Altered expression of hepatocyte growth factor in cardiac allografts of nonhuman primates.

Hepatocyte growth factor (HGF) plays a critical role in transplant rejection. Herein we addressed whether HGF expression could be used for accurate and early diagnosis of acute and chronic rejection in cardiac transplantation. We used a heterotopic cardiac transplantation model using nonhuman primates (Macaca fuscata, n = 7). The grafts were harvested on days 1, 7, 22, 28, 40, 41, and 95 for histology and immunohistochemistry. Histopathologically, HGF was expressed in the spindle-shaped cells of the acutely rejecting myocardium. The expression of HGF was enhanced in both thickened intima and media of the coronary arteries. Altered HGF expression is a sensitive indicator for acute and chronic cardiac rejection.

X-ray diffractometer combining synchrotron radiation and pulsed magnetic fields up to 40 T.

A synchrotron X-ray diffractometer incorporating a pulsed field magnet for high fields up to 40 T has been developed and a detailed description of this instrument is reported. The pulsed field magnet is composed of two coaxial coils with a gap of 3 mm at the mid-plane for passage of the X-rays. The pixel detector PILATUS 100K is used to store the diffracted X-rays. As a test of this instrument, X-ray diffraction by a powder sample of the antiferromagnet CoO is measured below the Néel temperature. A field-dependent lattice distortion of CoO due to magnetostriction is observed up to 38 T.

[Aortic valve replacement in a renal transplant recipient].

A 65-year-old male was admitted to our hospital for surgical treatment of congestive heart failure with aortic regurgitation. He had received renal transplantation 15 years before in the United States, and had been under immunosuppressive regimen with ciclosporin and mycophenolate mofetil. Although the renal allograft function had been gradually deteriorating, and preoperative serum creatinine level was 1.8 mg/dl, and it decreased to 1.5 mg/dl after aortic valve replacement. Cryopreserved aortic allograft was needed for the aortic valve replacement. The reasons are; the patient may need hemodialysis (HD) or retransplantation of the kidney in the future, and the immunosuppressive therapy for kidney will provide good immunologic environment for second allograft, i.e.--aortic valve. He tolerated the operation well and the immunosuppressive agents were continued in the perioperative period. He is now in New York Heart Association (NYHA) class I.

[Secondary left main trunk coronary artery shock syndrome].

A 71-year-old male patient was admitted to our hospital and diagnosed as inferior wall acute myocardial infarction (AMI). Coronary angiogram revealed 3 vessel disease and left main trunk coronary artery (LMT) lesion. Because right coronary artery (RCA) had been recanalised, he was scheduled to operation. On the 6th day after admission, another attack made him fell into secondary LMT shock syndrome and lung edema. Emergency operation was performed and he recovered from heart failure. Here we report the case and added some considerations.

Characterization of inhibitory action of concanamycins against herpes simplex virus.

Concanamycins A (Conmy A) and B (Conmy B), well-known inhibitors of the vacuolar proton-ATPase, were isolated from the culture broth of Streptomyces sp. strain FK51 as antiherpetic agents. These compounds showed potent inhibition of herpes simplex virus type 1 (HSV-1) replication in an in vitro assay system, having antiviral activities with 50% inhibitory concentrations of 0.072 and 0.51 ng/ml for Conmy A and Conmy B, respectively. While the attachment of HSV-1 to Vero cells was not inhibited, both of the compounds blocked the penetration of virus into host cells. When added to the late stages of virus replication, the concanamycins also exerted marked inhibitory effects on the production of viruses. Release of progeny viruses was found to be suppressed by the agents. SDS-PAGE analysis of isotope-labelled HSV-specific proteins revealed that the synthesis of beta proteins was moderately inhibited and some of the glycoproteins were synthesized with reduced molecular weights. Western blot analysis using antibodies against two HSV-specific glycoproteins (gC and gD) showed differences in their syntheses between untreated and Conmy A-treated cells. Syncytium formation by HSV-1 strain HF was inhibited, and small plaques with rounded cells were formed in Conmy A-treated cell cultures. When wild-type HSV-1 was serially propagated under the selective pressure of Conmy A, and the resulting progeny viruses were grown in drug-free medium, their plaque morphology of syncytium and sensitivity to Conmy A were the same as those of parent virus. From these findings, antiherpetic activities of Conmy A and B might be mainly dependent on their activities as vacuolar proton-ATPase inhibitors with intracellular translocation of glycoproteins and the inhibition of the maturation of virus glycoproteins.

Early growth-response factor 1 and basic transcriptional element-binding protein 2 expression in cardiac allografts.

