Genetic dissection of HLA-DRB1*15:01 and XL9 region variants in Japanese patients with systemic lupus erythematosus: primary role for HLA-DRB1*15:01.

OBJECTIVE: Major histocompatibility complex strongly contributes to susceptibility to systemic lupus erythematosus (SLE). In the European populations, HLA-DRB1*03:01 and DRB1*15:01 are susceptibility alleles, but C4 locus was reported to account for the association of DRB1*03:01. With respect to DRB1*15:01, strong linkage disequilibrium with a variant rs2105898T in the XL9 region, located between DRB1 and DQA1 and regulates HLA-class II expression levels, was reported; however, the causative allele remains to be determined. Leveraging the genetic background of the Japanese population, where DRB1*15:01 and DRB1*15:02 are commonly present and only DRB1*15:01 is associated with SLE, this study aimed to distinguish the genetic contribution of DRB1*15:01 and XL9 variants. METHODS: Among the XL9 variants, two (rs2105898 and rs9271593) previously associated variants in the European populations and two (rs9271375 and rs9271378) which showed a trend towards association in a Japanese Genome-Wide Association Study were selected. Associations of the XL9 variants and HLA-DRB1 were examined in 442 Japanese SLE patients and 779 controls. Genotyping of the XL9 variants was performed by TaqMan SNP Genotyping Assay and direct sequencing. HLA-DRB1 alleles were determined by PCR-reverse sequence-specific oligonucleotide probes. RESULTS: Among the XL9 variants, associations of rs2105898T and rs9271593C were replicated in the Japanese population. However, these associations became no longer significant when conditioned on DRB1*15:01. In contrast, the association of DRB1*15:01 remained significant after conditioning on the XL9 variants. CONCLUSION: In the Japanese population, HLA-DRB1*15:01 was found to be primarily associated with SLE, and to account for the apparent association of XL9 region.

Association of HLA-class II alleles with risk of relapse in myeloperoxidase-antineutrophil cytoplasmic antibody positive vasculitis in the Japanese population.

Background: Disease relapse remains a major problem in the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). In European populations, HLA-DPB1*04:01 is associated with both susceptibility and relapse risk in proteinase 3-ANCA positive AAV. In a Japanese population, we previously reported an association between HLA-DRB1*09:01 and DQB1*03:03 with susceptibility to, and DRB1*13:02 with protection from, myeloperoxidase-ANCA positive AAV (MPO-AAV). Subsequently, the association of DQA1*03:02, which is in strong linkage disequilibrium with DRB1*09:01 and DQB1*03:03, with MPO-AAV susceptibility was reported in a Chinese population. However, an association between these alleles and risk of relapse has not yet been reported. Here, we examined whether HLA-class II is associated with the risk of relapse in MPO-AAV. Methods: First, the association of HLA-DQA1*03:02 with susceptibility to MPO-AAV and microscopic polyangiitis (MPA) and its relationship with previously reported DRB1*09:01 and DQB1*03:03 were examined in 440 Japanese patients and 779 healthy controls. Next, the association with risk of relapse was analyzed in 199 MPO-ANCA positive, PR3-ANCA negative patients enrolled in previously reported cohort studies on remission induction therapy. Uncorrected P values (Puncorr) were corrected for multiple comparisons in each analysis using the false discovery rate method. Results: The association of DQA1*03:02 with susceptibility to MPO-AAV and MPA was confirmed in a Japanese population (MPO-AAV: Puncorr=5.8x10-7, odds ratio [OR] 1.74, 95% confidence interval [CI] 1.40-2.16, MPA: Puncorr=1.1x10-5, OR 1.71, 95%CI 1.34-2.17). DQA1*03:02 was in strong linkage disequilibrium with DRB1*09:01 and DQB1*03:03, and the causal allele could not be determined using conditional logistic regression analysis. Relapse-free survival was shorter with nominal significance in carriers of DRB1*09:01 (Puncorr=0.049, Q=0.42, hazard ratio [HR]:1.87), DQA1*03:02 (Puncorr=0.020, Q=0.22, HR:2.11) and DQB1*03:03 (Puncorr=0.043, Q=0.48, HR:1.91) than in non-carriers in the log-rank test. Conversely, serine carriers at position 13 of HLA-DRß1 (HLA-DRß1_13S), including DRB1*13:02 carriers, showed longer relapse-free survival with nominal significance (Puncorr=0.010, Q=0.42, HR:0.31). By combining DQA1*03:02 and HLA-DRß1_13S, a significant difference was detected between groups with the highest and lowest risk for relapse (Puncorr=0.0055, Q=0.033, HR:4.02). Conclusion: HLA-class II is associated not only with susceptibility to MPO-AAV but also with risk of relapse in the Japanese population.

