Non-viral in vivo thrombomodulin gene transfer prevents early loss of thromboresistance of grafted veins.

OBJECTIVE: Immediate loss of thrombomodulin activity in the endothelium of vein grafts has been demonstrated during 90 min exposure to arterial circulation; this loss of activity is ascribed as an important cause of early thrombosis. Conventional ex vivo gene transfection after vein harvest cannot cover this acute period immediately after implantation. We have established a highly efficient non-viral gene therapy protocol utilizing modified transferrin receptor-facilitated gene transfer. Using this technique, we examined whether in vivo thrombomodulin gene therapy, directed to the endothelium of rat veins 2 days prior to grafting, may prevent thromboresistance impairment of vein grafts under simulated arterial circulation. METHODS: Abdomen of SD rat was opened and cationic liposome:transferrin:thrombomodulin gene complexes or the vector without DNAs were applied to the inferior vena cava of rats while blood flow was reduced by proximal and distal clamping. After 2 days, the transfected veins were harvested and thrombomodulin expression and thromboresistance properties determined before and after exposure to an artificial circuit. RESULTS: The trial of gene transfection using variable doses of DNAs confirmed that 7.5 microg of total DNAs was the most efficient quantity for thrombomodulin gene transfection to IVCs, although accompanying an increase of gene expression in other downstream organs. By transfection of the thrombomodulin gene in IVCs, the generation capacity of activated protein C in venous endothelium increased three-fold compared with veins treated with vector alone (P<0.01). Under simulated arterial circulation, perfusion of veins treated with vector alone decreased thrombomodulin activity to 36% of preperfused levels (P<0.01), whereas transfected grafts preserved the activity at normal vein endothelium levels even after perfusion. Consequently, the increase in endothelial thrombin activity induced by simulated arterial circulation was markedly attenuated in transfected veins (P<0.01), while immunohistochemistry confirmed the preservation of endothelial lining. CONCLUSIONS: Transferrin receptor-facilitated in vivo gene transfer to the inferior vena cava resulted in sufficient thrombomodulin gene expression immediately after graft implantation and subsequent maintenance of thromboresistance even after exposure to arterial pressure. Although further studies are needed, the present results suggest the possibility of gene therapy targeting acute phases of vein graft disease.     

Pancreatic insulinoma combined with glucagon positive cell: A case report

We present a 70-year-old man who was referred for surgery with uncontrollable hypoglycemia. Ultrasonography and abdominal contrast computed tomography revealed a hypervascular tumor of 1 cm in diameter in the pancreatic tail. With a diagnosis of insulinoma, we performed a distal pancreatectomy. The patient showed a good postoperative course without any complications. The patient’s early morning fasting hypoglycemia disappeared. The respective levels of C-peptide and insulin dropped from 14.9 ng/mL and 4860 μIU/mL preoperatively to 5.3 ng/mL and 553 μIU/mL after surgery. A histopathological examination demonstrated that the tumor was a pancreatic neuroendocrine tumor, grade 1. Immunostaining was negative for insulin and positive for CD56, chromogranin A, synaptophysin and glucagon. These findings suggested that the tumor was clinically an insulinoma but histopathologically a glucagonoma. Among all insulinoma cases reported between 1985 and 2010, only 5 cases were associated with independent glucagonoma. In this report, we characterize and discuss this rare type of insulinoma by describing the case we experienced in detail.     

Reoperative surgery in cholelithiasis

From 1965 to 1980, reoperations for residual or recurrent stones were performed on 78 out of 962 Japanese patients with cholelithiasis. The majority of patients who required reoperation had intrahepatic stones. Most of the causes of reoperation were residual stones due to incomplete removal or the non-detection of intrahepatic stones at the previous surgery. Very careful examination of the intrahepatic biliary trees should be done in patients with biliary tract diseases, because in many, the first operation was done during their youth. To remove the intrahepatic calculi completely, hepatic lobectomy should be considered as a final procedure. The causes of reoperation of common duct stones were residual in 60 per cent and recurrent in 40 per cent. Definitive surgery should be done at the first or at least the second operation to avoid irreversible hepatic disorders which have untoward effects on the prognosis. It is important not only to remove the stones but also to relieve the bile stasis in the biliary tract.     

