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To determine the relationship between visual acuity and three-dimensional optical coherence tomographic (3D-OCT) findings of the macula in eyes with Vogt-Koyanagi-Harada (VKH) disease. Twelve eyes of six patients (three men and three woman, average age 53.2 years) in the acute phase of VKH disease were examined with a 3D-OCT instrument. All of the eyes had a serous macular detachment. The height of the sensory retinal detachment (SRD) and the sensory retinal thickness (SRT) were measured by OCT before treatment (acute stage) and at the convalescent stage. The correlation between the retinal morphology and visual acuity was evaluated. The height of the SRD and the SRT were 612.5 ± 371.2 and 136. 7 ± 22.0 μm, respectively. The initial visual acuity was significantly worse in eyes with a higher SRD (P = 0.014, r = 0.68) but the correlation between initial visual acuity and SRT was not significant. The recovery of visual acuity was attained in 50.7 ± 44.1 days and the complete resolution of the SRD was attained in 30.5 ± 23.2 days. The final visual acuity was attained several days after the complete resolution of the SRD in all four eyes of patients over 60 years of age, but the recovery of visual acuity often preceded the complete resolution of the SRD. The OCT images provided a noninvasive indicator of the severity of the disease and dynamic changes in the macular morphology, reflecting the effect of treatment in association with the improvement in visual acuity. Monitoring the SRD by 3D-OCT may guide the tapering of systemic corticosteroid treatment.

Purpose: The aim of this study was to determine whether a significant correlation exists between the scotopic and photopic components of electroretinograms (ERGs) and the degree of circulation disturbances caused by a central retinal artery occlusion (CRAO)., Design: Observational clinical study., Participants: Sixteen patients with a CRAO (16 eyes)., Methods: The circulatory disturbance in eyes with CRAO was graded as mild (group 1) when the arm-to-retina transmission time was <30 sec and severe (group 2) when the arm-to-retina transmission time was ≥30 sec. Scotopic and photopic ERG components in eyes with CRAO were compared with those in healthy fellow eyes with respect to the degree of circulation disturbance., Results: The scotopic and photopic b-waves were significantly reduced only in group 2, whereas the amplitudes of the photopic negative response (PhNR) of the photopic cone ERGs were significantly reduced in both groups. The amplitudes of each ERG component, except for the a-wave of the mixed rod-cone ERG, were significantly smaller in group 2 than in group 1., Conclusions: The PhNR was reduced even in group 1 with minimal circulatory disturbance and thus may be a good functional indicator.

Background: Transjugular intrahepatic portosystemic shunt (TIPS) has recently been reported to be effective in the treatment of cirrhotic patients with refractory ascites. However, the clinical utility of TIPS in the subset of refractory ascitic patients with good hepatic and renal function is uncertain. The aim of this study was to compare the efficacy of TIPS to that of large-volume paracentesis in cirrhotic patients with refractory ascites who have good hepatic and renal function., Methods: Sixty cirrhotic patients with refractory ascites who presented with a Child-Pugh score of <11, serum bilirubin of <3 mg/dl and creatinine of <1.9 mg/dl were assigned randomly to TIPS (n = 30) or large-volume paracentesis plus albumin (n = 30). The primary endpoint was survival. The secondary endpoints were response to treatment and development of hepatic encephalopathy., Results: The baseline characteristics were similar in the two groups. Seventeen patients treated with TIPS and 21 treated with paracentesis died during the study period. The cumulative probabilities of survival at 1 and 2 years were 80 and 64% in the TIPS group and 49 and 35% in the paracentesis group (p < 0.005). TIPS was significantly superior to paracentesis in the control of ascites (p < 0.005). Treatment failure was more frequent in the paracentesis group, whereas the frequency of hepatic encephalopathy was greater in the TIPS group., Conclusions: In cirrhotic patients with refractory ascites who have good hepatic and renal function, TIPS improves survival and provides better control of ascites than large-volume paracentesis.

Purpose: To determine the extent of retinal damage in Purtscher retinopathy (PR)., Methods: A longitudinal analysis of the retinal morphology and function was made by optical coherence tomography and electroretinography, respectively, on a patient with unilateral PR., Results: Optical coherence tomography showed a marked thickening of the inner retinal layers in the acute phase and a thinning of the inner retinal layers and alteration of the outer layers in the chronic phase. The site of these changes corresponded with the cotton-wool patches. The results of electroretinography indicated reduced inner layer function in the acute phase and partial recovery in the chronic phase., Conclusion: The inner and outer retinal layers are altered morphologically and functionally in eyes with PR. The dynamic evaluation on retinal morphology and function may be useful in understanding the pathophysiology of PR.

The purpose of this study was to clarify the effects of 2-year treatment with raloxifene on the proximal femoral geometry among Japanese patients with osteoporosis by hip structure analysis. One hundred ninety-eight community-dwelling postmenopausal women with osteoporosis were enrolled. The structural variables were areal bone mineral density (BMD), cross-sectional area (CSA), section modulus (index of resistance to bending forces), and buckling ratio (index of cortical instability). BMD, CSA, and section modulus at the narrow neck significantly increased by 1.27, 2.67, and 3.90% at 2 years, respectively. BMD, CSA, and section modulus at the intertrochanter significantly increased by 2.55, 4.49, and 6.60% at study termination, respectively. The buckling ratio at the intertrochanter decreased by 2.36% at 1 year, but differences at 2 years became non-significant. Parameters at the shaft were qualitatively similar to those of the narrow neck and intertrochanter. The percent change of the section modulus was significantly higher than that of BMD at 2 years in all three regions. The percent changes of the section modulus is strongly correlated with the percent changes of BMD and CSA, and negative correlated with the percent changes of buckling ratio in all regions. In conclusion, Japanese osteoporotic women on raloxifene therapy have significant improvements of both BMD and geometry in the proximal femur.

