Estrogen receptor beta (ERβ) is expressed in brain astrocytic tumors and declines with dedifferentiation of the neoplasm

Purpose Estrogen receptor (ER) is the second identified receptor mediating the effects of estrogen on target tissues. The role of ER in cancer pathobiology is largely unknown, because specific antibodies have not been available until recently. Initial studies have shown that ER expression declines in breast, ovarian, prostatic, and colon carcinomas. Tamoxifen, a synthetic anti-estrogen compound that is a mixed agonist/antagonist of estrogen receptor (ER) and a pure antagonist of ER, has moderate beneficial effects in human astrocytic neoplasms. However, most published studies agree that glial tumors do not express ER. The purpose of this study was to explore the expression of ER in astrocytic neoplasms.Methods ER expression was monitored immunohistochemically in 56 cases of astrocytomas of all grades (grade I–IV) and in adjacent non-neoplastic brain tissue.Results Moderate or strong nuclear immunopositivity was obtained in non-neoplastic astrocytes and in low-grade astrocytomas, whereas the majority of high-grade tumors were immunonegative or displayed weak immunoreactivity. The progressive decline in ER expression paralleled the increase in tumor grade.Conclusions In as much as ER is possibly the only ER expressed in astrocytes, its decreased expression may play an important role in astrocytic tumor initiation and in the potential response of glial neoplasms to tamoxifen.     

Presence of Two Signaling TGF-β Receptors in Human Pancreatic Cancer Correlates with Advanced Tumor Stage

Transforming growth factor- (TGF-)signal transduction is mediated via specific cellsurface signaling TGF- receptors, most notably thetype I ALK5 (TR-I_ALK5)and the type II(TR-II). We evaluated TR-I_ALK5 andTR-II expression in 41 human pancreatic cancertissue samples and correlated these findings withclinical data of the patients. Northern blot analysisindicated that, in comparison with the normal pancreas,pancreatic adenocarcinomas exhibited 8.0-fold and4.5-fold increases (P < 0.01), respectively, in mRNAlevels encoding TR-I_ALK5 andTR-II. In situ hybridization showed that both TR-I_ALK5 mRNAwere highly expressed in the majority of pancreaticcancer cells. Immunohistochemical analysis ofTR-I_ALK5 and TR-II revealedpositive immunostaining in 73% and 56% of the tumors, respectively. Both receptorswere concomitantly present in 54% of the pancreaticcancer samples. The presence ofTR-I_ALK5 or TR-II and theconcomitant presence of TR-I_ALK5 and TR-II in the cancer cells was associatedwith advanced tumor stage (P < 0.01). These findingsshow that in many human pancreatic cancers, increasedlevels of the two signaling TRs are present. The presence of the signaling TRs inadvanced tumor stages indicates a role in diseaseprogression.     

Pharmacological evidence for beta3 adrenoceptors in the control of rat gastric acid secretion

The effect of the ₃-adrenoceptor agonist BRL37344 on gastric acid secretion evoked by different secretory stimuli was investigated in anaesthetized rats with lumen-perfused stomachs in comparison with the ₂-adrenoceptor agonist clenbuterol. Intravenous injections of BRL37344 (1–10 mol/kg) and clenbuterol (0.01–1 mol/kg) dose-dependently reduced 2-deoxy-D-glucose-induced acid secretion, with BRL37344 about forty times less potent than clenbuterol. BRL37344 (0.1–3 mol/kg) inhibited pentagastrin-induced acid output, whereas clenbuterol was effective only at high doses (10–100 mol/kg). The inhibitory effect of BRL37344 on pentagastrin-induced acid secretion was not modified by the nonselective –adrenoceptor antagonist propranolol, but it was prevented by bupranolol, a ₃-adrenoceptor antagonist. Furthermore, neither BRL37344 (10 mol/kg) nor clenbuterol (100 mol/kg) modified the acid secretion induced by histamine. These data suggest that ₃ adrenoceptors have an inhibitory role in the control of rat gastric acid secretion induced by indirect stimuli.     

