Woon Heo

Long Segmental Reconstruction of Diffusely Diseased Left Anterior Descending Coronary Artery Using Left Internal Thoracic Artery with Extensive Endarterectomy

In coronary artery bypass grafting, a diffusely diseased left anterior descending coronary artery (LAD) is an obstacle to achieving complete revascularization, consequently leading to the possibility of a poor prognosis. Long segmental reconstruction with or without endarterectomy is a revascularization method for treating diffusely diseased coronary arteries. Herein, we report a successful case of long segmental reconstruction of a diffusely diseased LAD using a left internal thoracic artery onlay patch after endarterectomy.

The B cell death function of obinutuzumab-HDEL produced in plant (Nicotiana benthamiana L.) is equivalent to obinutuzumab produced in CHO cells

Plants have attracted attention as bio-drug production platforms because of their economical and safety benefits. The preliminary efficacy of ZMapp, a cocktail of antibodies produced in N. benthamiana (Nicotiana benthamiana L.), suggested plants may serve as a platform for antibody production. However, because the amino acid sequences of the Fab fragment are diverse and differences in post-transcriptional processes between animals and plants remain to be elucidated, it is necessary to confirm functional equivalence of plant-produced antibodies to the original antibody. In this study, Obinutuzumab, a third generation anti-CD20 antibody, was produced in N. benthamiana leaves (plant-obinutuzumab) and compared to the original antibody produced in glyco-engineered Chinese hamster ovary (CHO) cells (CHO-obinutuzumab). Two forms (with or without an HDEL tag) were generated and antibody yields were compared. The HDEL-tagged form was more highly expressed than the non-HDEL-tagged form which was cleaved in the N-terminus. To determine the equivalence in functions of the Fab region between the two forms, we compared the CD20 binding affinities and direct binding induced cell death of a CD20-positive B cells. Both forms showed similar CD20 binding affinities and direct cell death of B cell. The results suggested that plant-obinutuzumab was equivalent to CHO-obinutuzumab in CD20 binding, cell aggregation, and direct cell death via binding. Therefore, our findings suggest that Obinutuzumab is a promising biosimilar candidate that can be produced efficiently in plants.

Surgery for acute Type I aortic dissection without resection of supra-aortic entry sites leads to unfavourable aortic remodelling

OBJECTIVESnThis study aimed to evaluate the impact of remnant re-entries in arch branches on postoperative change in the aortic arch and descending aortic diameters and the rate of major adverse aortic events.nnnMETHODSnBetween January 2010 and December 2016, 249 patients underwent surgery for acute Type I aortic dissection. Patients who underwent total arch replacement, had Marfan syndrome or had intramural haematoma were excluded. Seventy-two patients with predischarge and follow-up computed tomography scans were enrolled. Patients with and without re-entries in the arch branches after surgery were assigned to the supra-aortic entry (SAE, nu2009=u200921) and no supra-aortic entry (nu2009=u200951) groups, respectively. Diameters were measured at 7 levels: the innominate artery, left common carotid artery, left subclavian artery, 20u2009mm distal to the left subclavian artery, pulmonary artery bifurcation, coeliac axis and maximal diameter of the descending thoracic aorta.nnnRESULTSnGrowth rates at the levels of the pulmonary artery bifurcation and 20u2009mm distal to the left subclavian artery were significantly higher in the SAE group than in the no supra-aortic entry group. The rate of freedom from major adverse aortic events (annual growth >5u2009mm or maximal diameter of the descending thoracic aorta >50u2009mm) at 5u2009years was significantly higher in the no supra-aortic entry group than in the SAE group.nnnCONCLUSIONSnRemnant SAE leads to unfavourable aortic remodelling after acute Type I aortic dissection repair.

Chronological Change of Right Ventricle by Chronic Intermittent Hypoxia in Mice

Study Objective No studies have investigated sequential changes in the heart on magnetic resonance imaging (MRI), along with observation of functional lung phenotypes and genetics, over the duration of chronic intermittent hypoxia (CIH). We investigated chronological changes in heart and lung phenotypes after CIH using a mouse model to provide new insights into the pathophysiology of sleep apnea‐induced cardiovascular disease. Methods C57BL/6J adult male mice were randomized to 4 or 8 weeks of CIH. Cardiac cine‐MRI images were analyzed to assess functional parameters of right ventricle (RV). Histopathological features of myocytes and pulmonary vessels, as well as genes involved in the endothelin (ET) system, were investigated. Results Function of the RV reduced significantly at 4 weeks and continuously decreased following another 4 weeks of CIH, although the rate of decrease was attenuated. Notably, persistence of reduced ejection fraction and end‐systole RV wall thickness (WT) and increases in the ET system of the lungs and blood strongly implied the development of pulmonary hypertension after 8 weeks of CIH. Conclusions RV dysfunction with reduced end‐systole RV WT could be a late phenotype in long‐standing CIH and possibly also in obstructive sleep apnea.

