Involvement of thromboxane A2, leukotrienes and free radicals in puromycin nephrosis in rats

Thromboxane A2 (TXA2), leukotrienes (LTs) and free radicals are considered to be possible mediators in the induction of glomerular injury and proteinuria. In this study, we examined the involvement of these three mediators and the protective effect of simultaneous inhibition of all three in puromycin aminonucleoside (PAN) nephrosis in rats. A single intraperitoneal injection of PAN (100 mg/kg) induced massive proteinuria and enhanced production of TXA2 and LTs from arachidonic acid in renal cortical slices and renal glomeruli, and increased malondialdehyde levels in plasma, urine and renal cortex. Oral administration of CV-6504(HCl) (3 to 20 mg/kg/day, for 1 to 2 weeks), a novel treble inhibitor of TXA2 synthetase, 5-lipoxygenase and lipid peroxidation, dose-dependently attenuated PAN-induced proteinuria and the increases in these three mediators. Any single specific inhibitor (CV-4151, a TXA2 synthetase inhibitor; AA-861, a 5-lipoxygenase inhibitor; or CV-3611, a radical scavenger) or a combination of two inhibitors showed no or only a slight antiproteinuric effect, but the combination of all three inhibitors significantly reduced PAN-induced proteinuria. These results suggest that, these three mediators may be involved in the pathogenesis of PAN nephrosis and that CV-6504(HCl), which can simultaneously inhibit all three, may be a useful therapeutic agent for nephrosis.     

Temporal profile of serum albumin extravasation following cerebral ischemia in a newly established reproducible gerbil model for vasogenic brain edema: a combined immunohistochemical and dye tracer analysis

Summary We investigated the temporal profile of the extravasation of serum albumin in a reproducible gerbil model of unilateral cerebral ischemia, using immunohistochemical and dye-tracer techniques to evaluate albumin accumulation and the occurrence of active extravasation, respectively. After 30 min of cerebral ischemia and subsequent reperfusion, immunostaining for albumin became visible in the lateral part of the thalamus during the first 3 h, and then expanded to other brain regions up to 24 h. At both 24 h and 3 days after reperfusion, massive extravasation of albumin was noted in the whole ischemic hemisphere, and this had decreased again by 7 days after reperfusion. The extent and the degree of albumin immunopositivity were almost the same in all animals examined at each period after reperfusion. The extravasation of Evans blue, which was allowed to circulate for 30 min before death, was limited to the lateral part of the thalamus during the first 6 h of reperfusion. In the circumscribed area of massive albumin extravasation, many neurons were immunopositive for albumin; most of these neurons appeared to be intact and also showed immunostaining for microtubule-associated protein 2. The current investigation clearly demonstrated that (1) albumin extravasation was produced with reliable reproducibility in this model, (2) the lateral part of the thalamus was the region most vulnerable to ischemic blood-brain barrier damage, and (3) many apparently intact neurons in the ischemic region were positive for albumin.Supported in part by a Grant-in-aid (01570485) from the Ministry of Education, Science and Culture and by a research grant for cardiovascular diseases (2A-2) from the Ministry of Health and Welfarc in Japan     

Factors influencing insulin secretion after pancreatoduodenectomy

Preoperative patients with periampullary cancer had a higher mean Σ IRI value than that of normal controls, and also had a delayed pattern of insulin response and a lower insulinogenic index during oral-GTT. Σ IRI levels after pancreatoduodenectomy were similar to those of normal controls when the pancreatic remnants were histologically intact at the time of surgery. Postoperative Σ IRI levels could not be predicted based on the extent of histological fibrosis of the distal pancreas at the time of surgery. Patency of pancreatojejunostomy was obtained with the modified Warren's method in 39 out of 40 patients, and Σ IRI levels were maintained up to 5 years postoperatively. No significant difference was found in Σ IRI levels between pancreatoduodenectomised patients with the conventional Roux-en-Y procedure and those with the inverted Roux-en-Y with jejunal interposition. The mean insulin peak value and Σ IRI level were higher in pancreatoduodenectomised patients than in normal controls, and higher in gastrectomised patients than in pancreatoduodenectomised patients. Pancreatoduodenectomy with superior mesenteric arterial dissection resulted in remarkably low Σ IRI levels.     

