Real-World Outcomes of Carotid Artery Stenting in Symptomatic and Asymptomatic Patients With Carotid Artery Stenosis.

BACKGROUND: The effectiveness and safety of carotid artery stenting (CAS) are comparable to those of carotid endarterectomy in both symptomatic and asymptomatic patients with carotid artery stenosis, but real-world outcomes are not well-known. OBJECTIVES: The purpose of this study was to investigate the real-world clinical outcomes of CAS in symptomatic and asymptomatic patients with carotid artery stenosis. METHODS: We conducted a nationwide retrospective registry study of 156 centers between January 2015 and December 2019. We enrolled consecutive patients with CAS managed by certified specialists from the Japanese Society of Neuroendovascular Therapy. Outcomes between symptomatic and asymptomatic patients were compared. The primary outcome was a composite of ischemic stroke and all-cause death at 30 days after CAS. Secondary outcomes were ischemic stroke, all-cause death, intracranial hemorrhage (ICH), and procedural complications. RESULTS: We analyzed 9,792 patients (symptomatic, n = 5,351; asymptomatic, n = 4,441). The mean age was 73.5 years, and men were dominant (86.4%). Embolism protection devices were used in 99% of patients. The primary outcome was not significantly different between the symptomatic and asymptomatic groups (120 [2.2%] vs 65 [1.5%]; adjusted OR: 1.30; 95% CI: 0.92-1.83). The incidences of symptomatic ICH, any ICH, acute in-stent occlusion, and hyperperfusion syndrome were significantly more prevalent in the symptomatic group (47 [0.9%] vs 8 [0.2%], aOR: 4.41 [95% CI: 1.68-11.6]; 73 [1.4%] vs 12 [0.3%], aOR: 3.56 [95% CI: 1.71-7.39]; 45 [0.8%] vs 19 [0.4%], aOR: 2.18 [95% CI: 1.08-4.40]; and 102 [1.9%] vs 36 [0.8%], aOR: 1.78 [95% CI: 1.17-2.71], respectively). Other secondary outcomes were not significantly different between the 2 groups. CONCLUSIONS: The complication rate after specialist-involved CAS at 30 days was low in real-world practice.

Early neurological changes following endovascular therapy for acute stroke due to intracranial atherosclerotic disease.

BACKGROUND: Endovascular therapy (EVT) reduces functional disability in patients with acute large vessel occlusion (LVO). However, the early neurological change after EVT may be limited in patients with intracranial atherosclerotic disease (ICAD). METHODS: We analyzed the Japanese Registry of NeuroEndovascular Therapy (JR-NET) 4 which was a retrospective, nationwide, multicenter registry of patients with LVO between 2015 and 2019. We compared the early neurological change, efficacy and safety of EVT for acute LVO in ICAD and other etiologies. The primary outcome was NIHSS improvement ≥10 points, and secondary outcome were NIHSS worsening ≥4 points 7 days after EVT, effective reperfusion rate, 30-day functional outcomes, and safety outcomes. RESULTS: Among the 6710 enrolled patients, 610 (9.1%) had ICAD. The ICAD group was younger (mean 72.0 vs. 75.8 years) and predominantly male (63.4% vs. 56.0%), had lower NIHSS scores before EVT (median 16 vs. 18), and underwent percutaneous transluminal angioplasty and stenting more frequently (43.0% vs. 4.4%, 12.3% vs. 4.4%). In the ICAD group, NIHSS improvement was significantly lower (adjusted odds ratio (aOR) [95% confidence interval (95%CI)] 0.52 [0.41-0.65]), NIHSS worsening was significantly higher (aOR [95%CI] 1.76 [1.31-2.34]), and effective reperfusion was significantly lower (aOR [95%CI] 0.47 [0.36-0.60]). Fewer patients with ICAD had modified Rankin scale 0-2 at 30 days (aOR [95%CI] 0.60 [0.47-0.77]). The risk of acute reocclusion was more prominent in the ICAD group (aOR [95%CI] 4.03 [1.98-8.21]). CONCLUSIONS: Improvement in neurological severity after EVT was lower in patients with LVO and ICAD.

