Intrathymic Plasmablasts Are Affected in Patients With Myasthenia Gravis With Active Disease.

BACKGROUND AND OBJECTIVES: To investigate intrathymic B lymphopoiesis in patients with myasthenia gravis (MG) and explore thymus pathology associated with clinical impact. METHODS: Thymic lymphocytes from 15 young patients without MG, 22 adult patients without MG, 14 patients with MG without thymoma, and 11 patients with MG with thymoma were subjected to flow cytometry analysis of T follicular helper (Tfh), naive B, memory B, plasmablasts, CD19+B220high thymic B cells, B-cell activating factor receptor, and C-X-C chemokine receptor 5 (CXCR5). Peripheral blood mononuclear cells of 16 healthy subjects and 21 untreated patients with MG were also analyzed. Immunologic values were compared, and correlations between relevant values and clinical parameters were evaluated. RESULTS: The frequencies of circulating and intrathymic plasmablasts were significantly higher in patients with MG than controls. On the other hand, the frequency of CD19+B220high thymic B cells was not increased in MG thymus. We observed a significant increase in CXCR5 expression on plasmablasts in MG thymus and an increased frequency of intrathymic plasmablasts that was correlated with preoperative disease activity. The frequency of intrathymic Tfh cells was significantly lower in patients who received immunosuppressive (IS) therapy than those without IS therapy. However, there was no significant difference in the frequency of intrathymic plasmablasts irrespective of IS therapy. DISCUSSION: Our findings confirmed a correlation between increased frequency of intrathymic plasmablasts and disease activity before thymectomy. We postulate that activated intrathymic plasmablasts endow pathogenic capacity in MG.

Effects of Transplanted Human Cord Blood-Mononuclear Cells on Pulmonary Hypertension in Immunodeficient Mice and Their Distribution.

OBJECTIVES: To investigate the effects of human umbilical cord blood-derived mononuclear cell (hUCB-MNC) transplantation on pulmonary hypertension (PH) induced by monocrotaline (MCT) in immunodeficient mice and their distribution. METHODS: MCT was administered to BALB/c Slc-nu/nu mice, and PH was induced in mice 4 weeks later. Fresh hUCB-MNCs harvested from a human donor after her delivery were injected intravenously into those PH mice. The medial thickness of pulmonary arterioles, ratio of right ventricular to septum plus left ventricular weight (RV/S+LV), and ratio of acceleration time to ejection time of pulmonary blood flow waveform (AT/ET) were determined 4 weeks after hUCB-MNC transplantation. To reveal the incorporation into the lung, CMTMR-labeled hUCB-MNCs were observed in the lung by fluorescent microscopy. DiR-labeled hUCB-MNCs were detected in the lung and other organs by bioluminescence images. RESULTS: Medial thickness, RV/S+LV and AT/ET were significantly improved 4 weeks after hUCB-MNC transplantation compared with those in mice without hUCB-MNC transplantation. CMTMR-positive hUCB-MNCs were observed in the lung 3 hours after transplantation. Bioluminescence signals were detected more strongly in the lung than in other organs for 24 hours after transplantation. CONCLUSIONS: The results indicate that hUCB-MNCs are incorporated into the lung early after hUCB-MNC transplantation and improve MCT-induced PH. J. Med. Invest. 64: 43-49, February, 2017.

[Reconstruction of pulmonary blood flow in the Norwood procedure; Blalock-Taussig shunt; from bench to surgery].

Although the right-ventricle to pulmonary artery( RV-PA) shunt as a source of pulmonary blood supply of Norwood procedure has improved early outcomes, disadvantages including right ventricular dysfunction or arrhythmias have been reported. So it has been still remained controversial whether BT shunt or RV-PA conduit should be selected. We examined the influence of Blalock-Taussig( BT) shunt size on regulation of the pulmonary blood flow in experimental model of a univentricular heart to determine the specific guidelines regarding suitable shunt size in the Norwood procedure. The canine univentricular heart model with the ratio of shunt size to body weight (SS/BW) of 0.8 to 1.1 showed significant negative correlation between the pulmonary/systemic blood flow ratio( Qp/Qs)and arterial PCo2, but those with SS/BW of 1.1 to 1.4 did not. Similar phenomena were shown with the grouped data on relationship between the Qp/Qs and inspired oxygen fraction. These findings imply that when SS/BW is 0.8 to 1.1, the Qp/Qs is controllable by physiologic respiratory manipulations. In the context of our clinical experiences, SS/BW of 0.9 to 1.0 is considered a useful index for suitable BT shunt in the Norwood procedure.

