Common and distinct risk profiles of asymptomatic extra- and intracranial atherosclerosis in the Nagahama cohort.

BACKGROUND AND PURPOSE: Atherosclerotic burden increases the risk of both extracranial internal carotid artery stenosis (ICS) and intracranial large artery disease (ICAD). However, the differences in risk profiles have not been thoroughly investigated. METHODS: Participants were recruited from the Nagahama study cohort in Japan. Individuals over 60 years old who underwent 1.5-T head and neck magnetic resonance angiography (MRA) between July 2013 and February 2017 were included. ICAD was defined as WASID ≥ 50 %, and ICS was defined as NSCET ≥ 30 %. The prevalence and association of risk factors, including proatherogenic and proinflammatory factors, and the p.R4810K variant in the RNF213 gene, were investigated. Multivariable logistic regression analyses were performed. RESULTS: A total of 3089 individuals participated in the study, with a mean age of 68.1 ± 5.3 years, and 36.0 % were males. Among them, 52 (1.7 %) had ICS, 119 (3.8 %) had ICAD, and 15 (0.49 %) had both conditions. Alopecia areata was an independent predictor for both ICS (Odds ratio [OR] 3.5; 95 % CI 1.3-8.3) and ICAD (OR 2.1; 95 % CI 1.0-3.9). Diabetes (OR 3.7; 95 % CI 2.0-7.0) and older age (OR 2.4; 95 % CI 1.2-4.5) were associated only with ICS, while the RNF213 variant was associated with only ICAD (OR 5.7; 95 % CI 1.6-16.0). ICS and ICAD were also independently associated with each other. CONCLUSIONS: In this MRA-based large scale study, alopecia areata, known as a systemic inflammatory disease, was shown to be a common risk factor for ICS and ICAD. While conventional atherosclerotic factors were associated with ICS, non-atherosclerotic factors appear to contribute to ICAD in Japan.

Niclosamide downregulates LOX-1 expression in mouse vascular smooth muscle cells and changes the composition of atherosclerotic plaques in ApoE-/- mice.

Genetic lineage tracing studies have shown that phenotypic switching of vascular smooth muscle cells (VSMCs) results in less-differentiated cells, including macrophage-like cells that lack traditional VSMC markers. This switching contributes to the formation of necrotic core in plaques and promotes atherosclerosis, which is important for plaque stability. Niclosamide, a commonly used anti-helminthic drug, has recently attracted attention as an anti-cancer drug that inhibits multiple signaling pathways. The expression of the S100A4 protein is upregulated in synthetic VSMCs and inhibited by niclosamide on metastatic progression in colon cancer. We aimed to test the effect of niclosamide on VSMC phenotype switching and plaque stability. To examine murine atherosclerosis, we induced experimental lesions by blood flow cessation in apolipoprotein E knockout mice fed a high-fat diet. Oral administration of niclosamide changed 4-week-old plaques to collagen-rich and less-necrotic core phenotypes and downregulated the expression of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in vivo. In vitro analysis indicated that niclosamide reduced LOX-1 expression in VSMCs in a concentration-dependent and S100A4-independent manner. The inhibitory effect of niclosamide on LOX-1 and collagen type I was associated with the inactivation of the nuclear factor-κB signaling pathway. We demonstrated that the administration of niclosamide reduced LOX-1 expression and altered the composition of murine carotid plaques. Our results highlight the potential of niclosamide as an atheroprotective agent that enhances atherosclerotic plaque stability.

Irradiation Accelerates Plaque Formation and Cellular Senescence in Flow-Altered Carotid Arteries of Apolipoprotein E Knock-Out Mice.