Oligosaccharides accumulated in the bovineβ-mannosidosis kidney

Summary The phenotype of bovine-mannosidosis (-mannosidase deficiency), recently identified in Salers cattle, is similar to the caprine form of the disease (Abbittet al., 1991). This investigation was designed to characterize accumulated kidney oligosaccharides in bovine-mannosidosis. Oligosaccharides were extracted from the kidney of an affected Salers calf and purified by chromatographic techniques. The amount of accumulating oligosaccharides in 1 g of wet tissue was about 21µmol. Structures of derivatized oligosaccharides were characterized by high-performance liquid chromatography, mass spectrometry, methylation analysis and sequential exoglycosidase digestions. The major accumulating oligosaccharides were Man1-4GlcNAc and Man1-4GlcNAc1-4GlcNAc. Oligosaccharides accumulating in minor amounts were Man1-4GlcNAc1-4Man1-4GlcNAc, Man1-6Man1-4GlcNAc1-4GlcNAc and Man1-4GlcNAc1-4Man1-4GlcNAc1-4GlcNAc. As in caprine-mannosidosis, oligosaccharides with terminal-mannose residues and cleaved as well as uncleaved chitobiose linkages were identified in bovine-mannosidosis kidney. The accumulating oligosaccharides in tissue were thus identical in bovine and caprine-mannosidosis; however, the source of the novel oligosaccharides remains to be determined.     

A new plasmidic cefotaximase in a clinical isolate of Escherichia coli

Summary Escherichia coli GRI was isolated from an ear exudate of a newborn. The strain was highly resistant to cefotaxime (MIC 128 mg/l). Resistance to cefotaxime and the majority of -lactam antibiotics was readily transferred to anEscherichia coli recipient strain. Both the wild type and the transconjugant strains are different in their resistance phenotype from TEM-3 -cefotaximase producers by higher MICs to the majority of -lactams and lower MICs to ceftazidime. The isoelectric point of the cefotaximase ofE. coli GRI was 8.9 in comparison with 6.3 for TEM-3. Thus, the enzyme produced byE. coli GRI represents a new plasmidic (plasmid pMVP-3) broad spectrum -lactamase (CTX-M) which may not be closely related to either the TEM- oder SHV-family of extended broad spectrum -lactamases.

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Eine neue plasmidische Cefotaximase in einem Escherichia coli Stamm. Escherichia coli

Zusammenfassung GRI wurde aus dem Ohrexsudat eines Neugeborenen isoliert. Der Stamm war hoch resistent gegenüber Cefotaxim (MHK 128 mg/l). Die Resistenz gegenüber Cefotaxim sowie den meisten übrigen -Laktamantibiotika war leicht übertragbar auf einen anderenEscherichia coli Stamm. Sowohl derE. coli Wildtypstamm als auch die Transkonjuganten unterscheiden sich in ihrem Resistenzmuster von den TEM-3-cefotaximase produzierenden Stämmen, und zwar durch höhere MHK-Werte gegenüber der Mehrzahl der -Laktamantibiotika, jedoch niedrigeren MHK-Werten für Ceftazidim. Zudem ist der isoelektrische Punkt der neuen Cefotaximase vonE. coli GRI mit 8,9 gegenüber 6,3 für das TEM-3 Enzym deutlich verschieden. Deshalb liegt mit dem vonE. coli GRI produzierten Enzym eine neue plasmidische (Plasmid pMVP-3) -Laktamase (CTX-M) mit erweitertem Breitspektrum vor. Sie unterscheidet sich sowohl von den bisher beschriebenen Enzymen der TEM- als auch denen der SHV-Gruppe.

     

Heat shock protein induction in rat pancreatic islets by recombinant human interleukin 1β