Objective: A 3-dimensional alginate bead culturing method using rabbit articular chondrocytes was studied for the screening of the effectiveness of drugs for articular diseases., Design: The beads cultured with IL-1β, TGF-β, and Hyaluronan (HA) were evaluated histochemically with Alecian blue and immunohistochemically with CS-56 antibody. Chondrocytes in alginate beads were arbitrarily classified into four groups: 1) chodrocyte surrounded with cell-associated matrix (CAM) in which proteoglycan (PG) was positively stained (PG-possitive chondrocyte); 2) chondrocyte with PG-negative CAM; 3) PG-positive CAM alone, and 4) PG-negative CAM alone. Total sulfated GAG concentrations in the culture media were quantitated by dimethylmethylene blue (DMMB) assay. ProMMP-3, TIMP-1 and -2 concentrations in the culture media were determined by sandwich enzyme immunoassays., Results: Significant increase of PG-nagative cells were immunohistochemically found by IL-1β stimulation. The pretreatment with TGF-β almost fully suppressed those increase of PG-negative cells by IL-1β. Both GAG and proMMP-3 concentrations in the culture media were significantly increased after IL-1β stimulation. There were no significant differences in both TIMP-1 and TIMP-2 concentrations in the culture media with or without IL-1β stimulation. 800-kDa HA reduced significantly the number of PG-negative cells and proMMP-3 concentration in the culture media, but showed no effects on the concentrations of both TIMPs., Conclusions: Because this 3-dimensional chondrocyte culture in alginate beads is close to in vivo conditions, this method can be used for evaluation of the effectiveness of novel drugs for articular diseases.

Purpose: The purpose of this study was to detect mutation of the p53 gene, to assess its relationship with p53 or p21(WAF1/CIP1) expression, and to evaluate the correlation between p53 mutation or p21(WAF1/CIP1) expression and clinicopathologic findings in sebaceous carcinoma of the eyelid., Methods: Fifteen conventional paraffin-embedded samples of sebaceous carcinoma of the eyelid were analyzed. Using the single-strand conformation polymorphism technique, the authors sequenced coding exons 5-8 of the p53 gene. The expression of p53 and p21(WAF1/CIP1) protein was analyzed by immunohistochemistry., Results: In 10 of the 15 cases (66.7%), point mutations were detected in the p53 gene. CC to TT double-base changes (tandem mutations), which are known to be induced only by UV, were not detected in any of the mutations. Correlations between p53 mutation and expression were found to be statistically significant (P = 0.007). There was no significant correlation between p53 mutation and clinicopathologic findings or p21(WAF1/CIP1) expression. However, there was a significant inverse correlation between p21(WAF1/CIP1) expression and presence of lymph node metastasis (P = 0.007)., Conclusions: Among human cancers, sebaceous carcinoma of the eyelid may be one of those showing most frequent mutation of the p53 gene, which may not be caused by exposure to UV. p21(WAF1/CIP1) downregulation may be associated with lymph node metastasis.

Background and Aim: Terlipressin has been shown to be effective in the management of hepatorenal syndrome. However, how terlipressin exerts its effect on the renal artery is unknown. The aim of the present study was to assess the effects of terlipressin on systemic, hepatic and renal hemodynamics in cirrhosis., Methods: Twenty-eight patients with cirrhosis and portal hypertension were studied. Systemic and hepatic hemodynamics, hepatic and renal arterial resistive indices and neurohumoral factors were measured prior to and 30 min after intravenous administration of 1 mg terlipressin (n = 19) or placebo (n = 9)., Results: After terlipressin, there were significant increases in both mean arterial pressure (P < 0.001) and systemic vascular resistance (P < 0.001), whereas heart rate (P < 0.001) and cardiac output (P < 0.001) decreased significantly. There was a significant decrease in the hepatic venous pressure gradient (P < 0.001). Portal venous blood flow also decreased significantly (P < 0.001). The mean hepatic arterial velocity increased significantly (P < 0.001). Although there was a significant decrease in the hepatic arterial resistive index (0.72 +/- 0.08 to 0.69 +/- 0.08, P < 0.001) and renal arterial resistive index (0.74 +/- 0.07 to 0.68 +/- 0.07, P < 0.001), portal vascular resistance was unchanged (P = 0.231). Plasma renin activity decreased significantly (P < 0.005), and there was a significant correlation between this decline and the decrease in renal arterial resistive index (r = 0.764, P < 0.005). The effects of terlipressin on systemic, hepatic and renal hemodynamics were observed similarly in patients with and without ascites. Placebo caused no significant effects., Conclusion: Terlipressin decreases hepatic and renal arterial resistance in patients with cirrhosis.

Background: To report the changes in the optical coherence tomography (OCT) images of the outer retinal layers after prolonged dark adaptation in a patient with Oguchi disease., Case: A 75-year-old woman showed the typical golden-yellow fundus reflex of Oguchi disease, and the coloration returned to normal after prolonged dark adaptation. Fourier domain OCT (FD-OCT) was performed on the patient's left eye before and after prolonged dark adaptation., Observations: Before dark adaptation, the FD-OCT images at the fovea had three identifiable reflection bands, namely, the external limiting membrane (ELM), the border between the photoreceptor inner and outer segments (IS/OS line), and the retinal pigment epithelium (RPE)/Bruch band. The paramacular area had only the ELM and RPE/Bruch bands. After 4 h of dark adaptation, the IS/OS line was also detected in the paramacular area., Conclusions: The absence of the IS/OS line in the extramacular regions in the partly dark adapted condition was most likely due to a defect in the rod photoreceptors of this area. The emergence of the IS/OS line after prolonged dark adaptation suggests that microarchitectural changes occur in the photoreceptors and that the changes may be correlated with the improvement of rod function.

