[Strategy for the development of small-molecule antidepressant targeting PAC1 receptor].

Major depressive disorder (MDD) is a psychiatric disorder that affects more than 300 million people worldwide and has a serious impact on society. Conventional antidepressants targeting monoamines in the brain based on the monoamine hypothesis are known to take a prolonged time to be effective or less effective in 30% of MDD patients. Hence, there is a need to develop antidepressants that are effective against treatment-resistant depression and have a new mechanism different from the monoamine hypothesis. An increasing number of research groups including us have been establishing that pituitary adenylate cyclase-activating polypeptide (PACAP) and one of its receptors, PAC1 receptor, are closely related to the etiology of stress-related diseases such as MDD. Therefore, it is strongly suggested that the PAC1 receptor is a promising target in the treatment of psychiatric disorders. We developed a novel, non-peptidic, small-molecule, high-affinity PAC1 receptor antagonists and conducted behavioral pharmacology experiments in mice to characterize a novel PAC1 receptor antagonist as a new option for MDD therapy. The results show that our novel PAC1 receptor antagonist has the potential to be a new antidepressant with a high safety profile. In this review, we would like to present the background of developing our novel PAC1 receptor antagonist and its effects on mouse models of acute stress.

Endovascular Aortic Repair for Heavily Calcified Abdominal Aortic Stenosis Using the Gore Viabahn Vbx Balloon-Expandable Covered Stent.

Open surgery for the treatment of focal infrarenal aortic stenosis in high-risk patients may result in complications and mortality. Endovascular aortic repair may be used to treat these lesions. Here, we present the case of a 78-year-old woman with severe, highly calcified stenosis of the infrarenal abdominal aorta, which was successfully treated with the GORE VIABAHN VBX (Gore Medical; Flagstaff, AZ) balloon-expandable covered stent. Long-term and randomized controlled studies comparing open surgery with EVAR are necessary to evaluate the usefulness of this novel device.

Isolated External Iliac Artery Aneurysm with Fibromuscular Dysplasia.

Isolated aneurysms of the external iliac artery are rare in patients with fibromuscular dysplasia. In this study, we report the case of a 74-year-old man with advanced gastric cancer who was found to have a medium-sized aneurysm of the external iliac artery (35 mm) on preoperative computed tomography angiograms. The patient underwent laparoscopic gastrectomy followed by replacement of the external iliac artery 6 months later. Histological examination of biopsy specimens revealed fibromuscular dysplasia. The 6 month postoperative course was uneventful. Such a case of external iliac artery aneurysm caused by fibromuscular dysplasia is very rare, and open surgery is recommended for its removal.

Small-molecule non-peptide antagonists of the PACAP receptor attenuate acute restraint stress-induced anxiety-like behaviors in mice.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a highly conserved pleiotropic neuropeptide, implicated in emotional stress responses and anxiety-related disorders. Here, we examined whether our recently developed small-molecule non-peptide PACAP receptor antagonists could ameliorate anxiety-like behaviors induced by acute restraint stress in mice. The antagonists PA-9 and its derivative PA-915 improved anxiety-like behaviors in mice subjected to restraint stress. An anxiolytic effect was observed with single acute dose, suggesting their fast-acting properties. PA-915 demonstrated a statistically significant anxiolytic effect whereas fluoxetine did not. These results indicate the potential of PAC1 antagonists as a novel treatment for anxiety.

Hemodynamic and clinical performance of the 25-mm Medtronic Mosaic porcine bioprosthesis in the mitral position.

