Cholecystokinin-B/Gastrin Receptor Blockade Suppresses the Activity of Rat Stomach ECL Cells

Abstract: Gastrin controls the histamine- and chromogranin A- producing enterochromaffinn-like (ECL) cells, the predominant endocrine cell population in the acid-producing part of the rat stomach. They are responsible for most of the circulating pancreastatin, a chromogranin A-derived peptide. The present study examines the ability of two potent and highly selective cholecystokinin-B/gastrin receptor antagonists. RP73870 and YM022, to incapacitate the ECL cells. The two antagonists were given by continuous subcutaneous infusion to otherwise untreated rats and to hypergastrinaemic rats treated with gastrin-17 (continuous subcutaneous infusion) or omeprazole (orally) for 7 days. Several parameters reflecting ECL cell activity were measured: The oxyntic mucosal histidine decarboxylase activity, the histamine concentration, the histidine decarboxylase mRNA and chromogranin A mRNA concentrations, and the serum pancreastatin concentration. In addition, the serum gastrin concentration was measured. RP73870 and YM022 greatly lowered the oxyntic mucosal histidine decarboxylase activity and the histidine decarboxylase mRNA and chromogranin A mRNA concentrations, and also reduced the oxyntic mucosal histamine concentration and the serum pancreastatin concentration. Moreover, they raised the serum gastrin concentration. With respect to blockade of histidine decarboxylase activity, 1.0 μmol· g^?1 · hr^?1 was an almost maximally effective dose for both RP73870 and YM022. The corresponding ID₅₀ values were 0.04 and 0.05 μmol- kg^?1 · hr^?1. RP73870 and YM022 inhibited the hypergastrinaemia-evoked rise in all ECL-cell parameters. The results suggest that sustained cholecystokinin-B/gastrin receptor blockade causes lasting deactivation of the ECL cells.     

Spontaneous intracerebral hemorrhage

We report on 146 patients with spontaneous intracerebral hemorrhage treated in the period between 1984 and 1988. The aim of this retrospective study was to point out factors for operative respectively conservative treatment.Looking for etiology, age, unconsciousness, localization and extension of hematoma as well as bleeding into the ventricles our results showed that patients over 70 years of age and/or in coma III and IV (Brussels Coma Scale) have a bad prognosis as well as patients with intraventricular bleeding. Patients seem to benefit from operation if hematoma is located in the hemisphere or cerebellar and the extension ranges from 3 to 5 cm.     

Combined Treatment Modalities in Esophageal Cancer: Should chemotherapy be included?

The poor prognosis of esophageal carcinoma patients after treatment with local modalities (surgery/radiotherapy) is well known. The purpose of this review is to assess the question whether addition of chemotherapy to local treatment of squamous cell carcinoma of the esophagus has had any beneficial effect on treatment results. In the absence of a sufficient number of randomized trials addressing this issue, data mainly from single-arm studies are discussed. Compiled data from studies on preoperative chemotherapy, preoperative chemoradiation and chemoradiation without surgery suggest that addition of chemotherapy to local treatment (surgery/radiotherapy) might increase short-term survival (2 years) compared to local therapy alone. In the case of chemoradiation without surgery this conclusion is strengthened by results from randomized trials. In general lack of long-term follow-up data limits conclusion whether to recommend the inclusion of chemotherapy into treatment of esophageal cancer or not. Treatment results, however, from studies utilizing combination chemotherapy given concomitant with radiotherapy support the contention that well-designed randomized trials with long-term follow-up should be performed. Outside controlled trials, however, surgery or radiotherapy should still be regarded as standard treatment modalities.     

Staff's Experiences with Patients' Assaults in a Norwegian Psychiatric University Hospital

This pilot study addressed the problem of patients' assaults on staff at a Norwegian psychiatric university hospital. The questionnaire-based study had a retrospective design, and involved a random sample of staff (n = 85). It revealed that 100% of the nursing staff and 60.9% of the therapists (doctors, psychologists, and social workers) had been physically assaulted by patients at least once during their careers at the hospital. Most of the assaults did not result in sick leave, and could as such be classified as not serious. There were no significant differences in the number of assaults on male and female staff or between staff in the emergency, intermediary, rehabilitation and psycho-geriatric wards. The staff responded that they believed male patients were more violent and threatening than female patients, although a majority had been assaulted more frequently by female than by male patients. Assault was the reason most frequently given for physically restraining patients, and most of the staff did not believe that physically restraining patients reduced their chances of recovery. The study suggests that patients' assaults on staff in Norwegian psychiatric hospitals is an important problem, which needs further attention.     