In this prospective cohort study, we evaluated the use of transjugular intrahepatic portosystemic shunt (TIPS) in 50 patients with refractory ascites and a Child-Pugh score of 9.8. The mean duration of follow-up was 592 days. Ascites improved in 96% at 1 year and in 93% at 2 years. The cumulative survival rate was 71%, 52% and 18% at 1, 2 and 5 years. The Child-Pugh score and the performance status score improved significantly after TIPS. Thirty six patients required shunt revision during follow-up, due to shunt stenosis. Hepatic encephalopathy which was able to be controlled medically occurred in 26 patients. Our results suggest that although shunt revision may be needed, TIPS can control refractory ascites in most survival cases and improve QOL. However, the 5-year survival rate is still low in our TIPS-treated patients with refractory ascites.

Purpose: To determine the relationship of the photopic negative response (PhNR) of the photopic electroretinogram (ERG) with the degree of circulatory disturbances in eyes following central retinal artery occlusion (CRAO)., Methods: The circulatory disturbance was graded as mild (group 1) when the arm-to-retina transmission time was <30 s, moderate (group 2) when the time was >30 s and severe (group 3) when concurrent choroidal circulatory damage was found. For statistical analysis, groups 1, 2 and 3 were scored as 1, 2 and 3, respectively. Photopic ERGs were elicited by either short-flash (SF) or long-flash (LF) stimuli., Results: Both the SF and LF PhNR were significantly reduced in groups 2 and 3. The PhNR amplitude was negatively correlated with the severity of the ocular circulatory disturbances (p = 0.0498, rho = -0.507 for SF PhNR; p = 0.0050, rho = -0.750 for LF PhNR)., Conclusion: The amplitude of the PhNR became more reduced as the severity of the circulatory disturbances increased in eyes with CRAO., (Copyright 2009 S. Karger AG, Basel.)

A healthy 40-year-old man developed unilateral ocular ischemic syndrome as the only manifestation of a spontaneous internal carotid artery dissection.

Early-onset familial Paget disease of bone (EoPDB) is a rare condition caused by a 27-bp insertion mutation affecting the signal peptide of TNFRSF11A, which encodes RANK. EoPDB shows phenotypic overlap to both familial expansile osteolysis and expansile skeletal hyperphosphatasia, which are caused by similar mutations in TNFRSF11A. Although EoPDB is characterized by elevated bone turnover, there is no published information on the response of this condition to antiresorptive therapy. Here, we describe the clinical and biochemical response to bisphosphonate therapy in three patients with EoPDB. In all cases, treatment with the first-generation bisphosphonate etidronate at high doses reduced biochemical markers of bone turnover but the response was incomplete and short-lived. In contrast, treatment with aminobisphosphonates resulted in greater suppression of biochemical markers of bone turnover with an extended duration of response. From a clinical perspective, the results were less impressive and there was no clear benefit from antiresorptive treatment in terms of bone deformity, deafness, and tooth loss, although bone pain improved in one patient. We conclude that intravenous aminobisphosphonate therapy may be the preferred mode of treatment for EoPDB to provide long-term suppression of bone turnover. The long-term clinical effects of treatment on the natural history of the bone disease remain uncertain however, and this will require further study.

Background: We investigated the relationship between the retinal thickness and electroretinogram (ERG) components in patients with central retinal artery occlusion (CRAO)., Methods: The optical coherence tomographic (OCT) images and ERGs of the nine patients (six men and three women; mean age, 61.8 years) were retrospectively analyzed. The thickness of the inner and outer retinal layers at 1 and 2 mm nasal and temporal to the fovea was measured in the horizontally scanned OCT images. The ratio of the inner layer thickness/sensory retinal thickness (IT/ST ratio) was calculated. The amplitudes of the a- and b-waves of the mixed rod-cone ERGs and the photopic negative response (PhNR) of the photopic ERGs were analyzed. The ratio of the amplitude of each component in the affected eye to that of the healthy fellow eye (a/f ratio) was calculated., Results: In the chronic phase (1 to 8 months after onset, eight eyes), the inner layer was significantly thinner than that in the acute phase (P = 0.0147, 0.0076, 0.002, and 0.0003 for 2 mm nasal, 1 mm nasal, 1 mm temporal, and 2 mm temporal respectively, within 5 days of onset, six eyes), while the thickness of outer layer was not significantly changed. The ERGs were recorded 6.4 +/- 1.5 days after the onset of CRAO. The median of the a/f ratio was 0.84 in the a-wave, 0.56 in the b-wave, and 0.27 in the PhNR. The IT/ST in the chronic phase was positively correlated with the a/f ratio of the amplitude of the PhNR., Conclusions: Measurement of retinal thickness by OCT can be useful for monitoring the changes following CRAO. The correlation between the retinal thickness, especially inner layer thickness, and the ERG components was determined, suggesting that the PhNR in the acute phase might be a good indicator for predicting the thinning of the damaged retina in the chronic phase.

