Pretreatment with a single bolus injection of polyoxyethylene-modified superoxide dismutase prevents reperfusion induced arrhythmias in the anesthetized rat

Effects of a newly introduced polyoxyethylene-modified superoxide dismutase (SOD-POE) on reperfusion induced arrhythmias were examined in the pentobarbital anesthetized rat. Reperfusion induced arrhythmias were elicited by occlusion of the left anterior descending coronary artery (LAD) for 15 min and subsequent release. The LAD occlusion was performed by compressing the artery using a suction cup of 2 mm in diameter placed on the LAD to which negative pressure was applied. The LAD occlusion and release was repeated at an interval of 30 min. SOD-POE or human SOD (h-SOD) (1000 U/kg) was injected intravenously 15 min prior to the occlusion at the second trial of the occlusion. In the control group, various types of arrhythmias including ventricular fibrillation (Vf), ventricular tachycardia (VT), premature ventricular contraction (PVC) and premature atrial contraction (PAC) were elicited immediately after release of the occlusion. In the SOD-POE-treated group, Vf and VT were completely prevented and the numbers of PVC and PAC significantly decreased, while pretreatment with h-SOD did not prevent the occurrence of reperfusion induced arrhythmias. The protective effects of SOD-POE lasted for more than 90-120 min. The plasma half life for SOD-POE was 10.8 hr, while that for h-SOD was 8.6 min. Results indicate that intravenous administration of SOD-POE would provide a new means of preventing reperfusion induced arrhythmias occurring in clinical situations.     

Deficiency of insulin receptor substrate-1 impairs skeletal growth through early closure of epiphyseal cartilage.

Morphological analyses in and around the epiphyseal cartilage of mice deficient in insulin receptor substrate-1 (IRS-1) showed IRS-1 signaling to be important for skeletal growth by preventing early closure of the epiphyseal cartilage and maintaining the subsequent bone turnover at the primary spongiosa. Introduction: IRS-1 is an essential molecule for intracellular signaling by IGF-I and insulin, both of which are potent anabolic regulators of cartilage and bone metabolism. To clarify the role of IRS-1 signaling in the skeletal growth, morphological analyses were performed in and around the epiphyseal cartilage of mice deficient in IRS-1 (IRS-1(-/-)), whose limbs and trunk were 20-30% shorter than wildtype (WT) mice. MATERIALS AND METHODS: The epiphyseal cartilage and the primary spongiosa at proximal tibias of homozygous IRS-1(-/-) and WT male littermates were compared using histological, immunohistochemical, enzyme cytohistochemical, ultrastructural, and bone histomorphometrical analyses. RESULTS: In and around the WT epiphyseal cartilage, IRS-1 and insulin-like growth factor (IGF)-1 receptors were widely expressed, whereas IRS-2 was weakly localized in bone cells. Chronological observation revealed that height of the proliferative zone and the size of hypertrophic chondrocytes were decreased in WT mice as a function of age, and these decreases were accelerated in the IRS-1 (-/-) cartilage, whose findings at 12 weeks were similar to those of WT at 24 weeks. In the IRS-1(-/-) cartilage, proliferating chondrocytes with positive proliferating cell nuclear antigen (PCNA) or parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor immunostaining had almost disappeared by 12 weeks. Contrarily, TUNEL+ apoptotic cells were increased in the hypertrophic zone, at the bottom of which most of the chondrocytes were surrounded by the calcified matrix, suggesting the closure of the cartilage. In the primary spongiosa, bone volume, alkaline phosphatase (ALP)+ osteoblasts, TRACP+ osteoclasts, and the osteopontin-positive cement line were markedly decreased. Bone histomorphometrical parameters for both bone formation and resorption were significantly lower in IRS-1(-/-) mice, indicating the suppression of bone turnover. CONCLUSION: The IRS-1(-/-) epiphyseal cartilage exhibited insufficient proliferation of chondrocytes, calcification of hypertrophic chondrocytes, acceleration of apoptosis, and early closure of the growth plate. Thus, the data strongly suggest that IRS-1 signaling is important for the skeletal growth by preventing early closure of the epiphyseal cartilage and by maintaining the subsequent bone turnover at the primary spongiosa.     

Preliminary results of intermittent retrograde cerebral perfusion during proximal aortic arch surgery.

OBJECTIVE: Continuous retrograde cerebral perfusion during aortic arch surgery is associated with cerebral edema. In this report, we describe the clinical use of a new type of intermittent retrograde cerebral perfusion. SUBJECTS AND METHODS: Fourteen patients with a Stanford type A dissection were included in this study. With the usual method of retrograde cerebral perfusion, about 2,500 mL venous blood is drained from bicaval cannulae into a hard-shell reservoir, and oxygenated blood is perfused through the superior vena caval cannula. The flow rate is 300 mL/min. After about 15 min, retrograde perfusion is discontinued, and drainage from the bicaval cannulae is restarted. When a bloodless field is necessary, perfusion also is discontinued. RESULTS: Two to seven cycles of intermittent retrograde cerebral perfusion were administered (average, 3.1+/-0.4, mean+/-SD). The total retrograde perfusion time was 36.0+/-1.9 min which was equivalent to 74.8% of the circulatory arrest time. No patient developed edema of the upper body. The time to wake-up was 3 to 14 h (average, 6.5+/-1.0 h). No patient suffered any neurologic complications even though the time of circulatory arrest was greater than 60 min in four cases. Head magnetic resonance imaging or computed tomography was performed in 12 cases, and no evidence of hypoxic brain injury was detected. CONCLUSIONS: Our clinical experience using a moderate amount of intermittent retrograde cerebral perfusion is superior to continuous retrograde cerebral perfusion for protecting the brain during aortic arch surgery.     

