[Minimally Invasive Direct Coronary Artery Bypass in a Patient with Osteopetrosis and Symptomatic Ischemic Heart Disease:Report of a Case].

Osteopetrosis is a heterogeneous group of heritable conditions. It varies greatly in severity, and fracture treatment remains a matter of controversy due to altered responses to fixation and the risk of osteomyelitis. Therefore, sternotomy outcomes in this condition are unclear. We report the case of a patient with osteopetrosis and coronary artery disease (CAD). A 78-year-old man with osteopetrosis presented with frequent chest pain. Coronary angiography revealed two-vessel CAD. Percutaneous coronary intervention was contraindication because of coronary aneurysm in the left main trunk. Considering risks in median sternotomy, we performed minimally invasive cardiac surgery through left minithoracotomy for coronary artery bypass grafting( CABG). But we needed to break the left fourth rib to obtain sufficient surgical views. To the best of our knowledge, this is the first case report on CABG for a patient with osteopetrosis and endoscopic surgery without rib retractor is recommended.

[Intraoperative Aortic Dissection during Mitral Valve Plasty:Report of a Case].

We report the case of a 74-year-old woman who underwent mitral valve plasty for mitral regurgitation. During the surgery, the ascending aorta was dilated and turned dark red after aortic cannulation. Intraoperative transesophageal echocardiography and direct epiaortic echography revealed type A aortic dissection. In addition to mitral valve plasty, replacement of the ascending aorta was performed under hypothermic circulatory arrest. The postoperative course was uneventful. Because intraoperative aortic dissection is a rare complication, its rapid identification and appropriate management is essential.

[Surgical Repair of Giant Coronary Artery Aneurysm Associated with Coronary-pulmonary Artery Fistulae;Report of a Case].

A 61-year-old woman was referred to our hospital with a complaint of chest compression. Coronary angiography revealed a giant coronary artery aneurysm, located in the middle of a coronary-pulmonary artery fistula originating from the right coronary artery. Another fistula was also shown between the left anterior descending artery and the pulmonary artery. Surgical correction was indicated due to the risks of the aneurysmal rupture and coronary events. Under cardiopulmonary bypass, suture-closure of the coronary artery aneurysm and ligations of the fistulae were carried. Postoperative coronary angiography showed no aneurysm or fistula, and she was discharged uneventfully on the 12th postoperative day.

[Giant Left Atrial Myxoma Found with Congestive Heart Failure;Report of a Case].

We report a case of giant left atrial myxoma in a 52-year-old woman who developed congestive heart failure. By echocardiography, not only the myxoma but moderate degree of mitral and tricuspid regurgitation was also found. The tumor was extensively attached to the left atrial endocardium, and was excised completely together with the endocardium. No valve surgery was added. Postoperative echocardiography showed no myxoma and no mitral valve regurgitation. She was discharged in good condition on postoperative day 14.

[Severe Calcification on Glutaraldehyde-treated Autologous Pericardium after Mitral Valve Repair by Leaflet Augmentation;Report of a Case].

We report a case of surgical treatment of mitral valve stenosis due to severe calcification on the glutaraldehyde-treated autologous pericardium. A 39-year-old woman presented with progressive dyspnea. She had undergone mitral valve repair by leaflet augmentation with a glutaraldehyde-treated autologous pericardium for mitral regurgitation 3 years before. Transthoracic echocardiography showed mitral valve stenosis with limited movement of the anterior leaflet. At redo surgery, severe calcification was observed of the glutaraldehyde-treated autologous pericardium patch on the anterior mitral leaflet. Mitral valve replacement was performed successfully, and she was discharged on postoperative day 14.

[Surgical Treatment of Right Ventricular Perforation by a Transvenous Electrode Catheter;Report of a Case].

We report a case of surgical treatment of iatrogenic right ventricular perforation. An 86-year-old woman with sick sinus syndrome was treated by insertion of transvenous electrode catheters. She was transferred to our hospital due to chest pain 9 days after the insertion. We found the ventricular electrode catheter had perforated the right ventricle by computed tomography (CT). This perforated lesion was repaired under beating heart using 2-0 monofilament mattress sutures reinforced by felt pledgets. The perforation may have occurred because the apex portion of the right ventricle was fragile. Iatrogenic cardiac trauma is rare, and prompt recognition and treatment are essential.

