Distribution of osteoprotegerin in unruptured intracranial aneurysms in humans: association with aneurysm wall protective remodeling.

OBJECTIVE: Aneurysm wall inflammation is associated with lesion instability in unruptured intracranial aneurysms (UIAs). However, most UIAs remain unruptured during lifelong follow-ups because of simultaneous protective remodeling against the inflammatory response. The protective effects of osteoprotegerin (OPG) in intracranial and abdominal aortic aneurysms have been suggested using rodent models; however, the role of this protein in UIAs in humans remains unclear. Herein, the authors examined the relationship between OPG expression and aneurysm wall integrity in intraoperatively resected UIAs by using immunohistochemical and immunofluorescence staining. METHODS: Sixteen UIA wall tissue specimens resected between 2017 and 2022 were analyzed. Aneurysm growth was defined as an enlargement > 1 mm or an obvious morphological change over the course of more than 6 months. Three high-power fields were randomly selected from areas expressing high and low levels of OPG within the same aneurysm. To clarify the role of OPG in the human aneurysm wall, the authors compared averaged values for the following pathological features between the 2 OPG expression groups: aneurysm wall thickness, collagen, macrophages, smooth muscle cells, and transforming growth factor beta 1 (TGF-ß1). Immunohistochemical staining within the entire tissue area was also analyzed to determine the relationships between OPG expression and different aneurysm growth patterns. Pathological findings were compared between high and low OPG expression levels using the Wilcoxon signed-rank test. RESULTS: The heterogeneous expression of OPG was detected in the walls of UIAs. Lesions expressing high OPG levels had thicker aneurysm walls (327 vs 180 µm, p = 0.002) and higher expression levels of TGF-ß1 (8.5% vs 5.4%, p = 0.002) than those expressing low OPG levels. The expression of TGF-ß1 was colocalized with that of OPG mainly in the tunica media. Furthermore, lesions expressing high OPG levels had larger α-SMA+ areas (25% vs 13%, p = 0.002). Aneurysm growth was observed in 6 of 9 UIAs with available data: whole sac expansion in 4 and secondary aneurysm formation in 2. Among the 6 UIAs with aneurysm growth, OPG expression was relatively higher in the UIAs with an internal elastic lamina than in those without (17% vs 6.9%). CONCLUSIONS: Aneurysm wall integrity was associated with OPG expression in the aneurysm wall. Collectively, the study results indicated that OPG is associated with protective remodeling, which may contribute to the retention of aneurysm wall structures.

Dual-energy Computed Tomography Iodine Map for Breast Cancer: Comparison With Dynamic Contrast-enhanced Magnetic Resonance Imaging.

BACKGROUND/AIM: The characteristics of different breast cancers imaged using dual-energy computed tomography (DECT) are unknown. Furthermore, the differences between DECT and magnetic resonance imaging (MRI) in the ability to assess tumor extent have not been clarified. Therefore, this study aimed to evaluate the effectiveness of DECT iodine maps compared to contrast-enhanced MRI in patients with operable breast cancer. PATIENTS AND METHODS: Clinicopathological data from 858 patients with breast cancer who underwent resection after DECT (100/140 kv) and MRI during 2012-2021 were collected. Tumoral iodine concentration (IC; max/Δ) was analyzed from iodine maps. Factors associated with the ability of iodine maps and MRI to predict tumor extent were analyzed with reference to resected specimens' pathological diagnosis. RESULTS: IC parameters varied according to the tumors' histological types and were correlated with the estrogen receptor, histological grade, and Ki-67 labeling index. In 86.2% of patients with invasive carcinoma with intraductal extension, images and resected specimen mapping were matched. Iodine maps were less accurate than MRI in identifying tumor borders in 9.8% and more accurate in 2.1% of patients. The discrepancies in assessing tumor borders between imaging modalities were associated with the tumor's IC parameters and mammary gland status. CONCLUSION: Differences in assessment between DECT and MRI in operable breast cancer are associated with IC parameters and background parenchymal enhancement. Therefore, evaluating tumor extent using DECT considering these characteristics appears to be a feasible approach.

Association between low levels of anti-inflammatory cytokines during pregnancy and postpartum depression.