Common null variant, Arg192Stop, in a G-protein coupled receptor, olfactory receptor 1B1, associated with decreased serum cholinesterase activity

Aim: Non-functioning single nucleotide polymorphisms (nSNPs) that result in premature termination codons, that is null-alleles of the respective genes, may have phenotypic effects on clinical parameters. We conducted association studies involving several G-protein coupled receptors (GPCRs) that harbor nSNPs, using clinical parameters of liver function in a general population consisting of 2969 Japanese adults. Methods: SNP typings were performed with TaqMan and Invader assays. Quantitative associations between genotypes and clinical parameters were analyzed by analysis of variance. Linkage disequilibrium (LD) was tested by Haploview Version 3.3. Haplotype-based association was performed using the haplo.stats program. Results: A significant correlation (P = 0.0057) was identified between serum cholinesterase activity (CHE) and an nSNP (Arg192Stop) in the olfactory receptor (OR) 1B1 gene, a member of the GPCR gene family. This nSNP was associated with decreased serum CHE (P = 0.0013). LD analysis based on eight selected SNPs at the locus revealed three LD blocks. The Arg192Stop nSNP was located on the second LD block, which covered one-third of the 3'-portion of the gene. Conclusion: These results suggested that the null-allele of OR1B1 might affect metabolism of serum cholinesterase in carriers of this nSNP.     

A Study of Malignant Bile Duct Stenosis Using Percutaneous Transhepatic Cholangioscopy

Abstract: From June, 1987 to November, 1989, 11 patients with malignant bile duct stenosis, which was later confirmed by surgery or autopsy, were examined by percutaneous transhepatic cholangioscopy (PTCS) and by an endoscopic biopsy. The endoscopic findings obtained with the usual observation methods and methylene blue staining and the histological findings of the biopsy specimens were compared. A fine vascular proliferation was seen in all of the patients and a granular appearance was noted in patients with carcinoma of the major papilla. The papillary appearance was noted in one case each of pancreatic carcinoma, bile duct carcinoma and carcinoma of the major papilla. Marginal protrusion was not noted in patients with pancreatic carcinoma. A distorted narrow segment was seen only in cases of pancreatic carcinoma. The presence of a granular appearance indicated that the carcinoma was exposed on the surface. A high degree of fine vascular proliferation and a papillary appearance tended to indicate a carcinoma which invaded mainly into the fibromuscular layer without invasion of the mucosa. The methylene blue staining method was simple and effective for better visualization of the surface structure of the abnormal area, normal mucosa and the border zone.     

Transformation of hamster spleen lymphocytes by human T-cell leukemia virus type I

Co-cultivation of spleen cells of Syrian golden hamsters with lethally irradiated MT-2 cells harboring human T-cell leukemia virus type I (HTLV-I) resulted in the establishment of lymphoid cell lines, HCT-1 and HCT-2, which exhibited the normal karyotype of golden hamsters. Cells of both the HCT-1 and HCT-2 lines lacked surface immunoglobulins and reacted with a monoclonal antibody (MAb) specific for hamster T cells. Some were positive for OKIa1. None of them expressed HTLV structural antigens (p19 and p24) or virus particles, but they contained HTLV-I proviral DNA monoclonally. By immunochemical analysis of the labelled cell antigens, sera from adult T-cell leukemia (ATL) patients reacted with the two polypeptides, p37 and p40, which may not be viral structural proteins and still remain to be characterized. HCT-1 and HCT-2 cells were transplantable into newborn hamsters, pre-treated with anti-hamster thymocyte serum and non-treated, respectively, producing diffuse malignant lymphoma. These findings indicated that HTLV-I not only immortalized but also transformed hamster T cells non-productively.     

Labour analgesia guided by echocardiography in a parturient with primary dilated cardiomyopathy

PURPOSE: To evaluate the effects of intrathecal analgesics on cardiac function during labour analgesia using echocardiography in a parturient with idiopathic dilated cardiomyopathy (DCM). CLINICAL FEATURES: Induction of labour was planned in a 35-yr-old primiparous woman suffering from DCM. In order to stabilize hemodynamics in this patient, we induced continuous spinal analgesia with an infusion of fentanyl and epinephrine. Although her analgesia was well maintained for three hours during the first stage of labour, the patient complained of pain towards the second stage of labour. At this point, we administered bupivacaine intrathecally to alleviate her pain. Transthoracic echocardiography showed that the left ventricular end-diastolic and systolic dimensions, as well as the ejection fraction were not impaired by use of these analgesic medications. CONCLUSION: Measurement of left ventricular dimensions by echocardiography allowed us to monitor the patient's response to intrathecal analgesic medications. In this patient with DCM, analgesia with intrathecal fentanyl and bupivacaine was well tolerated.