[Surgery of Papillary Adenoma;Report of a Case].

A 59-year-old man consulted our hospital because of an abnormal shadow on a chest X-ray without any symptoms. A chest computed tomography (CT) revealed growing pulmonary nodule in the right lower lobe. Benign lung tumor was suspected and the patient underwent right lower lobe partial resection. Pathological examination demonstrated the tumor to be pulmonary papillary adenoma within round atelectasis.

Chd7 Collaborates with Sox2 to Regulate Activation of Oligodendrocyte Precursor Cells after Spinal Cord Injury.

Oligodendrocyte precursor cells (OPCs) act as a reservoir of new oligodendrocytes (OLs) in homeostatic and pathological conditions. OPCs are activated in response to injury to generate myelinating OLs, but the underlying mechanisms remain poorly understood. Here, we show that chromodomain helicase DNA binding protein 7 (Chd7) regulates OPC activation after spinal cord injury (SCI). Chd7 is expressed in OPCs in the adult spinal cord and its expression is upregulated with a concomitant increase in Sox2 expression after SCI. OPC-specific ablation of Chd7 in injured mice leads to reduced OPC proliferation, the loss of OPC identity, and impaired OPC differentiation. Ablation of Chd7 or Sox2 in cultured OPCs shows similar phenotypes to those observed in Chd7 knock-out mice. Chd7 and Sox2 form a complex in OPCs and bind to the promoters or enhancers of the regulator of cell cycle (Rgcc) and protein kinase Cθ (PKCθ) genes, thereby inducing their expression. The expression of Rgcc and PKCθ is reduced in the OPCs of the injured Chd7 knock-out mice. In cultured OPCs, overexpression and knock-down of Rgcc or PKCθ promote and suppress OPC proliferation, respectively. Furthermore, overexpression of both Rgcc and PKCθ rescues the Chd7 deletion phenotypes. Chd7 is thus a key regulator of OPC activation, in which it cooperates with Sox2 and acts via direct induction of Rgcc and PKCθ expression.SIGNIFICANCE STATEMENT Spinal cord injury (SCI) leads to oligodendrocyte (OL) loss and demyelination, along with neuronal death, resulting in impairment of motor or sensory functions. Oligodendrocyte precursor cells (OPCs) activated in response to injury are potential sources of OL replacement and are thought to contribute to remyelination and functional recovery after SCI. However, the molecular mechanisms underlying OPC activation, especially its epigenetic regulation, remain largely unclear. We demonstrate here that the chromatin remodeler chromodomain helicase DNA binding protein 7 (Chd7) regulates the proliferation and identity of OPCs after SCI. We have further identified regulator of cell cycle (Rgcc) and protein kinase Cθ (PKCθ) as novel targets of Chd7 for OPC activation.

MEKK1-dependent phosphorylation of calponin-3 tunes cell contractility.

MEKK1 (also known as MAP3K1), which plays a major role in MAPK signaling, has been implicated in mechanical processes in cells, such as migration. Here, we identify the actin-binding protein calponin-3 as a new MEKK1 substrate in the signaling that regulates actomyosin-based cellular contractility. MEKK1 colocalizes with calponin-3 at the actin cytoskeleton and phosphorylates it, leading to an increase in the cell-generated traction stress. MEKK1-mediated calponin-3 phosphorylation is attenuated by the inhibition of myosin II activity, the disruption of actin cytoskeletal integrity and adhesion to soft extracellular substrates, whereas it is enhanced upon cell stretching. Our results reveal the importance of the MEKK1-calponin-3 signaling pathway to cell contractility.

Local cyclical compression modulates macrophage function in situ and alleviates immobilization-induced muscle atrophy.

