Endovascular electroencephalography (eEEG) can detect the laterality of epileptogenic foci as accurately as subdural electrodes.

Background: Traditional brain activity monitoring via scalp electroencephalography (EEG) offers limited resolution and is susceptible to artifacts. Endovascular electroencephalography (eEEG) emerged in the 1990s. Despite early successes and potential for detecting epileptiform activity, eEEG has remained clinically unutilized. This study aimed to further test the capabilities of eEEG in detecting lateralized epileptic discharges in animal models. We hypothesized that eEEG would be able to detect lateralization. The purpose of this study was to measure epileptiform discharges with eEEG in animal models with lateralization in epileptogenicity. Materials and methods: We inserted eEEG electrodes into the transverse sinuses of three pigs, and subdural electrodes (SDs) on the surfaces of the left and right hemispheres. We induced epileptogenicity with penicillin in the left brain of pigs F00001 and F00003, and in the right brain of pig F00002. The resulting epileptiform discharges were measured by eEEG electrodes placed in the left and right transverse sinuses, and conducted comparisons with epileptiform discharges from SDs. We also had 12 neurological physicians interpret measurement results from eEEG alone and determine the side (left or right) of epileptogenicity. Results: Three pigs were evaluated for epileptiform discharge detection using eEEG: F00001 (7 months old, 14.0 kg), F00002 (8 months old, 15.6 kg), and F00003 (8 months old, 14.4 kg). The eEEG readings were compared with results from SDs, showing significant alignment across all subjects (p < 0.001). The sensitivity and positive predictive values (PPV) were as follows: F00001 had 0.93 and 0.96, F00002 had 0.99 and 1.00, and F00003 had 0.98 and 0.99. Even though one of the neurological physicians got all sides incorrect, all other assessments were correct. Upon post-experimental dissection, no abnormalities were observed in the brain tissue or in the vascular damage at the site where the eEEG was placed, based on pathological evaluation. Conclusion: With eEEG, lateralization can be determined with high sensitivity (>0.93) and PPV (>0.95) that appear equivalent to those of subdural EEG in the three pigs. This lateralization was also discernible by neurological physicians on visual inspection.

Surgical outcome of ipsilateral anatomical resection for lung cancer after pulmonary lobectomy.

OBJECTIVES: Ipsilateral reoperation after pulmonary lobectomy is often challenging because of adhesions from the previous operation. We retrospectively examined the surgical outcome and prognosis of ipsilateral anatomical resection for lung cancer after pulmonary lobectomy using a multicentre database. METHODS: We evaluated the perioperative outcomes and overall survival of 51 patients who underwent pulmonary lobectomy followed by ipsilateral anatomical resection for lung cancer between January 2012 and December 2018. In addition, patients with stage I non-small-cell lung cancer (NSCLC) were compared with 3411 patients with stage I lung cancer who underwent pulmonary resection without a prior ipsilateral lobectomy. RESULTS: Ipsilateral anatomical resections included 10 completion pneumonectomies, 19 pulmonary lobectomies and 22 pulmonary segmentectomies. Operative time was 312.2 ± 134.5 min, and intraoperative bleeding was 522.2 ± 797.5 ml. Intraoperative and postoperative complications occurred in 9 and 15 patients, respectively. However, the 5-year overall survival rate after anatomical resection followed by ipsilateral lobectomy was 83.5%. Furthermore, in patients with c-stage I NSCLC, anatomical resection followed by ipsilateral lobectomy was not associated with worse survival than anatomical resection without prior ipsilateral lobectomy. CONCLUSIONS: Anatomical resection following ipsilateral lobectomy is associated with a high frequency of intraoperative and postoperative complications. However, the 5-year overall survival in patients with c-stage I NSCLC who underwent ipsilateral anatomical resection after pulmonary lobectomy is comparable to that in patients who underwent anatomical resection without prior pulmonary lobectomy.

Neuropeptide Y Antagonizes Development of Pulmonary Fibrosis through IL-1ß Inhibition.