Transport of the Proinflammatory Chemokines C-C Motif Chemokine Ligand 2 (MCP-1) and C-C Motif Chemokine Ligand 5 (RANTES) across the Intact Mouse Blood-Brain Barrier Is Inhibited by Heparin and Eprodisate and Increased with Systemic Inflammation.

One important function of the vascular blood-brain barrier (BBB) is to facilitate neuroimmune communication. The BBB fulfills this function, in part, through its ability to transport cytokines and chemokines. C-C motif chemokine receptor 2 (CCL2) (MCP-1) and C-C motif chemokine receptor 5 (CCL5) (RANTES) are proinflammatory chemokines that mediate neuroimmune responses to acute insults and aspects of brain injury and neurodegenerative diseases; however, a blood-to-brain transport system has not been evaluated for either chemokine in vivo. Therefore, we determined whether CCL2 and CCL5 in blood can cross the intact BBB and enter the brain. Using CD-1 mice, we found that 125I-labeled CCL2 and CCL5 crossed the BBB and entered the brain parenchyma. We next aimed to identify the mechanisms of 125I-CCL2 and 125I-CCL5 transport in an in situ brain perfusion model. We found that both heparin and eprodisate inhibited brain uptake of 125I-CCL2 and 125I-CCL5 in situ, whereas antagonists of their receptors, CCR2 or CCR5, respectively, did not, suggesting that heparan sulfates at the endothelial surface mediate BBB transport. Finally, we showed that CCL2 and CCL5 transport across the BBB increased following a single injection of 0.3 mg/kg lipopolysaccharide. These data demonstrate that CCL2 and CCL5 in the brain can derive, in part, from the circulation, especially during systemic inflammation. Further, binding to the BBB-associated heparan sulfate is a mechanism by which both chemokines can cross the intact BBB, highlighting a novel therapeutic target for treating neuroinflammation. SIGNIFICANCE STATEMENT: Our work demonstrates that C-C motif chemokine ligand 2 (CCL2) and C-C motif chemokine ligand 5 (CCL5) can cross the intact blood-brain barrier and that transport is robustly increased during inflammation. These data suggest that circulating CCL2 and CCL5 can contribute to brain levels of each chemokine. We further show that the transport of both chemokines is inhibited by heparin and eprodisate, suggesting that CCL2/CCL5-heparan sulfate interactions could be therapeutically targeted to limit accumulation of these chemokines in the brain.

Japan's comprehensive undescended testis screening program: incidence of ascending testis after screening.

PURPOSE: Screening for undescended testis (UDT) in Japan is performed as a neonate, then at 1, 3, 10, and 18 months old, and 3 years old. Incidence of ascending testis (AT) after screening was reviewed. METHODS: All orchiopexy/orchiectomy at a single institute between July 2005 and June 2022 were reviewed retrospectively. RESULTS: 376 boys had 422 procedures; 54/422 (12.8%) were in 48 boys ≥ 4 years old (mean age: 6.7 years; range: 4-13); testes were normal (n = 22; 40.7%), small (n = 25; 46.2%), or atrophied (n = 7; 1.3%). There were 47 orchiopexies and 7 orchiectomies for atrophy. Incidence of AT in boys ≥ 4 years old was 24/422 (5.7%). Of these, 16/422 (3.8%) developed after normal descent and 8/422 (1.9%) were associated with retractile testis (AT + RET). Other indications included delayed treatment for UDT (n = 13), late referral by pediatricians (n = 10), and iatrogenic UDT (n = 6). Surgical intervention in boys ≥ 4 years old (12.8%) was less than that reported in the West (range: 30-50%) as was AT: (5.7% versus 15.4%) and AT + RET (1.9% versus 13.8%). CONCLUSIONS: Comprehensive UDT screening probably contributed to the lower incidence of surgery and AT (especially AT + RET) in boys ≥ 4 years old.

Lower body mass index potentiates the association between skipping breakfast and prevalence of proteinuria.