Physical inactivity gives rise to numerous diseases and organismal dysfunctions, particularly those related to aging. Musculoskeletal disorders including muscle atrophy, which can result from a sedentary lifestyle, aggravate locomotive malfunction and evoke a vicious circle leading to severe functional disruptions of vital organs such as the brain and cardiovascular system. Although the significance of physical activity is evident, molecular mechanisms behind its beneficial effects are poorly understood. Here, we show that massage-like mechanical interventions modulate immobilization-induced pro-inflammatory responses of macrophages in situ and alleviate muscle atrophy. Local cyclical compression (LCC) on mouse calves, which generates intramuscular pressure waves with amplitude of 50 mmHg, partially restores the myofiber thickness and contracting forces of calf muscles that are decreased by hindlimb immobilization. LCC tempers the increase in the number of cells expressing pro-inflammatory proteins, tumor necrosis factor-α and monocyte chemoattractant protein-1 (MCP-1), including macrophages in situ The reversing effect of LCC on immobilization-induced thinning of myofibers is almost completely nullified when macrophages recruited from circulating blood are depleted by administration of clodronate liposomes. Furthermore, application of pulsatile fluid shear stress, but not hydrostatic pressure, reduces the expression of MCP-1 in macrophages in vitro Together with the LCC-induced movement of intramuscular interstitial fluid detected by µCT analysis, these results suggest that mechanical modulation of macrophage function is involved in physical inactivity-induced muscle atrophy and inflammation. Our findings uncover the implication of mechanosensory function of macrophages in disuse muscle atrophy, thereby opening a new path to develop a novel therapeutic strategy utilizing mechanical interventions.

Focal Adhesion Kinase Promotes the Progression of Aortic Aneurysm by Modulating Macrophage Behavior.

OBJECTIVE: Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease that is associated with persistent inflammation and extracellular matrix degradation. The molecular mechanisms underlying the macrophage-mediated progression of AAA remain largely unclear. APPROACH AND RESULTS: We show that focal adhesion kinase (FAK) expression and activity are enhanced in macrophages that are recruited to AAA tissue. FAK potentiates tumor necrosis factor-α-induced secretion of matrix-degrading enzymes and chemokines by cultured macrophages. FAK also promotes macrophage chemotaxis. In mice, the administration of a FAK inhibitor that tempers local macrophage accumulation markedly suppresses the development and progression of chemically induced AAA. CONCLUSIONS: FAK plays a key role in macrophage behavior, which underlies the chronic progression of AAA. These findings provide insights into AAA progression and identify FAK as a novel therapeutic target.

Oligodendrocyte Progenitor Cells Directly Utilize Lactate for Promoting Cell Cycling and Differentiation.

Oligodendrocyte progenitor cells (OPCs) undergo marked morphological changes to become mature oligodendrocytes, but the metabolic resources for this process have not been fully elucidated. Although lactate, a metabolic derivative of glycogen, has been reported to be consumed in oligodendrocytes as a metabolite, and to ameliorate hypomyelination induced by low glucose conditions, it is not clear about the direct contribution of lactate to cell cycling and differentiation of OPCs, and the source of lactate for remyelination. Therefore, we evaluated the effect of 1,4-dideoxy-1,4-imino-d-arabinitol (DAB), an inhibitor of the glycogen catabolic enzyme glycogen phosphorylase, in a mouse cuprizone model. Cuprizone induced demyelination in the corpus callosum and remyelination occurred after cuprizone treatment ceased. This remyelination was inhibited by the administration of DAB. To further examine whether lactate affects proliferation or differentiation of OPCs, we cultured mouse primary OPC-rich cells and analyzed the effect of lactate. Lactate rescued the slowed cell cycling induced by 0.4 mM glucose, as assessed by the BrdU-positive cell ratio. Lactate also promoted OPC differentiation detected by monitoring the mature oligodendrocyte marker myelin basic protein, in the presence of both 36.6 mM and 0.4 mM glucose. Furthermore, these lactate-mediated effects were suppressed by the reported monocarboxylate transporter inhibitor, α-cyano-4-hydroxy-cinnamate. These results suggest that lactate directly promotes the cell cycling rate and differentiation of OPCs, and that glycogen, one of the sources of lactate, contributes to remyelination in vivo. J. Cell. Physiol. 232: 986-995, 2017. © 2016 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.

