A study of the vascular and acid-secretory responses of the rat gastric mucosa to histamine

1. The effects of histamine on gastric mucosal blood flow in the presence and absence of gastric acid secretion were studied in the rat. 2. Histamine, in doses greater than those required to stimulate maximal acid secretion, caused a small increase in mucosal blood flow per unit acid output. 3. When acid secretion was inhibited by methyl analogues of prostaglandin E2, histamine reduced arterial blood pressure and gave a dose dependent rise in mucosal blood flow. 4. When acid secretion was inhibited by the histamine H2-receptor antagonists, burimamide and metiamide, histamine still increased mucosal blood flow. 5. The use of H1-receptor antagonists to inhibit the histamine-induced hyperaemia was made difficult by their vasodilator actions. 6. The selective histamine H2-receptor agonist, 4-methyl histamine, had no effect on arterial blood pressure in doses which stimulated acid secretion. The increase in mucosal blood flow which accompanied the stimulation of acid secretion was inhibited by the anti-secretory prostaglandins and H2-receptor antagonists. 7. The selective histamine H1-receptor agonist, 2-pyridyl ethylamine, had no effect on acid output but increased resting mucosal blood flow. 8. These results suggest that histamine H2-receptors, primarily concerned with acid secretion, and H1-receptors concerned with vasodilatation are both present in the rat gastric mucosa.     

Chorionic gonadotropin inhibits rat mammary carcinogenesis through activation of programmed cell death

Human chorionic gonadotropin (hCG) inhibits the progression of 7,12-dimethylbenz[a]anthracene (DMBA) induced mammary carcinomas. In order to determine whether this phenomenon was mediated by induction of programmed cell death or apoptosis, 45-day-old virgin Sprague-Dawley rats received 8 mg DMBA/100 g body weight; 20 days later they were injected daily with 100 IU hCG for 40 days (DMBA + hCG group). Age-matched untreated, hCG- and DMBA + saline treated rats were used as controls. Tissues were collected at the time of DMBA administration and at 5, 10, 20 and 40 days of hCG injection. RNA from mammary glands, adenocarcinomas and ovaries was probed for transforming growth factors (TGF) alpha and beta, and the apoptotic genes TRPM2, ICE, bcl2, bcl-XL, bcl-XS, p53 and c-myc. The mammary glands of hCG-treated animals with or without DMBA exhibited elevated expression of TRPM2, ICE, bcl-XS, c-myc and p53; and elevation in the apoptotic index. Mammary adenocarcinomas developed in those animals treated with hCG showed an elevation in the expression of p53, c-myc and ICE genes in comparison with the levels detected in the adenocarcinomas developed by the animals treated with DMBA alone. No significant alterations in the expression of any of the genes tested was observed in ovarian RNAs. These results led us to conclude that hCG induces programmed cell death in the mammary gland initiated in the carcinogenic process, that this process is p53 dependent, and is modulated by c-myc expression. Our data also indicate the possibility that a cell death program dependent on the bcl2 family exists, because of the potential involvement of p53, bcl-XS and Bax in apoptosis. This additional mechanism of tumor inhibition makes hCG treatment a useful approach for the prevention and therapy of breast cancer.     

The structure of normal human attention: The Test of Everyday Attention

A range of tests of everyday attention is described, based on ecologically plausible activities such as searching maps, looking through telephone directories, and listening to lottery number broadcasts. An age-, sex- and IQ-stratified sample of 154 normal participants was given these tests, along with a number of existing tests of attention. The factor structure revealed by this data set matched well contemporary evidence for a set of functionally independent attentional circuits in the brain, and included factors for sustained attention, selective attention, attentional switching and auditory-verbal working memory. The Test of Everyday Attention (TEA), which was developed and standardized on the basis of these subtests, has three parallel forms, high test-retest reliability, and correlates significantly with existing measures of attention. Furthermore, selected subtests successfully discriminate among a number of brain-impaired groups, including closed head injury versus age-matched controls, minimal versus mild Alzheimer's disease, and progressive supranuclear palsy patients versus age-matched controls.     