Hypothermia increases adenosine monophosphate and xanthosine monophosphate levels in the mouse hippocampus, preventing their reduction by global cerebral ischemia.

Global cerebral ischemia (GCI) caused by clinical conditions such as cardiac arrest leads to delayed neuronal death in the hippocampus, resulting in physical and mental disability. However, the mechanism of delayed neuronal death following GCI remains unclear. To elucidate the mechanism, we performed a metabolome analysis using a mouse model in which hypothermia (HT) during GCI, which was induced by the transient occlusion of the bilateral common carotid arteries, markedly suppressed the development of delayed neuronal death in the hippocampus after reperfusion. Fifteen metabolites whose levels were significantly changed by GCI and 12 metabolites whose levels were significantly changed by HT were identified. Furthermore, the metabolites common for both changes were narrowed down to two, adenosine monophosphate (AMP) and xanthosine monophosphate (XMP). The levels of both AMP and XMP were found to be decreased by GCI, but increased by HT, thereby preventing their decrease. In contrast, the levels of adenosine, inosine, hypoxanthine, xanthine, and guanosine, the downstream metabolites of AMP and XMP, were increased by GCI, but were not affected by HT. Our results may provide a clue to understanding the mechanism by which HT during GCI suppresses the development of delayed neuronal death in the hippocampus.

A Case of Atypical Hemolytic Uremic Syndrome Triggered by Acute Pancreatitis in a Patient with a Membrane Cofactor Protein (CD46) Genetic Variant.

Atypical hemolytic uremic syndrome (aHUS) is a type of HUS. We herein report a case of aHUS triggered by pancreatitis in a patient with a heterozygous variant of membrane cofactor protein (MCP; P165S), a complement-related gene. Plasma exchange therapy and hemodialysis improved thrombocytopenia and anemia without leading to end-stage kidney disease. This MCP heterozygous variant was insufficient to cause aHUS on its own. Pancreatitis, in addition to a genetic background with a MCP heterozygous variant, led to the manifestation of aHUS. This case supports the "multiple hit theory" that several factors are required for the manifestation of aHUS.

Early Initiation of Plasma Exchange Therapy for Anti-MDA5+Dermatomyositis with Refractory Rapidly Progressive Interstitial Lung Disease.

Objectives Dermatomyositis (DM) is often associated with fatal anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive rapidly progressive interstitial lung disease (RP-ILD). RP-ILD often fails to respond to intensive treatment and has a poor prognosis. We examined the effectiveness of early plasma exchange therapy plus intensive treatment with high-dose corticosteroids and multiple immunosuppressants. Methods Autoantibodies were identified by an immunoprecipitation assay and enzyme-linked immunosorbent assay. All clinical and immunological data were collected retrospectively from medical charts. We divided patients into two groups based on treatment regimen: intensive immunosuppressive therapy alone as initial treatment (IS group) and early initiation of plasma exchange (PE) plus intensive immunosuppressive therapy (ePE group). Early PE therapy was designated if PE therapy was initiated within two weeks of starting treatment. Comparisons of the treatment response and prognosis between groups were performed. Patients Anti-MDA5-positive DM with RP-ILD was screened. Results Forty-four RP-ILD and DM patients had anti-MDA5 antibodies. Four patients were excluded because they died before receiving sufficient combined immunosuppressive therapy or before the evaluation of the immunosuppressive treatment effectiveness (IS, n=31; ePE, n=9). All 9 patients in the ePE group had improved respiratory symptoms and were alive, whereas 12 of 31 patients in the IS group died (100 vs. 61%, p=0.037). Of the 8 patients who had 2 values for a poor prognosis, indicating the highest risk for death using the MCK model, 3 of 3 patients in the ePE group and 2 of 5 in the IS group were alive (100 vs. 40%, p=0.20). Conclusion The early initiation of ePE therapy plus intensive immunosuppressive therapy was effective for patients with DM and refractory RP-ILD.

First-in-human trial of a self-expandable, temporary dilation system for intracranial atherosclerotic disease in patients presenting with acute ischemic stroke.

