A case of spontaneous coronary artery dissection that later turned out to be Takayasu arteritis.

Spontaneous coronary artery dissection (SCAD) is a rare cause of acute coronary syndrome (ACS), which typically occurs in women at low risk of atherosclerosis. We herein report a case of SCAD in a 57-year-old man who later developed Takayasu arteritis. The patient presented to our hospital complaining of chest pain and was diagnosed with unstable angina. Emergent coronary angiography was performed, and optical coherence tomography revealed that ACS was caused by SCAD. The patient was treated medically without further ballooning or stenting. Because there was a bilateral difference in blood pressure, the systemic artery was screened by contrast-enhanced computed tomography, which showed left subclavian artery occlusion, proximal stenosis of the superior mesenteric artery, right common iliac artery dissection, and left external iliac artery dissection. Based on these results and 18F-fluorodeoxyglucose positron emission tomography findings, we diagnosed Takayasu arteritis. Prednisolone and tocilizumab were selected for medical treatment, and the patient was in a good condition at one year after the diagnosis. Takayasu arteritis can cause dissection of various arteries and should be suspected when atypical SCAD or multiple dissections are present. Early initiation of immunosuppressive therapy can control disease activity. Learning objective: Spontaneous coronary artery dissection (SCAD) is an important cause of acute coronary syndrome. In this case, we experienced a case of SCAD which turned out to be the first symptom of Takayasu arteritis. Immunosuppressive therapy was effective for both coronary lesion and systemic vasculitis. Not only fibromuscular dysplasia, but also various types of vasculitis should therefore be considered in the differential diagnosis when encountering atypical SCAD cases.

Neointimal characteristic changes following drug-coated balloons in lesions with repeated revascularization.

BACKGROUND: Since their emergence, drug-coated balloons (DCBs) have been used widely to treat in-stent lesions with coronary artery disease (CAD). However, despite their superior efficacy to balloon angioplasty, how DCBs affect neointimal characteristics is poorly understood. OBJECTIVES: We aimed to assess the neointimal characteristic changes following DCB treatment. METHODS: Using optical frequency domain imaging (OFDI), we serially observed the in-stent lesion site just after and 1 year after DCB angioplasty in 12 lesions of 11 patients with repeated revascularization. Neoatherosclerosis was defined as lipid-laden neointima with or without calcification in the stented lesion. Progression or regression of neoatherosclerosis, newly formed neointimal calcification, newly formed uncovered strut and newly formed evagination were assessed. Tiny tissue protrusion was also recorded as mushroom-like protrusion. RESULTS: Underlying stents were first-generation (n = 5) or newer (n = 7) drug-eluting stents (DESs) with implantation durations ranging from 1 to 15 years (median 8 years). Surprisingly, two-thirds of the lesions (67%, 8 of 12) showed progression of neoatherosclerosis, while a quarter of lesions (25%, 3 of 12) showed regression of neoatherosclerosis. The maximal lipid arc increased from 122° to 174°. Newly formed neointimal calcification was observed in 2 of 12 lesions (16%). Newly formed uncovered struts (33%; 4 of 12) and newly formed evaginations (33%; 4 of 12) were not rare. Mushroom-like protrusion was found in a quarter of lesions (25%; 3 of 12). CONCLUSION: Our study demonstrated that a considerable number of lesions showed varied neointimal characteristic changes in a small number of patients. Further studies in a larger population are needed to understand the clinical impact of these findings.

Angioscopic Findings of Stenosis Versus Occlusion in Femoropopliteal Artery Disease.