Neuropeptide Y (NPY), a 36 amino acid residue polypeptide distributed throughout the nervous system, acts on various immune cells in many organs, including the respiratory system. However, little is known about its role in the pathogenesis of pulmonary fibrosis. This study was performed to determine the effects of NPY on pulmonary fibrosis. NPY-deficient and wild-type mice were intratracheally administered bleomycin. Inflammatory cells, cytokine concentrations, and morphological morphometry of the lungs were analyzed. Serum NPY concentrations were also measured in patients with idiopathic pulmonary fibrosis and healthy control subjects. NPY-deficient mice exhibited significantly enhanced pulmonary fibrosis and higher IL-1ß concentrations in the lungs compared with wild-type mice. Exogenous NPY treatment suppressed the development of bleomycin-induced lung fibrosis and decreased IL-1ß concentrations in the lungs. Moreover, IL-1ß neutralization in NPY-deficient mice attenuated the fibrotic changes. NPY decreased IL-1ß release, and Y1 receptor antagonists inhibited IL-1ß release and induced epithelial-mesenchymal transition in human alveolar epithelial cells. Patients with idiopathic pulmonary fibrosis had lower NPY and greater IL-1ß concentrations in the serums compared with healthy control subjects. NPY expression was mainly observed around bronchial epithelial cells in human idiopathic pulmonary fibrosis lungs. These data suggest that NPY plays a protective role against pulmonary fibrosis by suppressing IL-1ß release, and manipulating the NPY-Y1 receptor axis could be a potential therapeutic strategy for delaying disease progression.

One-step nucleic acid amplification for intraoperative diagnosis of lymph node metastasis in lung cancer patients: a single-center prospective study.

One-step nucleic acid amplification (OSNA) is a rapid intraoperative molecular detection technique for sentinel node assessment via the quantitative measurement of target cytokeratin 19 (CK19) mRNA to determine the presence of metastasis. It has been validated in breast cancer but its application in lung cancer has not been adequately investigated. 214 LNs from 105 patients with 100 primary lung cancers, 2 occult primary lung tumors, and 3 metastatic lung tumors, who underwent surgical lung resection with LN dissection between February 2018 and January 2020, were assessed. Resected LNs were divided into two parts: one was snap-frozen for OSNA and the other underwent rapidly frozen histological examination. Intraoperatively collected LNs were evaluated by OSNA using loop-mediated isothermal amplification and compared with intraoperative pathological diagnosis as a control. Among 214 LNs, 14 were detected as positive by OSNA, and 11 were positive by both OSNA and intraoperative pathological diagnosis. The sensitivity and specificity of OSNA was 84.6% and 98.5%, respectively. The results of 5 of 214 LNs were discordant, and the remainder all matched (11 positive and 198 negative) with a concordance rate of 97.7%. Although the analysis of public mRNA expression data from cBioPortal showed that CK19 expression varies greatly depending on the cancer type and histological subtype, the results of the five cases, except for primary lung cancer, were consistent. OSNA provides sufficient diagnostic accuracy and speed and can be applied to the intraoperative diagnosis of LN metastasis for non-small cell lung cancer.

Endovascular Electroencephalogram Records Simultaneous Subdural Electrode-Detectable, Scalp Electrode-Undetectable Interictal Epileptiform Discharges.

INTRODUCTION: We hypothesized that an endovascular electroencephalogram (eEEG) can detect subdural electrode (SDE)-detectable, scalp EEG-undetectable epileptiform discharges. The purpose of this study is, therefore, to measure SDE-detectable, scalp EEG-undetectable epileptiform discharges by an eEEG on a pig. METHODS: A pig under general anesthesia was utilized to measure an artificially generated epileptic field by an eEEG that was able to be detected by an SDE, but not a scalp EEG as a primary outcome. We also compared the phase lag of each epileptiform discharge that was detected by the eEEG and SDE as a secondary outcome. RESULTS: The eEEG electrode detected 113 (97%) epileptiform discharges (97% sensitivity). Epileptiform discharges that were localized within the three contacts (contacts two, three and four), but not spread to other parts, were detected by the eEEG with a 92% sensitivity. The latency between peaks of the eEEG and right SDE earliest epileptiform discharge ranged from 0 to 48 ms (mean, 13.3 ms; median, 11 ms; standard deviation, 9.0 ms). CONCLUSION: In a pig, an eEEG could detect epileptiform discharges that an SDE could detect, but that a scalp EEG could not.