Iliac access conduit facilitates endovascular aortic aneurysm repair and ipsilateral iliofemoral bypass.

It may be difficult to access a route to deliver a stent-graft for abdominal aortic aneurysm in high-risk patients with bilateral iliofemoral occlusive disease. These two patients underwent both endovascular aortic aneurysm repair by a modified iliac access conduit technique and sequential ipsilateral iliofemoral artery bypass using the conduit, which provided excellent results. The iliac access conduit facilitates endovascular aortic aneurysm repair and ipsilateral iliofemoral bypass of high-risk patients with abdominal aortic aneurysm and bilateral iliofemoral occlusive disease.

Usefulness of central venous oxygen saturation monitoring during bidirectional Glenn shunt.

A PediaSat™ oximetry catheter (PediaSat: Edwards Lifesciences Co., Ltd., Irvine, CA, U. S. A.), which facilitates continuous measurement of central venous oxygen saturation (ScvO2), may be useful for surgery for pediatric congenital heart disease. We used PediaSat during a bidirectional Glenn shunt. The patient was a 13-month-old boy. Under a diagnosis of left single ventricle (pulmonary atresia, right ventricular hypoplasia, atrial septal defect) and residual left aortic arch/left superior vena cava, a modified right Blalock-Taussig shunt was performed. Cyanosis deteriorated, so a bidirectional Glenn shunt was scheduled. After anesthesia induction, a 4.5 Fr double-lumen (8 cm) PediaSat was inserted through the right internal jugular vein for continuous ScvO2 monitoring. Furthermore, the probe of a near-infrared, mixed blood oxygen saturation-measuring monitor was attached to the forehead for continuous monitoring of the regional brain tissue mixed blood oxygen saturation (rSO2) (INVOS™ 5100C, Covidien; Boulder, CO, U. S. A.). Blockage of the right pulmonary artery and right superior vena cava decreased the oxygen saturation, ScvO2, and rSO2, but increased the central venous pressure. Although changes in ScvO2 were parallel to those in rSO2, the former showed more marked changes. A combination of ScvO2 and rSO2 for monitoring during Glenn shunt may be safer.

Techniques and results in the management of multiple muscular trabecular ventricular septal defects.

The management of patients with multiple muscular trabecular ventricular septal defects (VSDs) remains controversial. In the past two decades, innovative techniques including a right ventricular apical infundibulotomy and transcatheter, intraoperative and perventricular device closure have been exploited, and essential right atrial approach and limited apical left ventriculotomy have also been refined. However, specific management guidelines for this difficult disease have not been established. In this article, the benefits and drawbacks of each technique are reviewed and discussed. Primary repair for infants with multiple muscular trabecular VSDs was associated with good late outcomes. The right atrial approach was satisfactory for all muscular VSDs, excluding apical defects that were well seen through a limited apical ventriculotomy. Surgical closure of apical defects could be achieved safely and completely in early infancy through a limited apical left ventriculotomy or a right ventricular apical infundibulotomy. Further follow-up and prudent evaluations of ventriculotomy-associated morbidities are needed. Pulmonary artery banding should be limited to a small infant with complex associated defects. Percutaneous device closure, the most desirable option, is impractical due to limitations between the delivery system and access route. Intraoperative device closure appears less successful than device closure in the catheterization laboratory. Perventricular device closure has a significant advantage of being a non-bypass procedure approach. A less invasive strategy for "true" Swiss cheese septum is needed. All may have an important role, and results obtained by using these techniques are encouraging. These hybrid approaches will promise future success on management guidelines of multiple muscular trabecular VSDs.