Alteration of Inflammatory Mediators in the Upper and Lower Airways under Chronic Intermittent Hypoxia: Preliminary Animal Study

Purpose We hypothesized that CIH may affect the upper airway immune system and aimed to verify whether CIH can induce airway inflammation in a murine obstructive sleep apnea (OSA) model. Methods C57BL6 male mice were exposed to intermittent hypoxia (CIH group; 5u2009~u200921% FiO2, 120u2009sec cycles, 12u2009h/d, n = 6) or room air (Sham group, n = 6) for up to 4 weeks in identical chambers. Nasal and lung tissues and lavage fluid were collected and analyzed by multiplex assay. Lung lavage fluid was also utilized for FACS analysis to determine eosinophil count. Results We determined the protein level of 24 different cytokines, chemokines, and inflammatory mediators. Among various cytokines, levels of IL-1α, IL-1β, IL-4, IL-6, and IL-13 were significantly elevated in nose or lung tissue from the CIH group. In addition, MCP-1 and periostin were elevated in nose and lung tissue and lavage fluid from the CIH group. Conclusions CIH for 4 weeks altered the levels of inflammatory mediators in both the nose and lungs of mouse model. We suggest that the airway immune system may be deteriorated by CIH and allergic inflammation in the upper or lower airway could be worsened by sleep apnea.

Favorable Aortic Remodeling Following Serial False Lumen Procedures in a Case of Chronic Type IIIb Dissection

We report a case of acute type I aortic dissection in which an emergency graft replacement of the ascending aorta and innominate artery was performed. We performed false lumen thrombosis through hybrid thoracic endovascular aortic repair to seal the primary entry tear, followed by false lumen obliteration at the level of the descending thoracic aorta, abdominal aorta, and right common iliac artery. Over a period of 4.5 years, we used Amplatzer vascular plugs and coils based on our computed tomography angiography follow-up protocol.

Outcomes of Stentless Thoracic Endovascular Aortic Repair for Chronic DeBakey IIIb Aneurysms

BACKGROUNDnWe introduce a new endovascular procedure for favorable aortic remodeling in patients with chronic DeBakey IIIb (CDIIIb) aneurysms and present outcomes.nnnMETHODSnThis study included 19 patients who underwent stentless thoracic endovascular aortic repair (TEVAR) for CDIIIb aneurysms between 2014 and 2016. Stentless TEVAR is defined as an endovascular procedure involving closure of communicating channels or obliteration of the false lumen itself using various materials. Thoracic false lumen thrombosis was defined as there was no flow in the false lumen of the thoracic aorta. Aortic diameter was measured at 3 levels (left subclavian artery, pulmonary artery bifurcation, and celiac axis).nnnRESULTSnFifteen of 19 (78.9%) patients demonstrated thoracic false lumen thrombosis. There was no mortality, and the mean follow-up duration was 16.8 months. False and true lumen diameters at the left subclavian and pulmonary artery levels significantly changed after the procedure (false lumen: 22.6 ± 16.6 versus 16.1 ± 14.4 mm, 23.2 ± 14.6 versus 18.0 ± 13.2 mm, pxa0= 0.001 and pxa0= 0.002, respectively; true lumen: 22.7 ± 8.7 versus 27.9 ± 6.3 mm, 19.0 ± 8.3 versus 24.3 ± 6.7 mm, pxa0= 0.001 and pxa0= 0.001, respectively). The number of visceral stent grafts and preoperative true lumen diameter at the pulmonary artery were independent predictors for thoracic false lumen thrombosis (hazard ratio, 3.445, 95% confidence interval, 1.494 to 7.946; pxa0= 0.004; and hazard ratio, 1.106; 95% confidence interval, 1.029 to 1.189; pxa0= 0.006, respectively).nnnCONCLUSIONSnStentless TEVAR seems to be a safe procedure and enables favorable aortic remodeling. Thus, this technique can be useful in a selected group of patients with CDIIIb aneurysms.

