C5a-C5AR1 axis as a potential trigger of the rupture of intracranial aneurysms.

Recent studies have indicated the involvement of neutrophil-mediated inflammatory responses in the process leading to intracranial aneurysm (IA) rupture. Receptors mediating neutrophil recruitment could thus be therapeutic targets of unruptured IAs. In this study, complement C5a receptor 1 (C5AR1) was picked up as a candidate that may cause neutrophil-dependent inflammation in IA lesions from comprehensive gene expression profile data acquired from rat and human samples. The induction of C5AR1 in IA lesions was confirmed by immunohistochemistry; the up-regulations of C5AR1/C5ar1 stemmed from infiltrated neutrophils, which physiologically express C5AR1/C5ar1, and adventitial fibroblasts that induce C5AR1/C5ar1 in human/rat IA lesions. In in vitro experiments using NIH/3T3, a mouse fibroblast-like cell line, induction of C5ar1 was demonstrated by starvation or pharmacological inhibition of mTOR signaling by Torin1. Immunohistochemistry and an experiment in a cell-free system using recombinant C5 protein and recombinant Plasmin indicated that the ligand of C5AR1, C5a, could be produced through the enzymatic digestion by Plasmin in IA lesions. In conclusion, we have identified a potential contribution of the C5a-C5AR1 axis to neutrophil infiltration as well as inflammatory responses in inflammatory cells and fibroblasts of IA lesions. This cascade may become a therapeutic target to prevent the rupture of IAs.

Hypoxic microenvironment as a crucial factor triggering events leading to rupture of intracranial aneurysm.

Subarachnoid hemorrhage being the rupture of intracranial aneurysm (IA) as a major cause has quite poor prognosis, despite the modern technical advances. Thereby, the mechanisms underlying the rupture of lesions should be clarified. Recently, we and others have clarified the formation of vasa vasorum in IA lesions presumably for inflammatory cells to infiltrate in lesions as the potential histopathological alternation leading to rupture. In the present study, we clarified the origin of vasa vasorum as arteries located at the brain surface using 3D-immunohistochemistry with tissue transparency. Using Hypoxyprobe, we then found the presence of hypoxic microenvironment mainly at the adventitia of intracranial arteries where IA is formed. In addition, the production of vascular endothelial growth factor (VEGF) from cultured macrophages in such a hypoxic condition was identified. Furthermore, we found the accumulation of VEGF both in rupture-prone IA lesions induced in a rat model and human unruptured IA lesions. Finally, the VEGF-dependent induction of neovessels from arteries on brain surface was confirmed. The findings from the present study have revealed the potential role of hypoxic microenvironment and hypoxia-induced VEGF production as a machinery triggering rupture of IAs via providing root for inflammatory cells in lesions to exacerbate inflammation.

Predicting the growth of middle cerebral artery bifurcation aneurysms using differences in the bifurcation angle and inflow coefficient.

OBJECTIVE: Growing intracranial aneurysms (IAs) are prone to rupture. Previous cross-sectional studies using postrupture morphology have shown the morphological or hemodynamic features related to IA rupture. Yet, which morphological or hemodynamic differences of the prerupture status can predict the growth and rupture of smaller IAs remains unknown. The purpose of this longitudinal study was to investigate the effects of morphological features and the hemodynamic environment on the growth of IAs at middle cerebral artery (MCA) bifurcations during the follow-up period. METHODS: One hundred two patients with MCA M1-2 bifurcation saccular IAs who underwent follow-up for more than 2 years at the authors' institutions between 2011 and 2019 were retrospectively identified. During the follow-up period, cases involving growth of MCA IAs were assigned to the event group, and those with MCA IAs unchanged in size were assigned to the control group. The morphological parameters examined were aneurysmal neck length, dome height, aspect ratio and volume, M1 and M2 diameters and their ratio, and angle configurations among M1, M2, and the aneurysm. Hemodynamic parameters were flow rate and wall shear stress in M1, M2, and the aneurysm, including the aneurysmal inflow rate coefficient (AIRC), defined as the ratio of the aneurysmal inflow rate to the M1 flow rate. Those parameters were compared statistically between the two groups. Correlations between morphological and hemodynamic parameters were also examined. RESULTS: Eighty-three of 102 patients were included: 25 with growing MCA IAs (event group) and 58 with stable MCA IAs (control group). The median patient age at initial diagnosis was 66.9 (IQR 59.8-72.3) years. The median follow-up period was 48.5 (IQR 36.5-65.6) months. Both patient age and the AIRC were significant independent predictors of the growth of MCA IAs. Moreover, the AIRC was strongly correlated with sharper bifurcation and inflow angles, as well as wider inclination angles between the M1 and M2 arteries. CONCLUSIONS: The AIRC was a significant independent predictor of the growth of MCA IAs. Sharper bifurcation and inflow angles and wider inclination angles between the M1 and M2 arteries were correlated with the AIRC. MCA IAs with such a bifurcation configuration are more prone to grow and rupture.