Delayed-onset severe heparin-induced thrombocytopenia after total arch replacement under cardiopulmonary bypass.

An extremely rare case with delayed-onset heparin-induced thrombocytopenia (HIT) is described. A 46-year-old man underwent arch replacement for aortic dissection under cardiopulmonary bypass and initial exposure of unfractionated heparin. In post operative 7 days, persistent atrial fibrillation was occurred, so a continuous infusion of heparin (10000 IU/day) and Vitamine K antagonist (Warfarin) taking was started for preventing thrombosis. By 32 days after the operation, his platelet count had fallen (3×10(3)/µL) and oral hematoma and ecchymoma of bilateral lower legs were occurred. The value of HIT antibodies and the IgG antibody was 2.485 and 1.586 on 32-postoperative day, respectively. Heparin was immediately discontinued, and argatroban administrated. Platelet exceeded above 100×10(3)/µL on 12 days of the therapy. To our knowledge, few cases of delayed-onset severe HIT associated with CPB surgery have been reported in Japan.

Functional restoration of endothelial cells of the cryopreserved heart valve.

PURPOSE: Although several approaches have been tried to improve the durability of cryopreserved valves, cellular restoration after thawing remains to be investigated. The aim of our study was to assess the functional restoration of endothelial cells of cryopreserved heart valves by in vitro culture for an alternative step to improving longevity. METHODS: Cryopreserved human umbilical vein endothelial cells (HUVECs) and porcine aortic cusps were cultivated for 14 days after thawing. Then the cellular activity of the enzymes cytosolic esterase and mitochondrial dehydrogenase was measured. The cellular viability of cryopreserved cusps was also assessed using confocal laser scanning microscopy. RESULTS: The number of viable HUVECs decreased markedly after cryopreservation and thawing but recovered to pre-cryopreservation level after 14 days of culture. In contrast, the enzyme activity of the cryopreserved porcine aortic cusps showed recovery at 7 days of in vitro tissue culture after thawing. Confocal laser scanning microscopy findings showed that the cellular cytosolic esterase activity of cryopreserved cusps deteriorated after thawing but displayed considerable recovery by day 14 of culture. CONCLUSION: The functional recovery of endothelial cells in cryopreserved heart valves seems to require tissue culture of at least 14 days. Ex vivo endothelial restoration of cryopreserved heart valves may add to heart valve durability.

Successful early resection of cardiac papillary fibroelastomas.

Two adult patients with previous transient cerebral ischemic attacks (TIAs) or chest oppression were referred for further investigation. A swaying pedicled tumor was detected in the left atrium of the former patient and in the left coronary cusp of the latter by echocardiography. The TIA, or angina-like attack, was anticipated to be caused by thromboembolism of the tumor. Both patients underwent tumor extirpation. The histological findings demonstrated that both tumors were benign papillary fibroelastoma limited to the endocardium/endothelium layer. In conclusion, early surgical resection of a cardiac papillary fibroelastoma should be performed.

Syngeneic bone marrow mononuclear cells improve pulmonary arterial hypertension through vascular endothelial growth factor upregulation.