Background: Proteinuria is an important predictor of cardiovascular disease and mortality. Several studies reported the association between skipping breakfast and the prevalence of proteinuria. Furthermore, skipping breakfast was associated with an increased risk of obesity. Although proteinuria is highly prevalent in obese individuals, the association between the prevalence of proteinuria and low body mass index (BMI) was reported in a previous cross-sectional study in asymptomatic individuals without known kidney diseases. The aim of this cross-sectional study was to assess the clinical impact of BMI on the association between skipping breakfast and the prevalence of proteinuria in normal renal function subjects. Methods: The present study included 26,888 subjects (15,875 males and 11,013 females) with an estimated glomerular filtration rate ≥60 ml/min/1.73 m2 and no history of kidney disease who underwent a health checkup in Sumitomo Hospital. The association between skipping breakfast and the prevalence of proteinuria (defined as dipstick proteinuria of ≥1+) was assessed using logistic regression models adjusted for clinically relevant factors. Results: Skipping breakfast was reported in 3,306 males (20.8%) and 1,514 females (13.8%). Multivariable adjusted logistic regression models showed that skipping breakfast was significantly associated with the prevalence of proteinuria above 1+. This association was evident in lower BMI subjects, even after adjusting for clinically relevant factors (adjusted odds ratios of males and females were 1.67 [1.17-2.38] and 1.92 [1.31-2.82], respectively), whereas this association was not evident in higher BMI subjects. Conclusion: Lower BMI subjects with proteinuria might need to be careful about skipping breakfast.

Increase in glycemic set point, alongside a decrease in waist circumference, in the non-diabetic population during the Japanese National Intervention Program for metabolic syndrome: A single-center, large-scale, matched-pair analysis.

BACKGROUND: In 2008, the Japanese government implemented a National Intervention Program for metabolic syndrome. Low-risk individuals were not direct targets of this intervention. Nevertheless, they were indirectly enlightened by this massive campaign. Documentation of the metabolic shifts in low-risk individuals following the program launch may inform public health policy regarding approaches to metabolic risks in the general population. METHODS: We conducted a cross-sectional analysis of data from non-diabetic participants who underwent general health check-ups at the Physical Check-up Center of Sumitomo Hospital. Participants during 2007-2008 were pair-matched with those during 2015-2016 with respect to sex, age, smoking status, hemoglobin level, and red blood cell (RBC) count. Each participant was included only once in the study. RESULTS: Totals of 3,140 men and 2,048 women were pair-matched. The non-diabetic participants showed lower waist circumference, blood pressure, heart rate, and serum lipid concentrations during the second study period. In contrast, the entire distributions of fasting plasma glucose (FPG) concentration in both sexes and glycated hemoglobin (HbA1c) in women were shifted upwards. In men, Δ FPG was +1.6 mg/dL (P < 0.001) and Δ HbA1c was ±0% (P = 0.6). In women, Δ FPG was +3.0 mg/dL (P < 0.001), and Δ HbA1c was +0.1% (P < 0.001). Δ Homeostasis model assessment of ß-cell function was -6.6 in men (P < 0.001) and -10.3 in women (P < 0.001). The homeostasis model assessment of insulin resistance did not change significantly. CONCLUSIONS: The "glycemic set point" has increased in non-diabetic people in Japan during recent years. Lifestyle or environmental changes may have caused this metabolic shift through obesity-independent pathways, possibly through effects on pancreatic ß-cell function. The underlying mechanism awaits further investigation.

Effects of fasudil on blood-brain barrier integrity.

