Large-Scale Membrane Permeability Prediction of Cyclic Peptides Crossing a Lipid Bilayer Based on Enhanced Sampling Molecular Dynamics Simulations.

Membrane permeability is a significant obstacle facing the development of cyclic peptide drugs. However, membrane permeation mechanisms are poorly understood. To investigate common features of permeable (and nonpermeable) designs, it is necessary to reproduce the membrane permeation process of cyclic peptides through the lipid bilayer. We simulated the membrane permeation process of 100 six-residue cyclic peptides across the lipid bilayer based on steered molecular dynamics (MD) and replica-exchange umbrella sampling simulations and predicted membrane permeability using the inhomogeneous solubility-diffusion model and a modified version of it. Furthermore, we confirmed the effectiveness of this protocol by predicting the membrane permeability of 56 eight-residue cyclic peptides with diverse chemical structures, including some confidential designs from a pharmaceutical company. As a result, a reasonable correlation between experimentally assessed and calculated membrane permeability of cyclic peptides was observed for the peptide libraries, except for strongly hydrophobic peptides. Our analysis of the MD trajectory demonstrated that most peptides were stabilized in the boundary region between bulk water and membrane and that for most peptides, the process of crossing the center of the membrane is the main obstacle to membrane permeation. The height of this barrier is well correlated with the electrostatic interaction between the peptide and the surrounding media. The structural and energetic features of the representative peptide at each vertical position within the membrane were also analyzed, revealing that peptides permeate the membrane by changing their orientation and conformation according to the surrounding environment.

A retrospective study on the outcomes of MPO-ANCA-associated vasculitis in dialysis-dependent patients.

OBJECTIVES: This study investigated the clinical course of myeloperoxidase-antineutrophil cytoplasm autoantibody (MPO-ANCA)-associated vasculitis after starting dialysis. METHODS: A retrospective review was conducted of the clinical charts of dialysis-dependent patients with MPO-ANCA-associated vasculitis who attended one of 8 associated clinics over the past 21 years. RESULTS: Eighty-nine patients were included in the study; 88 had microscopic polyangiitis (MPA) and 1 had granulomatosis with polyangiitis. Of the 88 patients with MPA, 18 had renal-limited vasculitis. Twenty-one relapses occurred among 13 patients (frequency, 0.05 relapses/person-year; 95% confidence interval, 0.03-0.08). Mean time from start of dialysis to relapse was 65 ± 59 months. Cox multivariate analysis showed that pulmonary involvement was a predictor of relapse (hazard ratio [HR], 21.4) and mortality (HR, 4.60), and that patient age (HR, 1.10) and cyclophosphamide use (HR, 0.20) were significant predictors of mortality. Postdialysis 1- and 5-year survival rates were 83.0% and 65.6%, respectively; infection was the most frequent cause of death. CONCLUSION: Pulmonary involvement was a predictor of relapse and mortality. Although relapse can occur long after the start of dialysis, incidence was low among dialysis-dependent patients. Prolonged maintenance immunosuppressive therapy might be limited to patients with pulmonary involvement in dialysis-dependent ANCA-associated vasculitis.

A prospective study on blood Aß levels and the cognitive function of patients with hemodialysis: a potential therapeutic strategy for Alzheimer's disease.

To obtain the proof of concept of a novel therapy for Alzheimer's disease (AD), we conducted two prospective studies with hemodialysis patients who had amyloid ß protein (Aß) removed from their blood three times a week. One major pathological change in the brain associated with AD is Aß deposition, mainly 40 amino acids Aß1-40 and 42 amino acids Aß1-42. Impaired Aß clearance is proposed to be one cause of increased Aß in the AD brain. Thus, we hypothesized that an extracorporeal removal system of Aß from the blood may remove brain Aß and be a useful therapeutic strategy for AD. In the first prospective study, plasma Aß levels and the cognitive function of 30 hemodialysis patients (65-76 years old) were evaluated at baseline as well as 18 or 36 months after. Although plasma Aß1-40 levels either decreased or remained unchanged, levels of Aß1-42 either remained unchanged or increased at the second time point. Mini-Mental State Examination scores of most subjects increased or were maintained at the second time point. Aß1-40 influx into the blood correlated with MMSE at the second time point. In the second prospective study, five patients (51-84 years old) with renal failure were evaluated before and after the initiation of hemodialysis. Plasma Aß levels decreased, while cognitive function improved after initiating blood Aß removal. Therefore, long-term hemodialysis, which effectively removes blood Aß, might alter Aß influx and help maintain cognitive function.