The impact of global left ventricular afterload on left ventricular reverse remodeling after aortic valve replacement.

BACKGROUND: Conventional indices such as prosthetic valve effective orifice area (EOA) or transvalvular pressure gradients (TPG) may be unreliable in predicting left ventricular (LV) reverse remodeling after aortic valve replacement (AVR). We hypothesized that the global LV afterload, including valvular and arterial impedance, could influence LV reverse remodeling after AVR. METHODS: Twenty-three consecutive aortic-stenosis patients (mean age, 76 ± 6.4 years) underwent isolated AVR using contemporary externally wrapped pericardial valves (19 mm, 10 patients; 21 mm 11; 23 mm, 2). Valvuloarterial impedance (Zva), a marker of global LV afterload, was measured on serial echocardiography in addition to indexed EOA, energy loss index (ELI), mean TPG, and stroke work loss. LV mass regression was used as a parameter of LV reverse remodeling. RESULTS: The Zva significantly decreased after AVR (5.05 ± 1.7 mmHg/mL/m2 , pre-operatively; 3.12 ± 1.0, postoperatively; 3.13 ± 0.89, at last follow-up) in parallel with increased indexed EOA (0.46 ± 0.13 cm2 /m2 ; 1.13 ± 0.24; 0.96 ± 0.19), ELI (0.55 ± 0.21 cm2 /m2 ; 1.74 ± 0.52; 1.47 ± 0.42), and decreased mean TPG (50.2 ± 19.6 mmHg; 11.1 ± 5.4; 14.7 ± 5.8). The stroke work loss also decreased (26.3 ± 8.5 %; 8.65 ± 4.0; 9.36 ± 3.4). The Zva at last follow-up was significantly correlated with LV mass regression (correlation coefficient, r = - 0.48; P = 0.002), and was a significant predictor of LV reverse remodeling on multiple regression analysis (adjusted odds ratio, -0.43; 95% confidence interval, -31.3 to -0.67, P = 0.042), while indexed EOA, ELI, mean TPG, or systemic arterial compliance were not. CONCLUSIONS: The postoperative Zva was significantly associated with LV mass regression after AVR. Maintaining low global LV afterload following AVR may enhance LV reverse remodeling.

Determinants of recurrent tricuspid regurgitation following tricuspid valve annuloplasty during mitral valve surgery.

BACKGROUND: The purpose of this study was to determine risk predictors for recurrent tricuspid regurgitation (TR) following tricuspid valve annuloplasty during mitral valve surgery. METHODS: Ninety-eight consecutive patients underwent tricuspid valve annuloplasty concomitant with mitral valve repair (71 patients), replacement (16 patients), or other procedures over a 10-year period. Fifty-seven patients underwent surgery with a flexible band and 41 with a rigid ring. RESULTS: Late TR progression (≥2/4) occurred in eight (14.0%) of flexible band patients, and in nine (22.0%) rigid ring patients. Multivariate analysis did not identify the superiority of one annuloplasty device over the other to prevent recurrent TR. Multivariate risk predictors of late TR progression were late atrial fibrillation (hazard ratio [HR]: 3.78; 95% confidence interval [CI]: 1.19-12.0), and recurrent mitral regurgitation; HR; 4.46; 95%CI; 1.52-13.1). Freedom from TR progression at 5 years was 89.2% in atrial fibrillation-free patients compared to 56.8% in those with atrial fibrillation (log-rank, P = 0.018), and 89.8% in mitral regurgitation-free patients compared to 55.3% in those with recurrent mitral regurgitation (log-rank, P = 0.003). CONCLUSIONS: A durable mitral valve repair and preservation of sinus rhythm are the keys to preventing late TR progression.

Displacement of p130Cas from focal adhesions links actomyosin contraction to cell migration.