Summary Interleukin 1, potentiated by tumour necrosis factor , is cytotoxic to pancreatic Beta cells in vitro. We have hypothesized that interleukin 1 induces oxygen free radicals in Beta cells. Since cytotoxicity induced by free radicals and by heat may activate the same cellular repair mechanism (the heat shock response), the aim of this study was to investigate the pattern of protein synthesis in isolated islets after exposure to interleukin 1 (150 pg/ml, 24 h), tumour necrosis factor (50 ng/ml, 24 h), heat shock (43°C, 30 min) and H₂O₂ (0.1 mmol/l, 20 min). By polyacrylamide gel electrophoresis, autoradiography, Western-blot analysis and partial peptide mapping of ³⁵S-methionine labelled islets, interleukin 1 was found to induce a 73 kilodalton protein belonging to the heat shock protein family heat shock protein 70, a heat shock protein 90, and haem oxygenase. A minor induction of heat shock protein 73 and haem oxygenase was seen after H₂O₂. Interleukin 1 did not induce heat shock proteins in rat thyroid cells, rat mesangial cells or in human monocytes. Tumour necrosis factor did not induce selective protein synthesis. Pre-exposure of islets to heat, tumour necrosis factor , or H₂O₂ did not prevent the impairment of glucose-stimulated insulin release seen after 24 h of interleukin 1 exposure. The data are compatible with free radical induction by interleukin 1. However, the heat shock response is not specific for oxidative injury, and previous studies have shown discrepant effects as to a protective effect of free radical scavengers against interleukin 1-mediated beta-cytotoxicity. Thus, a role for free radicals in this context is not definitely proven.     

Splenic marginal zone lymphoma presenting as myelofibrosis associated with bone marrow involvement of lymphoma cells which secrete a large amount of TGF-β

We report here on a patient with splenic marginal zone lymphoma presenting diffuse fibrosis of bone marrow and spleen. After splenectomy and chemotherapy, bone marrow biopsy demonstrated an improvement of fibrosis. Plasma concentration of transforming growth factor (TGF)- was much higher in this patient than in those of age-matched non-Hodgkins lymphoma patients (n=5) at diagnosis, decreasing after resolution of myelofibrosis. Immunostaining with the TGF- antibody revealed that the lymphoma cells in bone marrow and spleen were positive for TGF-. TGF- secreted by tumor cells was thought to stimulate the growth of fibroblasts and synthesize collagen in bone marrow and splenic fibroblasts, and play an important role in the development of marrow and splenic fibrosis in this patient. This is the first report of a patient with splenic marginal zone lymphoma presenting as myelofibrosis associated with bone marrow involvement of lymphoma cells which secrete a large amount of TGF-.     

Localization of Inhibin/Activin Subunits in Normal Pituitary and in Pituitary Adenomas

The localization of inhibin/activin (I/A) subunits was investigated in human normal adenohypophysial cells and in 87 pituitary adenomas of different types, using immunohistochemistry. Monoclonal antibodies directed against , A and B subunits of I/A were employed. In normal pituitary, subunit of inhibin was detected only in FSH-positive gonadotrophs, while A subunit of I/A was expressed in FSH-positive gonadotrophs, GH-cells and in a few PRL-cells. B subunit was found in FSH-positive gonadotrophs, TSH-cells and a few LH-positive gonadotrophs. The three subunits of I/A were detected in the majority of nonfunctioning tumors, while functioning adenomas showed a significantly lower expression. This study shows that , A and B subunits of I/A are expressed by specific adenohypophysial cell types and that they are characteristically present in nonfunctioning adenomas. These results suggest that inhibins and activins may play a role in the local regulation of pituitary hormonal secretion both in normal adenohypophysial cells and in pituitary adenomas.     

Perspectives of beta-lactamases inhibitors in therapy of infections caused by Escherichia coli or Klebsiella with plasmidic resistance to third generation cephalosporins

Summary New plasmidic -lactamases inactivating so far stable cephalosporins, aztreonam and cephamycins restrict the use of these antibiotics in therapy of infections, e.g., byEscherichia coli and Klebsiella. Thus, combinations of -lactamase inhibitors and -lactam antibiotics were investigatedin vitro with regard to their therapeutic perspectives. Minimal inhibitory concentrations and the kinetics of killing in a pharmacodynamic model were determined. Extended broad spectrum betalactamases (EBS--lactamases) representative both for the TEM- and SHV-type were included. None of the available fixed combinations of penicillins and -lactamase inhibitors appears useful for therapy of infections caused by producers of EBS--lactamases. In contrast, combinations of piperacillin and tazobactam or sulbactam plus cephalosporins (cefoperazone, cefotaxime, ceftazidime) or aztreonam are highly active (both by their MICs and bactericidal activity) against TEM-type EBS--lactamases, but less promising for the SHV-type EBS--lactamases, and plasmidic cephamycinase. Of the -lactams available, the monobactam carumonam and the carbapenems (imipenem, meropenem) remain safe in infections caused byE. coli and Klebsiella EBSBase producers.

