The expression of somatostatin receptors 1 and 2 in benign,pre‐malignant and malignant laryngeal lesions

The expression of somatostatin receptors 1 and 2 in benign, pre‐malignant and malignant laryngeal lesions The role of chemotherapy in squamous cell carcinoma of the larynx has not been clearly defined. Whilst toxic chemotherapy regimes may confer a marginal improvement in survival, surgery and radiotherapy remain the mainstay of treatment. Somatostatin is a naturally occurring peptide, which exerts antiproliferative and antiangiogenic effects via five membrane‐bound receptor subtypes. The expression of somatostatin receptor subtypes (SSTRs) 1 and 2 was studied in benign, pre‐malignant and malignant laryngeal specimens. Epithelial expression of SSTR1 was detected in 4/6 (67%) Reinke's oedema, 5/6 (83%) pre‐malignant and 8/12 (67%) malignant specimens, with virtually no stromal or vascular expression. High levels of epithelial SSTR2 expression were noted in all Reinke's oedema specimens, compared with low‐to‐moderate levels in only 2/6 (33%) pre‐malignant and 3/12 (25%) malignant specimens (P < 0.01). This ‘loss’ of epithelial SSTR2 expression may provide a growth advantage in pre‐malignant and malignant laryngeal lesions. Vascular expression of SSTR2 was ubiquitous in all groups, with scant stromal expression. Overall, most (>80%) pre‐malignant and malignant laryngeal specimens expressed at least one of the two SSTR subtypes studied. Somatostatin analogues may have a therapeutic role in squamous cell carcinoma of the larynx.     

Interleukin 1 receptor antagonist (IL1RA) in acute leukaemia: IL1RA is both secreted spontaneously by myelogenous leukaemia blasts and is a part of the acute phase reaction in patients with chemotherapy- induced leucopenia

Abstract: Blast cells derived from peripheral blood of patients with acute myelogenous leukaemia (AML) were cultured in vitro and interleukin 1 receptor antagonist (IL1RA) concentrations determined in culture supernatants. AML blasts derived from patients classified as AML-M4 and AML-M5 subtype showed an increased release of IL1RA. IL1α and IL1β caused a similar increase in AML blast release of IL1RA, and addition of anti-ILl antibodies decreased IL1RA release. IL1RA release from AML blasts was also increased by stem cell factor, tumour necrosis factor α (TNFα), granulocyte-macrophage colony-stimulating factor and macrophage colony-stimulating factor, whereas interleukin 3, interleukin 6, leukaemia inhibitory factor and granulocyte colony- stimulating factor did not significantly alter IL1RA release. When investigating IL1RA serum levels, serum concentrations were decreased in acute leukaemia patients with chemotherapy-induced cytopenia compared with healthy controls. Serum levels of both IL1RA as well as IL1β and soluble TNFα receptors increased when the leucopenic patients developed complicating bacterial infections.     

The effect of the selective PAF antagonist CIS-19 on PAF- and antigen-induced bronchoconstriction, microvascular leakage and bronchial hyperreactivity in guinea-pigs