Emergent carotid artery stenting for cervical internal carotid artery injury during carotid endarterectomy: A case report.

BACKGROUND: Carotid endarterectomy (CEA) has been the standard preventive procedure for cerebral infarction due to cervical internal carotid artery stenosis, and internal shunt insertion during CEA is widely accepted. However, troubleshooting knowledge is essential because potentially life-threatening complications can occur. Herein, we report a case of cervical internal carotid artery injury caused by the insertion of a shunt device during CEA. CASE DESCRIPTION: A 78-year-old man with a history of hypertension, diabetes, and hyperuricemia developed temporary left hemiplegia. A former physician had diagnosed the patient with a transient cerebral ischemic attack. The patient's medical history was significant for the right internal carotid artery stenosis, which was severe due to a vulnerable plaque. We performed CEA to remove the plaque; however, there was active bleeding in the distal carotid artery of the cervical region after we removed the shunt tube. Hemostasis was achieved through compression using a cotton piece. Intraoperative digital subtraction angiography (DSA) revealed severe stenosis at the internal carotid artery distal to the injury site due to hematoma compression. The patient underwent urgent carotid artery stenting and had two carotid artery stents superimposed on the injury site. On DSA, extravascular pooling of contrast media decreased on postoperative day (POD) 1 and then disappeared on POD 14. The patient was discharged home without sequela on POD 21. CONCLUSION: In the case of cervical internal carotid artery injury during CEA, hemostasis can be achieved by superimposing a carotid artery stent on the injury site, which is considered an acceptable troubleshooting technique.

Long-term Follow-up of Living-Donor Kidney Transplantation after Cadaveric Lung Transplantation.

Although chronic kidney disease (CKD) commonly develops after lung transplantation (LT), living-donor kid-ney transplantation (LDKT) for CKD after LT is known to provide favorable outcomes. We describe the long-term follow-up findings of a patient who underwent LDKT after bilateral cadaveric LT. A 37-year-old male underwent LDKT for CKD 18 years after receiving bilateral cadaveric LT. He developed chronic lung allograft dysfunction (CLAD) 20 years after the LT; however, at 26 years after the initial LT, he is still alive with no pro-gression of CLAD or CKD. KT could be a viable option for CKD even after LT in Japan.

The heterodimer S100A8/A9 is a potent therapeutic target for idiopathic pulmonary fibrosis.