The psychosocial impact of skin disease. An overview

When the skin is disfigured by disease, it has an impact on the afflicted person. The intensity of the effect depends on many variables including the natural history of the disease, the characteristics of the individual patients and their life situation, as well as the attitudes and assumptions of the culture at large about the meaning of skin disease. Fantasies about skin disease, shared by patients and onlookers alike, relate to guilt, control of bodily boundaries, and perfectionist yearnings. Some issues involved in these fantasies include distortions about contagion, dirt, and sexuality. Ways of helping patients to manage the impact of their skin disease include an empathic doctor-patient alliance, education of patients and the community, and if indicated, referral for psychiatric consultation.     

HAH1 is a copper-binding protein with distinct amino acid residues mediating copper homeostasis and antioxidant defense

HAH1 is a 68-amino acid protein originally identified as a human homologue of Atx1p, a multi-copy suppressor of oxidative injury in sod1 delta yeast. Molecular modeling of HAH1 predicts a protein structure of two alpha-helices overlaying a four-stranded antiparallel beta-sheet with a potential metal binding site involving two conserved cysteine residues. Consistent with this model, in vitro studies with recombinant HAH1 directly demonstrated binding of Cu(I), and site-directed mutagenesis identified these cysteine residues as copper ligands. Expression of wild type and mutant HAH1 in atx1 delta yeast revealed the essential role of these cysteine residues in copper trafficking to the secretory compartment in vivo, as expression of a Cys-12/Cys-15 double mutant abrogated copper incorporation into the multicopper oxidase Fet3p. In contrast, mutation of the highly conserved lysine residues in the carboxyl terminus of HAH1 had no effect on copper trafficking to the secretory pathway but eliminated the antioxidant function of HAH1 in sod1 delta yeast. Taken together, these data support the concept of a unique copper coordination environment in HAH1 that permits this protein to function as an intracellular copper chaperone mediating distinct biological processes in eucaryotic cells.     

Treatment of compulsive behaviour in eating disorders with intermittent ketamine infusions

We have previously shown that eating disorders are a compulsive behaviour disease, characterized by frequent recall of anorexic thoughts. Evidence suggests that memory is a neocortical neuronal network, excitation of which involves the hippocampus, with recall occurring by re-excitement of the same specific network. Excitement of the hippocampus by glutamate-NMDA receptors, leading to long-term potentiation (LTP), can be blocked by ketamine. Continuous block of LTP prevents new memory formation but does not affect previous memories. Opioid antagonists prevent loss of consciousness with ketamine but do not prevent the block of LTP. We used infusions of 20 mg per hour ketamine for 10 h with 20 mg twice daily nalmefene as opioid antagonist to treat 15 patients with a long history of eating disorder, all of whom were chronic and resistant to several other forms of treatment. Nine (responders) showed prolonged remission when treated with two to nine ketamine infusions at intervals of 5 days to 3 weeks. Clinical response was associated with a significant decrease in Compulsion score: before ketamine, mean +/- SE was 44.0 +/- 2.5; after ketamine, 27.0 +/- 3.5 (t test, p = 0.0016). In six patients (non-responders) the score was: before ketamine, 42.8 +/- 3.7; after ketamine, 44.8 +/- 3.1. There was no significant response to at least five ketamine treatments, perhaps because the compulsive drive was re-established too soon after the infusion, or because the dose of opioid antagonist, nalmefene, was too low.     

Arnold-Chiari malformation in a captive African lion cub

PURPOSE: Surgery and systemic chemotherapy offer modest benefit to patients with recurrent glioblastoma multiforme. These tumors are associated with rapid growth and progressive neurological deterioration. Radiosurgery offers a rational alternative treatment, delivering intensive local therapy. A pilot protocol to treat recurrent glioblastoma was developed using fractionated stereotactic radiosurgery with concurrent intravenous (i.v.) Taxol as a radiation sensitizer. METHODS AND MATERIALS: The treatment outcome was analyzed in 14 patients with recurrent glioblastoma treated with fractionated stereotactic radiosurgery and concurrent Taxol. Median tumor volume was 15.7 cc and patients received a mean radiation dose of 6.2 Gy at 90% isodose line, 4 times weekly. The median dose of Taxol was 120 mg/m2. RESULTS: The median survival was 14.2 months, 1-year survival was 50%. CONCLUSIONS: Survival for this small group of patients was similar to or better than historical controls or patients treated with single-fraction radiosurgery alone. This data should stimulate the investigation of both fractionated radiosurgery and the development of radiation sensitizers to further enhance treatment.