Toshihiro Onohara

Diabetic Microangiopathy in Ischemic Limb Is a Disease of Disturbance of the Platelet-Derived Growth Factor-BB/Protein Kinase C Axis but Not of Impaired Expression of Angiogenic Factors

Diabetic foot is caused by microangiopathy and is suggested to be a result of impaired angiogenesis. Using a severe hindlimb ischemia model of streptozotocin-induced diabetic mice (STZ-DM), we show that diabetic foot is a disease solely of the disturbance of platelet-derived growth factor B-chain homodimer (PDGF-BB) expression but not responses of angiogenic factors. STZ-DM mice frequently lost their hindlimbs after induced ischemia, whereas non-DM mice did not. Screening of angiogenesis-related factors revealed that only the expression of PDGF-BB was impaired in the STZ-DM mice on baseline, as well as over a time course after limb ischemia. Supplementation of the PDGF-B gene resulted in the prevention of autoamputation, and, furthermore, a protein kinase C (PKC) inhibitor restored the PDGF-BB expression and also resulted in complete rescue of the limbs of the STZ-DM mice. Inhibition of overproduction of advanced-glycation end product resulted in dephosphorylation of PKC-&agr; and restored expression of PDGF-BB irrespective of blood sugar and HbA1c, indicating that advanced-glycation end product is an essential regulator for PKC/PDGF-BB in diabetic state. These findings are clear evidence indicating that diabetic vascular complications are caused by impairment of the PKC/PDGF-B axis, but not by the impaired expression of angiogenic factors, and possibly imply the molecular target of diabetic foot.

DVC1-0101 to Treat Peripheral Arterial Disease: A Phase I/IIa Open-label Dose-escalation Clinical Trial

We here report the results of a Phase I/IIa open-label four dose-escalation clinical study assessing the safety, tolerability, and possible therapeutic efficacy of a single intramuscular administration of DVC1-0101, a new gene transfer vector based on a nontransmissible recombinant Sendai virus (rSeV) expressing the human fibroblast growth factor-2 (FGF-2) gene (rSeV/dF-hFGF2), in patients with peripheral arterial disease (PAD). Gene transfer was done in 12 limbs of 12 patients with rest pain, and three of them had ischemic ulcer(s). No cardiovascular or other serious adverse events (SAEs) caused by gene transfer were detected in the patients over a 6-month follow-up. No infectious viral particles, as assessed by hemagglutination activity, were detected in any patient during the study. No representative elevation of proinflammatory cytokines or plasma FGF-2 was seen. Significant and continuous improvements in Rutherford category, absolute claudication distance (ACD), and rest pain were observed (P < 0.05 to 0.01). To the best of our knowledge, this is the first clinical trial of the use of a gene transfer vector based on rSeV. The single intramuscular administration of DVC1-0101 to PAD patients was safe and well tolerated, and resulted in significant improvements of limb function. Larger pivotal studies are warranted as a next step.

Immunohistochemical phenotypic alterations of rabbit autologous vein grafts implanted under arterial circulation with or without poor distal runoff-implications of vein graft remodeling

Although intimal hyperplasia is a major cause limiting the long-term patency of the vein grafts, its precise mechanisms, including the effect of poor runoff, has not yet been well characterized. We thus designed the present study to try to determine the effect of poor runoff arterial flow to the phenotypic alterations of the graft wall by immnohistochemistry using anti-intermediate filaments (alpha-SM actin, desmin, and vimentin) and anti-myosin heavy chain (SM1, SM2, and SMemb) specific antibodies. Vein grafts implanted under the poor runoff hind limb of rabbits showed enhanced intimal hyperplasia, however, no apparent difference in the cytoskeleton expression, including intermediate filaments and MHC, between two groups until 4 weeks. Interestingly, six of eight vein grafts at 2 weeks after implantation in both groups showed the accumulations of perivascular fibroblast-like phenotype (negative for SM1, alpha-SM actin, and desmin) in some parts of the outer neointima, whereas the inner neointima at 2 weeks and the whole neointima at 4 weeks were mainly occupied by a smooth muscle phenotype (positive for these three). Although the cellular origin of these cells is still unknown, these results suggest that the migration of non-muscle mesenchymal cells is involved in the neointima and thus may provide a clue for better understanding vein graft remodeling.