The 25-mm Medtronic Mosaic porcine bioprosthesis (MB25) is the smallest bioprosthesis that has been approved for use in the mitral position in Japan. Various studies have reported satisfactory hemodynamic performance and good long-term outcomes of the Medtronic Mosaic porcine bioprosthesis. However, the hemodynamic and clinical performances of the MB25 in the mitral position remain unknown. This study aimed to evaluate the hemodynamic and clinical performance of the MB25 in mitral valve replacement (MVR). Twenty patients who underwent MVR using the MB25 between February 2013 and April 2018 were studied. We evaluated the hemodynamic performance of the MB25, cardiac chamber size, cardiac function, and systolic pulmonary artery pressure (PAP) using echocardiography during follow-up. The study outcomes were major adverse cardiac events (MACEs) and all-cause mortality. Sixteen patients (80%) had a patient prosthesis mismatch defined as an index effective orifice area of ≤ 1.2 cm2/m2. The left atrial dimension was significantly reduced after surgery (p = 0.0282). The mean pressure gradients (MPG) in the mitral position were 5.5 ± 1.7 mmHg at discharge and 4.2 ± 1.3 mmHg at 1 year postoperatively. The MPG in the mitral position significantly decreased during the follow-up period (p = 0.0489). Systolic PAP significantly improved postoperatively. The 1-, 3-, and 5-year survival rates were 87, 79, and 70%, respectively. No cardiac death occurred. There were no MACEs or reports of structural valve degeneration during the follow-up period. The hemodynamic and clinical performances of the MB25 in the mitral position were satisfactory as the smallest biological mitral valve. The MB25 is a reasonable option for MVR to reduce the surgical difficulty in high-risk patients with an advanced age, a small body size or MAC and when recurrent MVR or complex procedures are performed.

PACAP-PAC1 Signaling Regulates Serotonin 2A Receptor Internalization.

Mice lacking pituitary adenylate cyclase-activating polypeptide (PACAP) display psychomotor abnormalities, most of which are ameliorated by atypical antipsychotics with serotonin (5-HT) 2A receptor (5-HT2A) antagonism. Heterozygous Pacap mutant mice show a significantly higher hallucinogenic response than wild-type mice to a 5-HT2A agonist. Endogenous PACAP may, therefore, affect 5-HT2A signaling; however, the underlying neurobiological mechanism for this remains unclear. Here, we examined whether PACAP modulates 5-HT2A signaling by addressing cellular protein localization. PACAP induced an increase in internalization of 5-HT2A but not 5-HT1A, 5-HT2C, dopamine D2 receptors or metabotropic glutamate receptor 2 in HEK293T cells. This PACAP action was inhibited by protein kinase C inhibitors, ß-arrestin2 silencing, the PACAP receptor PAC1 antagonist PACAP6-38, and PAC1 silencing. In addition, the levels of endogenous 5-HT2A were decreased on the cell surface of primary cultured cortical neurons after PACAP stimulation and were increased in frontal cortex cell membranes of Pacap-/- mice. Finally, intracerebroventricular PACAP administration suppressed 5-HT2A agonist-induced head twitch responses in mice. These results suggest that PACAP-PAC1 signaling increases 5-HT2A internalization resulting in attenuation of 5-HT2A-mediated signaling, although further study is necessary to determine the relationship between behavioral abnormalities in Pacap-/- mice and PACAP-induced 5-HT2A internalization.

Cell barrier function of resident peritoneal macrophages in post-operative adhesions.

Post-operative adhesions are a leading cause of abdominal surgery-associated morbidity. Exposed fibrin clots on the damaged peritoneum, in which the mesothelial barrier is disrupted, readily adhere to surrounding tissues, resulting in adhesion formation. Here we show that resident F4/80HighCD206- peritoneal macrophages promptly accumulate on the lesion and form a 'macrophage barrier' to shield fibrin clots in place of the lost mesothelium in mice. Depletion of this macrophage subset or blockage of CD11b impairs the macrophage barrier and exacerbates adhesions. The macrophage barrier is usually insufficient to fully preclude the adhesion formation; however, it could be augmented by IL-4-based treatment or adoptive transfer of this macrophage subset, resulting in robust prevention of adhesions. By contrast, monocyte-derived recruited peritoneal macrophages are not involved in the macrophage barrier. These results highlight a previously unidentified cell barrier function of a specific macrophage subset, also proposing an innovative approach to prevent post-operative adhesions.

A lost suture needle in the left ventricle 4 years after cardiac surgery.

We present an unusual case of a patient with a lost suture needle in the left ventricle, 4 years after cardiac surgery. We show the temporal image comparison using computed tomography as well as the macro and pathological findings of the suture needle and myocardium.

Clinical outcome of cardiac surgery in patients with remitted or active hepatocellular carcinoma.