BACKGROUND: Cerebral infarction accounts for 85% of all stroke cases. Even in an era of rapid and effective recanalization using an intravascular approach, the majority of patients have poor functional outcomes. Thus, there is an urgent need for the development of therapeutic agents to treat acute ischemic stroke. We evaluated the effect of fasudil, a Rho kinase inhibitor, on blood brain barrier (BBB) functions under normoxia or oxygen-glucose deprivation (OGD) conditions using a primary cell-based in vitro BBB model. METHODS: BBB models from rat primary cultures (brain capillary endothelial cells, astrocytes, and pericytes) were subjected to either normoxia or 6 h OGD/24 h reoxygenation. To assess the effects of fasudil on BBB functions, we evaluated real time impedance, transendothelial electrical resistance (TEER), sodium fluorescein permeability, and tight junction protein expression using western blotting. Lastly, to understand the observed protective mechanism on BBB functions by fasudil we examined the role of cyclooxygenase-2 and thromboxane A2 receptor agonist U-46619 in BBB-forming cells. RESULTS: We found that treatment with 0.3-30 µM of fasudil increased cellular impedance. Fasudil enhanced barrier properties in a concentration-dependent manner, as measured by an increased (TEER) and decreased permeability. Fasudil also increased the expression of tight junction protein claudin-5. Reductions in TEER and increased permeability were observed after OGD/reoxygenation exposure in mono- and co-culture models. The improvement in BBB integrity by fasudil was confirmed in both of the models, but was significantly higher in the co-culture than in the monoculture model. Treatment with U-46619 did not show significant changes in TEER in the monoculture model, whereas it showed a significant reduction in TEER in the co-culture model. Fasudil significantly improved the U-46619-induced TEER reduction in the co-culture models. Pericytes and astrocytes have opposite effects on endothelial cells and may contribute to endothelial injury in hyperacute ischemic stroke. Overall, fasudil protects the integrity of BBB both by a direct protective effect on endothelial cells and by a pathway mediated via pericytes and astrocytes. CONCLUSIONS: Our findings suggest that fasudil is a BBB-protective agent against acute ischemic stroke.

Beyond Lipid-Lowering: Effects of Statins on Cardiovascular and Cerebrovascular Diseases and Cancer.

The 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, also known as statins, are administered as first-line therapy for hypercholesterolemia, both as primary and secondary prevention. Besides the lipid-lowering effect, statins have been suggested to inhibit the development of cardiovascular disease through anti-inflammatory, antioxidant, vascular endothelial function-improving, plaque-stabilizing, and platelet aggregation-inhibiting effects. The preventive effect of statins on atherothrombotic stroke has been well established, but statins can influence other cerebrovascular diseases. This suggests that statins have many neuroprotective effects in addition to lowering cholesterol. Furthermore, research suggests that statins cause pro-apoptotic, growth-inhibitory, and pro-differentiation effects in various malignancies. Preclinical and clinical evidence suggests that statins inhibit tumor growth and induce apoptosis in specific cancer cell types. The pleiotropic effects of statins on cardiovascular and cerebrovascular diseases have been well established; however, the effects of statins on cancer patients have not been fully elucidated and are still controversial. This review discusses the recent evidence on the effects of statins on cardiovascular and cerebrovascular diseases and cancer. Additionally, this study describes the pharmacological action of statins, focusing on the aspect of 'beyond lipid-lowering'.

Prolonged culturing of iPSC-derived brain endothelial-like cells is associated with quiescence, downregulation of glycolysis, and resistance to disruption by an Alzheimer's brain milieu.

BACKGROUND: Human induced pluripotent stem cell (hiPSC)-derived brain endothelial-like cells (iBECs) are a robust, scalable, and translatable model of the human blood-brain barrier (BBB). Prior works have shown that high transendothelial electrical resistance (TEER) persists in iBECs for at least 2 weeks, emphasizing the utility of the model for longer term studies. However, most studies evaluate iBECs within the first few days of subculture, and little is known about their proliferative state, which could influence their functions. In this study, we characterized iBEC proliferative state in relation to key BBB properties at early (2 days) and late (9 days) post-subculture time points. METHODS: hiPSCs were differentiated into iBECs using fully defined, serum-free medium. The proportion of proliferating cells was determined by BrdU assays. We evaluated TEER, expression of glycolysis enzymes and tight and adherens junction proteins (TJP and AJP), and glucose transporter-1 (GLUT1) function by immunoblotting, immunofluorescence, and quantifying radiolabeled tracer permeabilities. We also compared barrier disruption in response to TNF-α and conditioned medium (CM) from hiPSC-derived neurons harboring the Alzheimer's disease (AD)-causing Swedish mutation (APPSwe/+). RESULTS: A significant decline in iBEC proliferation over time in culture was accompanied by adoption of a more quiescent endothelial metabolic state, indicated by downregulation of glycolysis-related proteins and upregulation GLUT1. Interestingly, upregulation of GLUT1 was associated with reduced glucose transport rates in more quiescent iBECs. We also found significant decreases in claudin-5 (CLDN5) and vascular endothelial-cadherin (VE-Cad) and a trend toward a decrease in platelet endothelial cell adhesion molecule-1 (PECAM-1), whereas zona occludens-1 (ZO-1) increased and occludin (OCLN) remained unchanged. Despite differences in TJP and AJP expression, there was no difference in mean TEER on day 2 vs. day 9. TNF-α induced disruption irrespective of iBEC proliferative state. Conversely, APPSwe/+ CM disrupted only proliferating iBEC monolayers. CONCLUSION: iBECs can be used to study responses to disease-relevant stimuli in proliferating vs. more quiescent endothelial cell states, which may provide insight into BBB vulnerabilities in contexts of development, brain injury, and neurodegenerative disease.