AIM: Previous studies based on a relatively limited number of subjects have indicated potential associations between plasma cytokine concentrations in perinatal women and postpartum depression (PPD). This report aimed to examine alterations in cytokine levels during pregnancy and after delivery by measuring nine cytokines in prenatal and postnatal plasma samples in a large cohort. METHODS: A nested, case-control study was conducted using plasma samples from 247 women with PPD (Edinburgh Postnatal Depression Scale: EPDS ≥9) and 243 age-matched control (EPDS ≤2) women from among perinatal women who participated in the Tohoku Medical Megabank three-generation cohort. Concentrations of nine plasma cytokines (IFN-γ, IL-1ß, IL-4, IL-6, IL-10, IL-12p40, IL-12p70, IL-13, and TNF-α) in plasma collected at the time of enrollment during pregnancy and 1 month after delivery were determined using an immunoassay kit. RESULTS: Cross-sectional comparisons of cytokine levels during pregnancy and after delivery indicated that the PPD group maintained significantly lower plasma IL-4 levels during pregnancy and after delivery than the control group, and that plasma IL-4 levels decreased significantly during pregnancy regardless of PPD status. Plasma IL-10 levels were significantly higher during pregnancy than after delivery only among healthy controls, and plasma IL-10 levels were significantly higher in the control group than in the PPD group. Moreover, IFN-γ, IL-6, IL-12p40, and TNF-α levels were significantly lower during pregnancy compared with after delivery regardless of PPD status. CONCLUSIONS: These results suggest a potential protective effect of the anti-inflammatory cytokines IL-4 and IL-10 during pregnancy against the development of PPD.

N-Acetylcysteine Suppresses Microglial Inflammation and Induces Mortality Dose-Dependently via Tumor Necrosis Factor-α Signaling.

N-acetylcysteine (NAC) is an antioxidant that prevents tumor necrosis factor (TNF)-α-induced cell death, but it also acts as a pro-oxidant, promoting reactive oxygen species independent apoptosis. Although there is plausible preclinical evidence for the use of NAC in the treatment of psychiatric disorders, deleterious side effects are still of concern. Microglia, key innate immune cells in the brain, play an important role in inflammation in psychiatric disorders. This study aimed to investigate the beneficial and deleterious effects of NAC on microglia and stress-induced behavior abnormalities in mice, and its association with microglial TNF-α and nitric oxide (NO) production. The microglial cell line MG6 was stimulated by Escherichia coli lipopolysaccharide (LPS) using NAC at varying concentrations for 24 h. NAC inhibited LPS-induced TNF-α and NO synthesis, whereas high concentrations (≥30 mM) caused MG6 mortality. Intraperitoneal injections of NAC did not ameliorate stress-induced behavioral abnormalities in mice, but high-doses induced microglial mortality. Furthermore, NAC-induced mortality was alleviated in microglial TNF-α-deficient mice and human primary M2 microglia. Our findings provide ample evidence for the use of NAC as a modulating agent of inflammation in the brain. The risk of side effects from NAC on TNF-α remains unclear and merits further mechanistic investigations.

Headache characteristics to screen for cervicocerebral artery dissection in patients with acute onset unusual headache.

OBJECTIVES: The aim of this preplanned primary analysis was to investigate the clinical manifestations of headache to screen for CAD patients with acute onset headache only. BACKGROUND: Spontaneous cervicocerebral artery dissection (CAD) with acute onset headache is not rare in clinical practice; however, it is underdiagnosed. On the other hand, subsequent infarction or subarachnoid hemorrhage mainly occurs within 1 week of headache onset. METHODS: Between April 2017 and January 2022, we conducted a single-center, cross-sectional retrospective study on 197 consecutive referred patients from neurosurgical outpatient clinics with acute onset unusual headache (stronger or longer headache than usual). All patients underwent magnetic resonance imaging to screen for secondary headache and were diagnosed based on the diagnostic protocol. We examined patient background data and the following headache characteristics: distribution, condition at the onset of headache, accompanying vomiting or nausea, worsening headache, and analgesic effects against headache. These factors were analyzed to identify independent diagnostic predictors of CAD. In this study, the rate of missing data was 41% for improvement of headache by analgesia and multiple imputation by chained equations was performed. RESULTS: A total of 93 patients (46 men and 47 women; mean age: 48 years, range: 25-73 years) were diagnosed with CAD. Univariate logistic regression analysis showed CAD was associated with current smoking, systolic blood pressure >140 mmHg, unilateral headache, worsening headache, and no headache improvement by analgesia. Unilateral, worsening headache and no headache improvement by analgesia remained independent diagnostic predictors in multivariable logistic regression after multiple imputation. No headache improvement by analgesia had the highest sensitivity (86%), while worsening headache had the highest specificity (84%). CONCLUSIONS: CAD needs to be considered in patients with unilateral, worsening headache and no headache improvement by analgesia.