Background Chronic inflammation through cellular senescence, known as the senescence-associated secretory phenotype, is a mechanism of various organ diseases, including atherosclerosis. Particularly, ionizing radiation (IR) contributes to cellular senescence by causing DNA damage. Although previous clinical studies have demonstrated that radiotherapy causes atherosclerosis as a long-term side effect, the detailed mechanism is unclear. This study was conducted to investigate the relationship between radiation-induced atherosclerosis and senescence-associated secretory phenotype in murine carotid arteries. Methods and Results Partial ligation of the left carotid artery branches in 9-week-old male apolipoprotein E-deficient mice was performed to induce atherosclerosis. The mice received total body irradiation at a dose of 6 Gy using gamma rays at 2 weeks post operation. We compared the samples collected 4 weeks after IR with unirradiated control samples. The IR and control groups presented pathologically progressive lesions in 90.9% and 72.3% of mice, respectively. Plaque volume, macrophage accumulation, and phenotype switching of vascular smooth muscle cells were advanced in the IR group. Irradiated samples showed increased persistent DNA damage response (53BP1 [p53 binding protein 1]), upregulated cyclin-dependent kinase inhibitors (p16INK4a and p21), and elevated inflammatory chemokines expression (monocyte chemotactic protein-1, keratinocyte-derived chemokine, and macrophage inflammatory protein 2). Conclusions IR promoted plaque growth in murine carotid arteries. Our findings support the possibility that senescence-associated secretory phenotype aggravates atherogenesis in irradiated artery. This mice model might contribute to mechanism elucidation of radiation-induced atherosclerosis.

Long COVID presenting with intermittent fever after COVID-19 pneumonia.

A 72-year-old man presented to our hospital with a fever. Chest computed tomography showed typical coronavirus disease 2019 (COVID-19) pneumonia. The fever normalized after a few days, and the pneumonia was alleviated. However, the intermittent fever subsequently re-occurred and persisted for over a month. Various tests, including blood tests, culture tests, and image evaluations, were performed. However, the conclusion was that long COVID was the cause of the intermittent fever as an exclusion diagnosis. Many patients suffer from persistent symptoms of COVID-19, but the symptoms and their durations vary. Here we report a case of prolonged fever after COVID-19 pneumonia.

Calcium-Binding Protein S100A4 Is Upregulated in Carotid Atherosclerotic Plaques and Contributes to Expansive Remodeling.

Background Carotid plaques with expansive arterial remodeling are closely related to cerebral ischemic events. Although S100A4 (S100 calcium-binding protein A4) is expressed in atherosclerotic lesions, its role in atherosclerotic plaque progression remains unknown. In this study, we examined the association between carotid arterial expansive remodeling and S100A4 expression. Methods and Results Preoperative high-resolution magnetic resonance imaging was used to assess luminal stenosis and vascular remodeling in patients undergoing carotid endarterectomy. To examine murine carotid atherosclerosis, we induced experimental lesions by flow cessation in apolipoprotein E-deficient mice fed a high-fat diet. The role of S100A4 in plaque formation and smooth muscle cell proliferation was investigated in vivo and in vitro, respectively. Human carotid arterial expansive remodeling showed positive correlations with the expression of S100A4, MMP2, and MMP9. S100A4 mRNA levels were positively correlated with those of MMP2, MMP9, and MMP13. S100A4 was expressed in vascular smooth muscle cells (VSMCs) and VSMC-derived foam cells in the plaque shoulder and marginal areas. S100A4 expression increased concomitantly with plaque formation in our animal model. Exogenous recombinant S100A4 protein enhanced the levels of Mmp2, Mmp9, and Mmp13 and the cell proliferation ability in VSMCs. A chemotaxis assay indicated that extracellular S100A4 functions as a chemoattractant for VSMCs. Conclusions S100A4 expression was elevated in human carotid plaques and showed a positive correlation with the degree of expansive remodeling. S100A4-positive VSMC-derived cells are considered to play an important role in carotid expansive remodeling.

Association of zinc administration with growth suppression of intracranial aneurysms via induction of A20.

OBJECTIVE: Zinc is an essential micronutrient with multiple biological effects, including antiinflammation. Previously, the authors demonstrated that the pathogenesis of intracranial aneurysms (IAs) is strongly related to chronic inflammation. In this study, the authors investigated whether administration of zinc inhibits the growth of IAs in a rat model. METHODS: The authors analyzed surgically induced IAs in Sprague-Dawley male rats, which were subsequently treated with intraperitoneal injections of zinc sulfate heptahydrate (ZnSO4; 3 mg/kg/day) or vehicle for 4 weeks. RESULTS: Size and wall thickness ratios of experimentally induced IAs were assessed in both treatment groups after induction and in a control group. The effects of zinc administration in IAs were examined by immunohistochemistry and Western blotting. Zinc administration significantly suppressed aneurysm size and also preserved the internal elastic lumen. Administration of zinc significantly attenuated infiltration of macrophages into IAs. CONCLUSIONS: Zinc treatment significantly increased expression of the antiinflammatory signaling protein A20, an inhibitor of the nuclear factor κB (NF-κB) pathway, in rat IAs. Zinc administration may prevent the growth of rat IAs by inducing A20-attributed inactivation of NF-κB signaling.

