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IgA nephropathy (IgAN), an immune complex-mediated process and the most common primary glomerulonephritis, can progress to end-stage renal disease in up to 40% of patients. Accordingly, a therapeutic strategy targeting a specific molecular pathway is urgently warranted. Aided by structure characterisation and target identification, we predicted that a novel ring-fused 6-(2,4-difluorophenyl)-3-(3-(trifluoromethyl)phenyl)-2H-benzo[e][1,3]oxazine-2,4(3H)-dione (LCC18) targets the NLRP3 inflammasome, which participates in IgAN pathogenesis. We further developed biomarkers for the disease. We used two complementary IgAN models in C57BL/6 mice, involving TEPC-15 hybridoma-derived IgA, and in gddY mice. Moreover, we created specific cell models to validate therapeutic effects of LCC18 on IgAN and to explain its underlying mechanisms. IgAN mice benefited significantly from treatment with LCC18, showing dramatically improved renal function, including greatly reduced proteinuria and renal pathology. Mechanistic studies showed that the mode of action specifically involved: (1) blocking of the MAPKs/COX-2 axis-mediated priming of the NLRP3 inflammasome; (2) inhibition of ASC oligomerisation and NLRP3 inflammasome assembly by inhibiting NLRP3 binding to PKR, NEK7 and ASC; and (3) activation of autophagy. LCC18 exerts therapeutic effects on murine IgAN by differentially regulating NLRP3 inflammasome activation and autophagy induction, suggesting this new compound as a promising drug candidate to treat IgAN. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Objectives To investigate neuroendocrine carcinoma (NEC) of the uterine cervix cases for MRI features and staging, as well as pathological correlations and survival. Results FIGO was I in 42, II in 14, III in 1, and IV in 5 patients. T2-weighted MRI showed homogeneous slightly high signal intensity and obvious restricted diffusion (ADC map, low intensity; DWI, high intensity) throughout the tumor in most cases, and mild enhancement in two-thirds. In 50 patients who underwent a radical hysterectomy and lymphadenectomy without neoadjuvant chemotherapy (NAC), intrapelvic T staging by MRI overall accuracy was 88.0% with reference to pathology staging, while patient-based sensitivity, specificity, and accuracy for metastatic pelvic lymph node detection was 38.5%, 100%, and 83.3%, respectively. During a mean follow-up period of 45.6 months (range 4.3-151.0 months), 28 patients (45.2%) experienced recurrence and 24 (38.7%) died. Three-year progression-free and overall survival rates for FIGO I, II, III, and IV were 64.3% and 80.9%, 50% and 64.3%, 0% and 0%, and 0% and 0%, respectively. Materials and methods Sixty-two patients with histologically surgery-proven uterine cervical NEC were enrolled. Twelve received NAC. Clinical data, pathological findings, and pretreatment pelvic MRI findings were retrospectively reviewed. Thirty-two tumors were pure NEC and 30 mixed with other histotypes. The NECs were small cell type (41), large cell type (18), or a mixture of both (3). Conclusions Homogeneous lesion texture with obvious restricted diffusion throughout the tumor are features suggestive of cervical NEC. Our findings show that MRI is reliable for T staging of cervical NEC.

IgA nephropathy (IgAN), the most common primary glomerular disorder, has a relatively poor prognosis yet lacks a pathogenesis-based treatment. Compound K (CK) is a major absorbable intestinal bacterial metabolite of ginsenosides, which are bioactive components of ginseng. The present study revealed promising therapeutic effects of CK in two complementary IgAN models: a passively induced one developed by repeated injections of IgA immune complexes and a spontaneously occurring model of spontaneous grouped ddY mice. The potential mechanism for CK includes 1) inhibiting the activation of NLRP3 inflammasome in renal tissues, macrophages and bone marrow–derived dendritic cells, 2) enhancing the induction of autophagy through increased SIRT1 expression, and 3) eliciting autophagy-mediated NLRP3 inflammasome inhibition. The results support CK as a drug candidate for IgAN.