PURPOSE: Hepatocellular carcinoma (HCC) is one of the most common primary cancers worldwide. HCC has unique characteristics such as co-existing chronic liver damage and a high recurrence rate. A negative impact on the surgical outcome due to these backgrounds could be expected. We aimed to evaluate the clinical outcomes of cardiac surgery in these patients. METHODS: Between January 2000 and December 2019, 16 patients with remitted cancer and 5 patients with active HCC who underwent open heart surgery were studied. The clinical data were retrospectively evaluated from hospital records. Follow-up information was collected via telephone interviews. RESULTS: The major cause of HCC was viral hepatitis. Eighteen patients (86%) were classified as having Child-Pugh class A cirrhosis. The mean model of end-stage liver disease (MELD) score was 7.2 ± 5.2. There was no 30-day mortality. During follow-up, 11 patients died due to HCC. The 1-, 3-, and 5-year survival rates were 80.0, 42.5, and 22.3%, respectively. A univariate analysis identified a higher preoperative MELD score and lower serum cholinesterase levels as prognostic factors for long-term survival. CONCLUSION: We could safely perform cardiac surgery in selected patients with remitted and active HCC. The postoperative life expectancy of these patients was limited but acceptable.

Lipocalin-type prostaglandin D synthase regulates light-induced phase advance of the central circadian rhythm in mice.

We previously showed that mice lacking pituitary adenylate cyclase-activating polypeptide (PACAP) exhibit attenuated light-induced phase shift. To explore the underlying mechanisms, we performed gene expression analysis of laser capture microdissected suprachiasmatic nuclei (SCNs) and found that lipocalin-type prostaglandin (PG) D synthase (L-PGDS) is involved in the impaired response to light stimulation in the late subjective night in PACAP-deficient mice. L-PGDS-deficient mice also showed impaired light-induced phase advance, but normal phase delay and nonvisual light responses. Then, we examined the receptors involved in the response and observed that mice deficient for type 2 PGD2 receptor DP2/CRTH2 (chemoattractant receptor homologous molecule expressed on Th2 cells) show impaired light-induced phase advance. Concordant results were observed using the selective DP2/CRTH2 antagonist CAY10471. These results indicate that L-PGDS is involved in a mechanism of light-induced phase advance via DP2/CRTH2 signaling.

Use of Edoxaban for the Treatment of Heparin-Induced Thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) is a life-threatening adverse drug reaction of heparin therapy, which increases a patient's risk of developing venous and/or arterial thromboembolism. HIT should be treated through discontinuation of heparin and administration of nonheparin anticoagulants such as argatroban. For long-term anticoagulation, parenteral nonheparin anticoagulants are generally converted to oral treatment with a vitamin K antagonist such as warfarin. Although administration of warfarin is recommended to overlap with a nonheparin anticoagulant for a minimum of 5 days, overlapping with argatroban and warfarin presents high risks of bleeding. We describe a case of HIT treated with edoxaban. A 78-year-old man underwent surgery for esophageal cancer and was administered heparin perioperatively. After surgery, he was diagnosed with HIT and venous thromboembolism. We immediately stopped heparin and initiated parenteral argatroban. The patient was subsequently started on edoxaban without any overlap between the two drugs. The treatment was successful. The treatment of edoxaban following argatroban for HIT could reduce bleeding complications and shorten the length of hospital stay. To the best of our knowledge, this is the first report of the use of edoxaban for HIT treatment.

Acute heart failure due to large intimal flap associated with chronic aortic dissection.

Acute heart failure from aortic stenosis secondary to chronic aortic dissection is very rare. We describe a case of acute heart failure secondary to aortic arch stenosis resulting from subacute type A aortic dissection. Resection of large thickened immobile intimal flap with total aortic arch replacement was successful, and cardiac function improved.

Pathological Role of Receptor for Advanced Glycation End Products in Calcified Aortic Valve Stenosis.