Immediate therapeutic efficacy of low-density lipoprotein apheresis for drug-resistant nephrotic syndrome: evidence from the short-term results from the POLARIS Study.

BACKGROUND: Hyperlipidemia is not merely a complication but a major exacerbating factor in longstanding nephrotic syndrome (NS). Low-density lipoprotein apheresis (LDL-A) has been reported to ameliorate dyslipidemia and induce rapid remission of NS. Several clinical studies have suggested the therapeutic efficacy of LDL-A, but the level of clinical evidence is insufficient. Therefore, a multicenter prospective study, POLARIS (Prospective Observational Survey on the Long-Term Effects of LDL Apheresis on Drug-Resistant Nephrotic Syndrome), was initiated in Japan. METHOD: Patients with drug-resistant NS were prospectively recruited into the study and treated with LDL-A in facilities that were registered in advance. In the POLARIS study design, the clinical data are to be followed up for 2 years. In the current study, we aimed at evaluating the short-term efficacy based on the treatment outcome of LDL-A immediately after completion of treatment. RESULTS: Along with rapid improvement of hyperlipidemia, LDL-A significantly improved proteinuria and hypoproteinemia after treatment. More than half of the patients showed remission of NS based on the urinary protein level at the completion of LDL-A. The duration of NS before the start of treatment was significantly shorter in patients who responded to LDL-A. CONCLUSIONS: An analysis of patients registered in the POLARIS study indicated that LDL-A has short-term efficacy for drug-resistant NS. Rapid relief of dyslipidemia by LDL-A may provide early remission in about half of the NS patients who are resistant to conventional medication. Completion of the POLARIS study may reveal additional long-term effects of LDL-A in these patients.

Comparison of effective impact among tonsillectomy alone, tonsillectomy combined with oral steroid and with steroid pulse therapy on long-term outcome of immunoglobulin A nephropathy.

BACKGROUND: To clarify the therapeutic impact of tonsillectomy and combined therapies of tonsillectomy plus steroid on the long-term prognosis of immunoglobulin A nephropathy (IgAN). METHODS: A retrospective study was conducted on 208 patients with IgAN between 1986 and 2009. According to the strategies for treatments, patients were divided into four groups: tonsillectomy and steroid pulse (TSP, n = 47), tonsillectomy and oral steroid (TOS, n = 33), tonsillectomy alone (T, n = 56), and N group (no particular therapy, n = 72). Multivariate analysis based on the Cox's regression model was used to assess the relative risk of reaching the outcome of doubling creatinine based on the influence of baseline prognostic factors. RESULTS: The mean observation periods were 53.8 months in the TSP group, 122.0 months in the TOS group, 102.9 months in the T group, and 84.6 months in the N group. During an observation period, serum creatinine levels doubled as follows: one in the TSP group (2.1 %), two in the TOS group (6.1 %), five in the T group (8.9 %), histological severity, and 22 in the N group (30.6 %). The Cox's regression proportional hazard model showed that gender, age, histological activity, dialysis induction risk and therapy were associated with doubling creatinine levels. Hazard ratios (95 % CI) and (P value) in T, TOS, and TSP groups versus N were 0.314 (0.11-0.93, P = 0.037), 0.213 (0.04-1.10, P = 0.065), and 0.032 (0.00-0.28, P = 0.002), respectively. CONCLUSION: A combination therapy of tonsillectomy and steroid pulse had the most significant therapeutic impact compared to other therapies.

A potential therapeutic system for Alzheimer's disease using adsorbents with alkyl ligands for removal of blood amyloid ß.