BACKGROUND: Intracranial atherosclerotic disease (ICAD) significantly contributes to ischemic stroke, especially among Asian populations. Large vessel occlusion (LVO) due to underlying ICAD accounts for 15-35% of acute ischemic stroke cases requiring endovascular therapy. However, the successful recanalization rate of ICAD-related LVO remains lower. The TG dilator is a self-expandable device, temporarily dilating ICAD-related blocked blood vessels. OBJECTIVE: To demonstrate TG dilator safety and efficacy for ICAD-related acute ischemic stroke. METHODS: This was a single-arm, open-label, non-randomized, prospective, multicenter, and investigator-initiated trial that involved patients undergoing TG dilator application for acute ischemic stroke caused by ICAD-related LVO or severe stenosis. RESULTS: We enrolled 10 patients in this trial between November 2022 and April 2023. The median (IQR) age was 68 (59.3-75.3) years. Before using the dilator, seven patients received stent retriever treatment. All 10 patients were prescribed a loading dose of aspirin with prasugrel. The median application time was 10 (10-12) min. At the end of the procedure, we achieved significant recanalization immediately in all patients. The stenosis/occlusion decreased from 100% (100-100) to 68% (56.3-75.3). No patient experienced recurrent ischemic stroke or reocclusion within 90 days. We achieved a modified Rankin scale score of 0-2 in 8 patients by day 90. We detected no cases of intracranial hemorrhage, equipment failure, distal embolism, vasospasm, dissection, or perforation requiring intervention. CONCLUSIONS: Acute revascularization using the TG dilator on patients with ICAD-related LVO or severe stenosis did not cause any significant adverse event, and consistently improved blood flow at 90 days.

Ruptured thrombosed vertebral artery dissecting aneurysm treated with staged flow diverter after prediction of the rupture point by vessel wall MRI.

The safety and feasibility of using staged flow diverter (FD) for ruptured cerebral aneurysms, in which coil embolization is performed in the acute phase and FD is deployed in the subacute phase, has recently been reported. This strategy requires assuming the rupture point and performing coil embolization. Although vessel wall magnetic resonance imaging (VW-MRI) has been reported to be useful in predicting the rupture point of aneurysms, its use with staged FD has not yet been reported. We report the first case of staged FD with preoperative contrast-enhanced VW-MRI to predict the rupture point for partially thrombosed vertebral artery dissecting large aneurysm involving posterior inferior cerebellar artery (PICA) origin. This approach achieved a very good outcome, not only completely occluding the aneurysm, but also reconstructing the parent artery while maintaining the patency of the PICA.

Ruptured brainstem arteriovenous malformation associated with a thalamoperforating artery aneurysm arising from the P1 segment of the right posterior cerebral artery: illustrative case.

BACKGROUND: Cerebral aneurysms of perforating arteries are rare and can be difficult to detect on computed tomography angiography (CTA) and digital subtraction angiography. Treatment is challenging and associated with a significant risk of morbidity. Endovascular treatment of a thalamoperforating artery (TPA) aneurysm within the midbrain has not previously been reported. OBSERVATIONS: A 13-year-old girl with no previous medical history presented with unconsciousness and anisocoria. Head computed tomography showed a right midbrain hemorrhage. CTA showed a midbrain arteriovenous malformation fed by a TPA aneurysm arising from the P1 segment of the right posterior cerebral artery. The feeder had a small distal aneurysm, which increased in size over time. Endovascular embolization was then performed. LESSONS: Cerebral aneurysms of perforating arteries are rare and can be difficult to treat. This is the first report of the endovascular treatment of a TPA aneurysm within the midbrain. Understanding the individual patient's brainstem perforator anatomy and the associated blood flow is essential before occluding a TPA aneurysm to avoid causing ischemia or infarction. Arteriovenous malformation embolization within the brainstem should be avoided because of interperforator anastomoses.

Medical records as screening tools for child death review in Japan.