In patients with interstitial pneumonia, pulmonary fibrosis is an irreversible condition that can cause respiratory failure. Novel treatments for pulmonary fibrosis are necessary. Inflammation is thought to activate lung fibroblasts, resulting in pulmonary fibrosis. Of the known inflammatory molecules, we have focused on S100A8/A9 from the onset of inflammation to the subsequent progression of inflammation. Our findings confirmed the high expression of S100A8/A9 in specimens from patients with pulmonary fibrosis. An active role of S100A8/A9 was demonstrated not only in the proliferation of fibroblasts but also in the fibroblasts' differentiation to myofibroblasts (the active form of fibroblasts). S100A8/A9 also forced fibroblasts to upregulate the production of collagen. These effects were induced via the receptor of S100A8/A9, i.e., the receptor for advanced glycation end products (RAGE), on fibroblasts. The anti-S100A8/A9 neutralizing antibody inhibited the effects of S100A8/A9 on fibroblasts and suppressed the progression of fibrosis in bleomycin (BLM)-induced pulmonary fibrosis mouse model. Our findings strongly suggest a crucial role of S100A8/A9 in pulmonary fibrosis and the usefulness of S100A8/A9-targeting therapy for fibrosis interstitial pneumonia. HIGHLIGHTS: S100A8/A9 level is highly upregulated in the IPF patients' lungs as well as the blood. S100A8/A9 promotes not only the growth of fibroblasts but also differentiation to myofibroblasts. The cell surface RAGE acts as a crucial receptor to the extracellular S100A8/A9 in fibroblasts. The anti-S100A8/A9 antibody effectively suppresses the progression of IPF in a mouse model. In idiopathic pulmonary fibrosis (IPF), S100A8/A9, a heterodimer composed of S100A8 and S100A9 proteins, plays a crucial role in the onset of inflammation and the subsequent formation of a feed-forward inflammatory loop that promotes fibrosis. (1) The local, pronounced increase in S100A8/A9 in the injured inflammatory lung region-which is provided mainly by the activated neutrophils and macrophages-exerts strong inflammatory signals accompanied by dozens of inflammatory soluble factors including cytokines, chemokines, and growth factors that further act to produce and secrete S100A8/A9, eventually making a sustainable inflammatory circuit that supplies an indefinite presence of S100A8/A9 in the extracellular space with a mal-increased level. (2) The elevated S100A8/A9 compels fibroblasts to activate through receptor for advanced glycation end products (RAGE), one of the major S100A8/A9 receptors, resulting in the activation of NFκB, leading to fibroblast mal-events (e.g., elevated cell proliferation and transdifferentiation to myofibroblasts) that actively produce not only inflammatory cytokines but also collagen matrices. (3) Finally, the S100A8/A9-derived activation of lung fibroblasts under a chronic inflammation state leads to fibrosis events and constantly worsens fibrosis in the lung. Taken together, these findings suggest that the extracellular S100A8/A9 heterodimer protein is a novel mainstay soluble factor for IPF that exerts many functions as described above (1-3). Against this background, we herein applied the developed S100A8/A9 neutralizing antibody to prevent IPF. The IPF imitating lung fibrosis in an IPF mouse model was effectively blocked by treatment with the antibody, leading to enhanced survival. The developed S100A8/A9 antibody, as an innovative novel biologic, may help shed light on the difficulties encountered with IPF therapy in clinical settings.

Overcoming epithelial-mesenchymal transition-mediated drug resistance with monensin-based combined therapy in non-small cell lung cancer.

BACKGROUND: The epithelial-mesenchymal transition (EMT) is a key process in tumor progression and metastasis and is also associated with drug resistance. Thus, controlling EMT status is a research of interest to conquer the malignant tumors. MATERIALS AND METHODS: A drug repositioning analysis of transcriptomic data from a public cell line database identified monensin, a widely used in veterinary medicine, as a candidate EMT inhibitor that suppresses the conversion of the EMT phenotype. Using TGF-ß-induced EMT cell line models, the effects of monensin on the EMT status and EMT-mediated drug resistance were assessed. RESULTS: TGF-ß treatment induced EMT in non-small cell lung cancer (NSCLC) cell lines and the EGFR-mutant NSCLC cell lines with TGF-ß-induced EMT acquired resistance to EGFR-tyrosine kinase inhibitor. The addition of monensin effectively suppressed the TGF-ß-induced-EMT conversion, and restored the growth inhibition and the induction of apoptosis by the EGFR-tyrosine kinase inhibitor. CONCLUSION: Our data suggested that combined therapy with monensin might be a useful strategy for preventing EMT-mediated acquired drug resistance.

Antitumor Effects of Pan-RAF Inhibitor LY3009120 Against Lung Cancer Cells Harboring Oncogenic BRAF Mutation.

BACKGROUND/AIM: The therapeutic strategy for patients with non-small-cell lung cancer (NSCLC) harboring the BRAF non-V600E mutation has not been established. LY3009120, a newly discovered pan-RAF inhibitor, has shown strong antitumor effects in cancers with various BRAF genotypes. This study investigated the antitumor effects of LY3009120 in NSCLC cells harboring the BRAF non-V600E mutation. MATERIALS AND METHODS: We examined the antitumor effects of LY3009120 by MTS assay and flow cytometry. We analyzed the expression status of proteins by western blot. The mouse xenograft models were used for the in vivo experiments. RESULTS: LY3009120 suppressed BRAF-related downstream pathway molecules and induced cleavage of poly ADP-ribose polymerase in all examined NSCLC cell lines. LY3009120 also inhibited in vivo tumor growth in NSCLC cells harboring the BRAF non-V600E mutation. CONCLUSION: LY3009120 is a potent therapeutic agent for patients with BRAF non-V600E mutant NSCLC.

