Multifocal lesions with pancreatic atrophy in IgG4-related autoimmune pancreatitis: report of a case

We herein report a case of IgG4-related autoimmune pancreatitis (AIP). A 72-year-old male with jaundice visited our hospital complaining of epigastralgia. A blood chemistry analysis revealed elevated serum levels of total bilirubin and DUPAN-II. Computed tomography (CT) revealed irregularly shaped pancreatic masses with a stricture of the main pancreatic duct (MPD) in the head and tail that were interposed by marked atrophy with MPD dilation in the body. F-18 fluorodeoxyglucose (FDG)-positron emission tomography/CT revealed abnormally intense FDG uptake only at the masses. During surgery, another small tumor was also found in the atrophied body; therefore, a total pancreatectomy was performed under the diagnosis of multiple pancreatic cancers. The histological analysis revealed fibrosis with dense and diffuse infiltrations of lymphocytes and IgG4-positive plasma cells. The pancreatic parenchyma of the body was firmly replaced by fibrosis. AIP can lead to the formation of multiple pancreatic lesions, and thus the correct diagnosis is occasionally difficult to establish in atypical cases.     

Assessment of Demineralization Inhibition Effects of Dentin Desensitizers Using Swept-Source Optical Coherence Tomography

The purpose of this study was to evaluate the mechanism of action and the inhibiting effects of two types of desensitizers against dentin demineralization using pre-demineralized hypersensitivity tooth model in vitro. In this study, we confirmed that a hypersensitivity tooth model from our preliminary experiment could be prepared by immersing dentin discs in an acetic acid-based solution with pH 5.0 for three days. Dentin discs with three days of demineralization were prepared and applied by one of the desensitizers containing calcium fluoro-alumino-silicate glass (Nanoseal, NS) or fluoro-zinc-silicate glass (Caredyne Shield, CS), followed by an additional three days of demineralization. Dentin discs for three days of demineralization (de3) and six days of demineralization (de6) without the desensitizers were also prepared. The dentin discs after the experimental protocol were scanned using swept-source optical coherence tomography (SS-OCT) to image the cross-sectional (2D) view of the samples and evaluate the SS-OCT signal. The signal intensity profiles of SS-OCT from the region of interest of 300, 500, and 700 µm in depth were obtained to calculate the integrated signal intensity and signal attenuation coefficient. The morphological differences and remaining chemical elements of the dentin discs were also analyzed using scanning electron microscopy and energy-dispersive X-ray spectroscopy. SS-OCT images of CS and NS groups showed no obvious differences between the groups. However, SS-OCT signal profiles for both the CS and NS groups showed smaller attenuation coefficients and larger integrated signal intensities than those of the de6 group. Reactional deposits of the desensitizers even after the additional three days of demineralization were observed on the dentin surface in NS group, whereas remnants containing Zn were detected within the dentinal tubules in CS group. Consequently, both CS and NS groups showed inhibition effects against the additional three days of demineralization in this study. Our findings demonstrate that SS-OCT signal analysis can be used to monitor the dentin demineralization and inhibition effects of desensitizers against dentin demineralization in vitro.     

Intra-procedural anticoagulation and post-procedural hemoglobin fall in atrial fibrillation ablation with minimally interrupted direct oral anticoagulants: comparisons across 4 drugs

Journal of Interventional Cardiac Electrophysiology - Thromboembolic or hemorrhagic complications related to atrial fibrillation (AF) ablation are rare, and thus, it is difficult to compare their...     

Clinical study of IgA antibody against hepatitis C virus core antigen in patients with type C chronic liver disease

Immunoglobulin A class antibody to hepatitis C virus core antigen (IgA anti-HCc) was measured in the serum of 128 patients with type C chronic liver disease. Fifty-eight patients (45.3%) were seropositive. IgA anti-HCc was detected in only one of 20 patients with chronic persistent hepatitis; however, 52.3% (46/88) of patients with chronic active hepatitis and 55% (11/20) of patients with liver cirrhosis were seropositive. Histological examination revealed that 22 (71.0%) of 31 patients with severe disease activity were seropositive compared to 35 (44.9%) of 78 patients with moderate (P<0.05) and one (5.3%) of 19 patients with mild (P<0.01) histological changes. IgA anti-HCc was measured sequentially in 65 patients who underwent interferon therapy. There was a significant difference between responders and other patients in the mean ratio of IgA anti-HCc titers one month after therapy. Three months after therapy, IgA anti-HCc was detectable in only two of 15 responders who were IgA anti-HCc seropositive at the start of therapy. In contrast, IgA anti-HCc reappeared three months after therapy despite a temporary decrease to undetectable levels in all nonresponders. We conclude that IgA anti-HCc is a useful marker to identify the presence of active type C liver disease and that the disappearance of IgA anti-HCc three months after interferon therapy predicts a good response in treated patients.     