BACKGROUND: We investigated the effects and possible mechanism of syngeneic bone marrow mononuclear cell (BM-MNC) transplantation on pulmonary arterial hypertension induced by monocrotaline. METHODS: Monocrotaline (80 mg/kg body weight) was administrated to C57BL/6 mice, and pulmonary arterial hypertension was induced 4 weeks later. Bone marrow mononuclear cells harvested from syngeneic donor mice were injected intravenously into those mice 4 weeks after monocrotaline administration. The ratio of right ventricular to septum plus left ventricular weight, the number of small pulmonary arteries, and medial thickness of pulmonary arteries were measured. Western immunoblotting of the lung tissue was performed to observe vascular endothelial growth factor and its receptor expression 1 week after BM-MNC transplantation. Vascular endothelial growth factor receptor-2 inhibitor was administered to pulmonary arterial hypertension mice simultaneously with BM-MNC transplantation. RESULTS: The ratio of right ventricular to septum plus left ventricular weight increased, the number of pulmonary arteries decreased, and medial thickness increased significantly 4 weeks after monocrotaline injection compared with those of vehicle-injected mice. These indices of monocrotaline-injected mice improved significantly 4 weeks after BM-MNC transplantation compared with those of mice at 8 weeks after monocrotaline injection (0.22 +/- 0.02 versus 0.31 +/- 0.02; 17.1 +/- 2.6 versus 8.2 +/- 1.7; 7.7% +/- 2.2% versus 20% +/- 2.1%, respectively; p < 0.01). However, BM-MNCs were not incorporated into the lung at 1 week after transplantation, and significant vascular endothelial growth factor upregulation and without receptor expression was observed in lung tissue 1 week after transplantation. Improvement of pulmonary arterial hypertension was inhibited by simultaneous administration of vascular endothelial growth factor receptor-2 inhibitor with BM-MNC transplantation. CONCLUSIONS: These results indicate that syngeneic BM-MNC transplantation improves monocrotaline-induced pulmonary arterial hypertension by favorable pulmonary artery remodeling through vascular endothelial growth factor upregulation.

Pseudoaneurysm of the thoracoabdominal aorta caused by a severe migration of an anterior spinal device.

BACKGROUND CONTEXT: Case report. PURPOSE: To describe the case of pseudoaneurysm of the thoracoabdominal aorta caused by the severe migration of an anterior spinal device 5 years after surgery. STUDY DESIGN/SETTING: Case report. METHODS: A 70-year-old woman was referred to us because of migrated anterior spinal devices and a pseudoaneurysm of the thoracoabdominal aorta. This patient had undergone anterior corpectomy and spinal fusion from Th12 to L2 because of delayed palsy after a burst fracture using a smooth rod Kaneda device (SRK) with bioactive ceramic (apatite-wollastonite containing glass ceramic) at a local hospital. She had persistent low back pain after the surgery. RESULTS: Five years after the initial surgery, the patient was referred to us because of increasing of her low back pain and the migrated SRK devices shown on plain X-ray films. An enhanced computed tomography scan taken in our hospital clearly showed a pseudoaneurysm of the thoracoabdominal aorta surrounding the SRK devices. The pseudoaneurysm was resected, the aortic defect was repaired with an artificial patch, and the migrated SRK devices were removed. CONCLUSIONS: The pseudoaneurysm of the aorta can occur secondary to a migrated anterior spinal fixation device and can be successfully treated by revision anterior surgery with vascular repair and implant removal.

Significance of peritoneal fluid drainage in management after repair of complex heart defects in infancy: cytokine dynamics in vivo.

BACKGROUND: In vivo redundancy of pro-inflammatory cytokines results in a vicious cycle of systemic inflammatory response syndrome and low cardiac output syndrome (LOS). The purpose of this study was to elucidate the influence of peritoneal fluid (PF) drainage on cytokine dynamics in vivo and the significance of early induction for infants with LOS. METHODS AND RESULTS: Seven infants, who underwent early PF drainage to manage LOS after repair of complex heart defects under cardiopulmonary bypass, were enrolled. The serum and PF levels of the pro- and antiinflammatory cytokines, interleukin (IL)-6, -8, -10 and tumor necrosis factor (TNF)-alpha, were measured during the perioperative period. Clinical outcomes were observed simultaneously. There were no cases of early or late death, or infectious complications. Drainage volume of PF peaked just after operation, and decreased completely. The amount of proinflammatory cytokines in the PF increased for 3 days after operation. Of the proinflammatory cytokines in the PF IL-6 increased the earliest and cleared the fastest. The amount of cleared IL-8 and TNF-alpha peaked on the 3rd postoperative day and resembled the course of C-reactive protein (CRP). Serum levels of CRP and proinflammatory cytokines in patients with PF drainage decreased significantly more than those without PF drainage. CONCLUSIONS: Early initiation of PF drainage is useful in the postoperative critical care of infants with LOS by improving cytokine dynamics in vivo, although there are differences between the severity of patients undergoing PF drainage and those who do not.

A successful transatrial repair in redo surgery of postinfarction inferoposterior ventricular septal rupture.