Exploration of Pericyte-Derived Factors Implicated in Lung Cancer Brain Metastasis Protection: A Pilot Messenger RNA Sequencing Using the Blood-Brain Barrier In Vitro Model.

Metastatic brain tumors have poor prognoses and pose unmet clinical problems for the patients. The blood-brain barrier (BBB) implication is supposed to play a major role in brain metastasis. However, the role of pericytes remains to be elucidated in the brain metastasis. This pilot study described the expression profile of interactions between pericytes, endothelial cells, and cancer cells. We applied an in vitro BBB model with rat primary cultured BBB-related cells (endothelial cells and pericytes), and performed the gene expression analyses of pericytes under the lung cancer cells coculture conditions. Pericytes demonstrated inhibition of the cancer cell proliferation significantly (p < 0.05). RNA was extracted from the pericytes, complementary DNA library was prepared, and RNA-seq was performed. The sequence read data were analyzed on the Management and Analysis System for Enormous Reads and Tag Count Comparison-Graphical User Interface platforms. No statistically or biologically significant differentially expressed genes (DEGs) were detected in the explanatory analyses. Lot-specific DEG detection demonstrated significant decreases in the expression of two genes (Wwtr1 and Acin1), and enrichment analyses using Metascape software revealed the inhibition of apoptotic processes in fibroblasts. Our results suggest that the expression profiles of brain pericytes are partially implicated in the prevention of lung cancer metastasis to the brain. Pericytes exerted an anti-metastatic effect in the BBB model, and their neurohumoral factors remain to be elucidated.

Hematoma expansion unrelated to rebleeding in ruptured anterior cerebral artery aneurysms treated by early endovascular embolization.

BACKGROUND: Whether hematoma expansion after aneurysmal rupture is always a sign of rerupture remains unclear. Hence, the present study aimed to assess the incidence and risk factors of hematoma expansion unrelated to aneurysmal rerupture after endovascular embolization for ruptured cerebral aneurysms. METHODS: We included patients who underwent endovascular embolization for ruptured cerebral aneurysms within 48 h after onset at our institution between January 2009 and February 2014. The medical records of 70 consecutive patients were reviewed and analyzed retrospectively. RESULTS: Hematoma expansion unrelated to aneurysmal rerupture occurred in 7 (10%) of 70 patients. Interestingly, four of seven patients had distal anterior cerebral artery (ACA) aneurysms. The interval from onset to aneurysm coiling was shorter in patients with hematoma expansion than in those without (P = 0.040). CONCLUSION: Early embolization of ruptured ACA aneurysms might increase the risk of hematoma expansion unrelated to aneurysmal rerupture because the procedures were conducted under systemic anticoagulation. It would be better to refer the patient for direct clipping if the patient has a distal ACA aneurysm with parenchymal hematoma at interhemispheric fissure. Delayed coil embolization, which means around 12-18 h delayed, might be another option for ruptured distal ACA aneurysms to prevent hematoma expansion.

Partial Clipping Occlusion Including Rupture Point Is an Effective Strategy for Ruptured Giant Fusiform Basilar Artery Aneurysm: A Technical Case Report.

Treatment of fusiform basilar artery aneurysms is still challenging today. The authors present a case of a patient with a ruptured giant fusiform basilar artery aneurysm successfully treated by clipping occlusion of the rupture point. A 62-year-old man suddenly fell into a coma due to subarachnoid hemorrhage (SAH) with a ruptured giant fusiform basilar artery aneurysm with a bleb on the right shoulder. We considered treating the lesion with stent-assisted coil embolization because of the aneurysm's shape, but we had to give up because stents were off-label in the acute phase SAH in our country. Instead, we successfully performed clipping surgery to partially occlude the aneurysm, including the rupture point via the anterior transpetrosal approach. His postoperative course was uneventful, without rerupture of the aneurysm, and his conscious level tended to improve. The postoperative imaging studies showed no complications and disappearance of the rupture point of the aneurysm. Although direct surgery for the giant fusiform basilar artery aneurysms is one of the challenging operations, it is an essential and highly effective treatment as a last resort for complex aneurysms if other treatments are not available.