Shortening antibiotic duration in the treatment of acute cholangitis: rationale and study protocol for an open-label randomized controlled trial.

BACKGROUND: Antimicrobial therapy with appropriate biliary drainage is considered the standard of care for acute cholangitis, but the optimal duration of antimicrobial therapy remains unknown. Seven to 10 days of antimicrobial therapy are common for the treatment of acute cholangitis, but a recent retrospective cohort study suggested a shorter duration might be effective. A shorter duration of antimicrobial therapy can be beneficial in decreasing the length of hospital stay, improving patients' quality of life, decreasing adverse effects, and even contributing to a decrease in the occurrence of antimicrobial resistance. METHODS/DESIGN: We will conduct a multi-centre, open-label, randomized, non-inferiority trial to compare short-course therapy (SCT) with conventional long-course therapy (LCT) in treating patients with acute cholangitis. SCT consists of 5-day intravenous antimicrobial therapy if the patients had clinical improvement, while at least 7 days of intravenous antibiotics will be provided to the LCT group. The primary outcome is clinical cure at 30 days after onset. Patients will be randomly assigned in an open-label fashion. A total sample size of 150 was estimated to provide a power of 80% with a one-sided α level of 2.5% and a non-inferiority margin of 10%. DISCUSSION: This trial is expected to reveal whether SCT is non-inferior to conventional LCT or not, and may provide evidence that one can shorten the treatment duration for acute cholangitis for the benefit of patients. TRIAL REGISTRATION: University Hospital Medical Information Network, UMIN000028382. Registered on 30 August 2017.

Sequential Inward Bending of Arterial Bifurcations is Associated with Intracranial Aneurysm Formation.

OBJECTIVE: To investigate the association between vascular morphology and the development of intracranial aneurysms (IAs), the morphological changes of intracranial arteries after IA induction were examined using a rodent model. METHODS: The vascular morphology of the circle of Willis in rats was visualized at 1 week and at 3 months after IA induction using 7-T magnetic resonance imaging. The following 2 angle parameters were defined: the angle between the parent artery and the daughter arteries (PD angle), and the widening of the daughter arteries (DD angle). The correlations of the angle parameters with IA size and with the number of macrophages infiltrated in the IA wall by immunohistochemistry were examined. RESULTS: Magnetic resonance imaging showed bending of the arteries over time around the predilection site for IAs. The PD angle increased significantly 1 week after IA induction (P < 0.05) and correlated with IA size (P < 0.01). The DD angle did not increase after 1 week, but increased 3 months after IA induction (P < 0.01). The PD angle 1 week after surgery also correlated with the number of infiltrated macrophages in aneurysmal walls (P = 0.01). CONCLUSIONS: Sequential inward bending of arterial bifurcations occurred after IA induction in the rat model. The degree of arterial bending correlated with IA development and inflammation in the IA wall, suggesting that the vascular morphology may be strongly associated with IA development through a proinflammatory mechanism.

Acute tubulointerstitial nephritis caused by rifampicin: An increasing and often overlooked side effect in elderly patients
.

BACKGROUND: There are many side effects of antituberculous drugs, however, renal failure is relatively rare. Therefore, this side effect is thought to be unrecognized by most physicians. We experienced one case of acute renal failure caused by antituberculous therapy (rifampicin). CASE REPORT: A 64-year-old Japanese male developed tuberculous pleuritis. Six weeks after starting isoniazid (INH), rifampicin (RFP), and ethambutol (EB), his renal function worsened. We temporarily stopped antituberculous therapy, but the patient's renal failure did not improve, and he was admitted to our hospital for renal biopsy. Renal pathology indicated a diagnosis of acute interstitial nephritis. After starting prednisolone, his renal function slowly improved while INH was continued. A drug-induced lymphocyte stimulation test (DLST) of the antituberculous drugs did not reveal the causative agent. However, we consider RFP to be the most likely culprit. CONCLUSION: In recent reports, renal failure is not a rare complication during antituberculous treatment in the elderly population. Physicians who are involved with the administration of antituberculous therapy have to be aware of this side effect. DLST is not useful for identifying the causative agent of antituberculous drug side effects. Leukocyte migration test may be more useful than DLST for this purpose, but further clinical studies are necessary to verify effectiveness.
.