Sex-Specific Differences in the Transcriptome of the Human Dorsolateral Prefrontal Cortex in Schizophrenia.

Schizophrenia presents clinical and biological differences between males and females. This study investigated transcriptional profiles in the dorsolateral prefrontal cortex (DLPFC) using postmortem data from the largest RNA-sequencing (RNA-seq) database on schizophrenic cases and controls. Data for 154 male and 113 female controls and 160 male and 93 female schizophrenic cases were obtained from the CommonMind Consortium. In the RNA-seq database, the principal component analysis showed that sex effects were small in schizophrenia. After we analyzed the impact of sex-specific differences on gene expression, the female group showed more significantly changed genes compared with the male group. Based on the gene ontology analysis, the female sex-specific genes that changed were overrepresented in the mitochondrion, ATP (phosphocreatine and adenosine triphosphate)-, and metal ion-binding relevant biological processes. An ingenuity pathway analysis revealed that the differentially expressed genes related to schizophrenia in the female group were involved in midbrain dopaminergic and γ-aminobutyric acid (GABA)-ergic neurons and microglia. We used methylated DNA-binding domain-sequencing analyses and microarray to investigate the DNA methylation that potentially impacts the sex differences in gene transcription using a maternal immune activation (MIA) murine model. Among the sex-specific positional genes related to schizophrenia in the PFC of female offspring from MIA, the changes in the methylation and transcriptional expression of loci ACSBG1 were validated in the females with schizophrenia in independent postmortem samples by real-time PCR and pyrosequencing. Our results reveal potential genetic risks in the DLPFC for the sex-dependent prevalence and symptomology of schizophrenia.

Clinicopathological Insights From Vessel Wall Imaging of Unruptured Intracranial Aneurysms.

Background and Purpose- The clinical significance of vessel wall imaging (VWI) remains unclear in patients with unruptured intracranial aneurysms. This study was performed to investigate the correlations between aneurysm wall imaging findings and histopathologic aneurysm wall architectures. Methods- A total of 9 aneurysms was evaluated by VWI and subsequently characterized with histopathology. We used VWI to visualize the aneurysm wall and determine if there was aneurysm wall enhancement after gadolinium contrast administration. Results- Aneurysm wall structures were identified in 6 of 9 unruptured intracranial aneurysms by native VWI, and wall enhancement was identified in 5 of these 6 aneurysms. Histopathologic studies revealed that wall thickening accompanied by atherosclerosis, neovascularization, and macrophage infiltration corresponded to visualization of the aneurysm wall by native VWI and to aneurysm wall enhancement. Conclusions- VWI can visualize thickening of the aneurysm wall, and wall enhancement corresponded to histologically confirmed degenerative changes accompanied by neovascularization and prominent macrophage infiltration.

The VEGF gene polymorphism impacts brain volume and arterial blood volume.