Background IgA nephropathy (IgAN) begins with aberrant IgA deposition in glomeruli, progresses to IgM/IgG/complement codeposition, and results in chronic inflammation and glomerular damage. However, the mechanism that drives such phlogogenic cascade has been unclear. Recently, apoptosis inhibitor of macrophage (AIM) protein was shown to modulate macrophages' function in various pathologic conditions, thereby profoundly affecting the progression of renal disorders, including AKI. A spontaneous IgAN model, grouped ddY (gddY) mouse, revealed the requirement of AIM for the overall inflammatory glomerular injury following IgA deposition. Methods We established an AIM-deficient IgAN model (AIM -/- gddY) using CRISPR/Cas9 and compared its phenotype with that of wild-type gddY with or without recombinant AIM administration. An IgA-deficient IgAN model (IgA -/- gddY) was also generated to further determine the role of AIM. Results In both human and murine IgAN, AIM colocalized with IgA/IgM/IgG in glomeruli, whereas control kidneys did not exhibit AIM deposition. Although AIM -/- gddY showed IgA deposition at levels comparable with those of wild-type gddY, they did not exhibit glomerular accumulation of IgM/IgG complements, CD45+ leukocyte infiltration, and upregulation of inflammatory/fibrogenic genes, indicating protection from glomerular lesions and proteinuria/hematuria. Recombinant AIM administration reconstituted the IgAN phenotype, resulting in IgM/IgG/complement IgA codeposition. Neither spontaneous IgM/IgG codeposition nor disease was observed in IgA -/- gddY mice. Conclusions AIM may contribute to stable immune complex formation in glomeruli, thereby facilitating IgAN progression. Therefore, AIM deposition blockage or disassociation from IgM/IgG may present a new therapeutic target on the basis of its role in IgAN inflammation initiation.

Galactose-deficient IgA1 (Gd-IgA1) plays a crucial role in the development of IgA nephropathy (IgAN). However, the pathogenic mechanisms driving Gd-IgA1 production have not been fully elucidated. Innate-immune activation via Toll-like receptor 9 (TLR9) is known to be involved in Gd-IgA1 production. A proliferation inducing ligand (APRIL) and IL-6 are also known to enhance Gd-IgA1 synthesis in IgAN. With this as background, we investigated how TLR9 activation in IgA secreting cells results in overproduction of nephritogenic IgA in the IgAN-prone ddY mouse and in human IgA1-secreting cells. Injection of the TLR9 ligand CpG-oligonucleotides increased production of aberrantly glycosylated IgA and IgG-IgA immune complexes in ddY mice that, in turn, exacerbated kidney injury. CpG-oligonucleotide-stimulated mice had elevated serum levels of APRIL that correlated with those of aberrantly glycosylated IgA and IgG-IgA immune complexes. In vitro, TLR9 activation enhanced production of the nephritogenic IgA as well as APRIL and IL-6 in splenocytes of ddY mice and in human IgA1-secreting cells. However, siRNA knock-down of APRIL completely suppressed overproduction of Gd-IgA1 induced by IL-6. Neutralization of IL-6 decreased CpG-oligonucleotide-induced overproduction of Gd-IgA1. Furthermore, APRIL and IL-6 pathways each independently mediated TLR9-induced overproduction of Gd-IgA1. Thus, TLR9 activation enhanced synthesis of aberrantly glycosylated IgA that, in a mouse model of IgAN, further enhanced kidney injury. Hence, APRIL and IL-6 synergistically, as well as independently, enhance synthesis of Gd-IgA1.