A successful transatrial repair in redo surgery of postinfarction posterior ventricular septal rupture (VSR) was performed after an infarct exclusion technique through left ventriculotomy incision of the infarcted area. For the infarct lesion, this approach provides excellent results with sufficient closure of the VSR and prevention of the ventricular remodeling for five years. A right atrial approach for postinfarction posterior VSR is very useful for avoiding any further ventriculotomy in an already impaired ventricle, securing a stable suture, and preserving the left ventricular geometry and function.

Determination of plasma concentrations of endothelin-1(1-31) and endothelin-1 in healthy subjects and patients with atherosclerosis.

We previously found that human chymase cleaves big endothelins at the Tyr31-Gly32 bond and produces 31-amino-acid endothelins, endothelins(1-31). Endothelin-1(1-31) has been isolated from a number of human organs, including the heart and lungs. As endothelin-1 has been shown to play a significant role in the paracrine regulation of cardiovascular functions in humans, it is possible that endothelin-1(1-31) may also exhibit biological activity on human tissues. We previously reported that synthetic endothelin-1(1-31) exhibits a number of physiological actions on cultured cells in vitro. In the present study, we investigated the plasma concentrations of endothelin-1(1-31) and endothelin-1 in healthy subjects and compared them with those in patients with cardiovascular diseases. Endothelin-1(1-31) and endothelin-1 in human plasma was measured using a sandwich-enzyme-immunoassay system, which was recently described for measurement of endothelin-1(1-31). The plasma concentrations of endothelin-1(1-31) and endothelin-1 in healthy volunteers were 19.24 +/- 5.70 and 15.54 +/- 4.45 pg/ml (n = 5), respectively. We also measured plasma concentrations of endothelin-1(1-31) and endothelin-1 before and after surgery in patients with abdominal aortic aneurysms. Before surgery, plasma concentrations of endothelin-1(1-31) and endothelin-1 in these patients were higher than those in healthy individuals. After surgery, both endothelin-1(1-31) and endothelin-1 in plasma decreased to levels similar to those of healthy subjects. This suggests that endothelin-1(1-31) may have similar physiological significance to endothelin-1 in patients with atherosclerosis.

Suitable shunt size for regulation of pulmonary blood flow in a canine model of univentricular parallel circulations.

OBJECTIVE: We examined the influence of shunt size on regulation of the pulmonary blood flow in a canine model of a univentricular heart because specific guidelines regarding suitable shunt size in the Norwood operation remain undetermined. METHODS: Beagle dogs (n = 8) 3 to 7 months old and weighing 3.0 to 5.0 kg were used. Atrial septectomy and patch closure of the tricuspid valve were performed, and a systemic-pulmonary arterial shunt was created by interposing a 3.5- or 4.0-mm graft between the right subclavian artery and main pulmonary artery. After cardiopulmonary bypass, hemodynamic variables including pulmonary and systemic blood flow were measured consecutively according to physiologically respiratory manipulations. The ratio of shunt size to body weight ranged from 0.80 to 1.33 mm/kg (1.08 +/- 0.16 mm/kg). RESULTS: Each dog with a ratio of shunt size to body weight of 0.8 to 1.1 showed significant negative correlation between the pulmonary/systemic blood flow ratio and arterial Pco(2), but those with a ratio of shunt size to body weight of 1.1 to 1.4 did not. Consequently each dog with a ratio of shunt size to body weight of 0.8 to 1.0 got adequate systemic flow, whereas a ratio of 1.0 to 1.4 resulted in inadequate systemic flow and acidic status. Similar phenomena were shown with the grouped data on relationship between the pulmonary/systemic blood flow ratio and inspired oxygen fraction. CONCLUSIONS: These findings imply that when the ratio of shunt size to body weight is 0.8 to 1.1, the pulmonary/systemic blood flow ratio is controllable by physiologic respiratory manipulations. Larger shunts make pulmonary blood flow excessive and uncontrollable. We recommend that a ratio of shunt size to body weight of 0.9 to 1.0 be considered a useful index for suitable systemic-pulmonary arterial shunt in the Norwood operation.