Amyloid beta proteins (Aß) in the brain are the main cause of Alzheimer's disease. Peripheral administration of Aß-binding substances, which may act as a sink for Aß from the brain, has been reported to reduce brain Aß. We previously found C16-cellulose beads had high Aß-removal activity in vitro. In this study, we investigated the optimum surface properties of adsorbents for removal of Aß in vitro and in humans. Batch analysis was performed with porous cellulose beads or silica beads with or without 2-22 methylene groups. Aß-removal activity of C16-cellulose beads increased with increasing alkyl chain length. In contrast, with cellulose the amount of Aß removed by the silica beads decreased with increasing alkyl chain length. Cellulose beads with 16 or 22 methylene groups were best (over 99 % removal) among all the beads tested (p ≤ 0.01). The adsorbent surfaces were analyzed by near-infrared spectroscopy, which revealed that the optimum beads had a sufficiently hydrophobic surface with an appropriate amount of adsorbed water accessible on the surface. Aß removal efficiency by C16-cellulose beads was investigated for 5 renal failure patients on hemodialysis, resulting in 51.1 ± 6.6 % for Aß1-40 and 43.8 ± 4.5 % for Aß1-42 (p ≤ 0.01). In conclusion, cellulose beads with 16 or 22 methylene groups and an appropriate amount of adsorbed water were the optimum Aß adsorbents. The device with C16-cellulose beads had high Aß removal activity in humans. These adsorbents might be useful for Alzheimer's disease therapy.

Potential therapeutic system for Alzheimer's disease: removal of blood Aßs by hemodialzyers and its effect on the cognitive functions of renal-failure patients.

The pathological changes of Alzheimer's disease include the deposition of amyloid ß protein (Aß) as senile plaques in the brain. We hypothesized that the rapid removal of Aßs from the blood may act as a peripheral Aß drainage sink from the brain. In this study, the plasma Aß concentrations and the cognitive functions were investigated for in 57 patients on hemodailysis (69.4 ± 3.8 years), 26 renal-failure patients without hemodialysis (66.6 ± 14.7 years), and 17 age-matched healthy controls (66.6 ± 4.1 years). The concentrations of plasma Aßs increased along with the decline of renal functions. Moreover, the renal-failure patients without hemodialysis and with poorer renal functions showed lower cognitive functions. The plasma concentrations of Aß(1-42) correlated with serum creatinine (P < 0.001) and Mini-Mental-State Examination scores (P = 0.017). The dialyzers effectively removed Aßs in the blood during hemodialysis sessions. The plasma Aß concentrations showed steady or slightly decreasing along with duration of hemodialysis. The total amount of Aßs removed during a hemodialysis session was calculated to be comparable to the Aßs dissolved in the blood and the cerebrospinal fluid. The MMSE scores of the hemodialysis patients showed no clear decrease in longer hemodialysis duration. Therefore, the therapeutic approach for Alzheimer's disease by removing Aßs from the blood is worthy of further investigation, including whether or not Aßs in the brain decrease.

Proposal of selective inhibitor for bacterial zinc metalloprotease: Molecular mechanics and ab initio molecular orbital calculations.

The zinc metalloprotease pseudolysin (PLN) secreted from Pseudomonas aeruginosa degrades extracellular proteins to produce bacterial nutrition, and various types of PLN inhibitors have been developed to suppress the bacterial growth. However, as the structure of the ligand-binding pocket of PLN has large similarities to those of human matrix metalloproteinases (MMPs) and other human zinc metalloprotease, there is a risk that PLN inhibitors also inhibit human zinc proteases. In this study, we propose a novel agent that may bind stronger to PLN than to MMPs. The compound is proposed based on the specific molecular interactions between existing agents and PLN/MMP metalloproteases evaluated by the present molecular simulations. First, we confirmed that the binding energies of PLN agents evaluated using the ab initio fragment molecular orbital method were comparable to the IC50 values obtained through previous experiments. In addition, the specific molecular interactions between these agents and MMP-9 were investigated to elucidate the fact that some of the agents bind weaker to MMP than PLN. Based on the results, we proposed a novel agent having a succinimide group introduce by a hydroxamic acid group and investigated its binding properties with PLN and MMP. The results may provide useful information for the development of potent inhibitors for PLN with few potential side effects in human bodies.

Water molecule-mediated selective inhibition of bacterial zinc metalloproteinases by non-hydroxamate compounds: Ab initio molecular simulations.

UDP-3-O-acyl-N acetylglucosamine deacetylase (LpxC), Zn metalloenzyme for Gram-negative bacteria is an attractive target for developing novel therapeutic agents. Since LpxC has the similar binding pocket as the human matrix metalloproteinases (MMPs), LpxC inhibitors might also inhibit MMP functions producing side effects in human bodies. Here, we investigated specific interactions between LpxC/MMP and their inhibitors using ab initio molecular simulations to elucidate the reason of selective inhibition for LpxC by non-hydroxamate compounds. The evaluated binding properties between LpxC and the compounds are comparable to the trend of their observed inhibitory affinities. It was also elucidated that compound 22 binds most strongly to LpxC due to its specific interactions with Zn ion and Asp241 side chain of LpxC. In contrast, the interactions between the compounds and MMP are significantly weakened due to the water molecules, which are tightly coordinated with the Zn ion in MMP and interrupt the binding of the compounds to the Zn ion. Accordingly, the present molecular simulations revealed that these water molecules around the Zn ion in MMP are causally related to the selective inhibition of these compounds for LpxC rather than MMP.