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Therapeutische Perspektiven von -Laktamase-Inhibitoren bei Infektionen durch Escherichia coli oder Klebsiella mit plasmid-determinierter Resistenz gegenüber Drittgenerationscephalosporinen

Zusammenfassung Neue plasmid-kodierte -Laktamasen inaktivieren bisher stabile Cephalosporine, Aztreonam und Cephamycine. Sie schränken damit die therapeutische Sicherheit dieser Antibiotika bei Infektionen zum Beispiel durchEscherichia coli oder Klebsiellaarten ein. Deshalb wurden die therapeutischen Perspektiven von Kombinationen aus -Laktamase-Inhibitoren und -Laktam-Antibiotikain vitro analysiert. Die minimalen Hemmkonzentrationen (MHK) wurden gemessen. Zu einem pharmakokinetischen Modell wurde die Abtötungskinetik bestimmt. Einbezogen wurden Enzyme sowohl aus der TEM- als auch der SHV-Reihe. Keine der beiden zugelassenen festen Kombinationen aus Penicillinen und -Laktamase-Inhibitoren erwies sich als erfolgversprechend für die Therapie von Infektionen durch Stämme, welche -Laktamasen mit erweitertem Spektrum produzieren. Demgegenüber waren Kombinationen aus Piperacillin und Tazobactam oder Sulbactam mit Cephalosporinen (Cefoperazon, Cefotaxim, Ceftazidim) oder Aztreonam sowohl aufgrund ihrer MHK-Werte als auch ihrer bakteriziden Aktivität im pharmakodynamischen Modell hochaktiv gegenüber TEM--Laktamasen mit erweitertem Spektrum, jedoch weniger wirksam bei Stämmen mit neuen Enzymen der SHV-Reihe und plasmid-kodierter Cephamycinasen. Unter den derzeit vorhandenen -Laktam-Antibiotika kommt anhand ihrerIn-vitro-Aktivität dem Monobactam Carumonam sowie den Carbapenemen (Impipenem, Meropenem) auch ohne -Laktamase-Inhibitor die größte therapeutische Sicherheit bei Infektionen durchE. coli und Klebsiella-Stämme mit der Fähigkeit zur Synthese von -Laktamasen mit erweitertem Spektrum zu.

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Symposium 2nd Biennial Conference on Chemotherapy of Infectious Diseases and Malignancies, Montreux, March 5^th–8^th, 1989.

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Supported by Pfizer GmbH, Karlsruhe, FR Germany.     

Heterophilic interactions between cell adhesion molecule L1 and α<Subscript>v</Subscript> β<Subscript>3</Subscript>-integrin induce HUVEC process extension <Emphasis Type="Italic">in vitro</Emphasis> and angiogenesis <Emphasis Type="Italic">in vivo</Emphasis>

Cell adhesion molecule L1 was implicated in angiogenic processes, tumor formation and metastasis. Here, we provide evidence that the sixth Ig-like domain of L1 (L1Ig6) interacts with _{v 3} to induce process extension of human umbilical vein endothelial cells (HUVECs) in vitro and angiogenesis in vivo. HUVECs formed network-like structures on full-length L1 or L1Ig6 substrates comparable to structures found on matrigel. In the presence of mab _{v 3} or cyclic RGD, apoptosis was induced. In fibrin matrices where L1Ig6 was covalently incorporated, HUVECs formed multicellular and hollow processes through interactions between cell-surface _{v 3} and RGD-sites of matrix-immobilized L1Ig6. No such processes were induced by L1Ig6 having non-functional RDG-sites, or in the presence of mab _{v 3} or cyclic RGD. In those matrices, increased apoptosis was found. Co-immunoprecipitation of L1 or L1Ig6 with _{v 3} suggests close interactions. Furthermore, L1Ig6 stimulated HUVECs showed increased tyrosine phosphorylation of _{v 3} and phosphorylation of MAP kinases (ERK1 and ERK2) but not AKT indicating specific activation of _v and _{v 3} followed by activation of downstream kinases. Application of L1Ig6-modified fibrin matrices on CAMs induced 50–60% increased _v and _v3 protein expression and in vivo angiogenesis indicated by ~50% increased mean vascular length density. The results demonstrate angiogenic potential of L1Ig6 involving ligation and activation of _v3     