YES1 activation induces acquired resistance to neratinib in HER2-amplified breast and lung cancers.

Molecular-targeted therapies directed against human epidermal growth factor receptor 2 (HER2) are evolving for various cancers. Neratinib is an irreversible pan-HER tyrosine kinase inhibitor and has been approved by the FDA as an effective drug for HER2-positive breast cancer. However, acquired resistance of various cancers to molecular-targeted drugs is an issue of clinical concern, and emergence of resistance to neratinib is also considered inevitable. In this study, we established various types of neratinib-resistant cell lines from HER2-amplified breast and lung cancer cell lines using several drug exposure conditions. We analyzed the mechanisms of emergence of the resistance in these cell lines and explored effective strategies to overcome the resistance. Our results revealed that amplification of YES1, which is a member of the SRC family, was amplified in two neratinib-resistant breast cancer cell lines and one lung cancer cell line. Knockdown of YES1 by siRNA and pharmacological inhibition of YES1 by dasatinib restored the sensitivity of the YES1-amplified cell lines to neratinib in vitro. Combined treatment with dasatinib and neratinib inhibited tumor growth in vivo. This combination also induced downregulation of signaling molecules such as HER2, AKT and MAPK. Our current results indicate that YES1 plays an important role in the emergence of resistance to HER2-targeted drugs, and that dasatinib enables such acquired resistance to neratinib to be overcome.

Oxidative stress-responsive apoptosis inducing protein (ORAIP) plays a critical role in cerebral ischemia/reperfusion injury.

Oxidative stress is known to play a critical role in the pathogenesis of various disorders, especially in ischemia/reperfusion (I/R) injury. We identified an apoptosis-inducing humoral factor and named this novel post translationally modified secreted form of eukaryotic translation initiation factor 5A (eIF5A) "oxidative stress-responsive apoptosis inducing protein" (ORAIP). The purpose of this study was to investigate the role of ORAIP in the mechanisms of cerebral I/R injury. Hypoxia/reoxygenation induced expression of ORAIP in cultured rat cerebral neurons, resulting in extensive apoptosis of these cells, which was largely suppressed by neutralizing anti-ORAIP monoclonal antibody (mAb) in vitro. Recombinant-ORAIP induced extensive apoptosis of cerebral neurons. Cerebral I/R induced expression of ORAIP in many neurons in a rat tandem occlusion model in vivo. In addition, we analyzed the effects of intracerebroventricular administration of neutralizing anti-ORAIP mAb on the development of cerebral infarction. Cerebral I/R significantly increased ORAIP levels in cerebrospinal fluid. Treatment with intracerebroventricular administration of neutralizing anti-ORAIP mAb reduced infarct volume by 72%, and by 55% even when started after reperfusion. These data strongly suggest that ORAIP plays a pivotal role and will offer a critical therapeutic target for cerebral I/R injury induced by thrombolysis and thrombectomy for acute ischemic stroke.

Upregulation of Mobility in Pancreatic Cancer Cells by Secreted S100A11 Through Activation of Surrounding Fibroblasts.

S100A11, a member of the S100 family of proteins, is actively secreted from pancreatic ductal adenocarcinoma (PDAC) cells. However, the role of the extracellular S100A11 in PDAC progression remains unclear. In the present study, we investigated the extracellular role of S100A11 in crosstalking between PDAC cells and surrounding fibroblasts in PDAC progression. An abundant S100A11 secreted from pancreatic cancer cells stimulated neighboring fibroblasts through receptor for advanced glycation end products (RAGE) upon S100A11 binding and was followed by not only an enhanced cancer cell motility in vitro but also an increased number of the PDAC-derived circulating tumor cells (CTCs) in vivo. Mechanistic investigation of RAGE downstream in fibroblasts revealed a novel contribution of a mitogen-activated protein kinase kinase kinase (MAPKKK), tumor progression locus 2 (TPL2), which is required for positive regulation of PDAC cell motility through induction of cyclooxygenase 2 (COX2) and its catalyzed production of prostaglandin E2 (PGE2), a strong chemoattractive fatty acid. The extracellularly released PGE2 from fibroblasts was required for the rise in cellular migration as well as infiltration of their adjacent PDAC cells in a coculture setting. Taken together, our data reveal a novel role of the secretory S100A11 in PDAC disseminative progression through activation of surrounding fibroblasts triggered by the S100A11-RAGE-TPL2-COX2 pathway. The findings of this study will contribute to the establishment of a novel therapeutic antidote to PDACs that are difficult to treat by regulating cancer-associated fibroblasts (CAFs) through targeting the identified pathway.