Retinal pigment epithelium melanin distribution estimated by polarisation entropy and its association with retinal sensitivity in patients with high myopia.

PURPOSE: To investigate retinal sensitivity of highly myopic eyes without choroidal neovascularisation (CNV) or patchy chorioretinal atrophy (PCA) and investigated its association with anatomical characteristics including melanin distribution at the retinal pigment epithelium (RPE), which was evaluated with polarisation-sensitive optical coherence tomography (PS-OCT). DESIGN: Retrospective consecutive observational cohort study. METHODS: We included highly myopic eyes (refractive error ≤-8.0 dioptres or axial length of ≥26.5 mm) from patients at the University of Tokyo Hospital. Retinal sensitivity was measured by microperimetry at 25 sectors within 6 degrees from the fovea. Depolarisation value, which reflected melanin pigmentation, was measured by a clinical prototype of PS-OCT and was parameterised as polarimetric entropy. Retinal sensitivity or entropy at the RPE in high myopia was compared with emmetropic control subjects. The association of retinal sensitivity with age, axial length, entropy, or choroidal thickness was assessed in per-eye and per-sector analysis. RESULTS: Twenty-three highly myopic eyes (age, 66.6±12.3 years) were included. The average retinal sensitivity was 25.3±3.0 dB, which was significantly decreased compared with the control (p<0.0001). The average entropy at the RPE in the highly myopic eyes was significantly lower than in the control (p<0.0001). Univariate analysis followed by multivariate analysis showed that besides age, axial length or choroidal thickness, RPE entropy was independently associated with retinal sensitivity (ß=4.4; 95% CI 0.5 to 8.3; p=0.03). CONCLUSIONS: Decreased depolarisation at the RPE measured with PS-OCT, which reflected altered melanin pigmentation, was independently associated with reduced retinal sensitivity in patients with early stages of myopic maculopathy without CNV or PCA.

Retinal pigment epithelium melanin imaging using polarization-sensitive optical coherence tomography for patients with retinitis pigmentosa.

This study aimed to evaluate the distribution of retinal pigment epithelium (RPE) melanin in patients with retinitis pigmentosa (RP) using entropy measurements by custom-made polarization-sensitive optical coherence tomography (PS-OCT) images, and compare entropy with the intensity of short-wavelength (SW) and near-infrared (NIR) autofluorescence (AF). We retrospectively reviewed the retinal images, including PS-OCT, SW-AF, and NIR-AF of patients with RP who had a hyperautofluorescent ring on AF. A total of 12 eyes of 12 patients (8 women and 4 men; mean age: 37.9 years) were included. There was a strong positive correlation between entropy value and NIR-AF intensity (r = 0.626, p < 0.001), and there was a very weak negative correlation between entropy value and SW-AF (r = - 0.197, p = 0.001). The mean values of the entropy in the foveal, temporal (2 mm from the fovea), and nasal (2 mm from the fovea) sections were 0.41 (± 0.09), 0.29 (± 0.08), and 0.26 (± 0.08), respectively. The entropy was significantly higher in the foveal section than in the temporal and nasal sections (p = 0.002 and p = 0.003, respectively). There was no significant difference between the entropies values for the temporal and nasal sections (p = 0.157). Age, logMAR best-corrected visual acuity, ellipsoid zone width, and central retinal thickness were not correlated with foveal entropy. We presented RPE melanin imaging in patients with RP using PS-OCT for the first time. PS-OCT can be a useful tool for monitoring patients with RP.

Favorable therapeutic efficacy of low-density lipoprotein apheresis for nephrotic syndrome with impaired renal function.