Late Effects of Childhood Acute Leukemia and Its Treatment

Late effects of childhood acute leukemia and its treatment were studied in 766 patients (684 ALL, 73 ANLL, and 9 others) in Japan who had remained in remission for more than 1 year after their first complete remission. Delayed adverse sequelae involve a wide variety of organs and their functions. Short stature was present in 2.61%, obesity in 3.79%, abnormalities of growth hormone secretion in 1.5%, delayed secondary sex characteristics in 1.5% of males and 0.6% of females, motor disturbances in 1.17%, sensory disturbances in 0.91%, intellectual and learning disabilities in 2.48%, abnormal findings in routine neurologic examinations in 1.31%, EEG abnormalities in 4.30%, brain CT abnormalities in 5.09% and cardiac dysfunction in 1.07%. Various other disorders were seen in 20 patients. Many of these delayed adverse sequelae are caused by or related to central nervous system prophylaxis and systemic combination chemotherapy. The results suggest that it is needed to improve therapeutic methods through the stratification of patients by risk factors and detailed analysis of prognostic factors. Moreover it is important to render medical and psychosocial support to long-term survivors of childhood leukemia through interactions between the patient, parents and medical staff.     

Bipolar prosthetic replacement for the treatment of avascular necrosis of the femoral head.

Eighty-three hips in 66 patients with nontraumatic avascular necrosis of the femoral head (ANFH) showing evidence of severe collapse or secondary osteoarthritic changes were treated with surgical implantation of bipolar hip prostheses either with or without cement fixation of femoral stems. The cases were observed for more than three years (range, three to ten years seven months; average, five years seven months) and assessed in terms of functional and roentgenographic results. These data were compared with the results of classic hemiarthroplasties using fixed head prostheses (Austin-Moore-type with curved or straight stem) that were performed at the authors' institutions before 1980. The results confirm that the clinical outcome is improved with use of the bipolar prosthesis. Satisfactory results (a score of 80 or greater on a hip function scoring system proposed by the Japanese Orthopaedic Association) were maintained throughout the follow-up period in most cases (71 of 83 hips) with the bipolar prosthetic replacements. In a group of patients with unsatisfactory results (12 hips), proximal migration of prosthetic head was seen in two cases. The incidence of proximal migration of bipolar heads, including those exhibiting minimal movement, was significantly lower when compared with that observed in an Austin-Moore-type head-fixed prosthesis group (7/83 versus 12/19) during a comparable postoperative follow-up period. It is noteworthy that the proximal migration of the bipolar head was not progressive, and, in most cases observed more than five years, the cartilaginous spaces of acetabulum were preserved, whereas in the Austin-Moore-replaced group, the migration was evident and progression occurred within three years of surgery.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of epidermal growth factor on cadherin-mediated adhesion in a human oesophageal cancer cell line.

Epidermal growth factor (EGF) mediates many pleiotrophic biological effects, one of which is alteration of cellular morphology. In the present study, we examine the possibility that this alteration in cell morphology is caused in part by the dysfunction of cadherin-mediated cell-cell adhesion using the human oesophageal cancer cell line TE-2R, which expresses E-cadherin and EGF receptor. In the presence of EGF, TE-2R changed its shape from round to fibroblastic and its colony formation from compact to sparse. Vanadate, a tyrosine phosphatase inhibitor, further potentiated the EGF response, whereas herbimycin A, a tyrosine kinase inhibitor, interfered with it. Moreover, EGF enabled the cells to invade in organotypic raft culture. These phenomena were accompanied not by decreased expression of the E-cadherin molecule but by a change in its localisation from the lateral adhesion site to the whole cell surface. Both alpha- and beta-catenin, cadherin-binding proteins, were also expressed at the same level throughout these morphological changes. Finally, we examined tyrosine phosphorylation of E-cadherin and alpha- and beta-catenin, and observed tyrosine phosphorylation of beta-catenin induced by EGF. These results suggest that EGF counteracts E-cadherin-mediated junctional assembly through phosphorylation of beta-catenin and modulates tumour cell behaviour to a more aggressive phenotype.     

Successful surgical treatment of secondary kwashiorkor after total gastrectomy: Report of a case

We report herein the case of a 56-year-old woman who developed secondary Kwashiorkor 9 years after undergoing a total gastrectomy for early gastric cancer. Until she began developing the symptoms of Kwashiorkor, including general fatigue, edema of the face and extremities, anemia, alopecia, and weight loss, she had been leading a normal life post-gastrectomy. Her symptoms were alleviated by total parenteral nutrition (TPN) therapy, but reappeared soon after TPN therapy was discontinued. Therefore, she required several subsequent courses of TPN. In an attempt to permanently resolve the ongoing Kwashiorkor symptoms, reconstructive surgery involving transposition of the jejunum from the previous Graham method to the interposition method was performed 10 years after the initial gastrectomy. After the second operation, her malnutrition was completely alleviated, and she has been in good health for the 8 years since. To our knowledge, there has been no other report of the symptoms of secondary Kwashiorkor after total gastrectomy being alleviated by altering the procedure of reconstruction of the intestinal tract. Thus, we recommend surgical treatment to alter the digestive continuity to a more physiological pathway for selected patients with secondary Kwashiorkor syndrome.