Identification of sulfonylpyrimidines as novel selective aldosterone synthase (CYP11B2) inhibitors.

4-[(5-[2-Methyl-5-(methylsulfonyl)pentan-2-yl]sulfonylpyrimidin-4-yl)amino]benzonitrile 2 was identified as a novel potent aldosterone synthase inhibitor. Compound 2 was found to inhibit human CYP11B2 in the nanomolar range, and showed an aldosterone-lowering effect in a furosemide-treated cynomolgus monkey model. Although human CYP11B2 has the high homology sequence with human CYP11B1, compound 2 showed more than 80 times higher selectivity over human CYP11B1 in vitro.

4-Anilino-pyrimidine, novel aldosterone synthase (CYP11B2) inhibitors bearing pyrimidine structures.

2,2,2-Trifluoro-1-{4-[(4-fluorophenyl)amino]pyrimidin-5-yl}-1-[1-(methylsulfonyl)piperidin-4-yl]ethanol 1 was identified as a novel potent aldosterone synthase inhibitor. Despite large species differences, compound 1 inhibits both human and rodent CYP11B2 in a nano-molar range.

Candy-Plug Technique Using an Excluder Aortic Extender for Distal Occlusion of a Large False Lumen Aneurysm in Chronic Aortic Dissection.

PURPOSE: To describe the candy-plug technique using an Excluder aortic extender for distal occlusion of a large false lumen aneurysm in chronic aortic dissection. TECHNIQUE: A 60-year-old female patient with a history of chronic type B aortic dissection and high-dose steroid use for Churg-Strauss syndrome developed a large 6.2 cm maximum diameter false lumen aneurysm. She underwent thoracic endovascular aortic repair from the left common carotid artery to the descending aorta to cover the proximal entry at the level of distal arch, with coil embolization of the left subclavian artery. To occlude the large false lumen from the reentry just below the level of the left renal artery ostium, a modified 32×45-mm Excluder aortic extender was deployed in the false lumen through the reentry, and a 16-mm Amplatzer Vascular Plug I was deployed in the waist of the modified Excluder aortic extender for complete occlusion. No obvious technical complication was seen. Contrast-enhanced computed tomography at 1 and 14 months revealed no endoleaks and showed complete false lumen thrombosis. CONCLUSION: The candy-plug technique using the Excluder aortic extender is feasible for occlusion of a large false lumen aneurysm in chronic aortic dissection.

Synthesis and Structure-Activity Relationships of 2-Aminoacetamide Derivatives as Peroxisome Proliferator-Activated Receptor α/γ Dual Agonists.

We describe the design, syntheses, and structure-activity relationships of novel zwitterionic compounds as nonthiazolidinedion-based peroxisome proliferator-activated receptor (PPAR) α/γ dual agonists. In our previous report, we obtained compound 1 showing potent PPARα/γ dual agonistic activities, together with a sufficient glucose-lowering effect in db/db mice. However, this compound possessed an issue, i.e., the 1,3,4-oxadiazole ring was not stable in acidic conditions. Thus, we carried out further optimization to improve the stability while maintaining the other favorable profile features including potent PPARα/γ dual agonistic activity. We addressed the issue by changing the oxadiazole ring to a bioisostere amide group. These amide derivatives were stable in acidic conditions and decreased plasma glucose and plasma triglyceride levels significantly without marked weight gain.

[Right ventricular rupture due to blunt trauma diagnosed by MDCT; report of a case].

The survival rate of cardiac rupture due to blunt trauma is generally low. We experienced a case with right ventricular rupture due to blunt trauma. The patient was a 49-year-old man who was crushed in a traffic accident and transported to a local hospital in a shock state. He was diagnosed with cardiac tamponade due to cardiac rupture, and for pericardial drainage was immediately performed. He was then transferred to our hospital for emergency surgery. His hemodynamics was stable, and he was diagnosed with right ventricular rupture by multi-detector row computed tomography (MDCT). The operation was performed successfully without cardiopulmonary bypass, and his postoperative course was uneventful. MDCT is useful for detecting the rupture site of the heart.

[Acute abdominal aortic occlusion in a patient with a giant thrombus in the left atrium and mitral stenosis; report of a case].