Cell adhesion complexes provide platforms where cell-generated forces are transmitted to the extracellular matrix (ECM). Tyrosine phosphorylation of focal adhesion proteins is crucial for cells to communicate with the extracellular environment. However, the mechanisms that transmit actin cytoskeletal motion to the extracellular environment to drive cell migration are poorly understood. We find that the movement of p130Cas (Cas, also known as BCAR1), a mechanosensor at focal adhesions, correlates with actin retrograde flow and depends upon actomyosin contraction and phosphorylation of the Cas substrate domain (CasSD). This indicates that CasSD phosphorylation underpins the physical link between Cas and the actin cytoskeleton. Fluorescence recovery after photobleaching (FRAP) experiments reveal that CasSD phosphorylation, as opposed to the association of Cas with Src, facilitates Cas displacement from adhesion complexes in migrating cells. Furthermore, the stabilization of Src-Cas binding and inhibition of myosin II, both of which sustain CasSD phosphorylation but mitigate Cas displacement from adhesion sites, retard cell migration. These results indicate that Cas promotes cell migration by linking actomyosin contractions to the adhesion complexes through a dynamic interaction with Src as well as through the phosphorylation-dependent association with the actin cytoskeleton.

The crucial role of Erk2 in demyelinating inflammation in the central nervous system.

BACKGROUND: Brain inflammation is a crucial component of demyelinating diseases such as multiple sclerosis. Although the initiation of inflammatory processes by the production of cytokines and chemokines by immune cells is well characterized, the processes of inflammatory aggravation of demyelinating diseases remain obscure. Here, we examined the contribution of Erk2, one of the isoforms of the extracellular signal-regulated kinase, to demyelinating inflammation. METHODS: We used the cuprizone-induced demyelinating mouse model. To examine the role of Erk2, we used Nestin-cre-driven Erk2-deficient mice. We also established primary culture of microglia or astrocytes in order to reveal the crosstalk between two cell types and to determine the downstream cascades of Erk2 in astrocytes. RESULTS: First, we found that Erk is especially activated in astrocytes within the corpus callosum before the peak of demyelination (at 4 weeks after the start of cuprizone feeding). Then, we found that in our model, genetic ablation of Erk2 from neural cells markedly preserved myelin structure and motor function as measured by the rota-rod test. While the initial activation of microglia was not altered in Erk2-deficient mice, these mice showed reduced expression of inflammatory mediators at 3-4 model weeks. Furthermore, the subsequent inflammatory glial responses, characterized by accumulation of microglia and reactive astrocytes, were significantly attenuated in Erk2-deficient mice. These data indicate that Erk2 in astrocytes is involved in augmentation of inflammation and gliosis. We also found that activated, cultured microglia could induce Erk2 activation in cultured astrocytes and subsequent production of inflammatory mediators such as Ccl-2. CONCLUSIONS: Our results suggest that Erk2 activation in astrocytes plays a crucial role in aggravating demyelinating inflammation by inducing inflammatory mediators and gliosis. Thus, therapies targeting Erk2 function in glial cells may be a promising approach to the treatment of distinct demyelinating diseases.

New mouse model of skeletal muscle atrophy using spiral wire immobilization.

INTRODUCTION: Disuse-induced skeletal muscle atrophy is a serious concern; however, there is not an effective mouse model to elucidate the molecular mechanisms. We developed a noninvasive atrophy model in mice. METHODS: After the ankle joints of mice were bandaged into a bilateral plantar flexed position, either bilateral or unilateral hindlimbs were immobilized by wrapping in bonsai steel wire. RESULTS: After 3, 5, or 10 days of immobilization of the hip, knee, and ankle, the weight of the soleus and plantaris muscles decreased significantly in both bilateral and unilateral immobilization. MAFbx/atrogin-1 and MuRF1 mRNA was found to have significantly increased in both muscles, consistent with disuse-induced atrophy. Notably, the procedure did not result in either edema or necrosis in the fixed hindlimbs. CONCLUSIONS: This method allows repeated, direct access to the immobilized muscle, making it a useful procedure for concurrent application and assessment of various therapeutic interventions. Muscle Nerve 54: 788-791, 2016.

Efficacy of Tolvaptan on Fluid Management After Cardiovascular Surgery Using Cardiopulmonary Bypass.