Background Aortic stenosis (AS) is highly prevalent in patients with atherosclerotic cardiovascular disease. Advanced glycation end products (AGEs) and the receptor for AGEs (RAGE) play a pivotal role for vascular calcification in atherosclerosis. We hypothesize that the AGEs-RAGE axis could also be involved in the pathophysiological mechanism of calcified AS. Methods and Results A total of 54 patients with calcified AS who underwent aortic valve replacement were prospectively enrolled from 2014 to 2016 (mean age 75.3±7.7 years). Aortic valve specimens were obtained from 47 patients and 16 deceased control subjects without aortic valve disease (mean age 63.2±14.5 years). The valvular expression of RAGE was evaluated by immunohistochemistry. Serum levels of AGEs and soluble RAGE were measured in 50 patients with calcified AS and 70 age-matched and sex-matched control subjects without heart disease. The valvular RAGE expression in patients with calcified AS was higher than controls (P=0.004) and was significantly associated with a decreased ankle-brachial pressure index (P=0.007) and an increased intima-media thickness (P=0.026). RAGE and α-smooth muscle actin were coexpressed and were partially costained with osteocalcin and alkaline phosphatase. The serum levels of AGEs and soluble RAGE were significantly higher in the patients with calcified AS than in the controls (P=0.013 and P<0.001, respectively). Soluble RAGE (inversely) and use of aspirin were independently correlated with changes in left ventricular systolic function after aortic valve replacement (P=0.012 and P=0.002, respectively). Conclusions Our present study suggests that RAGE may play a role in the pathogenesis of calcified AS, which is a prognostic marker in patients with AS after aortic valve replacement.

The Role of Syk in Inflammatory Response of Human Abdominal Aortic Aneurysm Tissue.

Objective: Inflammatory response is central to pathogenesis of abdominal aortic aneurysm (AAA). Recently, we reported that Syk, a signaling molecule in inflammatory cells, promotes AAA development in a mouse model. In this study, we aimed to investigate the role of Syk in human AAA pathogenesis. Materials and Methods: We obtained human AAA wall samples during open surgical aortic repair at Kurume University Hospital. Immunohistochemical analyses of AAA samples were performed for Syk activation and cell type markers. Ex vivo culture of human AAA tissue was utilized to evaluate the effect of P505-15, a Syk inhibitor, on secretions of interleukin-6 (IL-6) and matrix metalloproteinases (MMPs). Results: Immunohistochemical analysis showed infiltration of B cells, T cells, and macrophages in AAA samples. Syk activation was localized mainly in B cells and part of macrophages. AAA tissue in culture secreted IL-6, MMP-9, and MMP-2 without any stimulation. The unstimulated secretions of IL-6, MMP-9, and MMP-2 were insensitive to P505-15. Secretions of IL-6 and MMP-9 were enhanced by exogenous normal human immunoglobulin G (IgG), which was suppressed by P505-15, whereas secretion of MMP-2 was insensitive to IgG or P505-15. Conclusion: These results demonstrate an important role of Syk for IgG-dependent inflammatory response in human AAA.

Aortic valve replacement with or without concomitant coronary artery bypass grafting in very elderly patients aged 85 years and older.

Degenerative aortic stenosis is the most common structural heart valve disease affecting the aging population. Catheter-based heart valve interventions are less invasive and very useful for very elderly patients. However, we often consider open heart surgery for these patients because of anatomical reasons and co-existing cardiac diseases, i.e., severe coronary artery disease. We aimed to analyze the outcomes of very elderly patients aged ≥ 85 years undergoing aortic valve replacement (AVR) with or without coronary artery bypass grafting (CABG). Twenty-nine very elderly patients aged ≥ 85 years who underwent AVR with CABG (n = 11, Group AC) or isolated AVR (n = 18, Group A) were examined. The overall mean age of the patients was 87.2 ± 2.6 (range 85-94) years. The estimated operative mortality rate, calculated using the Japan score, EuroSCORE II, and STS risk score, was 5.72%-10.88% in Group AC and 5.63%-8.30% in Group A. Aortic cross-clamp time (126.5 ± 29.0 vs. 96.9 ± 29.2 min, p = 0.016) was significantly longer in Group AC than in Group A. Although the major morbidity rate was higher in Group AC than in Group A (36% vs. 6%, p = 0.0336), the length of intensive care unit stay and hospital stay was comparable between both groups. There was no 30-day and hospital mortality in both groups. Eleven patients died during follow-up (senility, 5; cerebrovascular events, 2; renal failure, 1; unknown, 3). There were no significant differences in survival rates during follow-up (log-rank p value = 0.1051). The 1-, 2-, 3-, 4- and 5-year survival rates were 91%, 80%, 69%, 69% and 69%, respectively, in Group AC and 94%, 94%, 94%, 94% and 88%, respectively, in Group A. In conclusion, AVR with or without CABG could be safely performed in carefully selected very elderly patients with acceptable early- and long-term results. AVR with CABG in very elderly patients aged ≥ 85 offers similar results to isolated AVR in terms of 30-day mortality, hospital mortality, and long-term survival.