Many reports have shown the therapeutic efficacy of LDL apheresis (LDL-A) in drug-resistant nephrotic syndrome (NS) for improvement of heavy proteinuria and severely impaired renal function. To obtain comprehensive results in a large number of cases, a post hoc analysis of the Prospective Observational survey on the Long-Term Effects of the LDL-Apheresis on the Drug Resistant Nephrotic Syndrome (POLARIS) study was performed by stratifying enrolled cases according to the pretreatment estimated glomerular filtration rate (eGFR) levels indicating normal (N) (≥60 ml/min/1.73 m2 ), moderately impaired (M) (≥30 to <60 ml/min/1.73 m2 ), and severely impaired (S) (<30 ml/min/1.73 m2 ) renal function. Significant improvements of proteinuria and renal function were found in Group N and, most interestingly, in Group M. A tendency for improvement in proteinuria was found in Group S. Most cases in all groups had not entered end-stage renal disease at 2 years after LDL-A treatment. These results suggest that LDL-A has therapeutic efficacy even in cases in which renal function has declined to 30 ml/min/1.73 m2 .

Specific interactions between the alkaline protease of P. aeruginosa and its natural peptide inhibitor: ab initio molecular simulations.

Alkaline protease aeruginolysin (APR) is an important virulence factor in the evasion of the immune system by Pseudomonas aeruginosa (P. aeruginosa). The P. aeruginosa genome also encodes the highly potent and specific APR peptide inhibitor (APRin). However, the structural reason for the significant inhibition has not been revealed. Using ab initio molecular simulations, we here investigated the specific interactions between APR and APRin to elucidate which amino acid residues of APRin and APR contribute strongest to the inhibition. Since APR has a Zn2+ ion at the ligand-binding site and histidine and glutamic acid residues are coordinated with Zn2+, it is essential to precisely describe these coordination bonds to elucidate the specific interactions between APR and APRin. Therefore, we employed the ab initio fragment molecular orbital method to investigate the specific interactions at an electronic level. The results revealed that Ser1 and Ser2 at the N-terminus of APRin significantly contribute to the binding between APRin and APR. In particular, Ser1 binds strongly to Zn2+ as well as to the sidechains of His176(Hid), His180(Hid), and His186(Hid) in APR. This is the main reason for the strong interaction between APR and APRin. The results also elucidated significant contributions of the positively charged Arg83 and Arg90 residues of APRin to the binding with APR. These findings may provide information useful for the design of novel small agents as potent APR inhibitors.

Three-Dimensional Distribution Of Fundus Depolarization and Associating Factors Measured Using Polarization-Sensitive Optical Coherence Tomography.

Purpose: To investigate the three-dimensional distribution and associating demographic factors of depolarization, using polarization-sensitive optical coherence tomography (PS-OCT), to evaluate melanin pigmentation in the retinal pigment epithelium (RPE) and choroid in healthy eyes. Methods: In total, 39 unaffected healthy eyes of 39 subjects were examined using a PS-OCT clinical prototype. The degree of depolarization, expressed as the polarimetric entropy, was assessed in the RPE, the superficial and the total choroid layer, especially in the center, the inner, or the outer areas centered at the fovea. The values and their association with the demographic data were analyzed. Near-infrared fundus autofluorescence (NIRAF) was also used, in the same manner, for the comparison. Twenty-eight of 39 eyes were measured twice to evaluate intrasession repeatability. Results: Both the polarimetric entropy in the RPE and the gray level in NIRAF, decreased from the center to the periphery (P < 0.001). The polarimetric entropy in the RPE was significantly associated with age in each area (P ≤ 0.001). In the RPE and the superficial choroid, the polarimetric entropy was negatively associated with axial length in each area (P ≤ 0.002). The intraclass correlation coefficient of the polarimetric entropy in the same session was excellent in each area of the RPE, superficial choroid, or total choroid layer (0.94-0.98). Conclusions: The distribution of fundus melanin pigment-related depolarization was evaluated using PS-OCT. The depolarization was associated with the subjects' demographic data, such as age or axial length. Translational Relevance: The presented information in healthy eyes provides an essential basis for the investigation into a variety of chorioretinal pathologies.

Changes in entropy on polarized-sensitive optical coherence tomography images after therapeutic subthreshold micropulse laser for diabetic macular edema: A pilot study.