Some cirrhotic patients have hepatic veno-venous communications (HVVC) and large porto-systemic collaterals. However, the relationship between wedged hepatic vein pressure (WHVP) and portal vein pressure (PVP) in such patients is not clear. The aim of this study was to determine the relationships between simultaneously measured WHVP and PVP, and occluded hepatic and splenic portal venography in 100 cirrhotic patients (40 alcoholic and 60 hepatitis C virus (HCV)-related cirrhosis). PVP and WHVP were closely related in both groups (alcoholic-cirrhosis: 27.8 +/- 4.7 and 27.5 +/- 4.8 mmHg, HCV-cirrhosis: 27.3 +/- 3.7 and 26.2 +/- 4.4 mmHg, respectively). Occluded hepatic venography revealed that 13 of the 100 patients had HVVC (alcoholic-cirrhosis: 4, HCV-cirrhosis: 9). In patients with HVVC, PVP (27.9 +/- 3.0 mmHg) was significantly higher than WHVP (21.9 +/- 3.3 mmHg, P < 0.001). Large porto-systemic collaterals did not affect the relationship. We conclude that HVVC affects the relationship between PVP and WHVP. When WHVP is measured, occluded hepatic venography should be examined to detect HVVC.

Background: A primary conjunctival epithelial cyst is an uncommon lesion that consists of nonkeratized, stratified squamous epithelium without dermal appendages., Methods: Case report., Results: A 57-year-old woman presented with a soft mass in the anterior portion of the nasal orbit. Magnetic resonance imaging demonstrated a rounded, cystic lesion between the right eye and the nasal bone. Histopathological examination following complete surgical excision disclosed a conjunctival epithelial cyst lined by nonkeratinized cuboidal epithelium without goblet cells and adnexal structures., Conclusion: A conjunctival epithelial cyst should be considered in the differential diagnosis of a mass in the anterior portion of nasal or superonasal orbit.

Purpose: The purpose of this study was to evaluate the characteristics of Vogt-Koyanagi-Harada (VKH) disease in elderly (age > or =65 years) Japanese patients., Methods: We reviewed the medical records of all patients diagnosed with VKH disease at the Department of Ophthalmology, Oita University Hospital between October 1982 and March 2005. Data extracted included age, gender, prodromal symptoms, visual acuity, ocular manifestations, extraocular findings, human leukocyte antigen (HLA), ocular complications, treatment, and smoldering inflammation., Results: Of the 68 patients with VKH disease, seven (10%) were classified as elderly at onset. The incidence of optic disk hyperemia, choroidal detachment, and cataract was significantly higher in the elderly patients than the non-elderly patients (<65 years). The total dose of corticosteroid used was higher in the elderly. The incidence of smoldering inflammation was more frequent in the elderly. Final visual acuity was preserved relatively well in the elderly., Conclusion: The significantly higher incidence of optic disk hyperemia, choroidal detachment, and cataract, and the more frequent smoldering inflammation in elderly VKH patients indicate that special attention should be paid to these parameters in elderly patients.

Proliferative vitreoretinopathy (PVR) is a major cause of the failure of rhegmatogenous retinal detachment surgery. The pathogenesis of PVR includes a fibrotic reaction of retinal pigment epithelial (RPE) cells caused by transforming growth factor (TGF)-beta. The cellular mechanisms by which TGF-beta induces extracellular matrix protein synthesis are not fully understood. In this study, we examined whether the RhoA/Rho-kinase pathway was involved in TGF-beta2-induced collagen expression in a human RPE cell line, ARPE-19. The roles of RhoA and Rho-kinase were evaluated using biochemical inhibitors, RhoA inhibitor, simvastatin and Rho-kinase inhibitor, Y27632. The effects of simvastatin or Y27632 on the type I collagen mRNA (COL1A1 and COL1A2) expression induced by TGF-beta2 were evaluated by real-time RT-PCR. The effects of simvastatin or Y27632 on type I collagen synthesis induced by TGF-beta2 were assessed by immunocytochemical analysis with anti-type I collagen antibody. To examine the effects of simvastatin or Y27632 on COL1A2 promoter activity induced by TGF-beta2, luciferase reporter assays were also performed. Moreover, the role of RhoA itself on COL1A2 promoter activity was assessed using the constructs of constitutively active RhoA and dominant-negative RhoA. RhoA was activated within 5 min after stimulation with TGF-beta2, and its activation persisted for as long as 1 h in a dose-dependent fashion. Preincubation of ARPE-19 with simvastatin (5 microM) or Y27632 (10 microM) significantly prevented TGF-beta2-induced COL1A1 and COL1A2 gene expression. Inhibition of RhoA/Rho-kinase markedly suppressed TGF-beta2-induced type I collagen synthesis in ARPE-19. Moreover, the blockage of RhoA/Rho-kinase inhibited the increase in COL1A2 promoter activity when induced by TGF-beta2. Constitutively active RhoA increased COL1A2 promoter activity in the presence or absence of TGF-beta2. Simvastatin and Y27632 reduced active RhoA-induced COL1A2 promoter activity. The dominant-negative RhoA inhibited COL1A2 promoter activity augmentation induced by TGF-beta2. In the luciferase assay using a mutation construct of the Smad binding site in COL1A2 promoter (Smad-mut/Luc), the treatment with simvastatin and Y27632 significantly reduced TGF-beta2 induction of Smad-mut/Luc promoter activity. On the other hand, both simvastatin and Y27632 significantly reduced CAGA12-Luc activity induced by TGF-beta2. These results indicate that the RhoA/Rho-kinase pathway plays a role in relaying TGF-beta2 signal transduction to type I collagen synthesis in RPE cells in a Smad-dependent and Smad-independent fashion. The RhoA/Rho-kinase pathway may be a therapeutic target for treating PVR.