BACKGROUND: Although many child death review (CDR) systems have been developed in Japan, the optimal system is still being identified. The aim of this study is to identify the etiologies of child deaths and to propose a screening method for initiating the CDR process in Japan. METHODS: Clinical medical records (CMRs) in hospitals and autopsy records were surveyed for cases of deaths of children aged less than 15 years between 2014 and 2016 in Aichi Prefecture, Japan. The data were analyzed in three steps, and the findings were compared with the vital statistics. RESULTS: Of the 695 children whose death certificates were submitted to Aichi Prefecture, 590 could be traced to pediatric care hospitals. The distribution of causes of death was slightly different from the vital statistics, with 11.5% dying of extrinsic causes and 19.7% dying of unknown causes. Maltreatment was suspected in 64 cases, which was much higher than that in government statistics. Overall, 158 (26.8%) deaths were considered preventable. The number of unnatural deaths, which might be screened in, was calculated as 172 (29.2%) in the vital statistics, whereas the survey of CMRs revealed that 241 (40.8%) to 282 (47.8%) should be screened in. CONCLUSIONS: Surveying CMRs in hospitals may be a suitable method to detect and screen deaths to start the CDR process in Japan.

Partially thrombosed giant basilar artery aneurysm with attenuated contrast enhancement of the intraluminal thrombus on vessel wall MRI after flow diversion treatment: illustrative case.

BACKGROUND: The effect of vessel wall magnetic resonance imaging (VW-MRI) enhancement in partially thrombosed aneurysms has previously indicated aneurysmal instability and a rupture risk. However, whether the contrast effect of the wall changes before or after flow diversion treatment is still under investigation. OBSERVATIONS: The authors report a case of a partially thrombosed basilar artery aneurysm that increased in size over a short period, worsened brainstem compression symptoms, and was treated with a flow diverter stent with good results. In this case, VW-MRI after surgery showed a reduced contrast effect on the intraluminal thrombus within the aneurysm. The aneurysm thrombosed and markedly regressed over the next 5 months, with remarkable improvement in the brainstem compression symptoms. LESSONS: This finding on VW-MRI may indicate an attenuation of neovascularization in the thrombus wall and be a sign of aneurysm stabilization.

Thermally Stable Photomechanical Molecular Hinge: Sterically Hindered Stiff-Stilbene Photoswitch Mechanically Isomerizes.

Molecular photoswitches are extensively used as molecular machines because of the small structures, simple motions, and advantages of light including high spatiotemporal resolution. Applications of photoswitches depend on the mechanical responses, in other words, whether they can generate motions against mechanical forces as actuators or can be activated and controlled by mechanical forces as mechanophores. Sterically hindered stiff stilbene (HSS) is a promising photoswitch offering large hinge-like motions in the E/Z isomerization, high thermal stability of the Z isomer, which is relatively unstable compared to the E isomer, with a half-life of ca. 1000 years at room temperature, and near-quantitative two-way photoisomerization. However, its mechanical response is entirely unexplored. Here, we elucidate the mechanochemical reactivity of HSS by incorporating one Z or E isomer into the center of polymer chains, ultrasonicating the polymer solutions, and stretching the polymer films to apply elongational forces to the embedded HSS. The present study demonstrated that HSS mechanically isomerizes only in the Z to E direction and reversibly isomerizes in combination with UV light, i.e., works as a photomechanical hinge. The photomechanically inducible but thermally irreversible hinge-like motions render HSS unique and promise unconventional applications differently from existing photoswitches, mechanophores, and hinges.

Association between Intraoperative Early Warning Score and Mortality and In-Hospital Stay in Lower Gastrointestinal Spontaneous Perforation.