PURPOSE: To investigate the dynamics of the healing process after therapeutic subthreshold micropulse laser (SMPL) for diabetic macular edema (DME) using polarization-sensitive optical coherence tomography (PS-OCT). METHODS: Patients with treatment-native or previously-treated DME were prospectively imaged using PS-OCT at baseline, 1, 2, 3, and 6 months. The following outcomes were evaluated: changes in the entropy value per unit area (pixel2) in the retinal pigment epithelium (RPE) on the B-scan image; changes in the entropy value in each stratified layer (retina, RPE, choroid) based on the ETDRS grid circle overlaid with en face entropy mapping, not only the whole ETDRS grid area but also a sector irradiated by the SMPL; and the relationship between edema reduction and entropy changes. RESULTS: A total of 11 eyes of 11 consecutive DME patients were enrolled. No visible signs of SMPL treatment were detected on PS-OCT images. The entropy value per unit area (pixel2) in the RPE tended to decrease at 3 and 6 months from baseline (35.8 ± 17.0 vs 26.1 ± 9.8, P = 0.14; vs 28.2 ± 18.3, P = 0.14). Based on the en face entropy mapping, the overall entropy value did not change in each layer in the whole ETDRS grid; however, decrease of entropy in the RPE was observed at 2, 3, and 6 months post-treatment within the SMPL-irradiated sectors (P < 0.01, each). There was a positive correlation between the change rate of retinal thickness and that of entropy in the RPE within the SMPL-irradiated sector at 6 months (r2 = 0.19, P = 0.039). CONCLUSION: Entropy measured using PS-OCT may be a new parameter that facilitates objective monitoring of SMPL-induced functional changes in the RPE that could not previously be assessed directly. This may contribute to a more promising therapeutic evaluation of DME. CLINICAL TRIAL: This clinical study was registered in UMIN-CTR (ID: UMIN000042420).

Vitamin K2 supplementation and the progression of abdominal aortic calcification in dialysis patients.

OBJECTIVES: Vascular calcification is common in patients with advanced chronic kidney disease (CKD) and contributes to cardiovascular disease. Accumulating evidence indicates that CKD patients often acquire subclinical vitamin K deficiency, which is associated with vascular calcification. METHODS: This prospective, randomized, parallel group, multicenter trial (UMINID000011490) will include 200 dialysis patients in an open-label, two-arm design. After baseline computed tomography of the abdominal aorta, patients will be randomized to two groups that will either (1) continue receiving standard care or (2) receive additional oral supplementation with menatetrenone (45 mg/day). The treatment duration will be 24 months, and the computed tomography scan will be repeated after 12 and 24 months. The primary endpoint is the progression of abdominal aortic calcification, which is calculated as absolute changes based on the Agatston score. The secondary endpoints are the decrease in bone mineral density (measured by dual-energy X-ray absorptiometry), the biomarkers associated with vitamin K, vitamin K intake (evaluated by the food frequency questionnaire), and the biomarkers associated with vascular calcification. CONCLUSIONS: This study aims to confirm whether vitamin K has inhibitory effects on calcification that can be clinically determined. TRIAL REGISTRATION: UMINID000011490.

Development of aortic valve stenosis in myeloperoxidase antineutrophil cytoplasmic antibody-associated vasculitis with renal involvement.

INTRODUCTION: Degenerative aortic valve stenosis (AS) is a chronic progressive disease that resembles atherosclerosis development. Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is reportedly associated with accelerated atherosclerosis. This study aimed to examine the development of AS in patients with myeloperoxidase-AAV (MPO-AAV) with renal involvement at more than 1 year after the onset of vasculitis. METHODS: We performed a retrospective review of clinical records of MPO-AAV patients with renal involvement without AS at the onset of vasculitis who were treated in three hospitals and three dialysis clinics. RESULTS: The study included 97 MPO-AAV patients with renal involvement and 230 control patients with chronic kidney disease (CKD). Among them, 64 patients had AS. The prevalence rates of AS were 28.9% and 15.7% in MPO-AAV and control patients, respectively (p = 0.006). The multivariable logistic regression analysis showed that MPO-AAV, dialysis dependence, and hypertension were independently associated factors for AS. In MPO-AAV patients, systolic blood pressure was positively significantly associated with AS, whereas glucocorticoid dose of induction therapy was negatively significantly associated. The use of cyclophosphamide tended to be negatively associated with AS. The survival rate was significantly lower for patients with AS than for those without AS. CONCLUSIONS: The AS prevalence rate was significantly higher in MPO-AAV patients at more than 1 year after the onset of vasculitis than in control CKD patients. Therefore, regular monitoring of echocardiography during MPO-AAV treatment is suggested.

Imaging of a retinal pigment epithelium aperture using polarization-sensitive optical coherence tomography.