BACKGROUND: Despite the increase in the number of patients with peripheral artery disease (PAD), the pathophysiology is not fully elucidated. Recently, angioscopy with a 0.48-megapixel equivalent resolution camera became available for patients with PAD. We aimed to compare the plaque component between native stenosis and occlusion in the femoropopliteal artery using this modality. MATERIALS AND METHODS: Thirty-two consecutive patients who underwent endovascular treatment for native femoropopliteal artery disease with angioscopy were studied. The major angioscopic classifications of each lesion were defined as follows: atheromatous plaque (AP) was defined as luminal narrowing without any protrusion, calcified nodule (CN) was defined as a protruding bump with surface irregularity, a mainly reddish thrombus was defined as organizing thrombus (OG), and organized thrombus (OD) was defined by more than half of the thrombus showing a whitish intima-like appearance. RESULTS: A total of 34 lesions (stenosis, n=18; occlusion, n=16) from 32 patients were included. All stenotic lesions showed AP or CN (n=8 [44%], n=10 [56%], respectively), whereas all occluded lesions showed OG or OD (n=5 [31%], n=11 [69%], respectively), which amounted to a statistically significant difference (p<0.001). In occluded lesions, stiff wires (>3 g) were required to cross all lesions classified as OD, whereas this was not always necessary for lesions classified as OG (11 [100%] of 11, 1 [25%] of 5, respectively; p=0.04). Yellow color plaques were observed to a similar degree in all angioscopic classifications. Major adverse limb events, defined as amputation and any reintervention at 12 months, were highly variable, depending on the angioscopic findings, and tended to be more frequently observed in CN and OD (13% in AP, 40% in CN, 0% in OT, and 36% in OD, p=0.25). CONCLUSION: Angioscopy revealed varying components in stenosis and occlusion with different degrees of clinical impact. This may provide new information on the pathophysiology of PAD.

Effects of RORγt overexpression on the murine central nervous system.

OBJECTIVE: T helper 17 (Th17) cells are a subset of CD4+ T cells that produce interleukin (IL)-17A. Recent studies showed that an increase in circulating IL-17A causes cognitive dysfunction, although it is unknown how increased systemic IL-17A affects brain function. Using transgenic mice overexpressing RORγt, a transcription factor essential for differentiation of Th17 cells (RORγt Tg mice), we examined changes in the brain caused by chronically increased IL-17A resulting from excessive activation of Th17 cells. RESULTS: RORγt Tg mice exhibited elevated Rorc and IL-17A mRNA expression in the colon, as well as a chronic increase in circulating IL-17A. We found that the immunoreactivity of Iba1 and density of microglia were lower in the dentate gyrus of RORγt Tg mice compared with wild-type mice. However, GFAP+ astrocytes were unchanged in the hippocampi of RORγt Tg mice. Levels of synaptic proteins were not significantly different between RORγt Tg and wild-type mouse brains. In addition, novel object location test results indicated no difference in preference between these mice. CONCLUSION: Our findings indicate that a continuous increase of IL-17A in response to RORγt overexpression resulted in decreased microglia activity in the dentate gyrus, but had only a subtle effect on murine hippocampal functions.

Anomalous atrium associated with persistent left superior vena cava.

Persistent left superior vena cava (PLSVC) is the most common venous anomaly with an incidence of 0.3-0.5% in the general population. Here, we report a rare case of PLSVC with anomalous atrium in a cadaver during the student's dissection session at the University of Tsukuba. In this case, the coronary sinus had merged with the right atrium to form an enlarged sac-like structure and received systemic venous flow including inflow from the PLSVC. The roof of the coronary sinus with the right atrium was thicker than that of the control cases. We further found that the distance between the sinoatrial node and the opening of the coronary sinus was slightly more than half of that in control cases. This variant appears interesting and is worth reporting for developmental and clinical consideration.

An activity-dependent local transport regulation via degradation and synthesis of KIF17 underlying cognitive flexibility.

Synaptic weight changes among postsynaptic densities within a single dendrite are regulated by the balance between localized protein degradation and synthesis. However, the molecular mechanism via these opposing regulatory processes is still elusive. Here, we showed that the molecular motor KIF17 was locally degraded and synthesized in an N-methyl-d-aspartate receptor (NMDAR)-mediated activity-dependent manner. Accompanied by the degradation of KIF17, its transport was temporarily dampened in dendrites. We also observed that activity-dependent local KIF17 synthesis driven by its 3' untranslated region (3'UTR) occurred at dendritic shafts, and the newly synthesized KIF17 moved along the dendrites. Furthermore, hippocampus-specific deletion of Kif17 3'UTR disrupted KIF17 synthesis induced by fear memory retrieval, leading to impairment in extinction of fear memory. These results indicate that the regulation of the KIF17 transport is driven by the single dendrite-restricted cycle of degradation and synthesis that underlies cognitive flexibility.