The patient was a 69-year-old male who had had percutaneous transvenous mitral commissurotomy (PTMC) 15 years ago, and had stopped taking warfarin after PTMC. He was transferred to our emergency room( ER) because of sudden severe pain in his both lower legs. We recognized pulselessness in his both femoral arteries, and pallor, paresthesia and poikilothermia in his lower extremities. Electorocardiogram(ECG) showed arterial fibrillation, and computed tomography( CT) showed occlusion of the abdominal aorta just below inferior mesenteric artery( IMA) and both common iliac arteries. By echocardiography, a giant thrombus was detected in the left atrium with severe mitral stenosis. Thrombectomy and angioplasty were performed at about 5 hours after the onset of occlusion, and revascularization was successful. Three days after the operation, we excised the giant thrombus in the left atrium and performed mitral valve replacement because we considered that myonephropathic metabolic syndrome (MNMS) had been prevented. The postoperative course was uneventful and he was discharged on the 27th postoperative day.

The effect of conversation on altruism: A comparative study with different media and generations.

Despite the overwhelming evidence of climate change and its effects on future generations, most individuals are still hesitant to make environmental changes that would especially benefit future generations. In this study, we investigate whether dialogue can influence people's altruistic behavior toward future generations of humans, and how it may be affected by participant age and the appearance of the conversation partner. We used a human, an android robot called Telenoid, and a speaker as representatives of future generations. Participants were split among an old age group and a young age group and were randomly assigned to converse with one of the aforementioned representatives. We asked the participants to play a round of the Dictator Game with the representative they were assigned, followed by an interactive conversation and another round of the Dictator Game in order to gauge their level of altruism. The results show that, on average, participants gave more money after having an interactive conversation, and that older adults tend to give more money than young adults. There were no significant differences between the three representatives. The results show that empathy might have been the most important factor in the increase in altruistic behavior for all participants.

Synthesis and structure-activity relationships of novel zwitterionic compounds as peroxisome proliferator activated receptor α/γ dual agonists with improved physicochemical properties.

We describe herein the design, syntheses and structure-activity relationships (SAR) of novel zwitterionic compounds as non-thiazolidinedion (TZD) based peroxisome proliferator activated receptor (PPAR) α/γ dual agonists. In the previous report, we obtained compound 1 showing potent PPARα/γ dual agonistic activities, together with a great glucose lowering effect in the db/db mice. However, this compound possessed fatal issues such as potent cytochrome P450 (CYP)3A4 direct inhibitory activity. Thus, we carried out the medicinal optimization to improve these while maintaining the potent PPAR agonistic activity. As a result, the issues were addressed by changing the furan ring to a low lipophilic 1,3,4-oxadiazole ring. Additionally, these oxadiazole derivatives exhibited a significant decrease in plasma glucose and plasma triglyceride levels without marked weight gain.

Two Cases of Surgical Correction of Recurrent Mitral Regurgitation due to Failed Catheter- Delivered Mitral Clip (MitraClip).

From April 2018 to February 2021, 150 patients underwent MitraClip implantation for severe functional mitral regurgitation (MR) at our hospital. Two of our patients, an 85-year-old man and an 84-year-old woman, developed a single leaflet device attachment in the acute phase after the implantation and had severe residual MR requiring surgical correction. The recurrent MR was first pointed out on day 5 and day 4, and the duration between MitraClip implantation and surgery was 13 and 55 days, respectively. Due to strong adhesions with the clips and severe valve damage after MitraClip implantation, both cases underwent mitral valve replacement with a good postoperative course. In patients with a high-risk baseline profile, surgical mitral valve replacement after failed MitraClip implantation should be considered at an optimal timing, and a detailed echocardiographic follow-up is required.

A Case of Acute Type A Aortic Dissection after Coronary Artery Bypass Grafting.

The patient was a 69-year-old man who underwent emergency surgery for acute aortic dissection that developed 5 months after coronary artery bypass grafting. The left internal thoracic artery (LITA) graft anastomosed to the left descending artery was not affected by the aortic dissection, and during the ascending aortic replacement, the artery was not identified for clamping. Although fully sufficient cardioplegia was not achieved due to the patent LITA graft, the patient's postoperative cardiac function was good. The two anastomotic sites of the vein grafts to the ascending aorta were excised along with a remnant of the aortic wall in an island fashion and were reimplanted onto the artificial graft. Based on the site of intimal tear, we speculated that partial clamping during the previous surgery had caused the dissection.

Coil Embolization of Recurrent Internal Iliac Artery Aneurysm via the Superior Gluteal Artery.

We report a case of recurrent internal iliac artery aneurysm previously treated with a combination of stent graft placement and coil embolization in an 85 year-old male patient. The patient was scheduled for the direct puncture embolization of the superior gluteal artery. The patient was placed in a prone position under general anesthesia. An 18G-PTC needle was inserted into the superior gluteal artery under ultrasonographic guidance. A 2.2F microcatheter was inserted through an outer needle and advanced to the aneurysmal sac. Coil embolization was successfully performed without endoleaks. This approach is technically feasible when other treatment options fail or are deemed unsuitable.