Purpose This study aimed to examine MRI features and staging of neuroendocrine carcinoma (NEC) of the endometrium and evaluate survival. Materials and methods Clinical data, pathological, and preoperative pelvic MRI findings in 22 patients with histologically surgery-proven endometrial NEC were retrospectively reviewed. Tumors were pure NEC (n = 10) or mixed histotype (n = 12), with 13 large and nine small cell type. Results International Federation of Gynecology and Obstetrics (FIGO) staging was I, II, III, and IV in 6, 2, 12, and 2 patients, respectively. In 13 (76.4%) of 17 patients with pathological deep myometrial invasion, MRI showed abnormal diffusely infiltrative high T2 signal intensity throughout the myometrium with loss of normal uterine architecture. All tumors had restricted diffusion (apparent diffusion coefficient map low signal intensity, diffusion weighted imaging high signal intensity). Accuracy of T staging by MRI for all cases was 81.8%, with reference to pathology staging, while patient-based sensitivity, specificity, and accuracy for detecting metastatic pelvic lymph nodes was 60.0%, 100%, and 77.8%, respectively. Two intrapelvic peritoneal dissemination cases were detected by MRI. During follow-up (mean 30.4, range 3.3-138.4 months), 16 patients (72.7%) experienced recurrence and 12 (54.5%) died of disease. Two-year disease-free and overall survival rates for FIGO I, II, III, and IV were 66.7% and 83.3%, 50% and 100%, 10% and 33.3%, and 0% and 0%, respectively. Conclusion Abnormal diffusely infiltrative high T2 signal intensity throughout the myometrium with normal uterine architecture loss and obvious restricted diffusion throughout the tumor are suggestive features of endometrial NEC. Pelvic MRI is reliable for intrapelvic staging of affected patients.

Aim The aim of this study was to elucidate whether the presence of an ovarian endometrioma is associated with impaired vascular flow. We investigated changes in vascular flow on the ipsilateral and contralateral side of the endometrioma, before and after surgery. Methods This prospective case–control study included 144 women (ovarian endometrioma [n = 40], endometriosis without ovarian endometrioma [n = 33], non-endometriotic ovarian cyst [n = 17], and normal pelvis [n = 54]). The uterine artery (UtA) vascular resistance indices (pulsatility index [PI] and resistance index [RI]) were measured using transvaginal Doppler sonography, and UtA diameters were measured using magnetic resonance imaging. Results The UtA PI and RI were significantly higher on the ipsilateral side of the endometrioma than on the contralateral unaffected side in the endometrioma group (P < 0.01), as well as in the non-endometriotic ovarian cyst group (P < 0.05), and normal pelvis group (P < 0.01). The UtA PI and RI on the ipsilateral side of the endometrioma were significantly lower after cystectomy than before cystectomy (P < 0.01). The UtA diameters were significantly larger (P < 0.01) on the ipsilateral side of the endometrioma than on the contralateral side. Conclusion The UtA-vascular resistance might be higher on the ipsilateral side of the endometrioma than on the contralateral unaffected side, indicating a risk of subclinical atherosclerosis in women with endometriosis.

Aim To assess and compare the uterine volume and endometrium length between women with and without endometriosis, using pelvic magnetic resonance imaging scans. Methods In this case–control study, a total of 75 nulligravid women (aged 20–45 years) with regular menstrual cycles whose uterus were free of any surgically confirmed lesions were enrolled. The endometriosis group underwent surgery for endometrioma (n = 39), and the control group underwent surgery for non-endometrioma ovarian cysts (n = 36). The primary outcome was uterine corpus volume, which was assessed using three-dimensional reconstructions of preoperative pelvic magnetic resonance imaging scans. Results The mean uterine volume was significantly larger in the endometriosis group than in the control group (mean ± standard deviation, 50.9 ± 14.4 cm3 vs 41.7 ± 14.3 cm3; P < 0.01). The longitudinal length and transverse diameter of the corpus and the longitudinal length of the endometrium were also significantly greater in the endometriosis group (all, P < 0.01). Conclusions An increase in uterine volume and endometrium length was observed in women with endometriosis.