In order to define the histological components of ocular defense, the conjunctiva in Japanese monkeys was studied using a whole mount method, light microscopy, and electron microscopy. We investigated the distribution of the conjunctiva-associated lymphoid tissue (CALT) using stereoscopic observations of the conjunctiva immunostained with human leukocyte antigen (HLA)-DR antibody and /or stained with alcian-blue. The outer surface of the conjunctival fornix was lined by sheets of mucus secreting goblet cells, with small epithelial patches without goblet cells, scattered among them. The patches, termed CALT, consisted of flattened epithelial cells, intraepithelial lymphocytes and dendritic cells, and lymphoid follicles with a germinal center. The CALT in Japanese monkeys was fundamentally similar in structure to those found in other animal species. CALT patches ranged in size ranging from 200 microm to 300 microm in diameter. The number of patches varied from 20 to 40 in the superior eyelid and 10 to 20 in the inferior eyelid. Latex microspheres administrated as eye drops were selectively taken up first by flattened associated epithelial cells covering the surfaces of CALT patches and then by intraepithelial dendritic cells of the CALT. These morphological findings show that CALT patches in the eyelids of primates are focal sites for particulate uptake and contact with lymphoid constituents, indicating that they are inductive sites for the common mucosal immune system as well as important components in ocular defense.

Purpose: To investigate optic disc topographic parameters at every stage in glaucoma patients and to compare results with data from normal Japanese subjects. We used a Heidelberg Retina Tomograph II (HRT II), to evaluate the sector diagnostic capabilities of Moorfields regression analysis in early glaucoma patients, and to determine whether there is a correlation between the background factors and either the topographic parameters or the diagnostic capabilities., Subjects and Methods: We measured topographic parameters using HRT II, and examined static visual fields in 303 normal and 130 glaucoma eyes without high refractive error., Results: Mean disc area was 2.181 +/- 0.384 mm2 in the normal Japanese subjects. At the time visual field loss first appeared, disc damage was already advanced. Moorfields regression analysis of sensitivity and specificity was 81.3% and 90.1%, respectively, for early glaucoma. The best diagnostic precision was found in the temporal/inferior sector. Correlations were noted for normal subject topographic parameters and the disc area, age, sex, and conus, but not for Moorfields regression analysis and the disc area, refractive error, age, and sex, even though diagnostic capabilities declined with the presence of conus., Conclusions: HRT II is more useful in glaucoma diagnosis than in follow-up. Focus should be on the temporal/inferior sector as well as on the overall Moorfields regression analysis. Also, close attention should be paid to the presence of conus.

Purpose: To determine the effect of the spatial frequency of a small grating stimulus centered on the macula on the focal macular ERGs (fmacERGs) of monkeys., Methods: fmacERGs were recorded from eight eyes of four adult monkeys (Macaca fuscata). The spatial frequency of the stimulus was changed from 0.25 to 8 cycles/degree. The luminance of the light bars was 10 cd/m(2), and the contrast was 95%. The stimulus was flashed on and off with an on duration of 100 ms and an off duration of 150 ms (4 Hz). The stimulus was centered on the fovea and subtended 12.7 degrees at the cornea. The luminance of the steady light-adapting background was 3.5 cd/m(2). The location of the stimulus on the retina was monitored throughout the recordings. The effects of the spatial frequency of the stimulus on the amplitudes and implicit times of the a-waves, b-waves, and oscillatory potentials (OPs) were determined. fmacERGs were also recorded following intravitreal tetrodotoxin (TTX)., Results: The amplitudes of the a- and b-waves did not change with changes in the spatial frequency of the stimulus. The OPs, on the other hand, responded best to the lowest spatial frequency, and the OPs after the first two were attenuated at intermediate and higher frequencies (Wilcoxon signed-rank test: P < 0.05). TTX reduced all OP wavelets in monkeys., Conclusions: The OPs of the photopic macular ERGs are affected by the spatial frequency of the stimulus and are reduced by TTX, consistent with their being generated by inner retinal neurons.

Propeptides of type I procollagen are generated during the process of collagen formation in bone matrix. Among them measurements of circulating N-terminal propeptide (PINP) has been recognized as one of promising metabolic bone markers in the assessment of efficacy of pharmaceutical intervention for osteoporosis. Recently assays of PINP have been established to be supplied as measurement kits following those of C-terminal propeptide (PICP) and clinical data on usefulness of PINP in the evaluation of teriparatide an anabolic agent as well as various anti-catabolic agents have accumulated. Therefore, the measurement of PINP must be an essential tool in Japan at the time when newer agents for osteoporosis are applied to clinical practice in the future.

The present study aimed to evaluate the prevalence and clinical presentation of Paget's disease of bone (PDB) in Japan. As PDB is a very rare disease in Japan, a nationwide mail survey was conducted targeting doctors in the specialty most frequently diagnosing and treating PDB patients in Japan. First, the literature for all case reports in Japan published between January 1990 and December 2002 was reviewed to determine who was diagnosing and treating PDB in Japan. This literature review for all case reports in Japan revealed that 72.1% of cases in Japan were reported from departments of orthopedic surgery. A nationwide two-phase mail survey was conducted for the departments of orthopedic surgery of 2,320 general hospitals accredited by the Japanese Orthopaedic Association. Phase 1 involved determining how many patients with PDB were followed at each hospital. If the answer was one or more, phase 2 of the survey gathered information on the clinical presentation of current patients. The mail survey yielded a final response rate of 75.4% for phase 1 and 87.6% for phase 2. Phase 1 indicated that the prevalence of PDB in Japan is about 2.8 cases per million capita. Phase 2 revealed a slight female predominance, lower frequency of familial clustering, higher frequency of femoral fracture in the affected femur, and a higher ratio of symptomatic PDB in Japan compared with findings in countries displaying a higher prevalence of PDB. The present epidemiological study revealed that the disorder is extremely rare in Japanese individuals, and that some differences exist with regard to the clinical features of PDB between Japanese patients and patients from high-prevalence countries.