Endothelial cell malfunction in unruptured intracranial aneurysm lesions revealed using a 3D-casted mold.

Intracranial aneurysms (IA) are major causes of devastating subarachnoid hemorrhages. They are characterized by a chronic inflammatory process in the intracranial arterial walls triggered and modified by hemodynamic force loading. Because IA lesion morphology is complex, the blood flow conditions loaded on endothelial cells in each portion of the lesion in situ vary greatly. We created a 3D-casted mold of the human unruptured IA lesion and cultured endothelial cells on this model; it was then perfused with culture media to model physiological flow conditions. Gene expression profiles of endothelial cells in each part of the IA lesion were then analyzed. Comprehensive gene expression profile analysis revealed similar gene expression patterns in endothelial cells from each part of the IA lesion but gene ontology analysis revealed endothelial cell malfunction within the IA lesion. Histopathological examination, electron microscopy, and immunohistochemical analysis indicated that endothelial cells within IA lesions are damaged and dysfunctional. Thus, our findings reveal endothelial cell malfunction in IA lesions and provided new insights into IA pathogenesis.

Identification of The Unique Subtype of Macrophages in Aneurysm Lesions at the Growth Phase.

OBJECTIVES: Recent experimental studies have defined intracranial aneurysms as a macrophage-mediated chronic inflammatory disease affecting intracranial arteries. Although there are various subtypes in macrophages, what type of macrophages is present in lesions during the disease development remains to be elucidated. METHODS: The previously-established aneurysm model of rats was used. Macrophages were labeled with the fluorescent protein and isolated by a laser-microdissection method. The comprehensive gene expression profile analyses and gene ontology analyses was then done to identify a macrophage subtype present in lesions at the growth phase. RESULTS: The gene expression profile data of total 52 macrophages infiltrating into the lesions was acquired. The principal component analysis revealed the monotonous macrophage subtype. By comparing the profile identified with one from in vitro-differentiated M0 or M1 macrophages, the macrophages in the lesions were belonged to the simple and unique subtype. Because the perception of signaling from nervous system was highlighted as up-represented terms through gene ontology analyses, the macrophage subtype in lesions at the growth phase might be differentiated under the influence of nervous system in the microenvironment. The histopathological examinations supported the above notion by confirming the presence of nerves in the adventitia. CONCLUSIONS: The findings from the present study have provided the useful insights about the macrophage subtype in aneurysm lesions at the growth phase and also proposed its ability as a therapeutic target.

The Lack of Alterations in Metabolites in the Medial Prefrontal Cortex and Amygdala, but Their Associations with Autistic Traits, Empathy, and Personality Traits in Adults with Autism Spectrum Disorder: A Preliminary Study.

Proton magnetic resonance spectroscopy (1H-MRS) has shown inconsistent alterations in brain metabolites of adults with autism spectrum disorder (ASD). We investigated brain metabolites in the medial prefrontal cortex and amygdala of 24 drug-naive adults with ASD and no intellectual disability and 24 non-ASD control subjects, using 3 T 1H-MRS. Adults with ASD showed no significant differences from control in glutamate, glutamate plus glutamine, N-acetylaspartate, glycerophosphorylcholine plus phosphorylcholine, creatine plus phosphocreatine, or myo-inositol in either region. However, ASD subjects did show significant correlations of localized brain metabolites with autistic traits, empathy deficits, and personality traits using the Autism-Spectrum Quotient, Questionnaire of Cognitive and Affective Empathy, Interpersonal Reactivity Index, and NEO Personality Inventory-Revised. These findings should be taken as preliminary or exploratory.

