The identification of an osteoclastogenesis inhibitor through the inhibition of glyoxalase I

Osteoclasts, bone-resorptive multinucleated cells derived from hematopoietic stem cells, are associated with many bone-related diseases, such as osteoporosis. Osteoclast-targeting small-molecule inhibitors are valuable tools for studying osteoclast biology and for developing antiresorptive agents. Here, we have discovered that methyl-gerfelin (M-GFN), the methyl ester of the natural product gerfelin, suppresses osteoclastogenesis. By using M-GFN-immobilized beads, glyoxalase I (GLO1) was identified as an M-GFN-binding protein. GLO1 knockdown and treatment with an established GLO1 inhibitor in osteoclast progenitor cells interfered with osteoclast generation, suggesting that GLO1 activity is required for osteoclastogenesis. In cells, GLO1 plays a critical role in the detoxification of 2-oxoaldehydes, such as methylglyoxal. M-GFN inhibited the enzymatic activity of GLO1 in vitro and in situ. Furthermore, the cocrystal structure of the GLO1/M-GFN complex revealed the binding mode of M-GFN at the active site of GLO1. These results suggest that M-GFN targets GLO1, resulting in the inhibition of osteoclastogenesis.     

Cryofiltration Apheresis for Major ABO-Incompatible Kidney Transplantation

Abstract: The barrier of ABO-incompatible kidney transplantation is the presence of anti-A and anti-B antibodies in the recipient's circulating blood. Double filtration plasmapheresis (DFPP) is usually used to eliminate those antibodies. We tried cryofiltration apheresis (CRYO) in 2 recipients. Patient 1 was a 45-year-old male with B, Rh(±). The titers of IgM anti-A antibody were only reduced from ×64 to ×32 by the end of 3 sessions of standard CRYO. Renal allografting was not performed. Case 2 was a 29-year-old male with B, Rh(+). CRYO was introduced for 3 sessions. The initial IgM and IgG titers were ×128 and negative, respectively. The standard CRYO system was modified by temperature, treated volume, and filter pore size. The IgM anti-A antibody titer was markedly reduced to ×2 after the final session of CRYO. The donor was a 56-year-old father with A, Rh(+). Tacrolimus, azathio-prine, methylprednisolone, and antilymphocyte globulin were used as the introductory immunosuppression therapy.     

Diagnostic performance of a computer-assisted diagnostic system: sensitivity of BONENAVI for bone scintigraphy in patients with disseminated skeletal metastasis is not so high

Bone scintigraphy (BS) of disseminated skeletal metastasis is sometimes misinterpreted as normal. The use of computer-assisted diagnosis (CAD) may resolve this problem. We investigated the performance of a CAD system, BONENAVI, in the diagnosis of disseminated skeletal metastasis. Cases of disseminated skeletal metastasis were selected from a BS log. These patients’ BSs were analyzed by BONENAVI to obtain an artificial neural network (ANN) and bone scan index (BSI). Clinical features (type of primary cancer, CT type, and BS type) were compared with the BONENAVI (ANN and BSI) results. The BS findings (diffuse increased axial skeleton uptake, inhomogeneity of uptake, proximal extremity contrast, and degree of renal uptake) and ANN or BSI were evaluated. Then, negative ANN patients were presented. Fifty-four patients were diagnosed as having disseminated skeletal metastasis. Regarding the primary cancers, 12 had prostate cancer, 16 gastric cancers, 16 breast cancers, and 10 miscellaneous cancers. Total sensitivity of ANN (≥ 0.5) was 76% (41/54). ANN values correlated with the BS type among clinical features. Diffuse increased axial skeleton uptake was mostly correlated with ANN of the BS findings. The BONENAVI CAD system was partially helpful in diagnosing disseminated skeletal metastasis, but the sensitivity of BONENAVI was not sufficient and underestimated the disseminated skeletal metastasis. Further improvement of this CAD system is necessary to improve the detectability of disseminated skeletal metastasis.     