Increased In Vitro Intercellular Barrier Function of Lung Epithelial Cells Using Adipose-Derived Mesenchymal Stem/Stromal Cells.

With the emergence of coronavirus disease-2019, researchers have gained interest in the therapeutic efficacy of mesenchymal stem/stromal cells (MSCs) in acute respiratory distress syndrome; however, the mechanisms of the therapeutic effects of MSCs are unclear. We have previously reported that adipose-derived MSCs (AD-MSCs) strengthen the barrier function of the pulmonary vessels in scaffold-based bioengineered rat lungs. In this study, we evaluated whether AD-MSCs could enhance the intercellular barrier function of lung epithelial cells in vitro using a transwell coculture system. Transepithelial electrical resistance (TEER) measurements revealed that the peak TEER value was significantly higher in the AD-MSC coculture group than in the AD-MSC non-coculture group. Similarly, the permeability coefficient was significantly decreased in the AD-MSC coculture group compared to that in the AD-MSC non-coculture group. Immunostaining of insert membranes showed that zonula occuldens-1 expression was significantly high at cell junctions in the AD-MSC coculture group. Moreover, cell junction-related gene profiling showed that the expression of some claudin genes, including claudin-4, was upregulated in the AD-MSC coculture group. Taken together, these results showed that AD-MSCs enhanced the barrier function between lung epithelial cells, suggesting that both direct adhesion and indirect paracrine effects strengthened the barrier function of lung alveolar epithelium in vitro.

Pitavastatin Ameliorates Lipopolysaccharide-Induced Blood-Brain Barrier Dysfunction.

Statins have neuroprotective effects on neurological diseases, including a pleiotropic effect possibly related to blood-brain barrier (BBB) function. In this study, we investigated the effects of pitavastatin (PTV) on lipopolysaccharide (LPS)-induced BBB dysfunction in an in vitro BBB model comprising cocultured primary mouse brain endothelial cells, pericytes, and astrocytes. LPS (1 ng/mL, 24 h) increased the permeability and lowered the transendothelial electrical resistance of the BBB, and the co-administration of PTV prevented these effects. LPS increased the release of interleukin-6, granulocyte colony-stimulating factor, keratinocyte-derived chemokine, monocyte chemotactic protein-1, and regulated on activation, normal T-cell expressed and secreted from the BBB model. PTV inhibited the LPS-induced release of these cytokines. These results suggest that PTV can ameliorate LPS-induced BBB dysfunction, and these effects might be mediated through the inhibition of LPS-induced cytokine production. Clinically, therapeutic approaches using statins combined with novel strategies need to be designed. Our present finding sheds light on the pharmacological significance of statins in the treatment of central nervous system diseases.

Ischemic Stroke as a Warning Sign of Impending Aneurysmal Rupture: A Report of Two Cases.

Ischemic stroke associated with intracranial aneurysm is rare but potentially happens because of emboli originating from aneurysm sac or aneurysmal thrombosis extension to the parent artery. We describe two patients who present subarachnoid hemorrhage (SAH) soon after ischemic stroke. Case 1. A 51-year-old woman with a history of multiple endovascular therapy for ruptured basilar top aneurysm presented with double vision. Magnetic resonance imaging (MRI) revealed infarcts in the right thalamus and left occipital cortex. Four days after ischemic stroke, she suffered from sudden onset headache, computed tomography (CT) showed diffuse SAH with intraventricular hemorrhage. Case 2. A 62-year-old man presented with right facial palsy and sensory disorder. MRI revealed an infarct in the left pons. Four days after ischemic stroke, he became comatose and CT showed diffuse SAH. Both cases develop ischemic stroke adjacent to the aneurysms and subsequently cause devasting aneurysm rupture, suggesting ischemic stroke as a warning sign of aneurysm rupture. In such cases, early treatment of the aneurysm should be considered.

The Combination of High Levels of Adiponectin and Insulin Resistance Are Affected by Aging in Non-Obese Old Peoples.