Background: Early warning scores (EWSs) can be easily calculated from physiological indices; however, the extent to which intraoperative EWSs and the corresponding changes are associated with patient prognosis is unknown. In this study, we investigated whether EWS and the corresponding time-related changes are associated with patient outcomes during the anesthetic management of lower gastrointestinal perforation. Methods: This was a single-center, retrospective cohort study conducted at a tertiary emergency care center. Adult patients who underwent surgery for spontaneous lower gastrointestinal perforations between September 1, 2012, and December 31, 2019, were included. The National Early Warning Score (NEWS) and Modified Early Warning Score (MEWS) were calculated based on the intraoperative physiological indices, and the associations with in-hospital death and length of hospital stay were investigated. Results: A total of 101 patients were analyzed. The median age was 70 years, and there were 11 cases of in-hospital death (mortality rate: 10.9%). There was a significant association between the intraoperative maximum NEWS and in-hospital death (odds ratio (OR): 1.60, 95% confidence interval (CI): 1.10-2.32, p=0.013) and change from initial to maximum NEWS (OR: 1.60, 95% CI: 1.07-2.40, p=0.023) in the crude analysis. However, when adjustments were made for confounding factors, no statistically significant associations were found. Other intraoperative EWS values and changes were not significantly associated with the investigated outcomes. The preoperative sepsis-related organ failure assessment score and the intraoperative base excess value were significantly associated with in-hospital death. Conclusions: No clear association was observed between EWSs and corresponding changes and in-hospital death in cases of lower gastrointestinal perforation. The preoperative sepsis-related organ failure assessment score and intraoperative base excess value were significantly associated with in-hospital death.

Absence of anti-rabphilin-3A antibodies in children and young adults with idiopathic central diabetes insipidus: a potential clue to elucidating a tumor etiology.

BACKGROUND: Central diabetes insipidus (CDI) is a rare condition caused by various underlying diseases, including neoplasms, autoimmune diseases, and infiltrative diseases. Differentiating between CDI etiologies is difficult. What has initially been classified as "idiopathic" central diabetes insipidus might in fact underlie various pathogenic mechanisms that are less understood to date and/or are not obvious at initial presentation. Therefore, even if idiopathic CDI is diagnosed at the time of onset, it is common for tumors such as germinoma to develop during surveillance. Crucially, a delayed diagnosis of germinoma may be associated with a worse prognosis. Recently, the presence of anti-rabphilin-3A antibodies has been found to be a highly sensitive and specific marker of lymphocytic infundibuloneurohypophysitis, an autoimmune-mediated CDI. CASE PRESENTATION: We herein present two cases, namely, a 13-year-old boy (patient 1) and a 19-year-old young man (patient 2) who were diagnosed with idiopathic CDI. In both patients, panhypopituitarism developed. Magnetic resonance imaging revealed pituitary stalk thickening and pituitary swelling approximately 1 1/2 years after the onset of CDI. Western blotting did not reveal the presence of anti-rabphilin-3A antibodies in serum in either patient, suggesting that autoimmune mechanisms might not be involved. Both patients were subsequently diagnosed with germinoma on pathological examination. They received chemotherapy, followed by radiation therapy. Notably, testosterone and insulin-like growth factor-1 levels normalized, and libido and beard growth recovered after chemoradiotherapy in patient 2. CONCLUSION: Our data suggest that the absence of anti-rabphilin-3A antibodies in young patients clinically diagnosed with idiopathic CDI may increase the probability of the development of non-lymphocytic lesions, including germinoma. We thus recommend a more attentive approach at the onset of these diseases.

Acute osteomyelitis/septic pulmonary embolism associated with familial infections caused by PVL-positive ST6562 MRSA-IVa, a presumptive variant of USA300 clone.

Panton-Valentine leukocidin (PVL)-positive methicillin-resistant Staphylococcus aureus (MRSA) occasionally causes severe invasive infections. A 10-year-old immunocompetent boy in Hokkaido, the northern main island of Japan, was admitted with acute osteomyelitis of the right ilium, complicated by septic thrombophlebitis of the right common iliac vein and septic pulmonary embolism. As MRSA was isolated from blood and sputum samples of the patient, linezolid and vancomycin were initially used for treatment, and later clindamycin was added based on PCR-positive results for PVL genes. During his hospitalization, the patient was complicated by abscesses around the right ilium and septic arthritis of the right hip, which required surgical drainage. Prior to his admission, his youngest sister had developed a right breast abscess, and another sister and his mother developed contagious impetigo and hordeolum, respectively, during his hospitalization. These infections in the patient and his family members were caused by an identical PVL-positive MRSA strain belonging to ST6562, a single-locus variant of ST8. Due to the genetically close characteristics, this ST6562 MRSA was considered a genetic variant of the USA300 CA-MRSA clone (ST8-MRSA-IVa) predominating in the United States. The ST6562 MRSA-IVa is suggested to have occurred in Japan, associated with potential spread of the USA300 clone.