The bifurcation angle is associated with the progression of saccular aneurysms.

The role of the bifurcation angle in progression of saccular intracranial aneurysms (sIAs) has been undetermined. We, therefore, assessed the association of bifurcation angles with aneurysm progression using a bifurcation-type aneurysm model in rats and anterior communicating artery aneurysms in a multicenter case-control study. Aneurysm progression was defined as growth by ≥ 1 mm or rupture during observation, and controls as progression-free for 30 days in rats and ≥ 36 months in humans. In the rat model, baseline bifurcation angles were significantly wider in progressive aneurysms than in stable ones. In the case-control study, 27 and 65 patients were enrolled in the progression and control groups. Inter-observer agreement for the presence or absence of the growth was excellent (κ coefficient, 0.82; 95% CI, 0.61-1.0). Multivariate logistic regression analysis showed that wider baseline bifurcation angles were significantly associated with subsequent progressions. The odds ratio for the progression of the second (145°-179°) or third (180°-274°) tertiles compared to the first tertile (46°-143°) were 5.5 (95% CI, 1.3-35). Besides, the bifurcation angle was positively correlated with the size of aneurysms (Spearman's rho, 0.39; P = 0.00014). The present study suggests the usefulness of the bifurcation angle for predicting the progression of sIAs.

[Current Knowledge on the Genetic Analysis and Development of Medical Therapy for Intracranial Aneurysms].

Genetic studies on intracranial aneurysms(IAs), like genome-wide association studies, or studies analyzing familial intracranial aneurysms, have successfully revealed the potential contribution of a set of genes to the pathology of IAs. Some of the genes may promote the formation of IAs or the process leading to rupture of the lesions through exacerbating inflammatory responses or facilitating the degenerative changes of arterial walls. Many genes or single-nucleotide polymorphisms have been identified through extensive analyses, but they can only explain one-fifth of the IA pathology; therefore, the pathogenesis of IAs is influenced by many factors, including environmental factors, and not only genetic ones. Intriguingly, a somatic mutation in the PDGFRB gene has recently been identified in more than half of the cases with fusiform aneurysms, making the development of medical therapy targeting PDGFRß signaling realistic. Nowadays, following a series of recent experimental studies, IA is considered a chronic inflammatory disease affecting intracranial arteries, indicating the potential of anti-inflammatory drugs as therapeutic drugs for the treatment of IAs. No wonder, recently published observational studies have revealed the preventive effect of statins and aspirin, with potent anti-inflammatory effects on the rupture of IAs.

Associations among autistic traits, cognitive and affective empathy, and personality traits in adults with autism spectrum disorder and no intellectual disability.

Reported empathy deficits in autism spectrum disorder (ASD) could be attributable to other ASD-related features. We evaluated 28 ASD adults with no intellectual disability and 24 age-matched non-ASD control subjects using the Autism-Spectrum Quotient (AQ), Questionnaire of Cognitive and Affective Empathy (QCAE), Interpersonal Reactivity Index (IRI), and NEO Personality Inventory-Revised (NEO). Compared to the controls, ASD participants showed lower scores for perspective taking, online simulation, cognitive empathy, and peripheral responsivity on the QCAE, and lower scores for perspective taking and empathic concern on the IRI. Within the ASD group, the AQ scores showed significant relationships with perspective taking, online simulation and cognitive empathy on the QCAE, and perspective taking on the IRI. The ASD group also showed higher scores for neuroticism and lower scores for extraversion on the NEO compared to the controls. However, there were no relationships between AQ scores and NEO factors within the ASD group. Multiple regression analysis with stepwise linear regression demonstrated that perspective taking score on the QCAE and extraversion score on the NEO were good predictor variables to autistic traits on the AQ. These findings help us to understand empathy and personality traits in ASD adults with no intellectual disability.

Induction of CCN1 in Growing Saccular Aneurysms: A Potential Marker Predicting Unstable Lesions.

