Kensuke Esato

Regression of abdominal aortic aneurysm by inhibition of c-Jun N-terminal kinase.

Abdominal aortic aneurysm (AAA) is a common disease among elderly people that, when surgical treatment is inapplicable, results in progressive expansion and rupture of the aorta with high mortality. Although nonsurgical treatment for AAA is much awaited, few options are available because its molecular pathogenesis remains elusive. Here, we identify JNK as a proximal signaling molecule in the pathogenesis of AAA. Human AAA tissue showed a high level of phosphorylated JNK. We show that JNK programs a gene expression pattern in different cell types that cooperatively enhances the degradation of the extracellular matrix while suppressing biosynthetic enzymes of the extracellular matrix. Selective inhibition of JNK in vivo not only prevented the development of AAA but also caused regression of established AAA in two mouse models. Thus, JNK promotes abnormal extracellular matrix metabolism in the tissue of AAA and may represent a therapeutic target.

Video-assisted Thoracoscopic Lobectomy Achieves a Satisfactory Long-term Prognosis in Patients with Clinical Stage IA Lung Cancer

We designed a prospective trial to determine the long-term prognosis of video-assisted thoracoscopic (VATS) lobectomy versus conventional lobectomy for patients with clinical stage IA (T1N0M0) lung cancer. Between January 1993 and June 1994, 100 consecutive patients with clinical stage IA non-small cell lung carcinoma underwent either conventional lobectomy through an open thoracotomy (open group; n= 52) or VATS lobectomy (VATS group; n= 48). Lymph node dissections were performed in a similar manner in both groups. No significant differences were observed in the number of dissected lymph nodes between the 2 groups. Pathologic N1 and N2 disease was found in 3 and 1 patients, respectively, from the open group, and in 2 and 1 patients, respectively, from the VATS group. During the follow-up period, distant metastases and local or regional recurrences developed in 7 and 3 of the open group patients, respectively, and in 2 and 3 of the VATS group patients, respectively. Two and one of the open and VATS group patients developed second primary cancers, respectively. The overall survival rates 5 years after surgery were 85% and 90% in the open and VATS groups, respectively (log-rank test, p= 0.74; generalized Wilcoxon test, p= 0.91). VATS lobectomy with lymph node dissection achieved an excellent 5-year survival, similar to that achieved by the conventional approach.

Systematic Lymph Node Dissection for Clinically Diagnosed Peripheral Non-Small-Cell Lung Cancer Less Than 2 cm in Diameter

Abstract. The value of radical systematic lymphadenectomy for treatment of early-stage bronchial carcinoma is controversial. We performed a prospective randomized study to address this question. Altogether 115 patients with peripheral non-small-cell lung cancers smaller than 2 cm in diameter were enrolled in this study. They were randomly assigned into a lobectomy with lymph node sampling group (sampling group,n= 56) or a lobectomy with radical systematic lymph node dissection group (dissection group,n= 59). Inclusion criteria were based only on preoperative clinical studies. Four tumors were larger than 2 cm postoperatively. One patient had disseminated disease, and two had intrapulmonary metastases discovered at surgery. Two patients had small-cell carcinoma. There were four with pathologic N1 disease and seven with N2 disease in the dissection group and three with N1 and eight with N2 disease in the sampling group. The numbers of local and distant recurrences were two and six, respectively, in the dissection group and two and five in the sampling group. The overall 5-year survival was 81% in the dissection group and 84% in the sampling group. No significant differences in the recurrence rate or survival was seen between the groups. Our results demonstrate that clinically evaluated peripheral non-small-cell carcinomas smaller than 2 cm in diameter do not require radical systematic mediastinal and hilar lymph node dissection.

Impaired respiratory mechanics in pulmonary emphysema: Evaluation with dynamic breathing MRI