Multimodal imaging of cardiac-calcified amorphous tumor.

Cardiac-calcified amorphous tumor (CAT) is a rare non-neoplastic tumor and its origin and pathogenesis are still unclear. In addition, it is difficult to clinically diagnose as cardiac CAT without pathological findings. We present a case of a 78-year-male diagnosed with cardiac CAT after surgical resection. We could evaluate tumor aspects by multimodal imaging including echocardiography, contrast-enhanced computed tomography (CT), magnetic resonance image, and 18F-fluorodeoxyglucose-positron emission tomography/CT before surgery.

Left ventricular apical pseudoaneurysm with aortic prosthetic valve endocarditis.

We report an 83-year-old man with a mycotic left ventricular apical pseudoaneurysm and aortic prosthetic valve endocarditis caused by Enterococcus spp. Mycotic left ventricular pseudoaneurysm is very rare and is associated with a high risk of rupture. Here, we report the clinical presentation, diagnosis, prognosis, and treatment of a case of mycotic left ventricular pseudoaneurysm to raise awareness regarding this unusual and potentially fatal complication.

Pituitary Adenylate Cyclase-Activating Polypeptide Modulates Dendritic Spine Maturation and Morphogenesis via MicroRNA-132 Upregulation.

Alterations in pituitary adenylate cyclase-activating polypeptide (PACAP), a multifunctional neuropeptide, and its receptors have been identified as risk factors for certain psychiatric disorders, including schizophrenia. Increasing evidence from human genetic and animal model studies suggest an association between various psychiatric disorders and altered dendritic spine morphology. In the present study, we investigated the role of exogenous and endogenous PACAP in spine formation and maturation. PACAP modified the density and morphology of PSD-95-positive spines in primary cultured hippocampal neurons. Notably, PACAP increased the levels of microRNA (miR)-132 and decreased expression of corresponding miR-132 target genes and protein expression of p250GAP, a miR-132 effector known to be involved in spine morphology regulation. In corroboration, PSD-95-positive spines were reduced in PACAP-deficient (PACAP-/-) mice versus WT mice. Golgi staining of hippocampal CA1 neurons revealed a reduced spine densities and atypical morphologies in the male PACAP-/- mice. Furthermore, viral miR-132 overexpression reversed the reduction in hippocampal spinal density in the male PACAP-/- mice. These results indicate that PACAP signaling plays a critical role in spine morphogenesis possibly via miR-132. We suggest that dysfunction of PACAP signaling may contribute to the pathogenesis of neuropsychiatric disorders, at least partly through its effects on spine formation.SIGNIFICANCE STATEMENT Pituitary adenylate cyclase-activating polypeptide (PACAP) signaling dysfunction and dendritic spine morphology alterations have recently been suggested as important pathophysiological mechanisms underlying several psychiatric and neurological disorders. In this study, we investigated whether PACAP regulates dendritic spine morphogenesis. In a combination of pharmacological and viral gain- and loss-of-function approaches in vitro and in vivo experiments, we found PACAP to increase the size and density of dendritic spines via miR-132 upregulation. Together, our data suggest that a dysfunction of PACAP signaling may contribute to the pathogenesis of neuropsychiatric disorders, at least partly through abnormal spine formation.

Abdominal Aortic Aneurysm Caused by Aortic Fibromuscular Dysplasia: A Case Report.

Fibromuscular dysplasia (FMD) mainly develops in medium-sized arteries, including renal, extracranial, and extremity arteries, but it rarely causes abdominal aortic aneurysm (AAA). A 69-year-old woman with AAA diagnosed on ultrasonography by a home doctor visited our hospital. Contrast-enhanced computed tomography revealed a saccular aneurysm of terminal abdominal aorta. We performed abdominal aortic replacement and resected the section with aneurysm. Pathological examination of the wall tissue of the resected aneurysm revealed findings that are consistent with FMD. We report this case of AAA caused by aortic FMD because of its rarity.