Growing evidence has suggested that inflammatory responses promote the progression of saccular intracranial aneurysms (IAs). However, a biomarker predicting the progression has yet to be established. This study aimed to identify novel molecules upregulated during the progression using a previously established rat aneurysm model. In this model, aneurysms are induced at the surgically created common carotid artery (CCA) bifurcation. Based on sequential morphological data, the observation periods after the surgical manipulations were defined as the growing phase (on the 10th day) or the stable phase (on the 30th day). Total cell lysates from the CCA with or without an aneurysm lesion were prepared to perform protein array analysis. The protein array analysis revealed that the matricellular protein cellular communication network factor 1 (CCN1) is induced in lesions during the growing phase. Immunohistochemistry corroborated the significant upregulation of CCN1 in the growing phase compared with the stable phase. Simultaneously with the induction of CCN1, significant increases in the number of CD68-positive macrophages, myeloperoxidase-positive cells, and proliferating smooth muscle cells in lesions were observed. Immunohistochemistry of human IA specimens reproduced the induction of CCN1 in some lesions. These findings imply a potential role of CCN1 as a marker predicting the progression of saccular aneurysms.

Spontaneous Persistent Primitive Trigeminal Artery-Cavernous Sinus Fistula Successfully Treated by Multipronged Coil Embolization: Case Report and Literature Review.

BACKGROUND: A spontaneous persistent primitive trigeminal artery-cavernous sinus fistula (PCF) is extremely rare. Until recently, endovascular treatment for PCF involving transarterial and/or transvenous coil embolization of the cavernous sinus (with/without the persistent trigeminal artery) was commonly performed. However, it may result in remaining shunt flow or exacerbation of cranial nerve palsy. CASE DESCRIPTION: A 51-year-old woman presented with headache and left abducens palsy. Digital subtraction angiography demonstrated a direct fistula between the cavernous segment of the persistent primitive trigeminal artery (PPTA) and posterosuperior compartment of the left cavernous sinus (CS). Three microcatheters were guided into the fistula as follows: 1) through the PPTA to the CS from the left internal carotid artery, 2) through the PPTA to the CS from the basilar artery, and 3) through the CS to the PPTA from the internal jugular vein. Using the double-catheter technique in a multidirectional fashion, shunt occlusion was achieved with a small number of coils. No signs of recurrence were observed during the follow-up period. CONCLUSIONS: The multipronged approach is safe and effective for embolization of a small tortuous artery and shunt segment to avoid incomplete shunt occlusion.

Metabolism of an Oxime-Linked Antibody Drug Conjugate, AGS62P1, and Characterization of Its Identified Metabolite.

AGS62P1 is an antibody drug conjugate (ADC) composed of a human IgG1κ monoclonal antibody against FLT3 (FMS-like tyrosine kinase 3) with a p-acetyl phenylalanine (pAF) residue inserted at position 124 of each heavy chain linked to the proprietary microtubule disrupting agent AGL-0182-30 via an alkoxyamine linker that forms an oxime upon conjugation to the antibody. AGS62P1 is currently in Phase I human clinical trials for acute myelogenous leukemia (AML). The identified primary metabolite of an oxime-linked ADC is presented for the first time. AGS62P1 metabolism was assessed in xenograft tumor-bearing mice and rats treated with the ADC using liquid chromatography and mass spectrometry-based methods described herein. In this study, we identified the metabolite of AGS62P1 as pAF-AGL-0185-30, which contains a fragment resulting from the catabolism of the antibody component of the ADC and hydrolysis of the terminal amide portion of the linker-payload. We demonstrated that the metabolite of AGS62P1 is tolerated in rats above 1.5 mg/kg and above 0.334 mg/kg in cynomolgus monkeys when given as a single dose. Furthermore, we established in vitro that pAF-AGL-0185-30 does not significantly inhibit hERG or cytochrome P450 family enzymes (CYPs).

Introduction of 2-octyl cyanoacrylate (Dermabond®) for incisional hernia mesh repair.

PURPOSE: We developed a new technique, sutureless mesh fixation, using 2-octyl cyanoacrylate (Dermabond®, a surgical tissue adhesive) for incisional hernia repair. The objective of this article is to introduce the new technique and to examine whether the technique provides sufficient resistance to abdominal pressure. METHODS: We conducted two tests using a porcine model, a traction experiment and artificial pneumoperitoneum test. In the traction experiment, the adherence properties of Dermabond® with mesh and peritoneum were examined using a tissue fragment from a pig. In the artificial pneumoperitoneum test, which used an incisional hernia porcine model, mesh was implanted on the peritoneum in the abdominal cavity with Dermabond®. It was then determined whether sutureless mesh fixation could bear artificial abdominal air pressure. RESULTS: In the traction experiment, Dermabond®, which bonded the mesh to the peritoneum, tolerated pressure up to 2.45 × 103 mmHg. In the artificial pneumoperitoneum test, the mesh was strongly fastened to the peritoneum by means of only Dermabond®, and there was little air circulation even without closing the wound over the mesh. CONCLUSIONS: Sutureless mesh fixation with Dermabond® is technically feasible and promises to provide sufficient resistance to abdominal pressure.