Acute kidney injury (AKI) is associated with prolonged hospitalization and high mortality, and it predisposes individuals to chronic kidney disease. To date, no effective AKI treatments have been established. Here we show that the apoptosis inhibitor of macrophage (AIM) protein on intraluminal debris interacts with kidney injury molecule (KIM)-1 and promotes recovery from AKI. During AKI, the concentration of AIM increases in the urine, and AIM accumulates on necrotic cell debris within the kidney proximal tubules. The AIM present in this cellular debris binds to KIM-1, which is expressed on injured tubular epithelial cells, and enhances the phagocytic removal of the debris by the epithelial cells, thus contributing to kidney tissue repair. When subjected to ischemia-reperfusion (IR)-induced AKI, AIM-deficient mice exhibited abrogated debris clearance and persistent renal inflammation, resulting in higher mortality than wild-type (WT) mice due to progressive renal dysfunction. Treatment of mice with IR-induced AKI using recombinant AIM resulted in the removal of the debris, thereby ameliorating renal pathology. We observed this effect in both AIM-deficient and WT mice, but not in KIM-1-deficient mice. Our findings provide a basis for the development of potentially novel therapies for AKI.

Among diseases causing acute lower abdominal pain in women, isolated fallopian tube torsion is very rare, with an annual prevalence of 1 in 1.5 million. Because it has fewer findings on imaging compared to adnexal torsion, the correct diagnosis can rarely be made before an operation. We present a case of isolated fallopian tube torsion that was suspected preoperatively by its clinical course and findings on computed tomography. A 24-year-old woman repeatedly experienced acute colicky pain in the right lower back. Transvaginal ultrasonography and magnetic resonance imaging showed a right pelvic cystic lesion with intact ovaries; these findings led us to schedule a laparoscopic examination. However, the patient presented to the emergency room with acute severe right back pain. The preoperative diagnosis considering the computed tomography findings and clinical course was consistent with fallopian tube torsion. An earlier diagnosis may have helped to preserve the fallopian tube and future fertility.

To evaluate whether susceptibility-weighted MR imaging (SWI) findings are associated with tumor infarction on contrast-enhanced MRI (CE-MRI) after uterine artery embolization (UAE) for leiomyoma.This was a single institution, retrospective study. Between February 2016 and April 2017, 27 consecutive patients underwent UAE and completed SWI and CE-MRI before and 1 week after UAE. Two blinded readers independently reviewed the MRI of 261 tumors ≥1 cm in all patients. We evaluated the relationship between the hypointense peripheral rim observed on the tumor surface on post-procedural SWI and the infarction rates (≥90%,90%) of each tumor based on post-procedural CE-MRI. Inter-reader correlation coefficients (ICC) and the sensitivity and specificity of the rim were measured.Substantial inter-reader agreement was noted in post-procedural SWI interpretations (ICC = 0.681, 95% CI; 0.547, 0.771). The rim was observed in 66.7% (174/261) of tumors by reader 1 and 55.9% (146/261) of tumors by reader 2 on post-procedural SWI. Correlations were observed between the rim and ≥90% tumor infarction by readers 1 and 2 (Spearman's coefficient = 0.474 and 0.438, p 0.001 and p 0.001, respectively). The sensitivity and specificity of the rim to tumor infarction were 77.2 and 82.6% (reader 1), and 65.8 and 100% (reader 2), respectively.The present study demonstrated that the hypointense peripheral rim was observed on some leiomyomas on SWI immediately after UAE. The rim correlated with tumor infarction on post-procedural CE-MRI. This SWI finding was helpful for evaluating embolic effects on leiomyomas in the acute phase after UAE.

We present a rare case of testicular seminoma in persistent Mullerian duct syndrome (PMDS) with transverse testicular ectopia (TTE). A 42-year-old man noticed scrotal swelling a few weeks earlier and underwent magnetic resonance imaging (MRI) on suspicion of testicular tumor. MRI revealed a normal left testis on the left side of the left scrotum and a heterogeneous mass on the right side within the left scrotum. No right testis was found in the right scrotum. A blind-ending tubular structure with thickened wall showed a three-layer appearance on T2-weighted imaging and extended from the prostate through the left inguinal canal to the left scrotum. Findings during surgery suggested right testicular tumor associated with right TTE. The histopathological and immunohistochemical diagnoses of the testicular tumor and blind-ending tubular structure were seminoma and persistent Mullerian duct, respectively. Testicular tumor in PMDS with TTE is rare but may possess a characteristic appearance on imaging. Proper knowledge of these diseases will allow correct preoperative diagnosis.