Elevated Serum Levels of Astroglial S100β in Patients with Liver Cirrhosis Indicate Early and Subclinical Portal-Systemic Encephalopathy

Portal-systemic encephalopathy is the prototype among the neuropsychiatric disorders that fall under the term Hepatic Encephalopathies. Ammonia toxicity is central to the pathophysiology of Portal-systemic encephalopathy, and neuronal ammonia toxicity is modulated by activated astrocytes. The calcium-binding astroglial key protein S100 is released in response to glial activation, and its measurement in serum only recently became possible. Serum S100 was determined by an ultrasensitive ELISA in patients (n=36) with liver cirrhosis and transjugular intrahepatic portosystemic stent-shunt. Subclinical portal-systemic encephalopathy and overt portal-systemic encephalopathy were determined by age-adjusted psychometric tests and clinical staging, respectively. Serum S100 was specifically elevated in the presence of subclinical or early portal-systemic encephalopathy, but not arterial ammonia. S100 levels elevated above a reference value (S100 110pg/ml) or the cut off value determined in our group of patients (112pg/ml) predicted subclinical portal-systemic encephalopathy with a specificity and sensitivity of 100 and 56.5%, respectively. Serum S100 was significantly dependent on liver dysfunction (Child-Pugh score), but was more closely related to cognitive impairments than the score. Serum S100 seems to be a promising biochemical surrogate marker for mild cognitive impairments due to portal-systemic encephalopathy.     

B cell adrenoceptors and sulphonylurea-induced insulin release in mouse islets

Summary Interactions of tolbutamide and glibenclamide with B cell adrenoceptors have been reported. This study evaluated the possible role of such interactions in the stimulation of insulin release. Mouse islets were incubated in the presence of 10 mmol/l glucose alone or with tolbutamide (10 mol/l) or glibenclamide (0.02 mol/l). At 0.01–10 mol/l, blockers of ₂-adrenoceptors (yohimbine, idazoxan) or ₁-adrenoceptors (prazosin) had practically no effect on glucose-induced insulin release and did not affect its potentiation by sulphonylureas, except for a slight increase by 10 mol/l prazosin and idazoxan. Nonspecific -blockers (phentolamine, dihydroergotamine) increased control release at 10 mol/l, but only the latter amplified the response to tolbutamide. Blockers of -adrenoceptors were tested at 0.1–100 mol/l: propranolol (₁, ₂), metoprolol (₁) and compound ICI 118-551 (₂). They increased glucose-induced insulin release at 100 mol/l but variably altered the effect of sulphonylureas. Blockers of adrenoceptors have, thus, no effect on insulin release in vitro at therapeutic concentrations. At high concentrations, they non-specifically affect the action of sulphonylureas. We conclude that an interaction with B cell adrenoceptors is not involved in the insulinotropic action of sulphonylureas.     

Detection of anti-bovine β2-glycoprotein I antibody in sera from patients with antiphospholipid syndrome

We studied and characterized anti-bovine ₂ I antibodies (aB₂-GPI) in sera from patients with antiphospholipid syndrome (APS) by ELISA. Bovine ₂-glycoprotein I ₂-GPI was purified by heparin affinity and DEAE ion-exchange chromatography, and identified on immunoblots using a monoclonal antibody against human ₂-GPI and by amino acid sequence analysis. aB₂-GPI levels in the sera from 36 APS patients were measured by ELISA using purified bovine ₂-GPI as an antigen. The mean±standard deviation level of aB₂-GPI was 17.4±22.0 units in the 58% of APS patients who were positive. There was a significant correlation (P=0.003) between aB₂-GPI and anticardiolipin antibody (aCL) levels. aB₂-GPI from the sera of patients with APS was inhibited by bovine ₂-GPI itself. Purified IgG from the sera of patients with APS showed that bovine ₂-GPI was capable of acting as a cofactor for aCL. Purified bovine ₂-GPI was useful antigen for conventional ELISA. aB₂-GPI may contribute to the further development of aCL analysis and to the understanding of the pathogenesis of APS.     