Early growth-response factor 1 (Egr-1) and basic transcriptional element-binding protein 2 (BTEB2) are transcriptional factors that regulate multiple genes involved in phenotypic changes of smooth muscle cells (SMCs), one of the outstanding pathologic features of chronic cardiac allograft rejection. In this study, we used a heterotopic abdominal heart transplant model in monkeys to evaluate the roles of these molecules in graft coronary vasculopathy. We demonstrated that Egr-1 and BTEB2 are induced in vascular SMCs of rejected cardiac allografts well before morphologic changes, such as intimal thickening. These findings suggest that expression of Egr-1 and BTEB2 is one of the initial events in allograft angiopathy.

'No-Touch' isolation procedure for ruptured mycotic abdominal aortic aneurysm.

The present study reports a case of the successful surgical repair of a ruptured infra-renal mycotic abdominal aorta with Enterobactor cloacae in a 66-year-old man. During the operative procedure, an extra-anatomic bypass was installed before the laparotomy in order to avoid bacterial contamination. A complete resection of the infected aorta, tapering of the arterial stumps, wrapping of the omentum, and ligation of the aorta and arteries with Teflon tapes was carried out. The patient is alive and well 1 year postsurgery.

Expression of membrane-type 1 matrix metalloproteinase in coronary vessels of allotransplanted primate hearts.

BACKGROUND: The mechanisms of intimal thickening in cardiac allograft vasculopathy (CAV) remain controversial after heart transplantation. Matrix metalloproteinase-2 (MMP-2) plays a crucial role in degrading extracellular matrix (ECM) during neointimal formation. Recently, it has been revealed that MMP-2 is activated by membrane-type 1 matrix metalloproteinase (MT1-MMP). This process involves tissue inhibitor of MMP-2 (TIMP-2), forming an MT1-MMP/TIMP-2/pro-MMP-2 complex. In this study, we hypothesize that these components contribute to the pathogenesis of CAV. METHODS: Heterotopic cardiac allografting was performed in randomly paired Japanese monkeys with an immunosuppressive regimen of intravenous administration of antihuman CD18 monoclonal antibody. The donor hearts were harvested at Days 22, 28, 40, 41, and 95 posttransplantation. We examined expression of MMP-2, MT1-MMP, and TIMP-2 of graft vessels using immunohistochemistry and protein level by western blot analysis. RESULTS: Pathologically, various degrees of neointimal formation were observed. In the allografts harvested at Days 22, 28, 40, and 41, MT1-MMP was expressed in the endothelial cells and smooth muscle cells (SMCs) in media of some arteries without histological change, accompanied by expression of MMP-2 and TIMP-2. In the severely thickened neointima of the allograft harvested at Day 95, MMP-2 and faint MT1-MMP were expressed in SMCs of severely thickened neointima and media; TIMP-2 expression was seen only in noncollagenous tissue of severely thickened neointima. MMP-2 protein was more intensely expressed in the allograft harvested at Day 95 than in the allograft harvest at Day 41, while TIMP-2 protein level was almost same in the 2 samples. CONCLUSION: We observed the simultaneous expression of MMP-2, MT1-MMP, and TIMP-2. Thus, ECM degradation triggered by MT1-MMP/TIMP-2/pro-MMP-2 complex could be a novel mechanism of CAV.

Gene therapy for attenuating cardiac allograft arteriopathy using ex vivo E2F decoy transfection by HVJ-AVE-liposome method in mice and nonhuman primates.

Cardiac allograft arteriopathy, which limits the long-term survival of recipients, is characterized by diffuse intimal thickening composed of proliferative smooth muscle cells. The transcription factor E2F plays a pivotal role in the coordinated transcription of cell-cycle regulatory genes. To test the hypothesis that double-stranded DNA with specific affinity for E2F (E2F decoy) is effective in preventing intimal hyperplasia, we performed ex vivo single intraluminal delivery of E2F decoy into cardiac allografts of mice and Japanese monkeys using the hemagglutinating virus of Japan (HVJ) artificial viral envelope-liposome method. In murine models, antisense cyclin-dependent kinase 2 (cdk2) kinase oligodeoxynucleotide (ODN) and no transfers were performed to compare the effects. Severe intimal thickening was observed, and multiple cell-cycle regulatory genes were enhanced in untreated allografts. E2F decoy prevented neointimal formation and suppressed these genes for up to 8 weeks, whereas antisense cdk2 kinase ODN had limited effects. In primate models, E2F decoy dramatically prevented neointimal thickening and suppressed multiple cell-cycle regulatory genes, whereas intimal thickening developed in the nontransfected or mismatch decoy-transfected allografts. Gel mobility shift assay proved the specific effects of E2F decoy, and reverse transcriptase-polymerase chain reaction documented that neither complication nor dissemination of HVJ into other organs was observed. We demonstrate that ex vivo gene delivery to allografts is a potent strategy to modify allograft gene expression, resulting in prevention of graft arteriopathy without systemic adverse effects.