Factors influencing late survival after abdominal aortic aneurysm repair in Japanese patients

BACKGROUND To determine the factors influencing the prognosis of patients with abdominal aortic aneurysms (AAA), the clinical characteristics and long-term survival of 366 consecutive patients were examined and compared with those in previous Western studies. METHODS During the period from January 1979 to December 1995, 376 patients with AAA were admitted to our hospital. Among these, 332 consecutive patients underwent elective reconstruction of infrarenal AAAs. The remaining 44 patients were not surgically treated. With use of the data from the patients who underwent AAA resection, the relationship of various risk factors, such as cardiac dysfunction, hypertension, renal dysfunction, pulmonary dysfunction, and age, to survival rate was investigated by univariate and multivariate analysis. RESULTS The operative mortality rate was 0.6%. The survival of the patients who underwent the operation at 5 years was 71.0% and at 10 years 51.8%. The survival rate of the patients who were not surgically treated at 5 years was 26.0% and at 10 years 14.9%. There was a significant difference between the 2 groups. A univariate analysis was performed on each possible risk factor affecting survival rates. In relation to the survival rate of 5 and 10 years, there was no statistical significant difference between patients with or without heart disease or hypertension. By contrast, factors influencing long-term survival were associated with renal dysfunction, pulmonary dysfunction, and age at time of surgery. Multivariate analysis of risk factors affecting survival rates demonstrated that renal dysfunction, pulmonary dysfunction, and age at the time of operation were found to be significant, respectively. The main cause of the death for the long-term survival patients with AAA repair was malignancy, whereas that in the patients without repair was rupture. CONCLUSIONS Risk factors influencing survival after AAA repair were renal dysfunction, pulmonary dysfunction, and advanced age in Japanese patients. In addition, the main cause of death after aneurysmal resection was malignancy. These results were different from outcomes in Western patients. We need to carefully watch out for malignancy during the follow-up period after AAA resection.

Rupture of embolised coeliac artery pseudoaneurysm into the stomach: is coil embolisation an effective treatment for coeliac anastomotic pseudoaneurysm?

An elderly woman with an anastomotic pseudoaneurysm of the coeliac artery, after previous treatment of a thoraco-abdominal aortic aneurysm, was treated by stainless steel coil embolisation. One year later, the embolised pseudoaneurysm ruptured into the stomach and total gastrectomy and aneurysmorraphy was necessary. She is leading a normal life 6 months later.

Surgical strategy of abdominal aortic aneurysm with preoperative renal failure

OBJECTIVES To determine the effect of preoperative renal failure on the outcome of patients suffering from infrarenal abdominal aortic aneurysm (AAA). METHOD During the period from January 1979 to August 1995, 364 patients with AAA were admitted to our hospital and 323 underwent elective repair. The patients were retrospectively analysed in three groups. Group I was composed of 273 patients with a normal renal function who underwent an aneurysm repair. Group II was composed of 50 patients who demonstrated a preoperative renal dysfunction (creatinine above 2.0 mg/dl or creatinine clearance below 40 ml/min) and underwent an operation, including three patients maintained on chronic haemodialysis. Group III was composed of 18 patients with a renal dysfunction who did not undergo repair, including one patients maintained on chronic haemodialysis. RESULTS The operative mortality rate of groups I and II were 0.4% and 2.0%, respectively, although no significant difference was observed. The incidence of postoperative cardiac and pulmonary complications were also comparable in two groups. No patients required acute haemodialysis. The 5-year survival rate of group II (44%) was significantly higher than that of group III (20%), and seven of the 18 patients (39%) in group III ultimately died of a rupture of the AAA. CONCLUSIONS Patients with chronic renal failure can undergo an abdominal aortic aneurysm repair based on the same indications as those without renal failure.