17β-Estradiol Attenuates Quinolinic Acid Insult in the Rat Hippocampus

A number of studies have shown that 17-estradiol has neuroprotective properties. In this study the neuroprotective effect of 17-estradiol against quinolinic-acid-induced neuronal damage was investigated. Ovariectomized rats were separated into three groups of five animals each. Rats received daily subcutaneous injections of either olive oil or 17-estradiol in olive oil for 7 days prior to and following a single intrahippocampal injection of 1 mol quinolinic acid in 2 L phosphate-buffered saline. The brains were removed and the hippocampi either sectioned and stained for microscopic examination or used in glutamate receptor saturation binding studies. Glutamate receptor displacement binding studies were also performed using concentrations of 0.05 nM–5 M 17-estradiol or quinolinic acid. The results show that 17-estradiol protects hippocampal neurons from quinolinic-acid-induced neurodegeneration by competing with quinolinic acid to bind to the N-methyl-D-aspartate (NMDA) receptor. This would result in a decrease in intracellular free-calcium influx and resultant neuronal swelling.     

Role of Central Interleukin-1β in Gastrointestinal Motor Disturbances Induced by Lipopolysaccharide in Sheep

Cytokines are involved in the symptoms of theacute phase response induced by infectious diseases inhumans as well as in animals, and interleukin-1(IL-1 ) has a pivotal role in these changes. The role of central IL-1 in the gastrointestinalhypomotility and fever evoked by intravenousadministration of lipopolysaccharide (LPS) and themechanisms involved, were investigated in sheep as anexperimental model. LPS (0.1 g/kg, intravenously)induced gastrointestinal hypomotility and fever thatwere significantly reduced by priorintracerebroventricular administration of IL-1receptor antagonist protein (IL-1ra, 2 g/kg). The effects of LPS were mimickedby intracerebroventricular IL-1 (50 ng/kg),whereas IL-1 injected intravenously at the samedose only caused a slight and transient fever withoutmodifying the gastrointestinal motility. Priorintracerebroventricular administration of thecyclooxygenase inhibitor indomethacin (100 g/kg) butnot the corticotropin-releasing factor (CRF) receptorantagonist -helical CRF_9-41 (5 g/kg) blocked alleffects evoked by both LPS and IL-1. These resultssuggest that in sheep, LPS induces digestive motordisturbances through a central release of IL-1 andprostaglandins.     

Thalassemia intermedia: compound heterozygous β∘/β+-thalassemia and co-inherited heterozygous α+-thalassemia

Summary The relative excess of - over -globin chains in the erythroid precursors is the chief pathophysiological factor of homozygous -thalassemia. The clinical picture is usually characterized by a transfusion-dependent dyserythropoietic anemia (thalassemia major). However, some patients present with moderate anemia that does not require regular blood transfusions (thalassemia intermedia). The molecular heterogeneity of -thalassemia mutations and changes of - and -globin gene expression play an important role in modifying the clinical phenotype. We report here on a female Greek patient with homozygous -thalassemia but normal growth and development, excellent exercise tolerance, and no need of blood transfusions. She is thus mildly affected clinically, although there is marked pallor, jaundice, and hepatosplenomegaly. These signs correspond to her marked hypochromic, microcytic anemia with erythroid hyperplasia of the bone marrow. -Globin genotyping shows her to be compound heterozygous for the codon 39 C T -nonsense mutation and for the T C ⁺-mutation at position 6 of the splice consensus at the exon 1/intron 1 junction (CD39 C T/IVS 1–6 T C). -Globin gene mapping demonstrates the presence of a 3.7-kb ⁺-thalassemia deletion on one allele (–^3.7/). Taken together, this study identifies a complex interaction of genetic factors that do not significantly alter the clinical phenotype when present alone but ameliorate the course of homozygous -thalassemia when inherited in combination.Abbreviations Hb hemoglobin - Hct hematocrit - HPFH hereditary persistence of fetal hemoglobin - IVS intervening sequence - MCH mean corpuscular hemoglobin - MCV mean corpuscular volume - PCR polymerase chain reaction     

Serum beta 2 microglobulin in adult myeloid acute leukemias

Summary Serum ₂ microglobulin levels, measured by radioimmunoassay (Phadebas test), were found increased in acute myeloid leukemias at diagnosis. Serum ₂ microglobulin levels were significantly higher in patients with monocytic leukemias (13 patients, M4–M5 FAB classification) than in those with other cytological types (18 patients). ₂ microglobulin levels at diagnosis were correlated with serum lysozyme levels, but they were not correlated with blood blast counts, serum LDH and ferritin levels.195 serum ₂ microglobulin measurements were made serially in 30 patients with acute myeloid leukemias in first remission. Compared to values at diagnosis, ₂ microglobulin levels in remission were significantly decreased. Out of 30 patients in remission 12 had increased serum ₂ microglobulin levels (>3 mg/l). Serial measurements were not predictive for relapses.     