EP4 receptor-associated protein regulates gluconeogenesis in the liver and is associated with hyperglycemia in diabetic mice.

Prostaglandin E2 receptor 4-associated protein (EPRAP) is a key molecule in suppressing inflammatory responses in macrophages. EPRAP is expressed not only in macrophages but also in hepatocytes; however, the role of EPRAP in hepatocytes has not yet been defined. To examine the physiological role of hepatic EPRAP in mice, we performed the glucose tolerance test and the hyperinsulinemic-euglycemic clamp in high-fat sucrose diet (HFSD)-fed wild-type (WT) and Eprap null mice. We evaluated the contribution of EPRAP to gluconeogenesis by pyruvate tolerance test and primary hepatocyte experiments. Furthermore, lentivirus-expressing Eprap-specific small-hairpin RNA was injected in db/ db mice. HFSD-fed Eprap null mice had significantly lower blood glucose levels than HFSD-fed WT mice. Eprap null mice also had low glucose levels after fasting or pyruvic acid injection. Moreover, primary hepatocytes from Eprap-deficient mice showed decreased glucose production and lower expression of the Phosphoenol pyruvate carboxykinase and Glucose 6-phosphatase genes. Lentivirus-mediated hepatic Eprap suppression decreased glucose levels and the expression of gluconeogenic genes in db/ db mice. We conclude that EPRAP regulates gluconeogenesis in hepatocytes and is associated with hyperglycemia in diabetic mice. Our data suggest that suppression of EPRAP could be a novel strategy for the treatment of diabetes.

Carotid Endarterectomy for Medical Therapy-Resistant Symptomatic Low-Grade Stenosis.

BACKGROUND: Plaque characteristics play pivotal roles in ischemic events, but stenosis severity does not accurately reflect carotid plaque volume due to expansive remodeling in some patients with low-grade stenosis (LGS). This study aimed to assess the safety, efficacy, and durability of carotid endarterectomy (CEA) for symptomatic LGS. METHODS: Study participants comprised 61 consecutive patients who underwent CEA for symptomatic carotid stenosis. Patients were divided into an LGS group (<50%, n = 17) and a non-LGS group (≥50%, n = 44). Patient characteristics and short-term (within 30 days of CEA) and long-term outcomes were compared between groups for selective usage of internal shunt and known complications of CEA. RESULTS: Magnetic resonance imaging-detected intraplaque hemorrhage was more significant in LGS than in non-LGS (P = 0.04). For short-term outcomes, no symptomatic infarcts, hyperperfusion syndrome, or acute myocardial infarction was confirmed in either group. Internal shunts were used in 4 LGS (23.5%) and 6 non-LGS (13.6%). Asymptomatic diffusion-weighted imaging-positive lesions were confirmed in 2 LGS patients (11.8%) and 5 non-LGS patients (11.4%), neck hematoma in 1 LGS patient, and transient cranial nerve palsy in 1 LGS patient and 2 non-LGS patients, with no significant differences apparent between groups. For long-term outcomes, 5 non-LGS patients showed restenosis (P = 0.17). Hemorrhagic stroke was not observed in either group. No significant differences were seen for infarct in the ipsilateral carotid territory, any ischemic stroke, AMI, or mortality. CONCLUSIONS: CEA represents a safe and feasible therapeutic option for a subset of patients with symptomatic LGS.

SREBF1/MicroRNA-33b Axis Exhibits Potent Effect on Unstable Atherosclerotic Plaque Formation In Vivo.