We investigated the effects of a novel platelet-activating factor (PAF) receptor antagonist, CIS-19 [cis-2-(3, 4-dimethoxyphenyl)-6-isopropoxy-7-methoxy-1-(N-methylformamido)-1, 2, 3, 4-tetrahydronaphthalene], on PAF-, histamine-, substance P- and antigen-induced bronchoconstriction and microvascular leakage, as well as PAF- and antigen-induced bronchial hyperreactivity to methacholine in urethane-anesthetized guinea-pigs. Administration of CIS-19 (0.5–5 mg/kg, i.v.) inhibited the increase in lung resistance induced by PAF (30 ng/kg, i.v.) in a dose-dependent manner, but failed to inhibit the increase induced by histamine (30 μg/kg, i.v.) or substance P (6.5 μg/kg, i.v.). CIS-19 (5 mg/kg, i.v.) did not inhibit the increase in lung resistance induced by ovalbumin (2 mg/kg, i.v.) in actively sensitized guinea-pigs. PAF (30 ng/kg, i.v.)-induced microvascular leakage, measured by the extravasation of Evans blue dye, was dose-dependently inhibited by CIS-19 (0.5–5 mg/kg, i.v.) in the trachea, main bronchi and intrapulmonary airways, but it did not affect histamine (30 μg/kg, i.v.)- or substance P (6.5 μg/kg, i.v.)-induced microvascular leakage at all airway levels. CIS-19 (2.5 and 5 mg/kg) did not affect ovalbumin (2 mg/kg, i.v.)-induced microvascular leakage in all airway levels in actively sensitized guinea-pigs. CIS-19 (2.5 and 5 mg/kg, i.v.) significantly inhibited PAF-induced enhancement of the bronchial response to methacholine, but had no effect on ovalbumin (0.05 mg/kg, i.v.)-induced bronchial hyperreactivity in actively sensitized guinea-pigs. It is concluded that CIS-19 is a potent PAF receptor antagonist which inhibits PAF- but not antigen-induced bronchoconstriction, microvascular leakage and bronchial hyperreactivity. These results suggest that PAF plays little or no role in early airway responses following antigen challenge. Received: 29 April 1996 / Accepted: 10 October 1996     

Effects of synthetic C-terminal fragment of interferon-2α on Daudi cells

Synthetic fragment of human interferon-2α (124th–138th amino acid residue, laboratory code 2438) inhibits the growth of B lymphocytes (Daudi cell line) in a dose-dependent manner. Radiolabeled peptide 2438 binds to specific receptors on the cell surface and competes with interferon-2α for the common binding sites. Translated fromByulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 123, No. 4, pp. 446–448, April, 1997     

Down-Regulation of Estrogen Receptor Immunoreactivity by 17β-estradiol in the Guinea Pig Forebrain

Low amplitude pulses of estradiol-17β (E₂-17β) are more effective than large single bolus injections or constant exposure to E₂-17β in inducing progesterone-facilitated sex behavior in female rats and guinea pigs. The present study examined whether the increased responsiveness to E₂-17β is due to an increase in the number of estrogen receptors in the estrogen receptor rich areas of the hypothalamus and amygdala. Initial studies examined the rapid effects (20 min) of a high dose of E₂-17β (50 μg) on estrogen receptor immunostaining using either the H222 antibody or the ER 21 antiserum. ER 21 immunostaining was not affected by the E₂-17β treatment suggesting that it binds to both occupied and unoccupied estrogen receptors. Therefore the ER 21 antiserum was used to characterize the regulation of estrogen receptor immunoreactivity (ER-IR) by E₂-17β. ER-IR was examined for 48 h and serum E₂-17β for 24 h following a 2 μg s.c. injection of E₂-17β (a dose similar to that used in multiple pulse paradigms). Serum E₂-17β peaked 15 to 30 min following the injection and returned to baseline values by 1 h. In all but one area maximal suppression of ER-IR occurred at 12 h. In summary, 1) decreases in estrogen receptor immunoreactivity following E₂-17β are consistent with studies in which estrogen receptors were assayed by binding assays and estrogen receptor mRNA was determined by in situ hybridization; 2) the ER 21 antiserum is able to detect both occupied and unoccupied estrogen receptors and 3) H222 immunoreactivity is influenced by the presence of E₂-17β, so that the level of H222-IR is a reflection of ligand/receptor binding dynamics. The data suggest that up-regulation of estrogen receptors does not account for the increase in behavioral sensitivity which is observed following multiple pulses of E₂-17β.     

Up-regulation of nicotinic acetylcholine receptors following chronic exposure of rats to mainstream cigarette smoke or α4β2 receptors to nicotine