[A clinical study of posttraumatic hydrocephalus].

From 1989 to 1998, 721 patients with head injury were admitted to our department and 22 (3.1%) of them developed posttraumatic hydrocephalus. These patients included 16 males and 6 females, ranging in age from 17 to 86 years (mean age, 66 yrs) with peak incidence in the eighth decade. CT scan on admission immediately after head injury showed subarachnoid hemorrhage (SAH) in 18 cases. The other 4 cases without SAH had once suffered head injuries severe enough to give rise to consciousness disturbance. The typical clinical symptoms of hydrocephalus were observed in only 5 (23%) patients, and in the other 17 cases prolonged or deteriorated of consciousness disturbance were the main symptoms. Hydrocephalus was diagnosed between 1 and 3 months in 15 cases and in 7 cases after 4 months. Clinical improvement has been seen in 17 (77%) cases and marked recovery of consciousness was achieved in 12 cases after V-P shunt, but 5 cases with severe disturbance of consciousness revealed no improvement of clinical signs even after decrease of ventricular size. These results indicate that elderly patients with traumatic SAH should be followed up for at least 4 to 5 months, paying attention to development of hydrocephalus, and V-P shunt would be effective to improve consciousness disturbance in most of the cases.

Aortobronchial fistula late after transverse arch replacement.

We report an unusual case of aortobronchial fistula late after transverse arch replacement caused by the remnant of a temporary bypass near the ascending aorta. In reconstructive surgery of the ascending aorta, antegrade perfusion is preferably performed through a side branch after completion of the distal anastomosis by some surgeons. This report suggests possible risk of a serious late complication unless the side branch is placed and tailored properly.

Ontogeny of antipig xenoantibody and hyperacute rejection.

BACKGROUND: Neonatal primates have been reported to receive pig hearts without hyperacute rejection (HAR). We examined the ontogeny of the anti-pig xenoantibody (XenoAb) and HAR in the neonatal and infant monkeys. METHODS: Twenty-six serum samples from 15 monkeys ages 14-192 days were subjected to hemagglutination titration against pig erythrocytes. Ten pig hearts were heterotopically transplanted into the monkeys. RESULTS: Six monkeys, ages 52-114 days, received pig hearts without HAR, and those ages 129-191 days hyperacutely rejected them. XenoAb titers were increased according to the age (Spearman's rank correlation value=0.909 (P<0.01)). XenoAb titers in 16 monkeys <4 months were significantly (P<0.01) lower than those in 10 monkeys >4 months. CONCLUSIONS: Anti-pig XenoAb titers increased with the age of the monkeys. XenoAb levels in monkeys >4 months are high enough to reject pig hearts hyperacutely.

Metastatic hepatocellular carcinoma obstructing the right ventricular outflow tract.

A 49-year-old female with a past history of liver resection due to hepatocellular carcinoma was referred to our Department for treatment of a metastatic cardiac tumor obstructing the right ventricular outflow tract. She underwent operation twice with cardiopulmonary bypass, and symptoms were relieved. Metastasis from hepatocellular carcinoma to the heart is very rare, but should be taken into consideration during follow-up after treatment for a primary liver tumor.

Swinging motion of intimal flap through the aortic valve in acute aortic dissection.

The purpose of this article is to present a very rare case of Stanford type A acute aortic dissection featuring a swinging motion of the cylinder-shaped intimal flap through the aortic valve. The patient was a 62-year-old male suffering from severe cardiogenic shock. A transthoracic echocardiogram revealed aortic dissection and severe aortic regurgitation. A transesophageal echocardiogram demonstrated that the aortic dissection in the ascending aorta was circumferential and the proximal portion of the intimal flap was swinging through the aortic valve, ie., falling into the left ventricle during the diastolic phase and being ejected back into the ascending aorta during the systolic phase. An emergency graft replacement of the ascending aorta was performed. During ventricular fibrillation under total cardiopulmonary bypass, we performed cardiac massage to prevent myocardial ischemia, because blood flow from a heart lung machine inverted the intimal flap, which might have disturbed the coronary circulation. The patient's postoperative course was uneventful, and his postoperative echocardiogram revealed only a trace of regurgitant flow through the aortic valve. Back-and-forth movement of the cylinder-shaped intima requires coexistence of the following three conditions: severe aortic regurgitation, circumferential dissection, and complete transection of the intimal flap. We conclude that this movement of the intimal flap should be regarded as one of the most serious complications leading rapidly to cardiogenic shock. From a surgical point of view, it is most important to prevent myocardial ischemia during cardiopulmonary bypass especially in cases in which ventricular fibrillation has occurred. We describe the ways to prevent myocardial ischemia in this rare situation.