Clinicopathological studies of minimal thyroid and oridinary thyroid cancers

Clinicopathological studies were carried out on 27 patients with minimal thyroid cancer and 56 with ordinary thyroid cancer at Kanazawa University, from April, 1979 to December, 1982. There was a significant difference in the rate of preoperative diagnosis between the minimal and the ordinary cancer groups. Subtotal thyroidectomy with modified neck dissection was usually performed in both groups. The histological types in minimal cancer group included 16 papillary carcinomas, 7 nonencapsulated sclerosing carcinomas, one follicular carcinoma, one anaplastic carcinoma with squamous cell metaplasia and two multiple mixed carcinomas. There was no significant difference in the rates of intrathyroidal and lymph node metastases between the two groups. While the metastatic lesions of sclerosing carcinoma were localized to the central cervical lymph nodes, the ordinary cancer in general and the papillary variant of minimal cancer metastasized not only to the central cervical lymph nodes but also to the ipsilateral and even to the contralateral jugular lymph nodes.     

Coronary arterial remodeling in differing clinical presentations of unstable angina pectoris--an intravascular ultrasound study

BACKGROUND: Coronary arterial remodeling influences the clinical presentation of ischemic heart disease; however, there is little information on the relationship between coronary arterial remodeling and the type of angina pectoris that patients manifest. HYPOTHESIS: The study was undertaken to determine the difference of coronary arterial remodeling in patients with different types of angina pectoris. METHODS: We analyzed 100 patients with ischemic heart disease using intravascular ultrasound (IVUS). Intracoronary IVUS images of proximal reference (PR), distal reference (DR), and target lesion were recorded, and intraluminal area (LA) and external elastic membrane (EEM) were measured. We defined a remodeling index as 100 x (lesion EEM - [PR-EEM + DR-EEM]/2) / ([PR-EEM + DR-EEM]/2). Cases were classified into three groups according to the clinical history (Group 1a: de novo unstable angina pectoris, Group 1b: accelerating unstable angina pectoris, and Group 2; stable angina pectoris). RESULTS: The remodeling index in Group 1a was significantly larger than that in Groups 1b and 2 (18.6 +/- 28.5 vs. 5.3 +/- 27.1 and 18.6 +/- 28.5 vs. -2.7 +/- 17.6, p = 0.0347 and p = 0.0005, respectively), but there was no statistical difference in remodeling index between Groups 1b and 2. CONCLUSIONS: Our results indicate that positive coronary arterial remodeling is more prevalent in patients with new onset of angina pectoris. The specific type of coronary arterial remodeling may affect the clinical presentation of patients with coronary artery disease.     

Ultrasonographic Findings in Periventricular Leukomalacia in the Newborn: Two Cases Associated with Early Onset Group B Streptococcal Sepsis

The ultrasonographic findings in periventricular leukomalacia (PVL) in the newborn are described, and the relationship between PVL and group B streptococcal (GBS) infection is discussed. Two newborn infants (one preterm and one term) suffered from early onset GBS sepsis with shock; they showed increased echogenicity in the periventricular regions; one of them developed cystic changes. These findings might be due to decreased perfusion of the periventricular end arterial zone. It is suggested that serial ultrasonography should be performed in neonates who suffer hypoxic-ischemic brain injury.     

Intervention therapy for secondary hyperparathyroidism

We reported that selective PEIT in parathyroid glands guided by color doppler flow mapping is effective for severe secondary hyperparathyroidism (2HPT) in chronic dialysis patients. According to the recent Survey by the Japanese Working Group on PEIT of Parathyroid, more than 600 patients have been treated by PEIT in Japan by September, 1998. Based on the results of this survey and based on pathophysiological consideration, Working Group proposed a guideline of selective PEIT of parathyroid. I give a brief summary here. But PEIT has a risk of side effects such as recurrent nerve palsy. Recently another way of percutaneous injection therapy (PIT) using Calcitriol, maxacalcitol and acetic acid has been developed and used. These data suggest that parathyroid intervention (IVR) is an effective adjunct to medical therapy for the management of hyperparathyroidism in uremia.     