We here propose guidelines for the diagnosis and management of Paget's disease of bone (PDB) in Japan. These guidelines provide basic information on the epidemiology, pathophysiology, clinical signs and symptoms, diagnosis, indications for treatment, and available therapy, including orthopedic surgery. PDB is a chronic disorder characterized by focal abnormalities of bone turnover. The characteristic feature of PDB is excessive osteoclastic bone resorption coupled to increased and disorganized bone formation. The most common symptom of PDB is pain in involved bones. The most serious complication of PDB is malignant bone or soft-tissue tumor. PDB is uncommon in Japan; our survey in 2003 found 169 patients with PDB. The prevalence of PDB in Japan is 0.15/100 000; in patients aged 55 years or more, the proportion reaches 0.41/100 000. A careful medical history and physical examination are essential for the diagnosis. The diagnosis of PDB is based on finding the typical features on radiographs. Bone scintigraphy and measurement of serum alkaline phosphatase are sensitive means of screening for PDB. Since PDB is a rare disease in Japan, bone biopsy is quite often used to exclude bone metastases. The only evidence-based indication for treatment of PDB is pain in involved bones. In Japan, etidronate and calcitonin are approved by the Ministry of Health, Labour and Welfare for treating PDB, but currently risedronate is also under development for treating PDB in Japan. Indications for surgical intervention in PDB include unstable fractures, osteoarthritis, malignant soft-tissue tumor, osteosarcoma, and bone deformity.

A number of prospective studies in the USA and Europe have demonstrated that quantitative ultrasound (QUS) measurements predict fracture risk. To our knowledge, there has been no such study in a Japanese population, and very few studies have measured the prognostic value of QUS measurements among men, even in the USA and Europe. We performed a three-center prospective study to investigate the relationship between baseline heel QUS measurements and non-spine fracture risk. There were 4,028 subjects (1,004 men and 3,024 women), 67.5+/-8.9 years [mean +/- standard deviation (SD)] of age), who underwent heel QUS (Achilles device) at three centers between 1993 and 2000. In 2002, the subjects were mailed a standardized questionnaire that asked about their history of fracture. The mean follow-up period was approximately 5 years. The Achilles measured speed of sound (SOS) and broadband ultrasound attenuation (BUA). We used Cox regression analysis to determine the hazard ratio (HR), using weighted coefficients. SOS, BUA, and stiffness index (SI) predicted self-reported hip, wrist, and total non-spine fractures. After we had adjusted for age, gender, and weight, the HRs of total non-spine fracture were 1.54 [95% confidence interval (CI) 1.39-1.69], 1.53 (1.37-1.70), and 1.80 (1.62-1.98) for 1 SD decrease in SOS, BUA, and SI, respectively. In men, SOS and SI also predicted total non-spine fractures with HRs similar to those in women. The HR of prediction for hip fracture by SOS and SI was better in the short term than in the long term, and the prediction for hip, wrist, and non-spine fracture remained significant between 5 to 10 years of follow-up. Measurements obtained from heel QUS predicted non-spine fracture in Japanese men and women, and the HRs of Japanese of both genders was similar to the risk ratio (RR) of Caucasian men and women. QUS parameters can predict hip, wrist, and non-spine fracture up to 10 years.

Background: Oncocytoma is rarely found around the lacrimal punctum. We describe a case of oncocytoma of the peripunctum., Methods: Case report., Results: An 88-year-old patient presented with a upper peripunctal mass in the left eye. The tumor was completely excised including the lacrimal punctum and part of the canaliculus. The upper eyelid was reconstructed with a skin flap from the residual skin of the lid, and the lacrimal canaliclus was replaced by a silicone rubber tube. Histologically, the tumor had tubulo-papillary architecture and was composed of two layers of cuboidal cells. The cytoplasm of the tumor cells was rich in eosinophilic granules. The diagnosis was oncocytoma arising from the canaliculus., Conclusion: Oncocytoma should be considered in differential diagnosis of a peripunctal mass in elderly patients. In this patient it probably originated from the epithelium of the lacrimal canaliculus.

P-glycoprotein (P-gp) expels various drugs from cells, resulting in multidrug resistance, including against glucocorticoids. Here, we present a case of systemic lupus erythematosus (SLE) that suggests the importance of initial intensive treatment in overcoming unresponsiveness due to P-gp overexpression on activated lymphocytes. A 28-year-old woman had been diagnosed with highly active SLE including severe pericarditis, hemolytic anemia, lupus nephritis, and retinopathy. The disease activity of SLE progressed despite 1 mg/kg per day oral prednisolone. At the time, P-gp expression was extremely high, as evaluated by flow cytometric analysis on peripheral lymphocytes. After intensive treatment with three courses of methylprednisolone pulse therapy and plasmapheresis, we succeeded in controlling disease activity in association with marked reduction of P-gp overexpression; namely, the clinical symptoms immediately improved along with the reduction of P-gp expression. These results imply that patients with highly active SLE might have drug unresponsiveness that is mediated by P-gp overexpression on lymphocytes. Therefore, downregulation of P-gp by initial intensive immunosuppressive therapy might be important for overcoming glucocorticoid resistance. We also propose that measurement of P-gp on lymphocytes is a useful test for prediction of drug resistance and may assist in the selection of appropriate initial treatment.