Different solubilizing ability of cyclodextrin derivatives for cholesterol in Niemann-Pick disease type C treatment.

BACKGROUND: Niemann-Pick disease type C (NPC) is a fatal neurodegenerative disorder caused by abnormal intracellular cholesterol trafficking. Cyclodextrins (CDs), the most promising therapeutic candidates for NPC, but with concerns about ototoxicity, are cyclic oligosaccharides with dual functions of unesterified cholesterol (UC) shuttle and sink that catalytically enhance the bidirectional flux and net efflux of UC, respectively, between the cell membrane and the extracellular acceptors. However, the properties of CDs that regulate these functions and how they could be used to improve treatments for NPC are unclear. METHODS: We estimated CD-UC complexation for nine CD derivatives derived from native α-, ß-, and γ-CD with different cavity sizes, using solubility and molecular docking analyses. The stoichiometry and complexation ability of the resulting complexes were investigated in relation to the therapeutic effectiveness and toxicity of each CD derivative in NPC experimental models. FINDINGS: We found that shuttle and sink activities of CDs are dependent on cavity size-dependent stoichiometry and substituent-associated stability of CD-UC complexation. The ability of CD derivatives to form 1:1 and 2:1 complexes with UC were correlated with their ability to normalize intracellular cholesterol trafficking serving as shuttle and with their cytotoxicity associated with cellular UC efflux acting as sink, respectively, in NPC model cells. Notably, the ability of CD derivatives to form an inclusion complex with UC was responsible for not only efficacy but ototoxicity, while a representative derivative without this ability negligibly affected auditory function, underscoring its preventability. CONCLUSIONS: Our findings highlight the importance of strategies for optimizing the molecular structure of CDs to overcome this functional dilemma in the treatment of NPC.

Matrix metalloproteinase-10 deficiency has protective effects against peritoneal inflammation and fibrosis via transcription factor NFκΒ pathway inhibition.

One of the most common causes of discontinued peritoneal dialysis is impaired peritoneal function. However, its molecular mechanisms remain unclear. Previously, by microarray analysis of mouse peritoneum, we showed that MMP (matrix metalloproteinase)-10 expression is significantly increased in mice with peritoneal fibrosis, but its function remains unknown. Chlorhexidine gluconate (CG) was intraperitoneally injected to wild-type and MMP-10 knockout mice to induce fibrosis to elucidate the role of MMP-10 on peritoneal injury. We also examined function of peritoneal macrophages and mesothelial cells obtained from wild-type and MMP-10 knockout mice, MMP-10-overexpressing macrophage-like RAW 264.7 cells and MeT-5A mesothelial cells, investigated MMP-10 expression on peritoneal biopsy specimens, and the association between serum proMMP-10 and peritoneal solute transfer rates determined by peritoneal equilibration test on patients. MMP-10 was expressed in cells positive for WT1, a mesothelial marker, and for MAC-2, a macrophage marker, in the thickened peritoneum of both mice and patients. Serum proMMP-10 levels were well correlated with peritoneal solute transfer rates. Peritoneal fibrosis, inflammation, and high peritoneal solute transfer rates induced by CG were all ameliorated by MMP-10 deletion, with reduction of CD31-positive vessels and VEGF-A-positive cells. Expression of inflammatory mediators and phosphorylation of NFκΒ subunit p65 at S536 were suppressed in both MMP-10 knockout macrophages and mesothelial cells in response to lipopolysaccharide stimulation. Overexpression of MMP-10 in RAW 264.7 and MeT-5A cells upregulated pro-inflammatory cytokines with phosphorylation of NFκΒ subunit p65. Thus, our results suggest that inflammatory responses induced by MMP-10 are mediated through the NFκΒ pathway, and that systemic deletion of MMP-10 ameliorates peritoneal inflammation and fibrosis caused by NFκΒ activation of peritoneal macrophages and mesothelial cells.