Vascular endothelial growth factor (VEGF) plays a critical role in the angiogenesis and proliferation of various types of cells such as neurons, astroglia, and endothelial cells in the brain. A common polymorphism in the VEGF gene (-2578 C/A) is associated with circulating VEGF levels, cancers and Alzheimer's disease. Nonetheless, the effects of this polymorphism on normal human brain volume, arterial blood volume, and blood supply remain unclear. In this study, the effects of this polymorphism on the total gray matter volume (TGMV) and total white matter volume (TWMV) using T1-weighted structural images and the total arterial blood volume (TABV) and mean cerebral blood flow (mCBF) during rest using arterial spin labeling (ASL) in 765 young adult humans were investigated. Voxel-by-voxel whole-brain analyses of these measures were also performed. Multiple regression analyses with age and sex as covariates revealed that the VEGF genotype (number of C alleles) was significantly and positively correlated with TGMV, TWMV, and TABV as well as with regional gray and white matter volumes in widespread areas and regional arterial blood volume in some areas with high arterial blood volume. However, these regional associations were not seen when the corresponding global signal was included as a covariate in the multiple regression analyses, indicating that we failed to obtain evidence of region-specific associations between these brain measures and the genotype. The results suggest that the VEGF-2578C allele, is associated with changes in the vascular system that lead to increased blood volume and larger brain volume. Hum Brain Mapp 38:3516-3526, 2017. © 2017 Wiley Periodicals, Inc.

Microglial production of TNF-alpha is a key element of sustained fear memory.

The proinflammatory cytokine productions in the brain are altered in a process of fear memory formation, indicating a possibility that altered microglial function may contribute to fear memory formation. We aimed to investigate whether and how microglial function contributes to fear memory formation. Expression levels of M1- and M2-type microglial marker molecules in microglia isolated from each conditioned mice group were assessed by real-time PCR and immunohistochemistry. Levels of tumor necrosis factor (TNF)-α, but not of other proinflammatory cytokines produced by M1-type microglia, increased in microglia from mice representing retention of fear memory, and returned to basal levels in microglia from mice representing extinction of fear memory. Administration of inhibitors of TNF-α production facilitated extinction of fear memory. On the other hand, expression levels of M2-type microglia-specific cell adhesion molecules, CD206 and CD209, were decreased in microglia from mice representing retention of fear memory, and returned to basal levels in microglia from mice representing extinction of fear memory. Our findings indicate that microglial TNF-α is a key element of sustained fear memory and suggest that TNF-α inhibitors can be candidate molecules for mitigating posttraumatic reactions caused by persistent fear memory.

Three-dimensional CT imaging of flexor tendon ruptures in the hand and wrist.

OBJECTIVE: The purpose of this study is to determine the applicability of 3D CT imaging in the evaluation of flexor tendon rupture in the hand and wrist. DESIGN: Twenty-four digits in 22 patients (18 adults, 4 children) with a spectrum of finger flexion disturbances were investigated by a multidetector-row CT scanner, and diagnosed by 3D CT image with the volume rendering technique. The accuracy of the image diagnosis was confirmed operatively in 20 digits. RESULTS: 3D CT imaging gave a precise analysis in all adult cases. It clearly depicted the location of rupture and tendon stump. All of the 12 digits diagnosed from the images as tendon rupture were operated on, and the operational finding correlated well with the diagnosis based on the image. In the children, the image analysis was equivocal. CONCLUSIONS: 3D CT imaging can be useful when the diagnosis of flexor tendon rupture cannot be made based on trauma history and clinical examinations, and can be helpful in surgical planning.

[Is intravenous contrast enhancement effective in improving CT diagnosis of hepatic disease?].

PURPOSE: The purpose of this study was to evaluate the effectiveness of contrast enhancement in the diagnosis of hepatic disease. MATERIALS AND METHODS: 2761 cases involving CT of the liver and abdomen were analyzed using logistic analysis. CT was either helical-CT (SDCT) or multi-detector CT (MDCT), with power injector. RESULTS: Contrast enhancement use was 92% in liver disease and 95% in tumor cases. A typical case involved a 66-year-old man given 2-4 ml/sec of contrast material using dual injection. CT imaging was done in the equilibrium stage. The use of contrast material was effective for the diagnosis of liver tumor except in the qualitative diagnosis of hepatocellular carcinoma with SDCT where the odds ratio was 0.084. CONCLUSION: Intravenous contrast enhancement was effective for the CT diagnosis of hepatic tumor. Dynamic CT was effective using MDCT, and dual injection of contrast material was also valid for SDCT. Multiphasic studies were needed for detecting liver tumors not only on MDCT but also on SDCT. CT imaging during the equilibrium phase alone is inadequate to document diagnosis of metastatic liver tumors. The addition of various phasic contrast materials during CT was effective in evaluating liver tumors that showed angiogenesis.