Acceleration of impairment of endothelium-dependent responses under poor runoff conditions in canine autogenous vein grafts

OBJECTIVES To assess the effects of changes in shear stress on endothelium-dependent responses. MATERIALS AND METHODS Autologous vein grafts were implanted in poor or normal distal runoff limbs of 10 mongrel dogs. Six weeks after grafting the vein grafts were removed, cut into rings, and suspended in organ chambers for isometric tension recording. RESULTS The average value of intimal thickening was 110.7 +/- 45.2 microns in poor runoff limbs and 65.5 +/- 27.9 microns in control limbs, respectively. There was a significant difference between the two groups. Acetylcholine caused comparable endothelium-independent contractions in both groups. In the control group, adenosine diphosphate, thrombin and A23187 caused endothelium-dependent relaxations. In the poor runoff group, the endothelium-dependent relaxations caused by adenosine diphosphate and thrombin were impaired, while A23187 caused comparable endothelium-dependent relaxations. Direct relaxations in response to sodium nitroprusside were comparable between the two groups. CONCLUSIONS This dysfunction of the endothelium under conditions of abnormal flow may accelerate intimal thickening of the vein graft and result in late graft failure.

Malignant Adenomyoepithelioma of the Breast:A Case with Distant Metastases.

Adenomyoepithelioma is thought to be a low-grade malignancy, and cases showing malignant behavior are rare.A massive breast tumor with skin invasion in a 60-year-old woman was diagnosed as malignant adenomyoepithelioma. Despite the tumor size and skin invasion, no axillary lymph node metastases were detected. Light microscopy showed proliferation of tubular structures composed of atypical epithelial and myoepithelial cells and occasional anaplastic cells with mitotic figures extending to the epidermis of the skin.Twenty-four months after the surgery the patient complained of dull pain in the right thigh, and was found to have bone, lung and mediastinal lymph node metastases. There was neither local recurrence nor axillary lymph node metastasis. Subsequent femur fracture was treated by osteotomy. Despite additional chemoradiotherapy, the patient died 43 months after the first operation.Our case and literature review indicated that this tumor tends to show hematogenous metastasis.

Late graft failure of autologous vein grafts for arterial occlusive disease: Clinical and experimental studies

Late graft failure following arterial reconstructive surgery, especially after infrainguinal reconstruction, remains a major concern for vascular surgeons. To more effectively predict the outcome of reconstructed arteries, we herein propose an intraoperative flow waveform analysis which correlates well with the long-term patency rate of grafts. According to this flow waveform analysis, late graft failure was occasionally seen in grafts with type II waveforms when poor distal runoff vessels had been shown by the preoperative arteriogram. Next, to investigate which events occurring in autologous vein grafts under abnormal hemodynamics may contribute to late graft failure, a distal poor-runoff model was made in the canine femoral artery. In this review, we present the results of our investigation on autologous vein grafts using this poor-runoff model. We also relate our recent findings on the function of regenerated endothelium in autologous vein grafts.

Flow waveform analysis and long-term results of autogenous saphenous vein and polytetrafluoroethylene grafts in 140 arterial reconstructions of the lower limbs

In previous work we have found that the outcome of grafts in the lower limbs correlated with the flow waveform pattern of the artery. We have retrospectively reviewed 140 femoro-popliteal bypass operations involving the use of 75 saphenous vein grafts and 65 polytetrafluoroethylene (PTFE) grafts. For grafts with type 0 or I flow waveform pattern the patency at 4 years (56%) was superior to grafts with the type II, III or IV flow waveform (35%) patterns (P less than 0.05). For saphenous vein grafts with type 0 or I flow, the patency rate was 78% at 3 years and 69% at 5 and 8 years. In contrast with type II, III or IV flow the patency rate was 52% at 3 years, 48% at 5 years and 34% at 8 years, with a statistical significance at 4 years (P less than 0.05). PTFE grafts with type 0 or I flow showed a tendency toward an increased patency which was not significant in comparison with the grafts with type II, III or IV flow (P = 0.12). Saphenous vein grafts with type II flow patterns had an increased occlusive rate in the first year whereas PTFE grafts had the same tendency within 2 years. In both types of graft, early occlusions within a month of operation were encountered in grafts with a type III or IV flow waveform pattern. These results indicate that the fate of the reconstructed arteries of the lower limb could be predicted by flow waveform analysis, and a careful and serial postoperative evaluation of the graft should be made, particularly those with type II, III or IV flow waveform patterns.