PURPOSE: To evaluate cases with a retinal pigment epithelium (RPE) aperture using polarization-sensitive optical coherence tomography (PS-OCT). STUDY DESIGN: Retrospective consecutive case series. METHODS: A retrospective study that included three eyes (three patients) with RPE aperture and age-related macular degeneration (AMD) evaluated at the Macular Clinic in Tokyo University Hospital. A three-dimensional dataset of depolarization information was obtained with a clinical prototype of PS-OCT. RESULTS: All patients were categorized as intermediate AMD. RPE apertures were identified with PS-OCT as discontinuities of depolarization in the RPE layer of the pigment epithelial detachment (PED). A nonuniform decrease of depolarization in the RPE layer was also observed around the aperture. Two findings were observed above the aperture, intraretinal focal areas with high reflectivity and increased depolarization and subretinal bands with moderate reflectivity and low depolarization. Retinal sensitivity according to fundus microperimetry measured at 25 points was significantly associated with the degree of depolarization at the corresponding area (r-square = 0.60, p = 0.0001). CONCLUSION: The RPE aperture was characterized as a round discontinuity of depolarization. The findings with PS-OCT suggest atrophic changes in the overlying RPE of the PED. The degree of depolarization was associated with retinal sensitivity. The current results indicate that RPE apertures developed within the spectrum of atrophic AMD.

Assessment of macular function in patients with non-vascularized pigment epithelial detachment.

Non-vascularized pigment epithelial detachments (PED) are usually associated with dry age-related macular degeneration (AMD). In this study, we aimed to investigate the correlation between visual function and morphologic parameters. Seventeen eyes of eleven patients with non-vascularized AMD were enrolled. In addition to conventional optical coherence tomography (OCT), polarization-sensitive optical coherence tomography (PS-OCT) measurements were performed by evaluating the regularity of retinal pigment epithelium (RPE) entropy within the PED area. Retinal sensitivity was measured with MP-3 microperimetry, and retinal sensitivities within (RSin) and outside (RSout) the PED area were calculated. The relationship between OCT parameters and visual function was analyzed. As a result, there was a significant difference between the RSin and RSout (p < 0.001, Wilcoxon signed rank test). Moreover, RSin was significantly related to logMAR VA (p = 0.033, linear mixed model). The regularity of RPE entropy was significantly related to visual acuity and RSin (p = 0.00038, p = 0.031, linear mixed model), although neither the height nor area of PED correlated with visual function. Our results suggest that retinal sensitivity is significantly deteriorated within the PED area and RPE entropy measured with PS-OCT was closely related to visual function in eyes with non-vascularized PED.

Evaluation of the specific structures of IgA1 hinge glycopeptide in 30 IgA nephropathy patients by mass spectrometry.

BACKGROUND: Although many reports have described the abnormal structures of O-glycan in the IgA1 hinge region in IgA nephropathy (IgAN), the specific glycopeptide that can be used as a diagnostic biomarker for IgAN has not yet been identified. To pursue this diagnostic approach, we used mass spectrometric analysis to search for specific structures in IgA1 hinge glycopeptides in 30 IgAN patients contrasted with 30 healthy controls. METHOD: IgA1 hinge glycopeptides were individually purified from the sera of 30 biopsy-proven IgAN patients and 30 healthy controls. The structure of each glycopeptide was analyzed by ion trap mass spectrometry. Sugar conformations in each glycopeptide were estimated by collision-induced dissociation tandem mass spectrometry. Furthermore, to search for specific O-glycans in IgAN patients with a statistical significance, the identified hinge glycopeptides were analyzed by Fisher exact test. RESULT: A total of 57 hinge glycopeptides were identified from each of the 2 sample groups. Among the structures of the hinge glycopeptides identified, statistical significance was found for 6 glycopeptides (O-glycan compositions were 33-mer hinge core peptides + xGalNAc + yGal + zNeu5Ac; x:y:z = 5:3:3, 5:3:0, 5:2:1, 4:2:2, 3:1:1, 3:1:0) by Fisher exact test (p<0.05). In these 6 O-glycan compositions, 3 compositions (x:y:z = 4:2:2, 3:1:1, 3:1:0) were only observed in IgAN patients and were absent in the 30 controls. CONCLUSION: Statistically specific O-glycans were identified in 30 IgAN patients compared with 30 controls. These results open the possibility for preparation of lectin and/or antibodies binding to specific glycopeptides in IgAN.