A report of three cases of patients with tubulointerstitial nephritis with IgM-positive plasma cells, treatment, and serum-IgM as a sensitive marker for relapse.

BACKGROUND: Tubulointerstitial nephritis with IgM-positive plasma cells (IgMPC-TIN) is a newer disease about which there are many unclear points. Glucocorticoid therapy is effective in many cases of IgMPC-TIN; however, relapse during glucocorticoid tapering has been reported. Relapse and its treatment are poorly defined. CASE PRESENTATION: Case 1 was a 61-year-old man with renal dysfunction and proteinuria. Tubulointerstitial nephritis and IgM-positive plasma cells were observed in a renal biopsy. He was diagnosed with IgMPC-TIN accompanied by Fanconi syndrome and distal renal tubular acidosis (d-RTA). Prednisolone (PSL; 30 mg daily, 0.45 mg/kg/day) treatment was highly effective, and PSL was gradually tapered and discontinued after 1 year. However, 1 month after PSL discontinuation, therapeutic markers were elevated. Therefore, PSL (10 mg daily, 0.15 mg/kg/day) was administered, and the markers indicated improvement. Case 2 was a 43-year-old woman referred for renal dysfunction and proteinuria. Laboratory data revealed that she had primary biliary cholangitis (PBC), d-RTA, and Fanconi syndrome. A renal biopsy showed accumulation of IgM-positive plasma cells in the tubulointerstitium without any glomerular changes. A diagnosis of IgMPC-TIN was made and the patient was started on PSL (35 mg daily, 0.6 mg/kg/day). Therapeutic markers decreased immediately and PSL was discontinued after 1 year. Three months later, the proteinuria and Fanconi syndrome worsened. PSL treatment was restarted (20 mg daily, 0.35 mg/kg/day) and markers indicated improvement. Case 3 was a 45-year-old woman with renal dysfunction and proteinuria. Tubulointerstitial nephritis and IgM-positive plasma cells were observed in a renal biopsy. The patient had PBC, Sjögren syndrome, d-RTA, and Fanconi syndrome, and the diagnosis of IgMPC-TIN was made. The patient was started on PSL (30 mg daily, 0.4 mg/kg/day) and disease markers decreased immediately. However, when PSL was tapered to 15 mg daily (0.2 mg/kg/day), the patient's serum IgM levels increased; therefore, we maintained the PSL at 15 mg daily (0.2 mg/kg/day). CONCLUSION: We report three cases of relapsed IgMPC-TIN associated with reduction or discontinuation of glucocorticoid therapy. In these cases, elevation of serum IgM preceded that of other markers such as urinary ß2-microglobulin, proteinuria, and glycosuria. We recommend monitoring serum IgM levels while tapering glucocorticoids; a maintenance dose of glucocorticoid should be considered if relapse is suspected or anticipated.

Automatic Ischemic Core Estimation Based on Noncontrast-Enhanced Computed Tomography.

BACKGROUND: Evaluating the extent of ischemic change is an important step in deciding whether to use thrombolysis or mechanical thrombectomy, but the current standard method, Alberta Stroke Program Early CT Score, is semiquantitative and has low consistency among raters. We aim to create and test a fully automated machine learning-based ischemic core segmentation model using only noncontrast-enhanced computed tomography images. METHODS: In this multicenter retrospective study, patients with anterior circulation acute ischemic stroke who received both computed tomography (CT) and magnetic resonance imaging before thrombolysis or recanalization treatment between 2013 and 2019 were included. On CT, the ischemic core was manually delineated using the diffusion-weighted image and apparent diffusion coefficient maps. A deep learning-based ischemic core segmentation model (DL model) was developed using data from 3 institutions (n=272), and the model performance was validated using data from 3 institutions (n=106 Results: The median time ).between CT and magnetic resonance imaging in the validation cohort was 18 min. The DL model calculated ischemic core volume was significantly correlated with the reference standard (intraclass correlation coefficient, 0.90, P<0.01). Both the early time window (≤4.5 hours from onset; intraclass correlation coefficient, 0.90, P<0.01) and the late time window (>4.5 hours from onset; intraclass correlation coefficient, 0.93, P<0.01) had significant correlations. The median difference in ivolume between the model and the reference standard was 4.7 mL (interquartile range, 0.8-12.4 mL). The DL model performed well in distinguishing large ischemic cores (>70 mL), with a sensitivity of 84.2%, specificity of 97.7%, and area under the curve of 0.91. CONCLUSIONS: The deep learning-based ischemic core segmentation model, which was based on noncontrast-enhanced CT, demonstrated high accuracy in assessing ischemic core volume in patients with anterior circulation acute ischemic stroke.