To evaluate impaired respiratory mechanics in pulmonary emphysema, dynamic breathing magnetic resonance imaging (BMRI) was acquired with fast‐gradient echo pulse sequences at fixed thoracic planes over two to three slow, deep respiratory cycles in 6 controls and 28 patients with pulmonary emphysema including 9 patients undergoing lung volume reduction surgery (LVRS). Respiratory motions of the diaphragm and chest wall (D/CW) were assessed by a cineloop view, a fusion display of maximal inspiratory and expiratory images, and the time‐distance curves. By contrast with normal subjects with regular synchronous D/CW motions, the patients frequently showed reduced, irregular, or asynchronous motions, with significant decreases in the maximal amplitude of D/CW motions (MAD and MACW), and the length of apposition of the diaphragm (LAD) (P < 0.0001, P < 0.001, P < 0.01, respectively). After LVRS, nine patients showed improvements in D/CW configuration and mobility, with significantly increased MAD, MACW, and LAD (P < 0.01, P < 0.0001, and P < 0.05, respectively). In 40 studies of 28 patients including the post‐LVRS examinations, the normalized MAD and MACW significantly correlated with %FEV1 (r = 0.881 and r = 0.906; P < 0.0001, respectively). BMRI seems useful for noninvasively and directly assessing the impaired respiratory mechanics associated with abnormal ventilation in pulmonary emphysema, and also for monitoring the effects of LVRS. J. Magn. Reson. Imaging 1999;10:510–520.

Neovascularization induced by autologous bone marrow cell implantation in peripheral arterial disease.

Neovascularization has recently been used as a new treatment for severe ischemic disease. We tried to induce therapeutic neovascularization by autologous bone marrow cell implantation (BMCI) in eight selected patients with chronic peripheral arterial disease (PAD), in whom traditional treatments had failed. Improvement of subjective symptoms was seen in seven patients after treatment. Of three limbs with toe or finger ulceration, complete healing was achieved in two, while the other one became less severe after treatment. No relative toxicity was observed in any of the patients. BMCI might be a feasible treatment for selected patients with chronic PAD.

Angiogenesis induced by the implantation of self-bone marrow cells: a new material for therapeutic angiogenesis.

Bone marrow contains various primitive cells that are thought to secrete several angiogenic growth factors and may also differentiate into endothelial cells. The present study was conducted to investigate the possibility that bone marrow cells could be a novel material to induce angiogenesis. The expression of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in rat bone marrow cells was examined by immunohistochemistry. The production of VEGF was compared in tissue culture supernatant under the conditions of normoxia and hypoxia. The process of angiogenesis that occurred following the implantation of bone marrow cells was determined using a rat cornea model. VEGF- and bFGF-positive cells were found in rat bone marrow. The production of VEGF from bone marrow cells was significantly more enhanced by hypoxic conditions than by normoxic conditions. The rat cornea model showed that bone marrow cell implantation created new vessels. The implantation of self-bone marrow cells is a novel and simple method of inducing angiogenesis.

Alterations in cardiac sarcoplasmic reticulum Ca2+regulatory proteins in the atrial tissue of patients with chronic atrial fibrillation

OBJECTIVES Our purpose was to determine whether atrial fibrillation (AF) patients have alterations in sarcoplasmic reticulum (SR) Ca2+ regulatory proteins in the atrial myocardium. BACKGROUND Clinically, AF is the most frequently encountered arrhythmia. Recent studies indicate that an inability to maintain intracellular Ca2+ homeostasis with a consequent increase in membrane-triggered activity could be the primary initiating factor in some circumstances, and that cytosolic Ca2+ abnormalities are an important mediator of sustained AF. METHODS We measured the maximum number of [3H]ryanodine binding sites (Bmax) and the expression levels of ryanodine receptor (RyR) mRNA and calcium-adenosine triphosphatase (Ca2+-ATPase) mRNA in atrial myocardial tissue from 13 patients with AF due to mitral valvular disease (MVD) and 9 patients with normal sinus rhythm (NSR). RESULTS In AF patients, 1) Bmax was significantly lower in each atrium (0.21+/-0.03 pmol/mg [right], 0.16+/-0.04 pmol/mg [left]) than in the right atrium (0.26+/-0.08 pmol/mg) of NSR patients; 2) Bmax was significantly lower in the left atrium than in the right atrium; 3) Bmax in the left atrium was significantly lower at higher levels of pulmonary capillary wedge pressure; 4) the expression level of RyR mRNA was significantly lower in both the left (1.24 x 10(-2)+/-1.28 x 10(-2)) and right (1.70 x 10(-2)+/-1.78 x 10(-2)) atrium than in the right atrium of NSR patients (6.11 x 10(-2)+/-2.79 x 10(-2)); and 5) the expression level of Ca2+-ATPase mRNA was significantly lower in both the left (5.67 x 10(-2)+/-4.01 x 10(-2)) and right (7.71 x 10(-2)+/-3.56 x 10(-2)) atrium than in the right atrium (12.60 x 10(-2)+/-3.92 x 10(-2)) of NSR patients. CONCLUSIONS These results provide the first direct evidence of abnormalities in the Ca2+ regulatory proteins of the atrial myocardium in chronic AF patients. Conceivably, such abnormalities may be involved in the initiation and/or perpetuation of AF.