Successful treatment of non-occlusive mesenteric ischemia (NOMI) using the HyperEye Medical System™ for intraoperative visualization of the mesenteric and bowel circulation: report of a case.

Non-occlusive mesenteric ischemia (NOMI), leading to intestinal gangrene without a demonstrable occlusion in the mesenteric artery, is a rare condition with extremely high mortality. We report a case of NOMI diagnosed preoperatively by computed tomography and treated successfully with surgery, assisted by indocyanine green (ICG) fluorescence in the HyperEye Medical System (HEMS), a new device that can simultaneously detect color and near-infrared rays under room light. This allowed for precise intraoperative evaluation of the mesenteric and bowel circulation. Although the necrotic bowel wall of the distal ileum and the segmental ischemia of the jejunum were visible, the jejunum was finally preserved because perfusion of ICG fluorescence was confirmed. The patient, an 84-year-old man, had an uneventful postoperative course and is alive without critical illness 8 months after surgery. We report this case to demonstrate the potential effectiveness of HEMS during surgery for NOMI.

Modified gastroduodenostomy in laparoscopy-assisted distal gastrectomy: a 'tornado' anastomosis.

BACKGROUND/AIMS: This study was to examine the utility of a modified double-stapling end-to-end gastroduodenostomy method ('Tornado' anastomosis) compared to a method with an additional gastrotomy ('Anterior Incision' method) in laparoscopy-assisted distal gastrectomy. METHODOLOGY: Forty-two patients with gastric cancer who underwent laparoscopy-assisted distal gastrectomy were analyzed retrospectively. Billroth-I using an additional gastrotomy was performed in 24 patients (AI group) and Billroth-I without an additional gastrotomy was performed in 18 (TOR group). Clinicopathological features, operative outcomes (lymph node dissection, operative time, operative blood loss) and postoperative outcomes (complications, postoperative hospital stay, and body weight loss at one year after surgery) were evaluated and compared between groups. RESULTS: Operative time was significantly shorter in the TOR group (251 min) than in the AI group (282 min) (p < 0.01). There were no statistically significant differences in operative blood loss, postoperative complications, and hospital stay between the 2 study groups. Body weight loss at one year after surgery was -5.8 kg in the TOR group and -6.5 kg in the AI group, without a statistically significant difference. CONCLUSIONS: Completion time for Billroth-I anastomosis was significantly shorter with Tornado anastomosis than with the Anterior Incision method, with safety equal between the two methods.

Application of the HyperEye Medical System for esophageal cancer surgery: a preliminary report.

The HyperEye Medical System is a newly developed device that allows for the visualization of the fluorescent image of indocyanine green enhanced by near-infrared light among the surrounding vivid color images. We recently applied this system to confirm the blood flow of an esophageal substitute, and for sentinel node navigation during esophagectomy. Five consecutive patients with thoracic esophageal cancer who underwent a subtotal esophagectomy between June 2010 and May 2011 were enrolled in the study. The esophageal substitute used for reconstruction was the stomach and ileocecum in four and one cases, respectively. In all cases with a reconstructive stomach, fine arterial blood flow and venous perfusion were observed. The blood flow of the reconstructive colon was poor before microvascular anastomosis, however, it dramatically increased after anastomosis. Concerning the sentinel node navigation, the fluorescence of lymph nodes, lymphatic vessels, and the tumor site were detected. The postoperative courses of all cases were uneventful, with no mortalities or anastomotic leakage occurring.

Clinical experience with chemoradiotherapy comprising S-1 plus low-dose cisplatin in a patient with stage IV anal cancer.