Intraventricular IL-17A administration activates microglia and alters their localization in the mouse embryo cerebral cortex.

Viral infection during pregnancy has been suggested to increase the probability of autism spectrum disorder (ASD) in offspring via the phenomenon of maternal immune activation (MIA). This has been modeled in rodents. Maternal T helper 17 cells and the effector cytokine, interleukin 17A (IL-17A), play a central role in MIA-induced behavioral abnormalities and cortical dysgenesis, termed cortical patch. However, it is unclear how IL-17A acts on fetal brain cells to cause ASD pathologies. To assess the effect of IL-17A on cortical development, we directly administered IL-17A into the lateral ventricles of the fetal mouse brain. We analyzed injected brains focusing on microglia, which express IL-17A receptors. We found that IL-17A activated microglia and altered their localization in the cerebral cortex. Our data indicate that IL-17A activates cortical microglia, which leads to a cascade of ASD-related brain pathologies, including excessive phagocytosis of neural progenitor cells in the ventricular zone.

Kif1c regulates osteoclastic bone resorption as a downstream molecule of p130Cas.

Podosome formation in osteoclasts is an important initial step in osteoclastic bone resorption. Mice lacking c-Src (c-Src-/- ) exhibited osteopetrosis due to a lack of podosome formation in osteoclasts. We previously identified p130Cas (Crk-associated substrate [Cas]) as one of c-Src downstream molecule and osteoclast-specific p130Cas-deficient (p130CasΔOCL-/- ) mice also exhibited a similar phenotype to c-Src-/- mice, indicating that the c-Src/p130Cas plays an important role for bone resorption by osteoclasts. In this study, we performed a cDNA microarray and compared the gene profiles of osteoclasts from c-Src-/- or p130CasΔOCL-/- mice with wild-type (WT) osteoclasts to identify downstream molecules of c-Src/p130Cas involved in bone resorption. Among several genes that were commonly downregulated in both c-Src-/- and p130CasΔOCL-/- osteoclasts, we identified kinesin family protein 1c (Kif1c), which regulates the cytoskeletal organization. Reduced Kif1c expression was observed in both c-Src-/- and p130CasΔOCL-/- osteoclasts compared with WT osteoclasts. Kif1c exhibited a broad tissue distribution, including osteoclasts. Knockdown of Kif1c expression using shRNAs in WT osteoclasts suppressed actin ring formation. Kif1c overexpression restored bone resorption subsequent to actin ring formation in p130CasΔOCL-/- osteoclasts but not c-Src-/- osteoclasts, suggesting that Kif1c regulates osteoclastic bone resorption in the downstream of p130Cas (191 words). SIGNIFICANCE OF THE STUDY: We previously showed that the c-Src/p130Cas (Cas) plays an important role for bone resorption by osteoclasts. In this study, we identified kinesin family protein 1c (Kif1c), which regulates the cytoskeletal organization, as a downstream molecule of c-Src/p130Cas axis, using cDNA microarray. Knockdown of Kif1c expression using shRNAs in wild-type osteoclasts suppressed actin ring formation. Kif1c overexpression restored bone resorption subsequent to actin ring formation in osteoclast-specific p130Cas-deficient (p130CasΔOCL-/- ) osteoclasts but not c-Src-/- osteoclasts, suggesting that Kif1c regulates osteoclastic bone resorption in the downstream of p130Cas.

Kinesin Kif3b mutation reduces NMDAR subunit NR2A trafficking and causes schizophrenia-like phenotypes in mice.

The transport of N-methyl-d-aspartate receptors (NMDARs) is crucial for neuronal plasticity and synapse formation. Here, we show that KIF3B, a member of the kinesin superfamily proteins (KIFs), supports the transport of vesicles simultaneously containing NMDAR subunit 2A (NR2A) and the adenomatous polyposis coli (APC) complex. Kif3b+/- neurons exhibited a reduction in dendritic levels of both NR2A and NR2B due to the impaired transport of NR2A and increased degradation of NR2B. In Kif3b+/- hippocampal slices, electrophysiological NMDAR response was found decreased and synaptic plasticity was disrupted, which corresponded to a common feature of schizophrenia (SCZ). The histological features of Kif3b+/- mouse brain also mimicked SCZ features, and Kif3b+/- mice exhibited behavioral defects in prepulse inhibition (PPI), social interest, and cognitive flexibility. Indeed, a mutation of KIF3B was specifically identified in human SCZ patients, which was revealed to be functionally defective in a rescue experiment. Therefore, we propose that KIF3B transports NR2A/APC complex and that its dysfunction is responsible for SCZ pathogenesis.

