tissue samples from 28 patients, including 28 samples of IgA nephropathy, 5 samples of non-IgA mesangial proliferative glomerulonephritis (non-IgA nephropathy), and 10 samples with nonproliferative glomerulonephritis (membranous nephropathy [MN] n=5; minimal change nephrotic syndrome [MCNS]; n=5). Tissue sections were examined by Southwestern histochemistry and immunohistochemistry for monocyte chemoattractant protein-1 (MCP-1), granulocyte-macrophage colony-stimulating factor (GM-CSF), and intercellular cell adhesion molecule-1 (ICAM-1), which are regulated by NF-κB. Normal portions of surgically resected kidney with adenocarcinoma served as controls. Results: In normal kidney, MCNS, and MN sections, NF-κB expression was detected in a few mesangial cells and tubular epithelial cells. In IgA nephropathy and non-IgA nephropathy samples, NF-κB was expressed in mesangial, glomerular endothelial and epithelial cells, tubular epithelial cells, and infiltrating cells. Expression in both glomeruli and interstitium correlated with progression of tissue injury. In IgA nephropathy samples, MCP-1 and GM-CSF expression was increased in both glomeruli and interstitium and correlated with progression of tissue injury. Glomerular ICAM-1 expression was weaker in severe lesions, whereas interstitial expression correlated with progression of tissue injury. Conclusion: Our results indicate that NF-κB is involved in the progression of tissue injury in IgA nephropathy through the induction of transcriptionally regulated genes.

We report a patient with neuroleptic malignant syndrome (NMS) who developed acute renal failure and was successfully treated by hemodialysis. A 60-year-old man with a 26-year history of schizophrenia had been treated with thioridazine and sulpiride. He was admitted to our hospital for muscular rigidity and oliguria. After the diagnosis of NMS with acute renal failure was established, thioridazine and sulpiride were discontinued and hemodialysis was instituted. Renal function gradually improved and hemodialysis was discontinued after 17th treatment. We also reviewed 57 cases of NMS with acute renal failure reported in the literature. To our knowledge, 26 years is the longest latency between initiation of neuroleptic drug treatment and onset of NMS. Our review of reported NMS cases with acute renal failure identified those risks for poor prognosis as high level of BUN, age and female gender.

Enhanced expression of complement C5a receptor mRNA in human diseased kidney assessed by in situ hybridization. Background Anaphylatoxin C5a mediates inflammatory responses through interaction with a specific C5a receptor (C5aR), the expression of which is thought to be restricted to peripheral blood leukocytes. Although the presence of C5aR on cultured mesangial cells and tubular epithelial cells has recently been documented, the tissue distribution of C5aR in diseased kidney has not yet been determined. Methods Immunohistochemistry and nonradioactive in situ hybridization for C5aR were performed in 34 tissue samples of kidneys from patients with various renal diseases, including 4 with minimal change nephrotic syndrome (MCNS), 5 with membranous nephropathy (MN), and 25 with mesangial proliferative glomerulonephritis (mesGN; 15 patients with IgA nephropathy, 5 with non-IgA mesGN, and 5 with lupus nephritis). Normal portions of surgically resected kidney served as the control. Results In normal kidneys, C5aR protein was detected in tubular epithelial cells, while C5aR mRNA was detected in a few glomerular cells, tubular epithelial cells, and vascular endothelial and smooth muscle cells. In MCNS, the distribution of C5aR protein and mRNA was similar to that in normal kidneys. In MN and mesGN, C5aR protein and mRNA were detected in mesangial cells, glomerular epithelial and endothelial cells, Bowman's capsule cells, tubular cells, infiltrating cells, and vascular endothelial and smooth muscle cells. The glomerular expression of C5aR mRNA and protein correlated positively with the degree of mesangial hypercellularity and mesangial matrix expansion in mesGN. In the tubulointerstitium, interstitial expression of C5aR mRNA correlated positively with the degree of tubular atrophy and interstitial broadening in mesGN. Furthermore, the interstitial expression of C5aR mRNA correlated positively with the level of serum creatinine. Conclusions Our results indicate that renal cells produce C5aR and that activation of C5a/C5aR pathway on renal cells may be involved in tissue injury in mesGN.