We report a case of anal cancer in a 58-year-old woman who complained of narrow, bloody stools and anal pain. Physical examination revealed anal stenosis associated with a circular mass arising in the anal canal. Histological examination of biopsy specimens confirmed a diagnosis of moderately differentiated squamous cell carcinoma. Enhanced computed tomography revealed anal cancer invading the levator ani and the vagina, with lymph-node, multiple hepatic, and pulmonary metastases. The patient received two cycle of chemoradiotherapy with S-1 plus low-dose cisplatin with rest for 4 weeks, leading to complete response of the primary lesion and a partial response of the metastatic lesions. Each cycle included oral S-1 (120 mg/body; day 1-21), cisplatin (10 mg/body; day 1-5, 8-12) and radiotherapy (2 Gy/day; day 1-5, 8-12, 15-19). Adverse effects of treatment were mild perineal skin erosion and mild appetite loss, but no hematologic toxicity. Although the patient died 16 months after first admission, chemoradiotherapy with S-1 plus cisplatin is potentially effective for the management of advanced anal cancer.

Neuroendocrine carcinoma of the stomach: a case study.

Gastric neuroendocrine carcinomas are rare and have a poor prognosis, and the diagnostic criteria for this disease have recently changed. We herein report a case of sporadic gastric neuroendocrine carcinoma. A 75-year-old man was referred to our hospital with epigastric pain. Endoscopic examination revealed a localized ulcerative lesion (diameter, 4 cm) at the upper stomach. The diagnosis on biopsy was neuroendocrine carcinoma. Total gastrectomy with D2 lymphadenectomy, splenectomy, and cholecystectomy was performed. Pathologically, the tumor infiltrated the subserosal layer, and 6/49 lymph nodes were involved. The tumor was uniform in shape and arranged in a rosette-like structure to form solid nests, with medium-sized, round-to-cuboid-shaped tumor cells and intense mitosis 46/10 HPF. It was positive for synaptophysin and chromogranin A, and the Ki-67 labeling index was 70-80%. The diagnosis of neuroendocrine carcinoma was made according to the WHO 2010 criteria. The patient was followed up for three years without recurrence.

Radical and superoxide scavenging activities of matairesinol and oxidized matairesinol.

The radical and superoxide scavenging activities of oxidized matairesinols were examined. It could be assumed that the free benzylic position was important for higher radical scavenging activity. The different level of activity was observed between 7'-oxomatairesinol (Mat 2) and 7-oxomatairesinol (Mat 3). The activity of 8-hydroxymatairesinol was lower than that of matairesinol (Mat 1). The superoxide scavenging activity of the oxidized matairesinols was also demonstrated for the first time. It is assumed that the pKa value of phenol in the oxidized matairesinols affected this activity.

Inadvertent C2-C3 union after C1-C2 posterior fusion in adults.

INTRODUCTION: Some authors pointed out that there were more than a few patients with inadvertent C2-C3 union after C1-C2 posterior fusion, although few detailed studies of C2-C3 union have been reported. The purpose of this study was to clarify whether C2-C3 union accelerated adjacent C3-C4 disc degeneration after C1-C2 posterior fusion and to investigate the related factors for C2-C3 union. METHODS: Sixteen patients with rheumatoid arthritis (RA group) (4 males, 12 females, mean age 60 years, mean follow-up period 4 years and 3 months) and fifteen patients without RA (non-RA group) (11 males, 4 females, mean 52 years, mean follow-up period 3 years and 10 months) who underwent C1-C2 posterior fusion were radiologically assessed. The C2-C3 union was defined as trabecular bone formation at C2-C3 interlamina in lateral radiograph. C3-C4 disc height was measured to evaluate the disc degeneration. RESULTS: C2-C3 union rate was 56% and 60% in RA group and non-RA group, respectively. In RA group, postoperative C3-C4 disc height was lower (Student's t-test, P = 0.029) and the decrease rate of C3-C4 disc height was higher (Student's t-test, P = 0.015) in patients with C2-C3 union than in patients without C2-C3 union. In non-RA group, the age at operation was older (Student's t-test, P = 0.0007), and the C1-C2 fusion angle (Student's t-test, P = 0.012) was smaller in patients with C2-C3 union than in patients without C2-C3 union. CONCLUSIONS: C2-C3 union after C1-C2 posterior fusion occurred in more than half of both groups. Inadvertent C2-C3 union should be considered a radiological complication and a potential risk factor due to acceleration of C3-C4 disc degeneration in RA.