The recovery of α-adrenoceptor function and binding sites after phenoxybenzamine

Summary The recovery of peripheral -adrenoceptor function and binding sites was studied in male New Zealand white rabbits after treatment with the irreversible adrenoceptor antagonist phenoxybenzamine. Phenoxybenzamine (5 mg/kg) was administered intravenously and the animals studied 30 min to 12 days later. Pressor dose response curves to intravenous phenylephrine, noradrenaline and guanabenz were constructed in vivo in conscious animals. The contractile response of abdominal aorta and renal artery to phenylephrine and noradrenaline was examined in vitro and the recovery of specific prazosin and clonidine binding to spleen membranes investigated in radioligand binding studies.The half life (t _1/2) for recovery of maximum pressor response in vivo ranged from 0.9±0.2 days for phenylephrine to 1.4±0.1 days for guanabenz. The t _1/2 for recovery of ED₅₀ was not significantly different to t _1/2 for recovery of maximum pressor response and ranged from 0.8±0.2 days for noradrenaline to 1.3±0.3 days for phenylephrine.Half life for recovery of maximum response and EC₅₀ in the isolated tissues was similar to that obtained in vivo for recovery of pressor responses and ranged from 0.4±0.1 days for the EC₅₀ of noradrenaline in the renal artery to 1.2±0.6 days for maximum response to phenylephrine in the abdominal aorta.The rate of recovery of specific clonidine binding did not differ significantly from the rate of recovery of pressor responses to the ₂-selective agonist guanabenz. t _1/2 for maximum number of specific clonidine binding sites, B _max was 1.6±0.9 days. However t _1/2 for recovery of specific prazosin binding was significantly longer than recovery of responses to phenylephrine and noradrenaline, t _1/2 for B _max was 3.6 ±0.1 day.     

Strain difference in transgene-induced tumorigenesis and suppressive effect of ionizing radiation

Transgenic expression in medaka of the Xiphophorus oncogene xmrk, under a pigment cell specific mitf promoter, induces hyperpigmentation and pigment cell tumors. In this study, we crossed the Hd-rR and HNI inbred strains because complete genome information is readily available for molecular and genetic analysis. We prepared an Hd-rR (p53^+/−, p53^−/−) and Hd-rR HNI hybrid (p53^+/−) fish-based xmrk model system to study the progression of pigment cells from hyperpigmentation to malignant tumors on different genetic backgrounds. In all strains examined, most of the initial hyperpigmentation occurred in the posterior region. On the Hd-rR background, mitf:xmrk-induced tumorigenesis was less frequent in p53^+/− fish than in p53^−/− fish. The incidence of hyperpigmentation was more frequent in Hd-rR/HNI hybrids than in Hd-rR homozygotes; however, the frequency of malignant tumors was low, which suggested the presence of a tumor suppressor in HNI genetic background fish. The effects on tumorigenesis in xmrk-transgenic immature medaka of a single 1.3 Gy irradiation was assessed by quantifying tumor progression over 4 consecutive months. The results demonstrate that irradiation has a different level of suppressive effect on the frequency of hyperpigmentation in purebred Hd-rR compared with hybrids.     

Pilot study of an HLA-A2 peptide vaccine using flt3 ligand as a systemic vaccine adjuvant

A pilot vaccine study was conducted to test the safety and immunological efficacy of four monthly immunizations of an MHC class I peptide vaccine, the E75 HLA-A2 epitope from HER-2/neu, using flt3 ligand as a systemic vaccine adjuvant. Twenty HLA-A2-expressing subjects with advanced stage prostate cancer were randomly assigned to one of four immunization or treatment schedules: (a) Flt3 ligand (20 g/kg per day) administered subcutaneously daily for 14 days on a 28-day cycle, monthly for four months; (b) flt3 ligand course as above with the E75 peptide vaccine administered on day 7 of each flt3 ligand cycle; (c) flt3 ligand course as above with the E75 peptide vaccine administered on day 14 of each flt3 ligand cycle; or (d) E75 peptide admixed with granulocyte–macrophage colony-stimulating factor and administered intradermally once every 28 days, as has previously been reported. The primary endpoints of the study were the determination of safety and immunological efficacy in generating E75-specific T cells as determined by peptide-specific interferon-gamma ELIspot. Adverse events included one grade 3 skin reaction and the development of grade 2 autoimmune hypothyroidism in two subjects with preexisting subclinical autoimmune hypothyroidism. Dendritic cells were markedly increased in the peripheral blood of subjects receiving flt3 ligand with each repetitive cycle, but augmentation of antigen-presenting cells within the dermis was not observed. Apart from a single subject, no significant peptide-specific T-cell responses were detected by ELIspot, whereas delayed-type hypersensitivity responses were detectable in control subjects and in subjects receiving peptide vaccine early in the course of flt3 ligand administration. The absence of robust peripheral immune responses in the current study may be attributable to the small numbers of subjects or differences in the subject population. In addition, the inability of flt3 ligand to augment the number of peripheral skin antigen-presenting cells may have contributed to the absence of robust peptide-specific immunity detectable in the peripheral blood of immunized subjects treated with flt3 ligand.     