Objective- Atherosclerosis is a common disease caused by a variety of metabolic and inflammatory disturbances. MicroRNA (miR)-33a within SREBF2 (sterol regulatory element-binding factor 2) is a potent target for treatment of atherosclerosis through regulating both aspects; however, the involvement of miR-33b within SREBF1 remains largely unknown. Although their host genes difference could lead to functional divergence of miR-33a/b, we cannot dissect the roles of miR-33a/b in vivo because of lack of miR-33b sequences in mice, unlike human. Approach and Results- Here, we analyzed the development of atherosclerosis using miR-33b knock-in humanized mice under apolipoprotein E-deficient background. MiR-33b is prominent both in human and mice on atheroprone condition. MiR-33b reduced serum high-density lipoprotein cholesterol levels and systemic reverse cholesterol transport. MiR-33b knock-in macrophages showed less cholesterol efflux capacity and higher inflammatory state via regulating lipid rafts. Thus, miR-33b promotes vulnerable atherosclerotic plaque formation. Furthermore, bone marrow transplantation experiments strengthen proatherogenic roles of macrophage miR-33b. Conclusions- Our data demonstrated critical roles of SREBF1-miR-33b axis on both lipid profiles and macrophage phenotype remodeling and indicate that miR-33b is a promising target for treating atherosclerosis.

Imaging mass spectroscopy delineates the thinned and thickened walls of intracranial aneurysms.

OBJECT: The wall thickness of intracranial aneurysms (IAs) is heterogeneous. Although thinning of the IA wall is thought to contribute to IA rupture, the underlying mechanism remains poorly understood. Recently, imaging mass spectroscopy (IMS) has been used to reveal the distribution of phospholipids in vascular diseases. To investigate the feature of phospholipid composition of IA walls, we conducted IMS in a rat model of experimentally induced IA. MATERIAL AND METHODS: IAs were surgically induced in 7-week-old male rats and analyzed by IMS in negative-ion mode. RESULTS: A molecule at m/z 885.5 was more abundant in the thickened wall than in the thinned wall (P = 0.03). Multiple-stage mass spectroscopy revealed the molecule to be phosphatidylinositol containing stearic acid and arachidonic acid (PI 18:0/20:4). Immunohistochemistry indicated that vascular smooth muscle cells (SMCs) in the thickened wall had dedifferentiated phenotypes. To investigate the relationship between accumulation of PI (18:0/20:4) and phenotypic changes in SMCs, we subjected primary mouse aortic SMCs to liquid chromatography-tandem mass spectrometry. Notably, dedifferentiated SMCs had 1.3-fold more PI (18:0/20:4) than partly differentiated SMCs. CONCLUSIONS: Our study demonstrated the heterogeneity in phospholipid composition of the aneurysmal walls using experimentally induced IAs. PI (18:0/20:4) accumulated at high levels in the thickened aneurysmal wall where synthetic dedifferentiated SMCs exist, suggesting that this phospholipid may be involved in the phenotypic switching of medial SMCs in the IA wall.

Long-term efficacy of comprehensive multidisciplinary antibiotic stewardship programs centered on weekly prospective audit and feedback.

OBJECTIVE: To evaluate the long-term effects of comprehensive antibiotic stewardship programs (ASPs) on antibiotic use, antimicrobial-resistant bacteria, and clinical outcomes. DESIGN: Before-after study. SETTING: National university hospital with 934 beds. INTERVENTION: Implementation in March 2010 of a comprehensive ASPs including, among other strategies, weekly prospective audit and feedback with multidisciplinary collaboration. METHODS: The primary outcome was the use of antipseudomonal antibiotics as measured by the monthly mean days of therapy per 1000 patient days each year. Secondary outcomes included overall antibiotic use and that of each antibiotic class, susceptibility of Pseudomonas aeruginosa, the proportion of patients isolated methicillin-resistant Staphylococcus aureus (MRSA) among all patients isolated S. aureus, the incidence of MRSA, and the 30-day mortality attributable to bacteremia. RESULTS: The mean monthly use of antipseudomonal antibiotics significantly decreased in 2011 and after as compared with 2009. Susceptibility to levofloxacin was significantly increased from 2009 to 2016 (P = 0.01 for trend). Its susceptibility to other antibiotics remained over 84% and did not change significantly during the study period. The proportion of patients isolated MRSA and the incidence of MRSA decreased significantly from 2009 to 2016 (P < 0.001 and = 0.02 for trend, respectively). There were no significant changes in the 30-day mortality attributable to bacteremia during the study period (P = 0.57 for trend). CONCLUSION: The comprehensive ASPs had long-term efficacy for reducing the use of the targeted broad-spectrum antibiotics, maintaining the antibiotic susceptibility of P. aeruginosa, and decreasing the prevalence of MRSA, without adversely affecting clinical outcome.

Deficiency in EP4 Receptor-Associated Protein Ameliorates Abnormal Anxiety-Like Behavior and Brain Inflammation in a Mouse Model of Alzheimer Disease.