Boron neutron capture therapy of primary and metastatic brain tumors

Boron neutron capture therapy (BNCT) is based on the nuclear reaction that occurs when a stable isotope, boron-10, is irradiated with low energy (0.025 eV) thermal neutrons (n _th) to yield alpha (⁴He) particles and,⁷Li nuclei (¹⁰B+n _th→[¹¹B]→⁴He+⁷Li+2.79 MeV). The success of BNCT as a tumoricidal modality is dependent on the delivery of a sufficient quantity of¹⁰B andn _th to individual cancer cells to sustain a lethal¹⁰B(n, α)⁷Li reaction. Boron delivery agents include a variety of compounds, such as the sulfhydryl containing polyhedral borane sodium borocaptate (Na₂B₁₂H₁₁SH, [BSH]), boronoporphyrins, boronophenylalanine, carboranyl uridines (CBU), and boronated monoclonal antibodies (MAb). The present review will focus on three delivery systems that currently are under investigation in our laboratories, boronated monoclonal antibodies, carboranyl uridines, and boronophenylalanine. Methodology has been developed to heavily boronate MAb using a precision macromolecule, a “starburst” dendrimer, which can be linked to MAb by means of heterobifunctional reagents. Although the resulting immunoconjugates retain their in vitro immunoreactivity, they lose their in vivo tumor localizing properties and accumulate in the liver. In order to obviate this problem, work is now in progress to produce bispecific MAb, which can simultaneously recognize a tumor-associated antigen and a boronated macromolecule. Boron containing, nucleosides are potential vehicles for incorporating boron compounds into nucleic acids of neoplastic cells. For this purpose, carboranyl uridines have been synthesized with the boron moiety on either the pyrimidine base or on the carbohydrate component. Although such structures appear to be avidly taken up and retained by tumor cells in vitro, only the 5-carboranyl-nucleosides are converted biologically to the nucleotide. There is no evidence, however, that the latter are incorporated into nucleic acids. Other carboranyl nucleosides currently are being synthesized that may have better tumor localizing properties. The potential use of boronophenylalanine as a capture agent for the treatment of melanoma metastatic to the brain also is under investigation. A nude rat model has been developed using human melanoma cells that are stereotactically implanted into the brain. BNCT-treated animals have either had prolonged survival times or continue to live compared to control rats that invariably died of their tumors, thereby suggesting therapeutic efficacy.     

Protective Effect of Atrial Natriuretic Peptide on Electrical-Field-Stimulated Rat Ventricular Strips During Hypoxia

Abstract: We have previously shown that atrial natriuretic peptide reduces lactate accumulation in non-beating rat ventricular myocardium exposed to hypoxic conditions, and that hypoxia induces release of atrial natriuretic peptide from isolated rat atrial tissue. In these studies we suggested that atrial natriuretic peptide may be physiologically important for protection of the myocardium during periods of oxygen deficit. In the present study, we used isolated strips of rat right ventricle, contracted by electrical-field-stimulation, as a model of a beating myocardium. After contraction stabilization, hypoxic conditions were introduced through aeration with 20% O₂, held for 20 or 30 min., and then interrupted by reoxygenation with 95% O₂ The contractile force was recorded and the percentage regain of the contractions after reoxygenation was considered as an indication of the amount of cell damage induced during the period of hypoxia. The results show that after 30 min. of hypoxia and subsequent reoxygenation, ventricular strips treated with atrial natriuretic peptide (0.1 μM) recovered 67.9 ± 2.8% of the prehypoxic force of contraction; control strips from the same ventricle regained 44.9 ± 4.4% (P=0.015) of their initial contractile activity. After 20 min. of hypoxia followed by reoxygenation, a ventricular strip incubated together with an atrium regained 78.6 ± 2.4% of the prehypoxic force of contraction as compared to a 60.2 ± 2.7% regain (P=0.002) for the control strip. We conclude that atrial natriuretic peptide protects the working ventricular myocardium during hypoxia, which further supports our previously reported suggestion that the effect on myocardial metabolism is physiologically relevant during situations of oxygen deficit in heart muscle.