Macroscopic hematuria is a common symptom in IgA nephropathy and is also one of the most frequent complications after a percutaneous renal biopsy. Here, we describe a patient with IgA nephropathy and recurrent macroscopic hematuria who developed an arteriovenous fistula after renal biopsy.

The aim of this study was to elucidate whether the presence of an ovarian endometrioma is associated with impaired vascular flow. We investigated changes in vascular flow on the ipsilateral and contralateral side of the endometrioma, before and after surgery.This prospective case-control study included 144 women (ovarian endometrioma [n = 40], endometriosis without ovarian endometrioma [n = 33], non-endometriotic ovarian cyst [n = 17], and normal pelvis [n = 54]). The uterine artery (UtA) vascular resistance indices (pulsatility index [PI] and resistance index [RI]) were measured using transvaginal Doppler sonography, and UtA diameters were measured using magnetic resonance imaging.The UtA PI and RI were significantly higher on the ipsilateral side of the endometrioma than on the contralateral unaffected side in the endometrioma group (P0.01), as well as in the non-endometriotic ovarian cyst group (P0.05), and normal pelvis group (P0.01). The UtA PI and RI on the ipsilateral side of the endometrioma were significantly lower after cystectomy than before cystectomy (P0.01). The UtA diameters were significantly larger (P0.01) on the ipsilateral side of the endometrioma than on the contralateral side.The UtA-vascular resistance might be higher on the ipsilateral side of the endometrioma than on the contralateral unaffected side, indicating a risk of subclinical atherosclerosis in women with endometriosis.

To assess and compare the uterine volume and endometrium length between women with and without endometriosis, using pelvic magnetic resonance imaging scans.In this case-control study, a total of 75 nulligravid women (aged 20-45 years) with regular menstrual cycles whose uterus were free of any surgically confirmed lesions were enrolled. The endometriosis group underwent surgery for endometrioma (n = 39), and the control group underwent surgery for non-endometrioma ovarian cysts (n = 36). The primary outcome was uterine corpus volume, which was assessed using three-dimensional reconstructions of preoperative pelvic magnetic resonance imaging scans.The mean uterine volume was significantly larger in the endometriosis group than in the control group (mean ± standard deviation, 50.9 ± 14.4 cmAn increase in uterine volume and endometrium length was observed in women with endometriosis.

In 2011, simultaneous, widespread outbreaks of food poisoning by contaminated enterohemorrhagic Escherichia coli in beef, which killed four and hospitalized more than 30 people, occurred in Japan. While the press was widely reporting this disaster, two maintenance hemodialysis patients were suffering from Campylobacter bacteremia by eating undercooked meat. One patient was infected with C. upsaliensis and the other with C. fetus. Although these patients could be successfully treated, they led us to consider the characteristics of C. upsaliensis and C. fetus as opportunistic pathogens, as well as changes in dietary behaviors and food markets. Moreover, they emphasized the need for hemodialysis patients to be not only educated in that they should restrict potassium, phosphate and water intake, but also that they should take care of food sanitation.

Purpose To investigate the effect of gadolinium (Gd)-DTPA on the apparent diffusion coefficient (ADC) of breast carcinoma and to analyze the relationship between pre/postcontrast ADC and the degree of contrast enhancement. Materials and Methods Nineteen histopathologically confirmed breast carcinomas (mean size = 22 mm) were analyzed. Their ADCs before and after contrast administration were measured. The contrast-to-noise ratios (CNRs) of the tumors were measured on fat-suppressed 3D T1-weighted images in precontrast, early, and late postcontrast phases. These results were correlated with the measured ADC values. Results A significant decrease in the measured ADC was noted after contrast administration (−23%, P = 0.01). Lesions with relatively high ADC before contrast (>1.3 × 10−3 mm2/sec; n = 12) demonstrated a larger degree of ADC reduction (mean 34%) than lesions with low ADC (≤1.3 × 10−3 mm2/sec; n = 7) (mean 4.5%). When an early postcontrast image was used as a surrogate marker of malignant potential, we found a significant inverse correlation with postcontrast ADC (γ = −0.57, P = 0.02). Conclusion Postcontrast ADC exhibited lower values than precontrast ADC, which is thought to reflect suppression of the microperfusion-induced effect on diffusion-weighted imaging. Postcontrast ADC may be a better indicator than precontrast ADC to reflect malignant potential of tumors. J. Magn. Reson. Imaging 2009;29:1080–1084. © 2009 Wiley-Liss, Inc.