Background: Complement activation is thought to be pathologically important in IgA nephropathy (IgAN). Although C3 deposition in the mesangium is found in IgAN, the origin of C3 is not clear. We recently demonstrated intraglomerular C3 synthesis in the human kidney; however, the activation and pathological role of locally synthesized C3 remains unclear. Here we performed nonradioactive in situ hybridization for C3 mRNA and immunohistochemistry for C3 and its activation products, such as C3d and membrane attack complex (MAC), to determine whether locally produced C3 in glomeruli was activated in IgA nephropathy. Methods: Renal samples from 14 patients with IgAN and 5 with minimal change nephrotic syndrome (MCNS) were examined. Uninvolved portions of surgically removed kidneys with tumors served as normal controls. Results: C3 mRNA was not detected in glomeruli in control tissue and MCNS, but was strongly expressed in resident glomerular cells of IgAN, including mesangial cells, glomerular epithelial cells and the cells of Bowman’s capsule. Examination of serial sections disclosed that more than 70% of cells positive for C3 mRNA were also stained for C3 protein, C3d, and MAC. Double staining for in situ hybridization and immunohistochemistry also revealed that those C3 mRNA signals were present in intraglomerular cells positive for C3. The expression of C3 mRNA and MAC in glomeruli correlated significantly with the degree of mesangial matrix expansion. Conclusions: Our results demonstrated that locally synthesized C3 is activated in the glomeruli of IgAN and that its expression correlated with the severity of mesangial matrix expansion. These findings suggest that activation of C3 may be involved in tissue injury in IgAN through the formation of membrane attack complex.

症例は48歳, 女性. 平成11年12月下旬より感冒様症状が出現し, 近医で抗生剤を処方されていたが, 次第に眼瞼の浮腫を自覚するようになったため, 1月19日当院に入院した. 入院時には検尿にて尿蛋白 (+), 赤血球50-100個/視野を認め, 血液検査にて尿素窒素64.2mg/dl, 血清クレアチニン値8.2mg/dlの腎不全と, 血中ヘモグロビン値5.6g/dl, MCV 57.1fl, MCH 17.8pgの小球性低色素性貧血を認めた. 血痰, 喀血はなく, 胸部X線写真でも異常は認めなかった. 抗生剤による薬剤性の急性腎不全を疑っていたところ, 1月30日に肺野に異常陰影が出現し, 気管支鏡検査にて肺胞出血を認め, 抗糸球体基底膜抗体 (抗GBM抗体) が300EU/mlであったため, Goodpasture症候群の診断に至った. メチルプレドニゾロン500mgの点滴注射を3日間と6回の血漿交換で治療を行い, 抗GBM抗体は次第に低下し, 肺胞出血は軽快したが, 腎機能は回復せず, 透析を離脱できなかった. Goodpasture症候群は予後不良の疾患であり, 早期診断による早期治療が重要である. 急性腎不全の患者で著明な血尿と小球性低色素性貧血を認め, 原因疾患が明らかでない場合には, その鑑別診断としてGoodpasture症候群を考え, 早期診断と治療に努める必要がある.