Enhanced Expression of Matrix Metalloproteinase-9 in Abdominal Aortic Aneurysms

Abstract. Abdominal aortic aneurysms (AAAs) are characterized by structural alterations of the aortic wall resulting from degradation of collagen and elastin. Matrix metalloproteinases (MMPs), particularly MMP-2 and MMP-9, show strong elastinolytic activity. We examined the levels of mRNA for MMP-2, MMP-9, membrane type (MT)-MMP-1, tissue inhibitor of metalloproteinase-1 (TIMP-1), and TIMP-2 in AAAs (n= 8), atherosclerotic occlusive diseases (AOD) (n= 8), and normal subjects (n= 8) using the reverse transcription-polymerase chain reaction (RT-PCR). We also analyzed the gelatinolytic activity of these metalloproteinases using gelatin zymography. The levels of MMP-2 and MMP-9 mRNA were increased in the AAA group compared with those in the AOD group and normal subjects. The levels for TIMP-1 and TIMP-2 mRNA in the AAA group were also higher than those in the AOD and normal groups. Only in the case of MT-MMP-1 was the difference between AAA and AOD not statistically significant. By gelatin zymography with the same samples used for RT-PCR, gelatinolytic activity of MMP-9 was elevated in all AAA tissues. The 62-kDa form of MMP-2 was elevated in both the AAA and AOD groups and did not differ significantly between them. Linear regression analysis demonstrated a significant positive correlation between mRNA levels of MMPs and those of TIMPs. These observations suggest that aneurysm formation in patients with atherosclerosis is related to the degree of MMP-9 expression.

Up-regulation of inositol 1,4,5 trisphosphate receptor expression in atrial tissue in patients with chronic atrial fibrillation

BACKGROUND Abnormal intracellular Ca2+ homeostasis occurs in chronic atrial fibrillation(AF). The intracellular Ca2+ concentration is regulated by ryanodine and inositol 1,4,5-trisphosphate (IP3) receptors. Changes occur in ryanodine receptors in atrial tissue from patients in chronic AF. Whether AF patients have alterations in atrial IP3 receptors was investigated. METHODS IP3 receptor expression was analyzed in the right atrial myocardium from 13 mitral valvular disease (MVD) patients with AF (MVD/AF), 5MVD patients with normal sinus rhythm(MVD/NSR), and 8 control patients with NSR(tissue obtained during coronary artery bypass surgery). Hemodynamic and echocardiographic data were obtained preoperatively, and an immunohistochemical study was performed on the atrial tissue. RESULTS The relative expression level of IP3 receptor protein was significantly greater in MVD/AF (0.75 +/- 0.26) than in MVD/NSR (0.42 +/- 0.13, p < 0.01), and both were significantly above the control value (0.14 +/- 0.08). The relative expression level of IP3 receptor mRNA was significantly greater in MVD/AF(0.028 +/- 0.008) than in control subjects (0.015 +/- 0.004, p < 0.01), but MVD/AF patients did not differ from MVD/NSR (0.020 +/- 0.006) patients. The relative expression levels of IP3 receptor protein and mRNA were higher in patients with left atrial dimension > or = 40 mm, pulmonary capillary wedge pressure > or = 10 mmHg, and right atrial pressure > or = 5 mmHg. IP3 receptors were overexpressed in the cytosol and at the nuclear envelope of atrial myocytes in MVD. CONCLUSIONS Since chronic mechanical overload of the atrial myocardium increases IP3 receptor expression, especially in patients with chronic AF, up-regulation of IP3 receptors may be important in modulating intracellular Ca2+ homeostasis and initiating and/or perpetuating AF.

Laparoscopic repair of a diaphragmatic hernia through the foramen of Morgagni

AbstractA 78-year-old woman is described who presented with a diaphragmatic hernia through the foramen of Morgagni. A definitive diagnosis was confirmed by a sagittal view on magnetic resonance imaging prior to surgery. The hernia was repaired laparoscopically under an abdominal wall lifting technique without pneumoperitoneum, and her symptoms completely resolved postoperatively with no evidence of recurrence. The laparoscopic repair was considered a suitable and safe procedure for the treatment of a Morgagni hernia.