Relative risk of plaque erosion among different age and sex groups in patients with acute coronary syndrome

Postmortem studies reported plaque erosion is frequent in young women. Recent in vivo studies failed to show age and sex differences in the plaque erosion prevalence. The aim of this study was to investigate the prevalence of plaque erosion by age and sex among acute coronary syndromes (ACS) patients. From 1699 ACS patients, 1083 with plaque erosion or rupture were analyzed. Patients were categorized as 5 age groups (≤?50, 51–60, 61–70, 71–80,?≥?81 years). Overall prevalence of plaque erosion was similar between males and females (p?=?0.831). Males age?≤?50 had higher (p?=?0.018) and age 71–80 had lower (p?=?0.006) prevalence of plaque erosion. Females age 61–70 had higher (p?=?0.021) and age 71–80 had lower (p?=?0.045) prevalence of plaque erosion. In advanced age groups (≥?71 years), rupture was the dominant etiology in both sexes. In multivariate analysis of males, age?≤?50 demonstrated a trend to increase (OR 1.418, 95% CI 0.961–2.093, p?=?0.078) the erosion risk. Females age?≤?70 independently increased (OR 2.138, 95% CI 1.249–3.661, p?=?0.006) the risk for erosion. The prevalence of plaque erosion was similar between males and females. Plaque erosion risk was increased in the males age?≤?50 and in the females age?≤?70 among ACS patients.

     

Expression of cathepsin E in pancreas: A possible tumor marker for pancreas,a preliminary report

Ductal cancers of the pancreas frequently express markers of gastrointestinal epithelial cells. Cathepsin E (CTSE) is a non-secretory, intracellular, but non-lysosomal proteinase found in the highest concentration in the superficial epithelial cells of the stomach. The aims of our study were to examine the expression of CTSE in the pancreas, to establish an assay system of CTSE and to evaluate the diagnostic usefulness of CTSE in the pancreatic juice. Eleven patients with pancreatic ductal adenocarcinoma, 10 with mucin-producing adenoma, 3 with intraductal papillary hyperplasia and 43 with chronic pancreatitis were examined. Surgically resected pancreatic tissues were subjected to immunohistochemistry for CTSE. Pancreatic juice was collected from the patients and subjected to sandwich ELISA and Western analysis for detecting CTSE. Positive staining for CTSE was observed in pancreatic ductal adenocarcinoma by immunohistochemistry. CTSE was also expressed in mucin-producing adenoma, intraductal papillary hyperplasia and mucinous hyperplasia. CTSE in the pancreatic juice was present in 8 of 11 patients with pancreatic ductal adenocarcinoma, 5 of 10 patients with mucin-producing tumor, 1 of 3 patients with intraductal papillary hyperplasia and 4 of 43 patients with chronic pancreatitis. The detection frequency of CTSE in the pancreatic juice was significantly higher in the patients with pancreatic ductal adenocarcinoma than in the patients with chronic pancreatitis. Our findings suggest that the expression of CTSE is associated with the pathogenesis of pancreatic ductal adenocarcinoma, that CTSE in the pancreatic juice seems to be a useful marker for a definitive diagnosis and that CTSE may be expressed at a relatively early stage of multistep carcinogenesis in pancreatic lesions. © 1996 Wiley-Liss, Inc.     

Arthrodesis of knee joint by vascularized fibular graft

Knee arthrodesis has been performed in 17 patients using vascularized fibular graft (VFG); 15 of them could be followed more than 1 year. Twelve were bone defect following tumor resection, two were traumatic bone defect, and one was intractable traumatic non-union. Three types of graft were performed; single VGF as supplement (Type I) in 5 cases, double VFG for femoral defect (Type II) in 8 cases, and double VFG for tibial defect (Type III) in 4 cases. Bone union was achieved in all cases except one. The average time to primary bone union was 4.7 months. Hypertrophy of the graft was observed significantly in some of Type II and in all of Type III. VGF is a useful method for knee fusion in patients with a large bone defect or with an intractable non-union. © 1996 Wiley-Liss, Inc.     

Vulnerable atherosclerotic plaque features: findings from coronary imaging

Pathological studies have suggested that features of vulnerable atherosclerotic plaques likely to progress and lead to acute cardiovascular events have specific characteristics. Given the progress of intravascular coronary imaging technology, some large prospective studies have detected features of vulnerable atherosclerotic plaques using these imaging modalities. However, the rate of cardiovascular events, such as acute coronary syndrome, has been found to be considerably reduced in the limited follow-up period available in the statin era. Additionally, not all disrupted plaques lead to thrombus formation with clinical presentation. If sub-occlusive or occlusive thrombus formation does not occur, a thrombus on a disrupted plaque will organize without any symptoms, forming a “healed plaque”. Although vulnerable plaque detection using intracoronary imaging is focused on “thin-cap fibroatheroma” leading to plaque rupture, superficial plaque erosion is increasingly recognized; however, the underlying mechanism of thrombus formation on eroded plaques is not well understood. One of intravascular imaging, optical coherence tomography (OCT) has the highest image resolution and has enabled detailed characterization of the plaque in vivo. Here, we reviewed the status and limitations of intravascular imaging in terms of detecting vulnerable plaque through mainly OCT studies. We suggested that vulnerable plaque should be reconsidered in terms of eroded plaque and healed plaque and that both plaque and circulating blood should be assessed in greater detail accordingly.