We present 4 patients undergoing hemodialysis in whom thoracic computed tomography (CT) suggested a diagnosis of rounded atelectasis (RA) with pleural effusion. The clinical setting and follow-up CT of all 4 patients confirmed this diagnosis. The pleural fluid of each appeared serosanguineous or hemorrhagic and predominantly consisted of lymphocytes. Biochemical analysis of this fluid revealed high levels of total protein, lactate dehydrogenase and glucose. Bacterial culture and polymerase chain reaction for Mycobacterium tuberculosis DNA was negative. Pleural biopsy specimens from 2 of the 4 patients showed evidence of fibrinous change and mesothelial cell hyperplasia. Pleural effusion from all 4 patients did not respond to either fluid restriction or aggressive hemodialysis-induced dehydration. The subsequent clinical course and thoracentesis were repeated, and in 1 patient, this was followed by tetracycline pleurodesis. However, 2 patients died during pre-pleurodesis and 1 died during post-pleurodesis, all due to respiratory failure. We propose that the clinical setting and follow-up thoracic CT and thoracentesis of patients receiving long-term hemodialysis confirmed a diagnosis of rounded atelectasis with uremic pleural effusion. We also propose that the prognosis of patients with refractory pleural effusion receiving long-term hemodialysis would be improved by early pleurodesis.

In situ hybridization (ISH) is widely used to determine the expression of specific mRNA in tissues. However, the results of ISH are influenced by the amount of retained RNA in the tissue. Estimation of retained RNA in the tissue is very important and the results of ISH should be interpreted taking into consideration the amount of retained RNA in samples. In the present study, we determined the amount of retained RNA by performing ISH for 28S rRNA. We also analyzed the results of ISH semi−quantitatively by computer image analysis. The method was applied by calculating the ratio of specific mRNA to 28S rRNA in order to standardize the results of ISH among different tissue samples. Our method is useful for comparing the expression of specific mRNA in different tissue samples with variable levels of retained RNA. Since the conditions of fixation and storage of tissues differ among samples, especially in clinical samples, our semi−quantitative method allows a more precise evaluation of gene expression in different samples., Acta Histochemica et Cytochemica, 33(1), pp.39-47; 2000

We report a case of renal papillary necrosis with diabetes mellitus which was treated with prostaglandin E1. An intravenous infusion of 40 mg/day prostaglandin E1 was given for 14 days in an attempt to improve renal circulation. Treatment resulted in an improved creatinine clearance, renal plasma flow and renogram, and proteinuria was decreased. The administration of prostaglandin E1 produced an improvement in renal haemodynamics and can be considered as a possible therapy for renal papillary necrosis in diabetic patients.

Mac-1 (aM b2 integrin, CD11b/CD18), are expressed Results. The expression of VLA-4 on peripheral on macrophage-like cells that accumulate around the lymphocytes was not diVerent among the groups. vascular endothelium in the tenosynovium of patients However, the FACScan fluorescence histogram of with CTS. Other studies have shown that the induction VLA-4 expression on peripheral monocytes showed a of interleukin (IL)-1 and tumour necrosis factor bimodal pattern in the CTS group, and the rate of the ( TNF )-a is increased in peripheral blood mononuclear high intensity portion of the expressed VLA-4 on cells (PBMC ) of dialysis patients [2,3]. IL-1 and IL-6 monocytes was significantly higher in CTS than other are also synthesized by cultured tenosynovial cells of groups (P

Plasma exchange is used frequently in renal diseases for the removal of the humoral components of immune responses. Various pathological circulating factors are recognized in primary and secondary renal diseases. Recent advances in medical technology have allowed a wider clinical application of plasmapheresis in the clinical management of a variety of conditions. However, the clinical efficacy of plasmapheresis in renal diseases is still controversial. In this article, we review the therapeutic use of apheresis in different renal diseases.