The relationships among filling,voiding subscores from International Prostate Symptom Score and quality of life in Japanese elderly men and women

OBJECTIVES: Lower urinary tract symptoms (LUTS) are reported to influence the quality of life (QoL) of the elderly. The aim of this study was to elucidate the relationships among filling problems, voiding problems and QoL in elderly men and women. METHODS: A total of 450 males and 228 females, aged 50 years or older responded to a questionnaire, which included seven questions from the International Prostate Symptom Score (I-PSS) and 16 questions from the King's Health Questionnaire (KHQ). The relations among the filling, voiding subscores deliverable from I-PSS, and KHQ-QoL were investigated. RESULTS: The voiding subscore significantly correlated with the filling subscore with a considerably large standard deviation, and the filling subscore also significantly correlated with I-PSS in both genders. KHQ-QoL was significantly associated with the filling and voiding subscores in almost all domains of the KHQ. Multiple regression analyses demonstrated the filling, voiding subscores, and I-PSS explained the 55% or greater reduction in the QoL in six, four, six domains in men and four, three, four domains in women, respectively. CONCLUSIONS: The filling problems are slightly more associated with KHQ-QoL than voiding problems but filling problems did not appear to predominantly affect QoL as expected in both genders. We believe it valid to use I-PSS to evaluate voiding problems as well as filling problems in the elderly women.     

Prevention by natural food anthocyanins, purple sweet potato color and red cabbage color, of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-associated colorectal carcinogenesis in rats initiated with 1,2-dimethylhydrazine

The potential of purple sweet potato color (PSPC) and red cabbage color (RCC), natural anthocyanin food colors, to modify colorectal carcinogenesis was investigated in male F344/DuCrj rats, initially treated with 1,2-dimethylhydrazine (DMH) and receiving 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in the diet. After DMH initiation, PSPC and RCC were given at a dietary level of 5.0% in combination with 0.02% PhIP until week 36. No PSPC or RCC-treatment-related changes in clinical signs and body weight were found. Incidences and multiplicities of colorectal adenomas and carcinomas in rats initiated with DMH were clearly increased by PhIP. In contrast, lesion development was suppressed by RCC, or tended to be inhibited by PSPC administration. Furthermore, in the non-DMH initiation groups, induction of aberrant crypt foci (ACF) by PhIP was significantly decreased by RCC supplementation. The results thus demonstrate that while PhIP clearly exerts promoting effects on DMH-induced colorectal carcinogenesis, these can be reduced by 5.0% PSPC or 5.0% RCC in a diet under the present experimental conditions.     

Uptake of lamivudine by rat renal brush border membrane vesicles

Uptake of lamivudine, a nucleoside analogue antiviral agent, by brush border membrane vesicles (BBMV) prepared from rat renal cortex was investigated. Initial uptake of lamivudine by BBMV was stimulated in the presence of an outward pH gradient. Determination of the kinetic parameters of the initial uptake yielded apparent Km and Vmax values of 2.28 mm and 1.56 nmol (mg protein)(-1) (20 s)(-1), respectively. The pH-driven uptake of lamivudine was inhibited by organic cations such as trimethoprim and cimetidine. The inhibitory effect of trimethoprim on lamivudine uptake was competitive, with an apparent Ki of 27.6 microM. The uptake of lamivudine was also inhibited by nitrobenzylthioinosine, a representative inhibitor of nucleoside transport, and by other nucleoside analogues, such as azidothymidine and dideoxycytidine, that are excreted by renal tubular secretion. These findings suggest that efflux of lamivudine at the brush border membrane of renal tubular epithelium is mediated by an H+/lamivudine antiport system, which may correspond to the H+/organic cation antiport system, and that this system is also involved in the renal secretion of other nucleoside analogues.