De novo determination of near-surface electrostatic potentials by NMR

Electrostatic potentials computed from three-dimensional structures of biomolecules by solving the Poisson–Boltzmann equation are widely used in molecular biophysics, structural biology, and medicinal chemistry. Despite the approximate nature of the Poisson–Boltzmann theory, validation of the computed electrostatic potentials around biological macromolecules is rare and methodologically limited. Here, we present a unique and powerful NMR method that allows for straightforward and extensive comparison with electrostatic models for biomolecules and their complexes. This method utilizes paramagnetic relaxation enhancement arising from analogous cationic and anionic cosolutes whose spatial distributions around biological macromolecules reflect electrostatic potentials. We demonstrate that this NMR method enables de novo determination of near-surface electrostatic potentials for individual protein residues without using any structural information. We applied the method to ubiquitin and the Antp homeodomain–DNA complex. The experimental data agreed well with predictions from the Poisson–Boltzmann theory. Thus, our experimental results clearly support the validity of the theory for these systems. However, our experimental study also illuminates certain weaknesses of the Poisson–Boltzmann theory. For example, we found that the theory predicts stronger dependence of near-surface electrostatic potentials on ionic strength than observed in the experiments. Our data also suggest that conformational flexibility or structural uncertainties may cause large errors in theoretical predictions of electrostatic potentials, particularly for highly charged systems. This NMR-based method permits extensive assessment of near-surface electrostatic potentials for various regions around biological macromolecules and thereby may facilitate improvement of the computational approaches for electrostatic potentials.

Due to the fundamental importance of electrostatic interactions in chemistry and biology, electrostatic potentials are invaluable information for the understanding of molecular recognition, enzymatic catalysis, and other functions of proteins and nucleic acids (1–4). Quantification of electrostatics is also important for successful protein engineering (5) and structure-based drug design (6). Computational approaches based on the Poisson–Boltzmann theory are commonly used to calculate electrostatic potentials from three-dimensional (3D) molecular structures (1, 7). Owing to available software such as Adaptive Poisson-Boltzmann Solver (APBS) (8, 9) and DelPhi (10, 11), computation of the electrostatic potentials around biomolecules has gained widespread popularity in the fields of molecular biophysics, structural biology, and medicinal chemistry.However, the computed electrostatic potentials may not necessarily be accurate even if the 3D structures are precisely and accurately determined. Importantly, the Poisson–Boltzmann theory is approximate with known limitations. The electrostatic models based on this theory are valid under assumptions, which simplify the calculations (12). The lack of consideration of correlations between ions can diminish accuracy in calculations of electrostatic potentials for systems at high ionic strength (13). Due to the assumption of a dielectric continuum, the electrostatic potentials predicted with the Poisson–Boltzmann theory may be inaccurate for zones near the first hydration layer. Electrostatic potentials predicted for regions near highly charged molecular surfaces may also be inaccurate due to the assumption of linear dielectric response. Nonetheless, the Poisson–Boltzmann theory can accurately predict electrostatic interactions at longer range (7). The extent of validity for such electrostatic potentials near molecular surfaces remains to be addressed more rigorously through experiments.Despite the need, experimental validation of computed electrostatic potentials is rather rare and methodologically limited for biological macromolecules. The validity of electrostatic models has been examined using pK_a data on titratable side-chain moieties (14–16), redox potentials of redox-active groups (17, 18), and electron–electron double resonance (19). Among them, pK_a data have been most commonly used for the validation, but even fundamentally incorrect electrostatic models can reproduce pK_a data (20). Electrostatic fields can be experimentally determined by vibrational spectroscopy, for example, for nitrile groups that are conjugated to cysteine thiol moieties of proteins (21, 22). However, the approaches utilizing vibrational spectroscopy or electron–electron double resonance provide only limited information about the extrinsically introduced probes, which may perturb native systems.In this paper, we present a unique and powerful method for de novo determination of near-surface electrostatic potentials for many protein residues, regardless of their side-chain types, and without using any chemical modifications. In this method, data of NMR paramagnetic relaxation enhancement (PRE) arising from analogous charged paramagnetic cosolutes are analyzed for ¹H nuclear magnetizations of proteins (Fig. 1). The PRE data reflect the electrostatic biases in spatial distributions of charged paramagnetic cosolutes and permit the determination of near-surface electrostatic potentials around proteins without using any structural information. The de novo determination of near-surface electrostatic potentials can greatly facilitate the examination of theoretical models for electrostatics of biological macromolecules.Open in a separate windowFig. 1.NMR PRE arising from cationic amino-methyl-PROXYL or anionic carboxy-PROXYL reflects their spatial distribution bias due to near-surface electrostatic potentials around a biological macromolecule.     

Serum thioredoxin levels as a predictor of steatohepatitis in patients with nonalcoholic fatty liver disease

BACKGROUND/AIMS: Thioredoxin (TRX) is a stress-inducible thiol-containing protein. The aim of this study was to evaluate the clinical significance of serum TRX in patients with nonalcoholic steatohepatitis (NASH) or simple steatosis. METHODS: Serum TRX levels were determined using an enzyme-linked immunosorbent assay kit in 25 patients with NASH, 15 patients with simple steatosis, and 17 healthy volunteers. RESULTS: Serum TRX levels (medians and (ranges), ng/ml) were significantly elevated in patients with NASH (60.3 (17.6-104.7)), compared to those in patients with simple steatosis (24.6 (16.6-69.7), P=0.0009) and in healthy controls (23.5 (1.3-50.7), P<0.0001). Serum ferritin levels in patients with NASH were also significantly higher than the levels in patients with simple steatosis. The receiver operating characteristic curve confirmed that serum TRX and ferritin levels were predictors for distinguishing NASH from simple steatosis. Higher grades of histological iron staining were observed in NASH than in simple steatosis. Serum TRX tended to increase in accordance with hepatic iron accumulation and the histological severity in patients with NASH. CONCLUSIONS: The pathogenesis of NASH may be associated with iron-related oxidative stress. The serum TRX level is a parameter for discriminating NASH from simple steatosis as well as a predictor of the severity of NASH.