Extracellular S100A11 Plays a Critical Role in Spread of the Fibroblast Population in Pancreatic Cancers.

The fertile stroma in pancreatic ductal adenocarcinomas (PDACs) has been suspected to greatly contribute to PDAC progression. Since the main cell constituents of the stroma are fibroblasts, there is crosstalking(s) between PDAC cells and surrounding fibroblasts in the stroma, which induces a fibroblast proliferation burst. We have reported that several malignant cancer cells including PDAC cells secrete a pronounced level of S100A11, which in turn stimulates proliferation of cancer cells via the receptor for advanced glycation end products (RAGE) in an autocrine manner. Owing to the RAGE+ expression in fibroblasts, the extracellular abundant S100A11 will affect adjacent fibroblasts. In this study, we investigated the significance of the paracrine axis of S100A11-RAGE in fibroblasts for their proliferation activity. In in vitro settings, extracellular S100A11 induced upregulation of fibroblast proliferation. Our mechanistic studies revealed that the induction is through RAGE-MyD88-mTOR-p70 S6 kinase upon S100A11 stimulation. The paracrine effect on fibroblasts is linked mainly to triggering growth but not cellular motility. Thus, the identified pathway might become a potential therapeutic target to suppress PDAC progression through preventing PDAC-associated fibroblast proliferation.

Newly developed anti-S100A8/A9 monoclonal antibody efficiently prevents lung tropic cancer metastasis.

The metastatic dissemination of cancer cells to remote areas of the body is the most problematic aspect in cancer patients. Among cancers, melanomas are notoriously difficult to treat due to their significantly high metastatic potential even during early stages. Hence, the establishment of advanced therapeutic approaches to regulate metastasis is required to overcome the melanoma disease. An accumulating mass of evidence has indicated a critical role of extracellular S100A8/A9 in melanoma distant metastasis. Lung S100A8/A9 is induced by melanoma cells from distant organs and it attracts these cells to its enriched lung environment since melanoma cells possess several receptors that sense the S100A8/A9 ligand. We hence aimed to develop a neutralizing antibody against S100A8/A9 that would efficiently block melanoma lung metastasis. Our protocol provided us with one prominent antibody, Ab45 that efficiently suppressed not only S100A8/A9-mediated melanoma mobility but also lung tropic melanoma metastasis in a mouse model. This prompted us to make chimeric Ab45, a chimera antibody consisting of mouse Ab45-Fab and human IgG2-Fc. Chimeric Ab45 also showed significant inhibition of the lung metastasis of melanoma. From these results, we have high hopes that the newly produced antibody will become a potential biological tool to block melanoma metastasis in future clinical settings.

exSSSRs (extracellular S100 soil sensor receptors)-Fc fusion proteins work as prominent decoys to S100A8/A9-induced lung tropic cancer metastasis.

Within the "seed and soil" theory of organ tropic cancer metastasis is a growing compilation of evidence that S100A8/A9 functions as a soil signal that attracts cancer cells to certain organs, which prove beneficial to their growth. S100A8/A9-sensing receptors including Toll-like receptor 4 (TLR4), advanced glycation end products (RAGE), and also important receptors we recently succeeded in identifying (EMMPRIN, NPTNß, MCAM, and ALCAM) have the potential to become promising therapeutic targets. In our study, we prepared extracellular regions of these novel molecules and fused them to human IgG2-Fc to extend half-life expectancy, and we evaluated the anti-metastatic effects of the purified decoy proteins on metastatic cancer cells. The purified proteins markedly suppressed S100A8/A9-mediated lung tropic cancer metastasis. We hence expect that our novel biologics may become a prominent medicine to prevent cancer metastasis in clinical settings through cutting the linkage between "seed and soil".