Elevated maternal retinoic acid-related orphan receptor-γt enhances the effect of polyinosinic-polycytidylic acid in inducing fetal loss.

T helper 17 (Th17) cells have been suggested to play a crucial role in various complications during pregnancy by participating in maternal immune activation (MIA). To test a possible role for Th17 cells in MIA-mediated abortion, we analyzed transgenic mice overexpressing retinoic acid receptor-related orphan receptor gamma-t (RORγt), a master regulator of IL-17 producing cell development. These mutant mice (RORγt Tg mice) exhibited a constitutive upregulation of serum IL-17A and decreased E-cadherin expression in cell-cell junctions of placental tissues. Abortion after the administration of a viral-mimicking synthetic double-stranded RNA polyinosinic-polycytidylic acid was more frequent in RORγt Tg mice than wild-type mice. These results suggest that excessive Th17 cell activity alters immune responsiveness and increases the rate of abortion during gestation.

Inhibition of epidermal growth factor receptor stimulates prolactin expression in primary culture of the mouse pituitary gland.

The roles of epidermal growth factor (EGF) in the regulation of prolactin (PRL) gene expression in the normal pituitary gland remain poorly understood. In the present study, the effects of EGF and an inhibitor of the EGF receptor, erlotinib, on PRL gene expression were examined both in the pituitary tumour cell line GH3 and in a primary culture of the mouse pituitary gland under similar experimental conditions. The results showed that EGF stimulated PRL expression in GH3 cells, but not in normal cells. Erlotinib was found to counteract EGF in GH3 cells inhibiting the PRL expression enhanced by EGF. By contrast, erlotinib induced an elevation in the PRL mRNA levels in the primary culture of the adult pituitary gland and the initiation of PRL production in the culture of the foetal pituitary gland in which PRL production had not yet occurred. Western blot analyses showed that EGF induced and erlotinib inhibited the activation of extracellular regulated protein kinase equally in GH3 and normal cells. These results suggest that the consequences of EGF receptor activation in normal PRL cells contradict those in adenomatous PRL cells.

Myosin Id localizes in dendritic spines through the tail homology 1 domain.

Dendritic spines, the postsynaptic compartments at excitatory synapses, are capable of changing their shape and size to modulate synaptic transmission. The actin cytoskeleton and a variety of actin-binding proteins play a critical role in the dynamics of dendritic spines. Class I myosins are monomeric motor proteins that move along actin filaments using the energy of ATP hydrolysis. Of these class I myosins, myosin Id, the mammalian homolog of Drosophila Myo31DF, has been reported to be expressed in neurons, whereas its subcellular localization in neurons remained unknown. Here, we investigated the subcellular localization of myosin Id and determined the domain responsible for it. We found that myosin Id is enriched in the F-actin-rich pseudopodia of HEK293T cells and in the dendritic spines of primary hippocampal neurons. Both deletion and substitution of the tail homology 1 (TH1) domain drastically diminishes its colocalization with F-actin. In addition, the mutant form lacking the TH1 domain is less distributed in dendritic spines than is the full-length form. Taken together, our findings reveal that myosin Id localizes in dendritic spines through the TH1 domain.

Components of RNA granules affect their localization and dynamics in neuronal dendrites.