Background: Adipokine dysregulation is a key feature of insulin resistance and a metabolic syndrome associated with obesity. Low adiponectin levels are associated with higher risks of cardiovascular diseases (CVD). However, high adiponectin levels have also been associated with increased all-cause and cardiovascular mortality in the elderly. This adiponectin paradox has yet to be clarified, which has hindered our understanding of the biological role of adiponectin. Adipokine dysregulation and insulin resistance are also associated with energy-deprivation conditions, such as frailty in old age. The objective of this study was to investigate the association between plasma adiponectin and insulin resistance using the homeostasis model assessment for insulin resistance (HOMA-IR) classified by age. In particular, we sought to determine the factors of the subjects associated with both high adiponectin levels and HOMA-IR (H-adiponectin/H-HOMA) and high adiponectin levels and low HOMA-IR (H-adiponectin/L-HOMA). Methods: The eligible subjects in this cross-sectional study were 33,216 individuals who had undergone health checkups at the Physical Checkup Center of Sumitomo Hospital between April 2008 and December 2018. After excluding 26,371 individuals who were under 60 years old, 529 who had been taking medications for diabetes mellitus, and 690 with missing data, the present study included 5,673 (3,467 males, 2,206 females) subjects with no missing data. The relationship between serum adiponectin levels and HOMA-IR was assessed using logistic regression models adjusted by clinically relevant factors. Results: In the multivariable logistic regression analysis, age and low BMI were shown to positively correlate with the characteristics of H-adiponectin/H-HOMA. In females, systolic blood pressure was also shown to be an associated factor. Conclusion: In conclusion, this study showed that aging or a low BMI may contribute to high adiponectin levels and insulin resistance.

A Case of Invasive Sphenoid Sinus Aspergillosis Presenting as Oculomotor Nerve Palsy in a Healthy Patient.

Invasive sphenoid sinus aspergillosis is a rare infection and usually affecting immunocompromised patients. We describe an invasive sphenoid sinus aspergillosis patient with immunocompetent who present progressive ocular dysfunctions. A 66-year-old woman with no history of immune dysfunction was referred to our hospital with orbital complications. Computed tomography (CT) scan and magnetic resonance imaging (MRI) showed a mass lesion extending from the left orbital apex to the sphenoid sinus. Inflammatory diseases were not suspected by laboratory findings, but a transnasal endoscopic biopsy revealed sphenoid sinus aspergillosis. After treatment of antifungal medication, this patient showed improvement and no sign of recurrence during the follow-up period. Diagnosis of invasive sphenoid sinus aspergillosis in an immunocompetent, healthy individual, was challenging. However, if patients have sinus wall deformities and orbital complications, early surgery is necessary to improve their prognosis.

Vasospasm and Hydrocephalus Following Subarachnoid Hemorrhage Are Less Frequent in Coil Embolization Than in Clipping.

Objective: The effects of treatment methods for ruptured aneurysms on the incidence of vasospasm and normal pressure hydrocephalus (NPH) following subarachnoid hemorrhage (SAH) are controversial. We retrospectively examined the Nagasaki SAH registry data, and the complication rates of symptomatic vasospasm and NPH were analyzed based on the treatment methods. Methods: Between January 2015 and December 2017, 800 SAH patients were registered from 18 hospitals, and their age, sex, World Federation of Neurological Societies (WFNS) grade, Fisher group, size and location of cerebral aneurysms, treatment methods, incidence of symptomatic vasospasm and shunt-dependent hydrocephalus, and prognosis (discharge or 3 months later) were retrospectively analyzed. The effects of treatment methods for the ruptured aneurysm on the incidence of symptomatic vasospasm and shunt-dependent hydrocephalus were then statistically analyzed. Results: The mean age was 66.2 years old. There were 245 (30.6%) male patients and 555 (69.3%) female patients. Cerebral aneurysms were identified in 708 patients (87.5%) and surgical treatments were performed for 620. Neck clipping was employed in 416 patients (67.1%) and coil embolization was employed in 180 (29.0%). Symptomatic vasospasm developed in 118 (28.4%) in the clipping group and 30 (16.7%) in the coiling group (P = 0.0024). NPH developed in 148 (35.6%) in the clipping group and 42 (23.3%) in the coiling group (P = 0.0032). Vasospasm was listed as a major factor for an unfavorable outcome in 23 patients (8.9%) and as a minor factor in 33 (13.3%). NPH was listed as a major factor for an unfavorable outcome in 19 patients (3.5%) and as a minor factor in 46 (18.5%). Conclusions: The multicenter registry study demonstrated lower incidences of both symptomatic vasospasms and NPH in the coiling group than in the clipping group. This superiority may result in better outcomes in the coiling group.