Smokers are reported to have a higher density of central nicotinic acetylcholine receptors (nAChRs) that non-smokers at autopsy. Whether this increased receptor density is a response to smoking or a result of genetic variability is not known. While sub-chronic treatment of rats and mice with nicotine results in upregulation of central nAChRs, changes in receptor density in response to cigarette smoke have not been studied previously. In this study, male Sprague-Dawley rats were exposed nose-only for 13 weeks to mainstream cigarette smoke followed by assessment of [³H]nicotine binding in five brain regions of smoke- and sham-exposed animals. In smoke-exposed animals, there was a significant increase in nAChR density in the cortex, striatum, and cerebellum (35, 25, and 31% increases, respectively), while there was no significant change in receptor density in the thalamus and hippocampus. Smoke exposure did not alter markedly the affinity of the receptor for nicotine in these brain regions. Furthermore, up-regulation of nAChRs did not alter the biphasic binding properties by which nicotine binds to its receptor. There were no changes in the association (fast phase) or isomerization (slow phase) rate constants, and the percent contribution of slow and fast phase binding to nAChRs was not altered in the up-regulated receptor population compared with control. Similar results were observed following chronic nicotine exposure of cultured cortical cells from fetal rat brain or cells transfected with the α4β2 nAChR subtype. These results show that the up-regulation following smoke exposure in the rat is phenomenologically similar to that observed in vitro. These data provide preliminary evidence for a relationship between cigarette smoking and nAChR up-regulation in vivo and suggest that similar mechanisms of upregulation may underlie chronic smoke exposure of live animals and nicotine exposure of artificially expressed α4β2 receptors in vitro.     

EndocrinologyHormonal profile during the follicular phase in cycles stimulated with a combination of human menopausal gonadotrophin and gonadotrophin-releasing hormone antagonist (Cetrorelix)

A third-generation gonadotrophin-releasing hormone antagonist(Cetrorelix) was used during ovarian stimulation in 32 patientsundergoing assisted reproduction, in order to prevent the prematureluteinizing hormone (LH) surge. In all patients, ovarian stimulationwas carried out with two or three ampoules of human menopausalgonadotrophin (HMG), starting on day 2 of the menstrual cycle.In addition, 0.5 mg of Cetrorelix was administered daily fromday 6 of HMG treatment until the day of ovulation inductionby human chorionic gonadotrophin (HCG). A significant drop inplasma LH concentration was observed within a few hours of thefirst administration of Cetrorelix (P<0.005). Moreover, noLH surge was detected at any point in the treatment period inany of the 32 patients. A mean oestradiol concentration of 2122±935ng/1 was observed on the day of the HCG administration, indicatingnormal folliculogenesis. Like LH, progesterone concentrationalso dropped within a few hours of the first administrationof Cetrorelix (P< 0.005). A 0.5 mg daily dose of Cetrorelixprevented a premature LH surge in all the 32 patients treated.     

Ca antagonist ameliorates glomerular injury via suppression of glomerular hypertrophy in spontaneously hypertensive rats

Summary: A study was conducted to determine whether calcium blockers (CCB) have renoprotective effects, and if so to elucidate the mechanisms of such effects.
A total of 30 uninephrectomized (UNX) spontaneously hypertensive rats (SHR), 5 weeks of age, were divided into three groups. Group 1 was fed a diet containing 0.01% manidipine and 8% NaCl, while groups 2 and 3 were fed diets containing only 8 and 0.5% NaCl, respectively. Feeding of these diets began 7 days after UNX (experimental day 0). Bodyweight, urinary protein /24 h, urinary sodium excretion/24 h, and food intake were measured at certain time intervals.
At time of death (day 9 or 21), estimations of inulin clearance (Cin) and morphological evaluations, determination of glomerular sclerosis index (GSI), tubulointerstitial index (TII) and glomerular volume were performed.
Urinary protein was significantly higher in groups 1 and 2 than in group 3 from day 7 onward, but did not differ between the former two groups. Cin in group 2 was higher than in groups 1 and 3 on day 9, but declined to lower levels than in groups 1 and 3 by day 21. There was no difference in Cin between group 1 and group 3 on day 21. Morphometry (GSI and TII) revealed that renal lesions were more progressive in group 2 than in group 1. Glomeruli in group 2 were markedly larger than those in group 1, but no difference in glomerular volume was noted between groups 1 and 3.
Our findings suggest that CCB prevent progression of renal injury induced by accelerated hypertension in UNX SHR. the mechanisms of prevention may, at least in part, be related to suppression of glomerular hypertrophy. Inhibition of renal injury can be achieved without significant reduction of proteinuria.