The plicae palmatae is a developmental remnant of the Mullerian ductal fusion, which is demonstrated as a ridge of low intensity in the cervical canal on axial T2-weighted MR images. The identification of the plicae palmatae on MR imaging is beneficial for avoiding misinterpretation of this finding as anomalous uterine septum. The current study is performed to investigate the frequency of this finding and its variation among different age groups. Axial T2-weighted images in 433 subjects were evaluated regarding the presence of the plicae palmatae and uterine anomaly. The frequency of the plicae palmatae was 47.5–53.2% in the third to fifth decade groups, but it was significantly lower in the sixth decade group (24.8%) than in the fifth decade group (53.2%). In three subjects with uterine anomalies, the plicae palmatae was recognized in a bicornuate uterus with single cervix, whereas it was not identified in unicornuate uterus and bicornuate uterus with duplicated cervices. The plicae palmatae is commonly encountered in routine MR images of normal uterus, especially in reproductive-aged women.

BACKGROUND AND PURPOSE: The Vim and VPL are important target regions of the thalamus for DBS. Our aim was to clarify the anatomic locations of the ventral thalamic nuclei, including the Vim and VPL, on MR imaging. MATERIALS AND METHODS: Ten healthy adult volunteers underwent MR imaging by using a 1.5T whole-body scanner. The subjects included 5 men and 5 women, ranging in age from 23 to 38 years, with a mean age of 28 years. The subjects were imaged with STIR sequences (TR/TE/TI = 3200 ms/15 ms/120 ms) and DTI with a single-shot echo-planar imaging technique (TR/TE = 6000 ms/88 ms, b-value = 2000 s/mm2). Tractography of the CTC and spinothalamic pathway was used to identify the thalamic nuclei. Tractography of the PT was used as a reference, and the results were superimposed on the STIR image, FA map, and color-coded vector map. RESULTS: The Vim, VPL, and PT were all in close contact at the level through the ventral thalamus. The Vim was bounded laterally by the PT and medially by the IML. The VPL was bounded anteriorly by the Vim, laterally by the internal capsule, and medially by the IML. The posterior boundary of the VPL was defined by a band of low FA that divided the VPL from the pulvinar. CONCLUSIONS: The ventral thalamic nuclei can be identified on MR imaging by using reference structures such as the PT and the IML.

Immunoglobulin (Ig) A nephropathy (IgAN) is the most common form of glomerular disease worldwide and is associated with a poor prognosis. Thus, development of a curative treatment and strategies for early diagnosis and treatment are urgently needed. Pathological analysis of renal biopsy is the gold standard for the diagnosis and assessment of disease activity; however, immediate and frequent assessment based on biopsy specimens is difficult. Therefore, a simple and safe alternative is desirable. On the other hand, it is now widely accepted that multi-hit steps, including production of aberrantly glycosylated serum IgA1 (first hit), and IgG or IgA autoantibodies that recognize glycan containing epitopes on glycosylated serum IgA1 (second hit) and their subsequent immune complex formation (third hit) and glomerular deposition (fourth hit), are required for continued progression of IgAN. Although the prognostic and predictive values of several markers have been discussed elsewhere, we recently developed a highly sensitive and specific diagnostic method by measuring serum levels of glycosylated serum IgA1 and related IgA immune complex. In addition, we confirmed a significant correlation between serum levels of these essential effector molecules and disease activity after treatment, suggesting that each can be considered as a practical surrogate marker of therapeutic effects in this slowly progressive disease. Such a noninvasive diagnostic and activity assessment method using these disease-oriented specific biomarkers may be useful in the early diagnosis of and intervention in IgAN, with appropriate indication for treatment, and thus aid in the future development and dissemination of specific and curative treatments.