Residual Arch Tears and Major Adverse Events After Acute DeBakey Type I Aortic Dissection Repair

BACKGROUNDnTear-oriented surgical procedure is considered a standard treatment for acute DeBakey type I aortic dissection (AIAD). However, long-term surgical outcomes, including aortic growth and rate of major adverse aortic events (MAAEs), have yet to be clarified.nnnMETHODSnOf the 274 patients who underwent surgical repair for AIAD between 2009 and 2016, 105 patients with both predischarge and follow-up computed tomographic scans were enrolled. The surgical extent was determined by primary entry tear location. We measured aortic diameters (pulmonary artery bifurcation, maximum diameter of the descending thoracic aorta [maxDTA], andxa0celiac axis) and compared MAAEs (aorta growth rate ≥ 5 mm/year or maxDTA ≥ 55 mm according to surgical extent).nnnRESULTSnTwenty-nine patients underwent total arch replacement (TAR); 76 underwent non-TAR. In the non-TAR group, patients with or without residual tears in the arch vessels were classified as having complete arch repair (non-TAR-CAR, nxa0= 52) or incomplete arch repair (non-TAR-IAR, nxa0= 24). Considerable differences were found in the aortic growth rate between the TAR and non-TAR groups and the non-TAR-CAR and non-TAR-IAR groups. Freedom from MAAEs at 5 years was considerably higher in the non-TAR-CAR group than in the non-TAR-IAR group (84.5% versus 31.1%). However, no differences were observed in the aortic growth rate and freedom from MAAEs between the TAR and non-TAR-CAR groups.nnnCONCLUSIONSnClassic tear-oriented surgical procedure is insufficient for optimal long-term surgical outcomes, mainly regarding aortic dilation. CAR without residual arch vessel tears leads to favorable aortic remodeling in the residual DTA and prevents MAAEs after AIAD repair.

NPP1 is responsible for potent extracellular ATP hydrolysis as NTPDase1 in primary cultured murine microglia

The movement of microglia is regulated mainly by P1 and P2 purinergic receptors, which are activated by various nucleotides and their metabolites. Recently, such purinergic signalling has been spotlighted because of potential roles in the pathophysiologies of neurodegenerative and neuropsychiatric disorders. To understand the characteristics of microglia in relation of P1 and P2 signalling, we investigated the ectoenzymes expressed in microglia. At first, we profiled the expression of all known ectoenzymes in cultured microglia. We found that, like NTPDase1 (ectonucleoside triphosphate diphosphohydrolase 1, CD39), NPP1 (ectonucleotide pyrophosphatase/phosphodiesterase 1, PC-1) is also highly expressed in primary cultured murine microglia. Knockdown of NPP1 significantly reduced ATP hydrolysis and Pi production in cultured microglia. In addition, the knockdown of NPP1 enhanced basal nucleotide-stimulating responses of cultured microglia, such as phagocytosis and cell migration, and these results were very similar to NTPDase1 knockdown results. Moreover, inhibition of the adenosine receptors by caffeine treatment reduced phagocytosis of NPP1 knock downed-cultured microglia. In conclusion, we suggest that these potent ectoenzymes of primary cultured murine microglia, NPP1 together with CD73 (ecto-5′-nucleotidase) maintain the adenosine levels for triggering nucleotide-stimulating responses.

Overexpression of WNK1 in POMC-expressing neurons reduces weigh gain via WNK4-mediated degradation of Kir6.2

Abstract“With no lysine” (WNK) kinases have been shown to regulate various ion transporters in various tissues, but studies on the function of WNK kinases in the brain have been limited. In this study, we discovered that WNK1 and WNK4 in POMC-expressing neuronal cells in WNK1 overexpressed transgenic mice (WNK1 TG) decrease appetite via degradation of Kir6.2. Weight gain after 20xa0weeks of age was delayed in WNK1 TG mice as a result of reduced food intake. Expression of WNK1 and proopiomelanocortin (POMC) was higher in POMC-expressing neurons in the hypothalamus of WNK1 TG mice than in WT mice. Immunostaining of serial sections of the hypothalamus revealed that POMC-expressing neurons were smaller in WNK1 TG mice than in WT mice. In addition, expression of Kir6.2 was significantly reduced in WNK1 TG mice. Overexpression and knockdown of WNK4 demonstrated that WNK4 regulates protein expression of Kir6.2 via protein–protein interaction. Accordingly, reduced age-dependent weight gain of WNK1 TG mice seems to be related with the decreased Kir6.2 expression via WNK1- and WNK4-regulated protein stability of Kir6.2.