OBJECTIVE: To investigate the efficacy of the selective vasopressin V2-receptor antagonist tolvaptan in postoperative fluid management after cardiovascular surgery using cardiopulmonary bypass. DESIGN: A retrospective cohort study. SETTING: A tertiary care center. PARTICIPANTS: The study comprised 99 patients undergoing cardiovascular surgery using cardiopulmonary bypass. INTERVENTIONS: Oral tolvaptan was administered after surgery. MEASUREMENTS AND MAIN RESULTS: Fifty-one patients treated with tolvaptan were compared with 48 patients treated with intravenous diuretics. Urine volume, the time interval until the patients' body weight returned to the preoperative value, and the length of oxygen dependency after extubation were assessed as surrogate markers for resolution of fluid overload. Urine output on postoperative days 1 and 2 was significantly higher in the tolvaptan-treated patients (29.2 v 20.1 mL/kg/day, p = 0.001; 43.0 v 27.4 mL/kg/day, p<0.001, respectively). Postoperative body weight returned to baseline in 49 tolvaptan-treated patients compared with 33 patients treated with intravenous diuretics (96.1% v 68.8%, p<0.001). Among those with successful body weight reduction, the time interval was shorter in the tolvaptan-treated patients (5 v 7 days, p = 0.006). The length of oxygen dependency after extubation also was shorter in the tolvaptan-treated patients (2 v 3 days, p = 0.006). The urine osmolarity reduction rate before and 4 hours after the first dose of tolvaptan emerged as a significant predictor of its efficacy with a cutoff point of 33.7%, sensitivity of 0.73, and specificity of 0.67 (p = 0.030). CONCLUSION: Tolvaptan facilitated early improvement of postoperative fluid overload after cardiovascular surgery.

[p130Cas-Mediated Regulation of Mechanical Functions of Cells.]

It is 10 years since we reported Cas as a cell mechano-sensor that converts stretching force to a biochemical signal. While we have been looking into the mechanism of how Cas molecules are extended, it appears that the source of stretching force does not derive from actomyosin contraction, but originates from actin polymerization. Furthermore, we have found that phosphorylated Cas links actomyosin contraction to cell migration by tensin 1-mediated association with inwardly moving actin filaments. Collectively, Cas serves as a force sensor at the cell leading edges as well as a part of force transmission machinery, i.e. clutch, which drives the cell forward.

The expression of Fn14 via mechanical stress-activated JNK contributes to apoptosis induction in osteoblasts.

Bone mass is maintained by the balance between the activities of bone-forming osteoblasts and bone-resorbing osteoclasts. It is well known that adequate mechanical stress is essential for the maintenance of bone mass, whereas excess mechanical stress induces bone resorption. However, it has not been clarified how osteoblasts respond to different magnitudes of mechanical stress. Here we report that large-magnitude (12%) cyclic stretch induced Ca(2+) influx, which activated reactive oxygen species generation in MC3T3-E1 osteoblasts. Reactive oxygen species then activated the ASK1-JNK/p38 pathways. The activated JNK led to transiently enhanced expression of FGF-inducible 14 (Fn14, a member of the TNF receptor superfamily) gene. Cells with enhanced expression of Fn14 subsequently acquired sensitivity to the ligand of Fn14, TNF-related weak inducer of apoptosis, and underwent apoptosis. On the other hand, the ASK1-p38 pathway induced expression of the monocyte chemoattractant protein 3 (MCP-3) gene, which promoted chemotaxis of preosteoclasts. In contrast, the ERK pathway was activated by small-magnitude stretching (1%) and induced expression of two osteogenic genes, collagen Ia (Col1a) and osteopontin (OPN). Moreover, activated JNK suppressed Col1a and OPN induction in large-magnitude mechanical stretch-loaded cells. The enhanced expression of Fn14 and MCP-3 by 12% stretch and the enhanced expression of Col1a and OPN by 1% stretch were also observed in mouse primary osteoblasts. These results suggest that differences in the response of osteoblasts to varying magnitudes of mechanical stress play a key role in switching the mode of bone metabolism between formation and resorption.