Association of TERT and DSP variants with microscopic polyangiitis and myeloperoxidase-ANCA positive vasculitis in a Japanese population: a genetic association study.

BACKGROUND: Interstitial lung disease (ILD) is a severe complication with poor prognosis in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Prevalence of AAV-associated ILD (AAV-ILD) in Japan is considerably higher than that in Europe. Recently, we reported that a MUC5B variant rs35705950, the strongest susceptibility variant to idiopathic pulmonary fibrosis (IPF), was strikingly increased in AAV-ILD patients but not in AAV patients without ILD; however, due to the low allele frequency in the Japanese population, the MUC5B variant alone cannot account for the high prevalence of AAV-ILD in Japan. In this study, we examined whether other IPF susceptibility alleles in TERT and DSP genes are associated with susceptibility to AAV subsets and AAV-ILD. METHODS: Five hundred and forty-four Japanese patients with AAV and 5558 controls were analyzed. Among the AAV patients, 432 were positive for myeloperoxidase (MPO)-ANCA (MPO-AAV). A total of 176 MPO-AAV patients were positive and 216 were negative for ILD based on CT or high-resolution CT. Genotypes of TERT and DSP variants were determined by TaqMan SNP Genotyping Assay, and their association was tested by chi-square test. RESULTS: When the frequencies of the IPF risk alleles TERT rs2736100A and DSP rs2076295G were compared between AAV subsets and healthy controls, both alleles were significantly increased in microscopic polyangiitis (MPA) (TERT P = 2.3 × 10-4, Pc = 0.0023, odds ratio [OR] 1.38; DSP P = 6.9 × 10-4, Pc = 0.0069, OR 1.32) and MPO-AAV (TERT P = 1.5 × 10-4, Pc = 0.0015, OR 1.33; DSP P = 0.0011, Pc = 0.011, OR 1.26). On the other hand, no significant association was detected when the allele frequencies were compared between MPO-AAV patients with and without ILD. CONCLUSIONS: Unexpectedly, TERT and DSP IPF risk alleles were found to be associated with MPA and MPO-AAV, regardless of the presence of ILD. These findings suggest that TERT and DSP may be novel susceptibility genes to MPA/MPO-AAV and also that some susceptibility genes may be shared between IPF and MPA/MPO-AAV.

Plasma Level of von Willebrand Factor Propeptide at Diagnosis: A Marker of Subsequent Renal Dysfunction in Autoimmune Rheumatic Diseases.

INTRODUCTION: Patients with systemic autoimmune rheumatic diseases (SARDs) such as rheumatoid arthritis, systemic lupus erythematosus (SLE), Sjögren syndrome, and systemic sclerosis, which are chronic inflammatory diseases, are prone to develop renal dysfunction, which is related to vascular endothelial cell damage. MATERIAL AND METHODS: We evaluated plasma levels of von Willebrand factor (VWF), VWF propeptide (VWF-pp), disintegrin-like and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13), and VWF multimer pattern in patients with SARDs at diagnosis and investigated whether they may serve as markers to identify patients destined to develop renal dysfunction within 1 year. Renal dysfunction was defined as subsequent reduced estimated glomerular filtration rate (eGFR) by >25% or the new appearance of abnormal urine findings such as proteinuria (protein > 30 mg/dL) or hematuria (red blood cells >20/HPF in urine sediments). Overall, 63 patients with SARDs were studied. RESULTS AND CONCLUSIONS: We observed a significant increase of VWF-pp and a significant decrease of ADAMTS13 in patients with SARDs compared with normal healthy controls. The highest level of VWF-pp was observed in patients with SLE among the groups. The levels of VWF and multimer pattern of VWF were not different compared with normal healthy controls. Von Willebrand factor propeptide predicted a subsequent decrease in eGFR at a cutoff point of 210% (sensitivity, 78.6%; specificity, 73.5%) and new urinary abnormal findings at a cutoff point of 232% (sensitivity, 77.8%; specificity, 77.8%) Using these cutoff points, multivariable analysis revealed that VWF-pp was a significant risk factor for renal dysfunction at an odds ratio of 8.78 and 22.8, respectively, and may lead to a new therapeutic approach to prevent vasculitis and renal dysfunction.