Interleukin-1β Inhibits Growth Factor-Stimulated Restoration of Wounded Rat Gastric Epithelial Cell Monolayers

We examined the effect of interleukin-1(IL-1) on spontaneous and enhanced restoration(cell migration and proliferation) using an in vitrowound model comprising a confluent monolayer of ratgastric epithelial RGM1 cells. Repair of an artificialwound in a cell monolayer was found to be time- andconcentration-dependent when the cells were incubatedwith epidermal growth factor (EGF) or transforming growth factor (TGF)- alone for up to 24hr. The growth factors also stimulated DNA synthesissignificantly for 24 hr in a concentration-relatedmanner. IL-1 had no effect on wound restoration in the absence of the growth factors. However, itmarkedly inhibited the restoration enhanced by EGF andTGF-, the inhibition being about 60% and 70%,respectively. In addition, IL-1 significantly reduced the DNA synthesis stimulated by thegrowth factors. The EGF- and TGF--enhancedrestoration was reduced by about 30% by mitomycin C,which potently inhibited the stimulated DNA synthesis.Mitomycin C had no effect on the spontaneous restoration.Even when treated with mitomycin C, the inhibitoryeffect of IL-1 on the enhanced wound repair wasstill observed; however, the extent of the inhibition was decreased. These results indicate thatIL-1 inhibits the migration as well as theproliferation of gastric epithelial cells enhanced byEGF and TGF-, resulting in a failure of woundhealing.     

Distribution of β-Adrenoceptor Subtypes in Gastrointestinal Tract of Nondiabetic and Diabetic BB Rats A Longitudinal Study

The effects of aging and diabetes on thedistribution of -adrenoceptor subtypes in the gutwere investigated in the BB rat.[¹²⁵I]Cyanopindolol binding to 10-msections was evaluated using film autoradiography. Cyanopindolol binding to -,₁-, and₂-adrenoceptors was displaced by 1M propranolol, 50 nM ICI-89-406, and 100 nMICI-118-551, respectively. -Adrenoceptor bindingwas highest in the circular muscle of proximal colon and lowest in thepylorus of 4- to 5-month-old rats. Aging (8- to10-month-old vs. 4- to 5-month-old rats) was associatedwith increased -adrenoceptor binding in thepylorus and reduced binding in the proximal colon.Diabetes had a time-dependent effect on the level of-adrenoceptor binding. It was increased in theantral and pyloric stomach but longer periods ofdiabetes caused a reduction in -adrenoceptorbinding in the pylorus. Those in the intestine werereduced time-dependently and involved₁- or ₂-adrenoceptorsor both.     

Pharmacological basis for duration of effect: Formoterol and salmeterol versus short-acting β2-adrenoceptor agonists

The mechanisms behind the long duration of bronchodilating action of the ₂-adrenoceptor agonists formoterol and salmeterol are only partially understood. This review compares pharmacological characteristics of long-acting versus short-acting ₂-adrenoceptor agonists in human and animal airways. Based upon the reviewed evidence, it is concluded that for ₂-adrenoceptor agonists, long duration of action may depend upon several factors. Both formoterol and salmeterol display a higher lipophilicity and have a higher affinity, selectivity, and potency than most short-acting agonists at the ₂-adrenoceptor. Of these factors, lipophilicity may prove to be one of the most important ones by determining the amount of drug entering into the cell membrane in the vicinity of the ₂-adrenoceptor. However, the receptor affinity, maximal relaxant effect (efficacy or intrinsic activity), potency, and receptor selectivity may also be of importance in determining how much ₂-adrenoceptor agonist must remain at the receptor for sustained action.