Vessel wall imaging and carotid artery stenting for recurrent cervical internal carotid artery vasospasm syndrome: illustrative case.

BACKGROUND: Recurrent cervical internal carotid artery vasospasm syndrome (RCICVS) causes cerebral infarction, ocular symptoms, and occasionally chest pain accompanied by coronary artery vasospasm. The etiology and optimal treatment remain unclear. OBSERVATIONS: The authors report a patient with drug-resistant RCICVS who underwent carotid artery stenting (CAS). Magnetic resonance angiography revealed recurrent vasospasm in the cervical segment of the internal carotid artery (ICA). Vessel wall imaging during an ischemic attack revealed vascular wall thickening of the ICA, similar to that in reversible cerebral vasoconstriction syndrome. The superior cervical ganglion was identified at the anteromedial side of the stenosis site. Coronary artery stenosis was also detected. After CAS, the symptoms of cerebral ischemia were prevented for 2 years, but bilateral ocular and chest symptoms did occur. LESSONS: Vessel wall imaging findings suggest that RCICVS is a sympathetic nervous system-related disease. CAS could be an effective treatment for drug-resistant RCICVS to prevent cerebral ischemic events.

Dual deletion of guanylyl cyclase-A and p38 mitogen-activated protein kinase in podocytes with aldosterone administration causes glomerular intra-capillary thrombi.

Natriuretic peptides exert not only blood-lowering but also kidney-protective effects through guanylyl cyclase-A (GC-A), a natriuretic peptide receptor. Signaling through GC-A has been shown to protect podocytes from aldosterone-induced glomerular injury, and a p38 mitogen-activated protein kinase (MAPK) inhibitor reduced glomerular injury in aldosterone-infused podocyte-specific GC-A knockout mice. To explore the role of p38 MAPK in podocytes, we constructed podocyte-specific p38 MAPK and GC-A double knockout mice (pod-double knockout mice). Unexpectedly, aldosterone-infused and high salt-fed (B-ALDO)-treated pod-double knockout mice resulted in elevated serum creatinine, massive albuminuria, macrophage infiltration, foot process effacement, nephrin and podocin reduction, and additionally, intra-capillary fibrin thrombi, indicating endothelial injury. Microarray analysis showed increased plasminogen activator inhibitor-1 (PAI-1) in glomeruli of B-ALDO-treated pod-double knockout mice. In B-ALDO-treated pod-double knockout mice, PAI-1 increased in podocytes, and treatment with PAI-1 neutralizing antibody ameliorated intra-capillary thrombus formation. In vitro, deletion of p38 MAPK by the CRISPR/Cas9 system and knockdown of GC-A in human cultured podocytes upregulated PAI-1 and transforming growth factor- ß1 (TGF-ß1). When p38 MAPK knockout podocytes, transfected with a small interfering RNA to suppress GC-A, were co-cultured with glomerular endothelial cells in a transwell system, the expression of TGF-ß1 was increased in glomerular endothelial cells. PAI-1 inhibition ameliorated both podocyte and endothelial injury in the transwell system signifying elevated PAI-1 in podocytes is a factor disrupting normal podocyte-endothelial crosstalk. Thus, our results indicate that genetic dual deletion of p38 MAPK and GC-A in podocytes accelerates both podocyte and endothelial injuries, suggesting these two molecules play indispensable roles in podocyte function.