Microglia are thought to play key roles in the progression of Alzheimer disease (AD). Overactivated microglia produce proinflammatory cytokines, such as tumor necrosis factor-α, which appear to contribute to disease progression. Previously, we reported that prostaglandin E2 type 4 receptor-associated protein (EPRAP) promotes microglial activation. We crossed human amyloid precursor protein transgenic mice from strain J20+/- onto an EPRAP-deficient background to determine the role of EPRAP in AD. Behavioral tests were performed in 5-month-old male J20+/-EPRAP+/+ and J20+/-EPRAP-/- mice. EPRAP deficiency reversed the reduced anxiety of J20+/- mice but did not affect hyperactivity. No differences in spatial memory were observed between J20+/-EPRAP+/+ and J20+/-EPRAP-/- mice. In comparison with J20+/-EPRAP+/+, J20+/-EPRAP-/- mice exhibited less microglial accumulation and reductions in the Cd68 and tumor necrosis factor-α mRNAs in the prefrontal cortex and hippocampus. No significant differences were found between the two types of mice in the amount of amyloid-ß 40 or 42 in the cortex and hippocampus. J20+/-EPRAP-/- mice reversed the reduced anxiety-like behavior and had reduced microglial activation compared with J20+/-EPRAP+/+ mice. Further research is required to identify the role of EPRAP in AD, but our results indicate that EPRAP may be related to behavioral and psychological symptoms of dementia and inflammation in patients with AD.

Dipeptidyl Peptidase-4 Inhibitor Anagliptin Prevents Intracranial Aneurysm Growth by Suppressing Macrophage Infiltration and Activation.

BACKGROUND: Chronic inflammation plays a key role in the pathogenesis of intracranial aneurysms (IAs). DPP-4 (dipeptidyl peptidase-4) inhibitors have anti-inflammatory effects, including suppressing macrophage infiltration, in various inflammatory models. We examined whether a DPP-4 inhibitor, anagliptin, could suppress the growth of IAs in a rodent aneurysm model. METHODS AND RESULTS: IAs were surgically induced in 7-week-old male Sprague Dawley rats, followed by oral administration of 300 mg/kg anagliptin. We measured the morphologic parameters of aneurysms over time and their local inflammatory responses. To investigate the molecular mechanisms, we used lipopolysaccharide-treated RAW264.7 macrophages. In the anagliptin-treated group, aneurysms were significantly smaller 2 to 4 weeks after IA induction. Anagliptin inhibited the accumulation of macrophages in IAs, reduced the expression of MCP-1 (monocyte chemotactic protein 1), and suppressed the phosphorylation of p65. In lipopolysaccharide-stimulated RAW264.7 cells, anagliptin treatment significantly reduced the production of tumor necrosis factor α, MCP-1, and IL-6 (interleukin 6) independent of GLP-1 (glucagon-like peptide 1), the key mediator in the antidiabetic effects of DPP-4 inhibitors. Notably, anagliptin activated ERK5 (extracellular signal-regulated kinase 5), which mediates the anti-inflammatory effects of statins, in RAW264.7 macrophages. Preadministration with an ERK5 inhibitor blocked the inhibitory effect of anagliptin on MCP-1 and IL-6 expression. Accordingly, the ERK5 inhibitor also counteracted the suppression of p65 phosphorylation in vitro. CONCLUSIONS: A DPP-4 inhibitor, anagliptin, prevents the growth of IAs via its anti-inflammatory effects on macrophages.

Extracranial internal carotid artery dissection caused by compression from a giant osteophyte due to atlantoaxial osteoarthritis: case report.

Deformed osseous structures have been reported as rare causes of extracranial internal carotid artery (ICA) dissection, including the styloid process and the hyoid bone. Here, the authors describe the first known case of symptomatic ICA dissection caused by a giant osteophyte due to atlantoaxial osteoarthritis. The left ICA was fixed at the skull base and at the ICA portion compressed by the osteophyte, and it was highly stretched and injured between the two portions during neck rotation. The patient was successfully treated with ligation of the affected ICA following balloon test occlusion. Atlantoaxial osteoarthritis should be considered in the differential diagnosis of ICA dissection in patients with a severely deformed cervical spine.