A social-psychological perspective on successful community control of high blood pressure: A review

This review brings together studies dealing with factors that affect participation in screening, referral, and treatment for high blood pressure (HBP). Community-based screening programs are examined first, in order to describe the changing and the current distribution of hypertensives as unaware, untreated, treated but uncontrolled, and controlled by treatment. Factors influencing this distribution are examined. Next, data on referral, acceptance of treatment, and staying in treatment are discussed, with a special reference to intervention studies. The review then brings in the broader social science literature on the psychosocial dynamics of health-maintaining and risk-reducing behaviors. The article concludes with an interpretive summary and some suggestions for further action.     

Osteosarcoma occurring in osteogenesis imperfecta

We describe a case history of a 24-year-old male with osteogenesis imperfecta (OI) who developed osteosarcoma of the left thigh. High-dose ifosfamide therapy caused marked tumor regression of multiple lung metastases. Immunohistochemically, the tumor cells were diffusely positive for the p53 protein. Mutation of the p53 gene was not detected by direct genomic sequencing of exons 4–8. The radiographic characteristics, including irregularly distributed osteolytic lesions and cortical discontinuity, should not be confused with hyperplastic callus formation, a benign process. A biopsy is critical to establish the differential diagnosis between osteosarcoma and common hyperplastic callus formation in OI; however, it must be applied with great care.     

Electrophoretic investigation of nuclear membrane ribonucleases of rat liver and hepatoma-27 cells

Preparations of the nuclear membranes were obtained from purified nuclei of rat liver and hepatoma-27 cells, and from them enzyme-containing extracts of acid-soluble proteins were then prepared. The protein extracts were subjected to disk electrophoresis in 15% polyacrylamide gel. Ribonucleases (RNases) which are constituents of the acid-soluble proteins of the nuclear membranes of normal liver were found to be present as several different components which differed in their electrophoretic mobility and in several physicochemical properties from crystalline bovine RNase and the RNase of nuclear chromatin.Institute of Problems in Oncology, Academy of Sciences of the Ukrainian SSR, Kiev. N. K. Kol'tsov Institute of Developmental Biology, Academy of Sciences of the USSR, Moscow. (Presented by Academician of the Academy of Medical Sciences of the USSR R. E. Kavetskii.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 84, No. 12, pp. 670–672, December, 1977.     

Tumor suppressor genes,growth factor genes,and oncogenes in hepatitis B virus-associated hepatocellular carcinoma

A series of changes in the genes that control hepatocyte growth, or interference with the protein products of these genes, appears to have an important role in the etiology of hepatocellular carcinoma (HCC). Mutations of the p53 tumor suppressor gene have been identified in 30-50% of HCC patients in some geographic areas. Abnormalities of the RB tumor suppressor gene have been found in 20-25% of HCCs, including 80-86% of HCCs with p53 mutations. Overexpression of transforming growth factor α (TGF-a), insulin-like growth factor II (IGF-II), and the oncogenes N-ras, c-myc, and c-fos have been found in high percentages of HCC patients. The cumulative effect of these changes may be more important than the order in which they occur. Some of these changes may explain the mechanism(s) by which the hepatitis B virus participates in the development of HCC. © 1994 Wiley-Liss, Inc.     

Effects of chronic antidepressant treatment on α1- and α2-adrenoceptors in the rat anococcygeus muscle

Summary The effects of a single administration (48 hours) and of chronic (14 days) treatment with tricyclic (desipramine, nortryptiline) and nontricyclic (mianserin, nomifensine) antidepressant drugs on responses of the isolated anococcygeus muscle to the ₂-adrenoceptor agonist xylazine (inhibition of contraction to field stimulation at 1 Hz) and to the ₁-adrenoceptor agonist phenylephrine (contraction of the muscle) have been studied.Of the drugs used only desipramine and nortryptiline administered chronically reduced the responsiveness of the anococcygeus muscle to phenylephrine suggesting a desensitization of postsynaptic ₁-adrenoceptors. Long-term but not acute administration of antidepressants resulted in significant decrease in sensitivity of presynaptic ₂-adrenoceptors to xylazine. These results show that the adaptative changes of -adrenoceptors in the rat anococcygeus muscle following long-term administration may depend on the efficiency to inhibit the neuronal uptake and the ability to antagonize ₁-adrenoceptors.