The aim of this prospective study was to investigate the incidence, clinical features and the short- and long-term clinical course of hepatic encephalopathy (HE) after transjugular intrahepatic portosystemic shunt (TIPS) in Japanese patients. Eighty-seven consecutive patients with liver cirrhosis presenting with complications of portal hypertension underwent TIPS. The mean follow-up period after TIPS was 866 days. During the follow-up, HE occurred in 52% of patients throughout the follow-up period. The cumulative incidence of post-TIPS HE was 50.5+/-5.6% at 1 year (mean+/-S.D.). Most cases (89%) occurring within 7 days were easily controlled by the conventional therapy. Only two patients developed severe chronic HE, which was treated by reducing the shunt diameter. Older age, indication for TIPS (ascites) and higher retention rate of indocyanine green at 15min were identified as risk factors for post-TIPS HE. During long-term follow-up, the incident of post-TIPS HE decreased among survivals. The cumulative survival rate was similar in patients with or without post-TIPS HE. Our results indicate that post-TIPS HE are a frequent complication, particularly in the early months after TIPS. However, it can be easily managed in the majority of patients. The development of post-TIPS HE is not associated with poor prognosis in TIPS patients.

A 18-year-old female had low grade fever, butterfly rush, proteinuria, leukocytopenia and hypocomplimentemia in 1988, and she was diagnosed as systemic lupus erythematosus (SLE) with lupus nephritis (WHOIIb). Treatments with prednisolone and mizoribine resulted in the remission for three years. In May 2001, she presented neurosis and polakisuria despite of the increase of prednisolone to 20 mg/day. Finally, she admitted in our hospital because of manic and repressive state and disorientaion. A brain MRI revealed high intensity lesions in bilateral basal ganglia in T2 weighted images, and cerebrospinal fluid showed elevated protein and IFN-alpha (421 IU/ml). In addition, she manifested neurogenic bladder, muscle weakness and hyperactive deep tendon reflex of bilateral lower limbs due to both supranuclear disorder and hypesthesia under the Th 10 level. Spinal MRI revealed marked atrophy and high intensity signals at the middle to lower thoracic spinal cord in T2 weighted images, indicating complication of lupus myelitis as well as cerebral involvement. Although the symptoms of CNS lupus did not respond to prednisolone, twelve monthly cyclophosphamide pulse therapy (IV-CY) has resolved urinary disturbance, muscle weakness and sensory loss, along with the improvement of both cerebral and spinal MRI images. Lupus myelitis and neurogenic bladder are the rare, but very refractory manifestation among CNS involvement of SLE. We here propose IV-CY as an invaluable choice for the treatment of not only active lupus myelitis but also neurogenic bladder resisted for steroid.

Purpose: Transforming growth factor (TGF)-beta has been implicated as the key mediator of proliferative vitreoretinopathy, but the cellular mechanisms by which TGF-beta induces extracellular matrix protein (ECM) synthesis are not fully understood. The current study was conducted to examine whether the mitogen-activated protein kinase (MAPK) pathway is involved in TGF-beta 2-induced collagen expression in retinal pigment epithelial cells., Methods: Human retinal pigment epithelial cells ARPE-19 were cultured and stimulated with various concentrations of TGF-beta 2. The type I collagen gene (COL1A1, COL1A2) expression induced by TGF-beta 2 was evaluated by real-time RT-PCR. Synthesis of type I collagen was evaluated by the concentration of the C-terminal propeptide of type I (PICP) in the medium. The activation of MAPK pathways by TGF-beta 2 was assessed by immunoblot with anti-phospho-p38 and anti-phospho-extracellular signal-regulated kinase (ERK)1/2 antibodies. The role of MAPK was assessed using biochemical inhibitors. To examine the transcriptional activities of COL1A1 and COL1A2, luciferase reporter assays were also performed., Results: mRNA expression of COL1A1 and COL1A2 and type I collagen synthesis were activated by TGF-beta 2. Both ERK and p38 MAPK pathways were also activated by TGF-beta 2. The biochemical blockade of p38 MAPK activation, but not ERK activation, inhibited TGF-beta 2-induced type I collagen mRNA expression and type I collagen synthesis. Moreover, blockade of the p38 MAPK pathway inhibited the increase in both COL1A1 and COL1A2 promoter activities when induced by TGF-beta 2., Conclusions: TGF-beta 2 activates p38 MAPK and p38 MAPK plays a role in relaying the TGF-beta 2 signal to type I collagen production in the retinal pigment epithelium.

Background: Fibroblast growth factor (FGF)-23 is a recently identified circulating factor which causes renal phosphate wasting disorders. Although the mechanism of regulation of FGF-23 secretion is unknown, plasma FGF-23 level may be regulated or affected by serum phosphate levels because of its hypophosphatemic effect., Methods: We tested the hypothesis that plasma FGF-23 levels may be increased in hyperphosphatemia in patients with end-stage renal disease (ESRD) on maintenance hemodialysis. We measured plasma FGF-23 levels in 158 male uremic patients on maintenance hemodialysis. Plasma samples were obtained before starting dialysis sessions to determine FGF-23 levels by enzyme-linked immunosorbent assay (ELISA)., Results: Plasma FGF-23 level exhibited significant and positive correlations with inorganic phosphate, intact parathyroid hormone (PTH), corrected calcium, and duration of hemodialysis on simple regression analyses. All these associations remained significant in multiple regression analyses., Conclusion: Serum phosphate, calcium, and intact PTH could be regulators of FGF-23 levels in uremic patients on maintenance hemodialysis. Our results may provide new insights into the pathophysiologic effects of FGF-23 on calcium-phosphate homeostasis.