Acute coronary syndrome (ACS) remains a major cause of morbidity and mortality worldwide. For decades, pathological and fundamental studies have primarily focused on “vulnerable plaque” resulting in ACS. The term “vulnerable plaque”, introduced in the late 1980s, refers to a coronary plaque that is most likely to result in plaque rupture.^[1] Although plaque rupture is the most frequent autopsy finding in patients with sudden cardiac death,^[2–4] plaque erosion or calcified nodules are reported to be other underlying mechanisms contributing to ACS.^[2] In the clinical setting, optical coherence tomography (OCT), a high resolution intracoronary imaging modality, has enabled characterization of the culprit plaque that are more in line with the aforementioned diagnosis of the three pathologies in the autopsy studies.^[5] Moreover, studies using OCT have demonstrated plaque erosion to be more common than previously considered.^[6] The representative three types of culprit plaque on OCT images are shown in Figure 1. Naghavi, et al.^[7] recommended that vulnerable plaque be defined in terms of morphological features to include all dangerous plaques that involve a risk of thrombosis and/or rapid progression. In addition, they suggested that not only plaque but also circulating blood plays an important role in the development of ACS.^[7] However, most intracoronary imaging studies concerning vulnerable plaque as a predisposition to ACS have focused on plaque rupture, which is frequently referred to as thin-cap fibroatheroma (TCFA). Figure 2 shows a typical OCT image of TCFA. Additionally, although ACS predominantly arises from occlusive or sub-occlusive coronary thrombosis due to disrupted plaques, non-flow-limiting thrombus may heal without clinical manifestations^[8] and it has been proposed that the healing process of disrupted plaques contributes to the episodic progression of coronary artery stenosis.^[9–12] Herein, we review the present status and the limitations of current intracoronary imaging modalities based on ACS pathogenesis, and we reevaluate the nature of vulnerable plaque through mainly OCT studies. Open in a separate windowFigure 1Representative OCT images of three types of ACS pathologies.(A): Plaque rupture was defined as the presence of fibrous cap discontinuity with a communication between the lumen and the inner core of plaque or with a cavity formation within the plaque; (B): plaque erosion was identified as the presence of an attached thrombus overlying an intact and visualized plaque, luminal surface irregularity at the culprit lesion in the absence of a thrombus, or attenuation of the underlying plaque by a thrombus without superficial lipid or calcification immediately proximal or distal to the site of the thrombus; and (C): calcified plaque was defined as the presence of superficial substantive calcium at the culprit site without evidence of a ruptured lipid plaque. ACS: acute coronary syndrome; OCT: optical coherence tomography.Open in a separate windowFigure 2Representative OCT image of TCFA.(A): Lipid plaque, defined as a signal poor region with a poorly defined or diffuse border, is shown in the whole circumference (white asterisks); and (B): the minimum fibrous thickness was measured as < 65 μm (enlarged view). OCT: optical coherence tomography; TCFA: thin cap fibroatheroma.     

Longitudinal Analysis of Neutralizing Potency against SARS-CoV-2 in the Recovered Patients after Treatment with or without Favipiravir

The effect of treatment with favipiravir, an antiviral purine nucleoside analog, for coronavirus disease 2019 (COVID-19) on the production and duration of neutralizing antibodies for SARS-CoV-2 was explored. There were 17 age-, gender-, and body mass index-matched pairs of favipiravir treated versus control selected from a total of 99 patients recovered from moderate COVID-19. These subjects participated in the longitudinal (>6 months) analysis of (i) SARS-CoV-2 spike protein’s receptor-binding domain IgG, (ii) virus neutralization assay using authentic virus, and (iii) neutralization potency against original (WT) SARS-CoV-2 and cross-neutralization against B.1.351 (beta) variant carrying triple mutations of K417N, E484K, and N501Y. The results demonstrate that the use of favipiravir: (1) significantly accelerated the elimination of SARS-CoV-2 in the case vs. control groups (p = 0.027), (2) preserved the generation and persistence of neutralizing antibodies in the host, and (3) did not interfere the maturation of neutralizing potency of anti-SARS-CoV-2 and neutralizing breadth against SARS-CoV-2 variants. In conclusion, treatment of COVID-19 with favipiravir accelerates viral clearance and does not interfere the generation or maturation of neutralizing potency against both WT SARS-CoV-2 and its variants.