Expression of decay accelerating factor mRNA and complement C3 mRNA in human diseased kidney. Background Decay accelerating factor (DAF), a product of mesangial cells in vitro , is expressed on the surface of cells and is a candidate for the focal suppression of complement activation. It is not clear at present whether the levels of expression of DAF and intrarenal C3 synthesis correlate with the level of tissue injury. Methods Immunohistochemistry for DAF and C3 and nonradioactive in situ hybridization with digoxigenin-labeled oligonucleotide probe for DAF and C3 mRNA were performed in 22 tissue samples of kidneys from patients with IgA nephropathy (IgAN), 6 with membranous nephropathy (MN), 6 with lupus nephritis (LN), and five normal kidneys. Results In the normal kidney, DAF was confined to the juxtaglomerular apparatus and little or no C3 was detected; however, a few glomerular cells were positive for DAF mRNA but no C3 mRNA positive cells were detected. In diseased kidneys, DAF and C3 as well as their mRNAs were detected in mesangial cells, tubular cells and infiltrating cells. Glomerular epithelial cells and Bowman's capsule cells contained little or no DAF and C3 but were positive for their mRNAs. The mean percentages of mesangial cells positive for DAF and C3 mRNAs were 49.3 ± 11.5% and 50.7 ± 10.3% in IgAN, and 17.0 ± 6.3% and 19.4 ± 9.0% in MN, respectively. The percentage of mesangial cells positive for DAF and C3 mRNAs among intraglomerular cells correlated positively with the degree of mesangial proliferation and glomerular sclerosis in IgAN. In contrast, in LN the percentage of glomerular cells positive for DAF mRNA correlated negatively with the degree of glomerular injury, while the percentage of cells positive for C3 mRNA did not change with the progression of the disease. The ratio of C3 mRNA/DAF mRNA of glomerular cells correlated with the degree of glomerular injury in both IgAN and LN. In the tubulointerstitium, the percentage of cells expressing mRNA, and C3 mRNA/DAF mRNA ratio correlated with the degree of tubular atrophy and interstitial broadening in both IgAN and LN. Conclusions We conclude that DAF and C3 mRNAs are synthesized in human diseased kidneys, and that a balance between locally synthesized DAF and C3 may be important in the progression of glomerulonephritis.

近年, 透析患者の増加に伴い, 動脈硬化性疾患の合併は大きな問題となっている. 腹部大動脈瘤 (abdominal aortic aneurysm, AAA) や閉塞性動脈硬化症 (arteriosclerosis obliterans, ASO) は, その治療として外科手術を要することがあり, 透析患者の生命予後, quality of lifeの観点からも重要な疾患である. 今回我々は, 当院における透析患者のAAA4例およびASO3例の血行再建術症例の臨床的検討を行った.AAAの症例は年齢45-61歳で, 全例高血圧を伴い, 透析導入後6か月-6年であった. 2症例が腹痛ないし背部痛を訴えたが, 2症例は腹部腫瘤触知が発見の契機であった. 4例ともinfrarenal typeで, 3例にY graft, 1例にstraight graft置換を施行し, 全例とも予後は良好である.3例のASOは年齢51-67歳で, 2例で高血圧を伴い, 発症は透析導入後5年4か月-19年3か月とAAAに比し長期間の症例が多かった. いずれの症例も, 下肢痛・間歇性跛行・足趾壊死などの症状, 所見を認めた. 2例は左側のiliac～popliteal arteryの閉塞で, 自己大伏在静脈によるfemoro-popliteal bypass術を施行, 他の1例は右側のcommon～external iliac arteryの閉塞で, femoro-femoral cross over bypass術を2回施行した. 術後1例は予後良好であるが, 2例はASO以外の死因で死亡した.近年, 手術手技の向上および周術期の透析管理の進歩により, 透析患者に対し安全に手術が施行し得るようになってきたが, ASOの症例は, 必ずしも予後が良好でない場合もあり, 治療法選択, 手術時期に対するさらなる検討が必要と思われた.

Forms of hemophagocytic syndrome,which affects mainly children, vary from mild to very severe and often fatal. Wedescribe an adult patient with hemophagocytic syndrome in whom severe liver dysfunction developed.The condition continued to deteriorate despite treatment with plasma exchange,high-dose gamma globulin, and corticosteroid therapy. Treatment with cyclosporine (2.3 mg/kg/day) dramatically improved the conditionand normalized liver function. Cyclosporine reduced the serum levels of ferritin, interferon-T,interleukin-6, and soluble interleukin-2 receptor.These findings suggest that hemophagocytic syndrome accompanied with severe liver dysfunction results from hypercytokinemia,and cyclosporine is useful in preventing a fatal outcome during the acute phase.