Objectives: We evaluated the polymerase chain reaction (PCR) detection of Pneumocystis carinii DNA in induced sputum of patients with connective tissue diseases and assessed the clinical features of patients positive for P. carinii., Methods: Sputum was induced by nebulization in 29 in-patients with various connective tissue diseases who presented with symptoms suggestive of P. carinii pneumonia (PCP), and was examined by PCR., Results: Detection of P. carinii DNA by PCR was significantly more sensitive than cytology; 54.5% patients were positive by PCR and only 4.5% by cytology. The prevalence of PCP was higher than previously considered and was especially high in patients receiving > 30 mg/day prednisolone with or without other immunosuppressants. P. carinii-positive patients had significant lymphocytopenia and a low serum IgG level compared with P. carinii-negative patients. P. carinii disappeared within 7-10 days after therapy with trimethoprim/sulfamethoxazole., Conclusion: We propose that the use of PCR for detection of P. carinii using induced sputum is a useful and non-invasive method that has high sensitivity and specificity for the early diagnosis of PCP.

Background: The Bio-Intact parathyroid hormone (1-84) assay (Bio-PTH), a newly developed two-site immunochemiluminometric assay, measures exclusively PTH (1-84) in contrast to second-generation "intact PTH" (I-PTH) assays. We investigated the technical performance and clinical significance of this new assay., Methods: PTH was measured simultaneously by the Bio-PTH assay and Allegro intact PTH IRMA in sera from Japanese patients with calcium disorders., Results: Measured Bio-PTH in serum was unaffected by six freeze-thaw cycles and was stable at 4 degrees C for 7 days and during storage at -20 or -80 degrees C over 28 days. The calibration curve was linear to 1800 ng/L. The detection limit was 3.9 ng/L. The intra- and interassay imprecision was <2.8% and 3.5%, respectively, for analyte concentrations spanning the range of the calibration curve. Bio-PTH was unaffected by a 1000-fold excess of PTH (7-84), although I-PTH reacted equally with PTH (7-84) and PTH (1-84). Bio-PTH was correlated with I-PTH in healthy individuals (r = 0.953; P <0.0001; n = 26) and in the full population without renal dysfunction (r = 0.994; P <0.0001; n = 62). In 72 volunteers, mean (SD) Bio-PTH was 22.2 (7.1) ng/L, or 62% of the mean I-PTH [36.1 (22.3) ng/L]. This ratio was 51% in hemodialysis patients (n = 177). Mean Bio-PTH was high in patients with primary hyperparathyroidism [121 (85) ng/L; n = 18] and hemodialysis patients [102 (104) ng/L; n = 177], low in idiopathic hypoparathyroidism [5.5 (2.8) ng/L; n = 4], and within 2 SD of the mean for healthy controls in Paget disease of the bone [34 (15) ng/L; n = 9] and bone metastasis [24 (12) ng/L; n = 8]., Conclusion: The Bio-PTH assay is sensitive and precise and produces expected results for patients with the studied disorders of calcium metabolism.

A 49-year-old Japanese woman was diagnosed with rheumatoid arthritis (RA) based on ACR criteria in May 1999. She developed liver injury after initiation of disease-modifying antirheumatic drugs (DMARDs) and was found to have contracted HCV infection. RA disease activity worsened following restriction of medication due to liver dysfunction. However, 3 mg/day of prednisolone (PSL) resulted in a temporary but marked improvement of RA in December 2001; but arthritis recurred along with Raynaud's phenomenon and palpable purpura. Differential diagnosis between arthritis caused by cryoglobulinemia and exacerbation of RA was important for the selection of appropriate treatment. She manifested non-erosive arthritis on medium and large joints with proteinuria, hematuria and hypocomplementemia. In addition, type III cryoglobulin was detected and chronic active hepatitis was observed on liver biopsy in March 2002. We considered that the main cause for the arthritis was HCV-related mixed cryoglobulinemia. Administration of IFN-alpha resulted in the disappearance of HCV-RNA and cryoglobulin followed by amelioration of arthritis without exacerbation of RA.

The newly developed Elecsys Beta-CrossLaps/serum assay measures C-terminal telopeptide of type I collagen and has thus been proposed as a reliable serum marker for bone resorption. We investigated its usefulness for monitoring the therapeutic effect of estrogen replacement therapy on bone turnover and bone mineral density (BMD) in patients with postmenopausal osteoporosis. Serum Beta-CTx decreased by 43.2% +/- 9.2% (mean +/- SD), and 55.1% +/- 7.0% at 3 and 6 months, respectively, after initiation of estrogen replacement therapy (ERT), which was significantly greater than the respective value of urinary excretion of deoxypyridinoline (DPD) (27.8% +/- 4.1%, 34.1% +/- 4.9%, respectively) or pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (ICTP) assay (14.5% +/- 4.1%, 13.1% +/- 5.0%, respectively). The percent reduction in serum Beta-CTx at 1, 3, and 6 months after initiation of ERT was significantly correlated in a negative manner with the percent increase in spinal BMD at 6 months. Further, ROC analysis to determine the significance of the percent change in bone resorption markers after 3 months of ERT in predicting the gain in spine BMD after 6 months suggested that serum Beta-CTx and urinary DPD might provide a more discriminating indicator than serum ICTP. In conclusion, the findings suggest that the Elecsys Beta-CrossLaps/serum assay provides a sensitive, and thus useful, tool for assessing bone resorption state in Japanese patients.