Iliac neck dilatation causes rupture of abdominal aortic aneurysm previously treated with endovascular aortic aneurysm repair.

A 78-year-old male had undergone endovascular aortic aneurysm repair (EVAR) 7 years prior to presentation. Although the sac was stable 6 months ago, the patient presented with shock at arrival, and CT showed aortic rupture with rapid expansion due to type Ib endoleak caused by iliac neck dilatation (IND). The aneurysm sac was excluded using an endovascular strategy. Bell-bottom iliac limbs can cause IND associated with type Ib endoleak. Additionally, the risk of rupture is high when re-expansion of an aneurysm occurs after sac regression after EVAR. Therefore, close follow-up is mandatory for patients with IND after EVAR.

[Cardiac failure caused by intrapericardial chronic expanding hematoma 18 years after CABG].

Chronic expanding hematoma(CEH)was first recognized by Reid in 1980. It begins to expand chronically more than 1 month after surgery or trauma, which is considered the possible cause of bleeding. It resembles chronic subdural hematoma. Most of the reports on CEH are those in the thoracic cavity or muscles, and few are in the pericardial cavity after open heart surgery. Our case was a 64-year-old male, who had undergone coronary artery bypass grafting (CABG) 18 years before. He presented with symptoms of heart failure such as exertional dyspnea, general fatigue and appetite loss. Computed tomography( CT) scan showed severe compression of the left ventricle by a large mass, and he was diagnosed with intrapericardial CEH. Resection of the severely calcified epicardium as well as removal of the hematoma in the pericardial cavity was performed, and the symptoms of heart failure improved. No recurrence has been noted for 1 year since the operation. A long-term follow-up will be necessary.

Midterm Results of Thoracic Endovascular Aortic Repair with Reentry Closure for Chronic Type B Aortic Dissection with Aneurysmal Dilatation.

Objectives: This study aims to discuss the midterm results of thoracic endovascular aortic repair (TEVAR) with reentry closure for chronic type B aortic dissection (CTBAD). Materials and Methods: This retrospective study analyzed 13 patients with CTBAD who underwent TEVAR with reentry closure between July 2014 and December 2020. We evaluated the false lumen (FL) cross-sectional area using computed tomography images of the descending aorta at the level of the bronchial bifurcation, Valsalva sinus, celiac artery, and infrarenal abdominal aorta pre- and postoperation. The study endpoints were technical and clinical success rates, freedom from additional aortic reintervention or surgery, and survival. Results: Technical success was obtained in 12 patients (92.3%) with no hospital mortality and neurological complications. The postoperative observation period was 49.2±21.5 months. The clinical success rate was 76.9% (10 cases), and a postoperative reduction of the FL cross-sectional area was obtained in 53.8% of patients. The 5-year overall survival rate was 64.8% with no aortic-related deaths while the 5-year freedom from additional aortic surgery rate was 66.7%. Conclusions: TEVAR with reentry closure suggests preventing FL dilatation or rupture in CTBAD, but the revision of our devices and further research with more patients and longer follow-up periods are required.

Longterm Followup of a Pediatric Patient with Congenital Abdominal Aortic Aneurysm with Coarctation.

Congenital abdominal aortic aneurysm (AAA) with coarctation has been considered an extremely rare condition. In this study, we present a 3-year-old boy, who was diagnosed by chance with congenital AAA at first operation. We replaced the AAA+coarctation with a 6-mm polytetrafluoroethylene (PTFE) graft. Histological examination of the aortic wall revealed no particular abnormalities. Collateral vessels were noted to develop over 14 years of followup. Good blood flow to both lower limbs and no intermittent claudication were observed. After growth, at the age 17, he underwent extra-anatomical bypass using a 12-mm PTFE graft. This is the first report of successful treatment of congenital AAA+coarctation with longterm followup.

A Successful Endovascular Technique for Complete False Lumen Thrombosis in Chronic Abdominal Aortic Dissection.

A 66-year-old man presented with an enlarging abdominal aorta false lumen, after type A aortic dissection repair. Residual entries were located at the left renal artery, abdominal aorta, and left external iliac artery. The patient underwent endovascular aortic repair with left renal artery stenting to close the entries. Completion aortography showed no false lumen flow without an endoleak, and contrast-enhanced computed tomography 1 month after the procedure demonstrated complete false lumen thrombosis. A total endovascular approach is possible for abdominal aneurysmal dilation in chronic aortic dissection when all entries can be closed using a one-stage procedure with stent grafts and/or branch stenting.

Clinical Utility of the Candy-Plug Technique Using an Excluder Aortic Extender.