Behavioral abnormalities and reduced norepinephrine in EP4 receptor-associated protein (EPRAP)-deficient mice.

EP4 receptor-associated protein (EPRAP) is a newly identified molecule that regulates macrophage activation. We recently demonstrated the presence of EPRAP in the mice brain; however, little is known about the function of EPRAP in this tissue. Therefore, we investigated the role of EPRAP in behavior and emotion using behavioral analysis in mice. In this study, we subjected EPRAP-deficient (KO) mice and wild-type C57BL/6 (WT) mice to a battery of behavioral tests. EPRAP-KO mice tended to have shorter latencies to fall in the wire hang test, but had normal neuromuscular strength. EPRAP-KO mice exhibited elevated startle responses and reduced pre-pulse inhibition. Compared with WT mice, EPRAP-KO mice increased depression-like behavior in the forced swim test. These abnormal behaviors partially mimic symptoms of depression, attention deficit hyperactivity disorder (ADHD) and schizophrenia. Methylphenidate administration increased locomotor activity less in EPRAP-KO mice than in WT mice. Finally, levels of norepinephrine were reduced in the EPRAP-KO mouse brain. These behavioral abnormalities in EPRAP-KO mice may result from the dysfunction of monoamines, in particular, norepinephrine. Our results suggest that EPRAP participates in the pathogenesis of various behavioral disorders.

EP4 Receptor-Associated Protein in Macrophages Protects against Bleomycin-Induced Pulmonary Inflammation in Mice.

Excessive activation of inflammatory macrophages drives the pathogenesis of many chronic diseases. EP4 receptor-associated protein (EPRAP) has been identified as a novel, anti-inflammatory molecule in macrophages. In this study, we investigated the role of EPRAP using a murine model of bleomycin (BLM)-induced pulmonary inflammation. When compared with wild-type mice, EPRAP-deficient mice exhibited significantly higher mortality, and increased accumulation of macrophages and proinflammatory molecules in the lung 7 d post-BLM administration. Accordingly, the levels of phosphorylated p105, MEK1/2, and ERK1/2 were elevated in EPRAP-deficient alveolar macrophages following BLM administration. In contrast, macrophage-specific EPRAP overexpression decreased the production of proinflammatory cytokines and chemokines, suggesting that EPRAP in macrophages plays a key role in attenuating BLM-induced pulmonary inflammation. As EPRAP is phosphorylated after translation, we examined the role of posttranslational modifications in cellular inflammatory activation using mouse embryo fibroblasts (MEFs) expressing mutant EPRAP proteins. Expression of mutant EPRAP, in which serine-108 and serine-608 were replaced with alanine (EPRAP S108A/S608A), markedly suppressed TNF-α production in LPS-treated MEFs. Conversely, the serine phosphatase 2A (PP2A) inhibitor, cantharidic acid, increased LPS-induced TNF-α production in MEFs expressing wild-type EPRAP, but not in MEFs expressing EPRAP S108A/S608A. Immunoprecipitation analyses demonstrated that EPRAP associated with PP2A in both MEFs and alveolar macrophages from BLM-treated mice. Our data suggest that PP2A dephosphorylates EPRAP, which may be a crucial step in exertion of its anti-inflammatory properties. For these reasons, we believe the EPRAP-PP2A axis in macrophages holds the key to treating chronic inflammatory disorders.

Distal renal tubular acidosis without renal impairment after use of tenofovir: a case report.

BACKGROUND: Tenofovir, one of antiretroviral medication to treat human immunodeficiency virus (HIV) infection, is known to cause proximal renal tubular acidosis such as Fanconi syndrome, but cases of distal renal tubular acidosis had never been reported. CASE PRESENTATION: A 20-year-old man with HIV infection developed nausea and vomiting without diarrhea after starting antiretroviral therapy. Arterial blood gas revealed non-anion-gap metabolic acidosis and urine test showed positive urine anion gap. Tenofovir, one of antiretroviral medicine the patient received, was considered to be the cause of this acidosis and all antiretroviral drugs were discontinued. Symptoms disappeared promptly without recurrence of symptoms after resuming antiretroviral medications without tenofovir. CONCLUSION: Distal renal tubular acidosis caused by tenofovir, without renal impairment is very rare. Since causes of nausea and vomiting among HIV/AIDS patients are very diverse, awareness of this phenomenon is useful in diagnosing and managing the problem.