In neurons, RNA transport is important for local protein synthesis. mRNAs are transported along dendrites as large RNA granules. The localization and dynamics of Puralpha and Staufen1 (Stau1), major components of RNA transport granules, were investigated in cultured hippocampal neurons. Puralpha-positive granules were localized in both the shafts and spines of dendrites. In contrast, Stau1-positive granules tended to be localized mainly in dendritic shafts. More than 90% of Puralpha-positive granules were positive for Stau1 in immature dendrites, while only half were positive in mature dendrites. Stau1-negative Puralpha granules tended to be stationary with fewer anterograde and retrograde movements than Stau1-positive Puralpha granules. After metabotropic glutamate receptor 5 activation, Stau1-positive granules remained in the dendritic shafts, while Puralpha granules translocated from the shaft to the spine. The translocation of Puralpha granules was dependent on myosin Va, an actin-based molecular motor protein. Collectively our findings suggest the possibility that the loss of Stau1 in Puralpha-positive RNA granules might promote their activity-dependent translocation into dendritic spines, which could underlie the regulation of protein synthesis in synapses.

Transforming growth factor-ß1 in the cerebrospinal fluid of patients with distinct neurodegenerative diseases.

A chronic inflammatory condition may underlie neurodegenerative disorders, including Parkinson's disease (PD) and Alzheimer's disease (AD). For example, both PD and AD patients show an increase in transforming growth factor-ß1 (TGF-ß1) levels in their cerebrospinal fluid (CSF). TGF-ß1 is a cytokine that inhibits inflammation. In the present study, using an enzyme-linked immunosorbent assay, we tested the hypothesis that the level of TGF-ß1 in the CSF of patients with amyotrophic lateral sclerosis (ALS), spinocerebellar degeneration (SCD), or multiple system atrophy-cerebellar subtype (MSA-C) would be elevated compared with that of normal controls. We found that TGF-ß1 levels in the CSF were not significantly different between these patients and normal controls. Our data suggest that the level of TGF-ß1 in the CSF is an unreliable biomarker of ALS, SCD, and MSA-C.

MafB is required for development of the hindbrain choroid plexus.

The choroid plexus (ChP) is a non-neural epithelial tissue that produces cerebrospinal fluid (CSF). The ChP differentiates from the roof plate, a dorsal midline structure of the neural tube. However, molecular mechanisms underlying ChP development are poorly understood compared to neural development. MafB is a bZip transcription factor that is known to be expressed in the roof plate. Here we investigated the role of MafB in embryonic development of the hindbrain ChP (hChP) using Mafb-deficient mice. Immunohistochemical analyses revealed that MafB is expressed in the roof plate and early hChP epithelial cells but its expression disappears at a later embryonic stage. We also found that the Mafb-deficient hChP exhibits delayed differentiation and results in hypoplasia compared to the wild-type hChP. Furthermore, the Mafb-deficient hChP exhibits increased apoptotic cell death and decreased proliferating cells at E12.5, an early stage of hChP development. Collectively, our findings reveal that MafB play an important role in promoting hChP development during embryogenesis.

Defects in Synaptic Plasticity, Reduced NMDA-Receptor Transport, and Instability of Postsynaptic Density Proteins in Mice Lacking Microtubule-Associated Protein 1A.

Microtubule-associated protein 1A (MAP1A) is a member of the major non-motor microtubule-binding proteins. It has been suggested that MAP1A tethers NMDA receptors (NRs) to the cytoskeleton by binding with proteins postsynaptic density (PSD)-93 and PSD-95, although the function of MAP1A in vivo remains elusive. The present study demonstrates that mouse MAP1A plays an essential role in maintaining synaptic plasticity through an analysis of MAP1A knock-out mice. The mice exhibited learning disabilities, which correlated with decreased long-term potentiation and long-term depression in the hippocampal neurons, as well as a concomitant reduction in the extent of NR-dependent EPSCs. Surface expression of NR2A and NR2B subunits also decreased. Enhanced activity-dependent degradation of PSD-93 and reduced transport of NR2A/2B in dendrites was likely responsible for altered receptor function in neurons lacking MAP1A. These data suggest that tethering of NR2A/2B with the cytoskeleton through MAP1A is fundamental for synaptic function. SIGNIFICANCE STATEMENT: This work is the first report showing the significance of non-motor microtubule-associated protein in maintaining synaptic plasticity thorough a novel mechanism: anchoring of NMDA receptors to cytoskeleton supports transport of NMDA receptors and stabilizes postsynaptic density scaffolds binding to NMDA receptors. Newly generated mutant mice lacking MAP1A exhibited learning disabilities and reduced synaptic plasticity attributable to disruptions of the anchoring machinery.