Objective: To describe the clinical utility and technical aspects of the candy-plug technique using an Excluder aortic extender (Ex-cuff) for false lumen (FL) occlusion in chronic aortic dissection. Materials and Methods: This is a retrospective study analyzing seven consecutive patients (mean age, 63 years; range, 44-78 years; 6 men) with aneurysmal dilatation or rupture in chronic aortic dissection. All patients had undergone thoracic endovascular aortic repair with FL occlusion using this technique. We assessed technical (deployment accuracy) and clinical (no FL backflow on the latest contrast-enhanced computed tomography) success. Results: Technical success was obtained in six patients (86%). Technical failure was caused by the malposition of the candy-plug. The mean follow-up period was 593 days (range, 222-1225 days). Clinical success was obtained in four (57%), and incomplete Amplatzer Vascular Plug (AVP) embolization was seen in two. There was no enlarged FL after the procedure, and all patients are alive during the follow-up periods. Conclusion: The candy-plug technique using an Ex-cuff may be a feasible option; however, it takes time to achieve complete AVP embolization. Therefore, using additional embolic materials should be considered when we use it for the rupture case. (This is a translation of Jpn J Endovasc Interv 2018; 19: 29-35.).

Clinical Utility of Coil in Plug Method (CIP) for Internal Iliac Artery Embolization during Endovascular Aortic Aneurysm Repair.

Objective: To evaluate the clinical utility of the coil in plug (CIP) method in internal iliac artery (IIA) embolization during endovascular aortic aneurysm repair (EVAR) compared to conventional coil embolization (CCE). Material and Methods: From July to December 2018, 10 patients who underwent IIA embolization during EVAR were divided into CIP (n=5) and CCE (n=5) groups. In the CIP technique, the AVP-1 with a size more than 30%-50% of that of the embolized IIA diameter was used. The AVP-1 was deployed in the IIA. Before detachment of the AVP-1, a 2.2-F micro catheter was inserted through the 6-F delivery guiding sheath, and entered the plug. The AVP-1 was then packed with hydrogel micro coils. We compared number of coils used, embolization length, embolization time, volume embolization ratio, and embolic material cost between the groups. Results: The CIP method achieved shorter embolization length with fewer coils used compared to CCE. The CIP method decreased the cost of total embolic materials. Conclusion: The CIP method can achieve shorter embolization length with fewer coils used compared to CCE.

Stent-Graft Relining by Combined Aortic Cuff with Double-D Technique for Type IIIb or V Endoleak after Endovascular Aneurysm Repair: A Case Report.

We report the case of a 83-year-old man with aneurysmal sac enlargement after endovascular aneurysm repair for an abdominal aortic aneurysm, despite no overt endoleak (EL) detected on imaging. Occult type II EL was suspected, and treatment was performed. However, the aneurysm continued to enlarge. Thus, we diagnose with type V EL as exclusion diagnosis. We combined an aortic cuff and stent-graft leg to cover the initially inserted stent graft, as a diagnostic treatment for unrefined type IIIb EL. Subsequently, the aneurysm diameter decreased. This technique and concept may be effective for type V EL, which may include another type occult EL.

Novel quantitative and objective structured assessment of technical skill for slip knotting.

OBJECTIVE: Currently, no quantitative and objective method has been established for evaluating competencies in basic surgical techniques. The aim of this study was to develop a structured assessment tool for slip knotting and verify how well current board certification system discriminates the level of basic surgical skill. METHODS: We examined 171 cardiovascular surgical fellows using a novel assessment method for slip knotting that was developed by the committee of the Under-Forty of the Japanese Society of Cardiovascular Surgery. We compared the scores and examinees' surgical experience for validation. We analyzed the relationship between board certification and the scores. RESULTS: The scores differentiated the general surgical board-certified surgeons from those without certification. Surgical experiences such as training years and number of operated cases and scores were correlated. Among the board-certified surgeons, the group with daily off-the-job training, or simulator-based skill training had a significantly higher mean score (67.4 ± 3.0 vs 55.4 ± 3.1, p = 0.008) and lower rate of poor scorers (7.1% vs 38.5%, p = 0.004). A multivariate analysis revealed that board certification did not predict high scores. Daily off-the-job training was the only independent predictor of high scores (odds ratio: 2.41, 95% confidence interval: 0.01-1.20, p = 0.014). CONCLUSIONS: This novel quantitative and objective assessment tool for technical skill in slip knotting was found to be valid to examine the skill for slip knotting. In this study, current board certification discriminated the level of basic surgical skill. However, it could not distinguish extremely low scorers perfectly. Some board-certified surgeons showed poor technical competency, especially those without off-the-job training.