Blunt Abdominal Aortic Injury Associated with L2 Vertebral Fracture.

Blunt abdominal aortic injury (BAAI) is very rare. In general, BAAI occurs in high-energy accidents. Here, we present a case of BAAI in a low-energy accident. A 70-year-old female was injured after falling 3 m. Her vital signs were stable. She had lumbar fractures (L1, L2) and BAAI associated with a fragment of the fractured L2 vertebral body. On the fifth posttrauma day, we performed an operation because computed tomography showed a bone fragment of the lumbar fractures (L1, L2) threatening the abdominal aorta. The aortic injury site was transected, and the fragment of the L2 vertebral body was removed. Even in low-energy accidents, BAAI should be considered. BAAI with stable vital signs can be electively treated.

[A case of possible immunoglobulin G4-related disease (IgG4-RD) with retroperitoneal fibrosis and central diabetes insipidus due to infundibulohypophysitis].

We report a case of possible immunoglobulin G4-related disease(IgG4-RD)that resulted in complications such as retroperitoneal fibrosis and infundibulohypophysitis. The patient was a 72-year-old male who presented with polyuria and polydipsia. Magnetic resonance imaging(MRI)revealed a thickened pituitary stalk and contrast enhancement with gadolinium. T1-weighted imaging revealed that the posterior pituitary high-signal zone had disappeared. Central diabetes insipidus was diagnosed on the basis of results of the hypertonic saline test. In addition, pressure due to retroperitoneal fibrosis resulted in hydronephrosis and elevated serum IgG4 levels. Because it was determined that the patient could have IgG4-RD, he was administered prednisolone, following which a decrease in the size of the pituitary stalk and retroperitoneal fibrosis was observed. IgG4-RD is characterized by elevated serum IgG4 levels and the infiltration of IgG4-positive plasma cells into various organs, including the central nervous system. Recently, IgG4-RD research teams organized by the Ministry of Health, Labour and Welfare established guidelines for the diagnosis of IgG4-RD. According to these guidelines, this case would fall under the category of "possible IgG4-RD." This case suggested that when infundibulohypophysitis is detected by neuroradiology, further investigation into the possibility of IgG4-RD should be recommended.

Organ-specific sulfation patterns of heparan sulfate generated by extracellular sulfatases Sulf1 and Sulf2 in mice.

Heparan sulfate endosulfatases Sulf1 and Sulf2 hydrolyze 6-O-sulfate in heparan sulfate, thereby regulating cellular signaling. Previous studies have revealed that Sulfs act predominantly on UA2S-GlcNS6S disaccharides and weakly on UA-GlcNS6S disaccharides. However, the specificity of Sulfs and their role in sulfation patterning of heparan sulfate in vivo remained unknown. Here, we performed disaccharide analysis of heparan sulfate in Sulf1 and Sulf2 knock-out mice. Significant increases in ΔUA2S-GlcNS6S were observed in the brain, small intestine, lung, spleen, testis, and skeletal muscle of adult Sulf1(-/-) mice and in the brain, liver, kidney, spleen, and testis of adult Sulf2(-/-) mice. In addition, increases in ΔUA-GlcNS6S were seen in the Sulf1(-/-) lung and small intestine. In contrast, the disaccharide compositions of chondroitin sulfate were not primarily altered, indicating specificity of Sulfs for heparan sulfate. For Sulf1, but not for Sulf2, mRNA expression levels in eight organs of wild-type mice were highly correlated with increases in ΔUA2S-GlcNS6S in the corresponding organs of knock-out mice. Moreover, overall changes in heparan sulfate compositions were greater in Sulf1(-/-) mice than in Sulf2(-/-) mice despite lower levels of Sulf1 mRNA expression, suggesting predominant roles of Sulf1 in heparan sulfate desulfation and distinct regulation of Sulf activities in vivo. Sulf1 and Sulf2 mRNAs were differentially expressed in restricted types of cells in organs, and consequently, the sulfation patterns of heparan sulfate were locally and distinctly altered in Sulf1 and Sulf2 knock-out mice. These findings indicate that Sulf1 and Sulf2 differentially contribute to the generation of organ-specific sulfation patterns of heparan sulfate.