Neurotransmitters and memory: role of cholinergic, serotonergic, and noradrenergic systems

In Alzheimer's disease (AD), pathological changes are found in the basal forebrain cholinergic system (BFCS), serotonergic raphe (RA), and noradrenergic locus coeruleus (LC) systems. The present study was designed to determine the extent to which selective damage in each of these systems individually could produce an impairment of memory, one of the clinical symptoms of AD. Rats were given selective lesions by injecting ibotenic acid into the nucleus basalis magnocellularis and medial septal area (i.e., BFCS); 5,7-dihydroxytryptamine into the medial and dorsal RA; and 6-hydroxydopamine (6-OHDA) into the LC or by ip injections of (2-chloroethyl)N-ethyl-2-bromobenzylamine HCl (DSP4). Levels of choline acetyltransferase (ChAT), norepinephrine, and serotonin verified lesion effectiveness and selectivity. Chronic changes in serotonergic-2 and beta-adrenergic receptors were also determined. Rats were tested in a delayed spatial alternation in a T-maze. BFCS lesions impaired choice accuracy with intertrial delays of 5, 30, and 60 s. RA lesions or DSP4 injections impaired choice accuracy only when the intertrial delay was 60 s. LC lesions (by 6-OHDA) did not impair choice accuracy at any delay. The results suggest that the pathological changes in the BFCS and RA are sufficient to produce the types of memory impairments associated with dementia, but the quantitative effects of pathology in these two systems are different.     

Melbourne trial of adjuvant immunotherapy in operable large bowel cancer

A controlled randomized clinical trial was undertaken to assess the ability of combined non-specific and specific immunotherapy to alter the disease-free interval and overall survival of patients with Stage B or C large bowel cancer. The immunotherapy consisted of a 2 year programme of vaccinations with BCG and neuraminidase-treated autologous tumour cells. Three hundred and one patients entered the trial. At 5 years of follow-up there is no evidence that this form of immunotherapy can alter either the disease-free interval or survival in this group of patients.     

Immunogenic and Antigenic Epitopes of Immunoglobulins Binding of Human Monoclonal Anti-D Antibodies to FcRI on the Monocyte-Like U937 Cell Line

Seventeen human monoclonal IgG1- or IgG3 anti-D-secreting clones have been examined for their ability to sensitise O+ red cells for Fc-receptor-mediated rosette formation with U937 cells. IgG3 but not IgG1 anti-D antibodies were able to mediate stable rosette formation with unstimulated U937 cells via interaction with the FcRI receptor. Decreasing FcRI density by incubating U937 cells with di-butyryl cAMP almost completely abolished rosette formation, whilst increasing FcRI density by incubating U937 cells with interferon-gamma increased the percentage of cells forming rosettes with IgG3- and IgG1-sensitised red cells. These data suggest that rosette formation between IgG anti-D-sensitised red cells and FcRI-expressing cells is dependent upon the density of IgG3 on the red cell surface, the density of FcRI on the effector cell, multiple FcRI/IgG interactions are required for stable rosette formation and that more FcRI/IgG1 than FcRI/IgG3 interactions are required.     

Design and fabrication of cementless hip stems

Theoretical and experimental studies before and after stem insertion demonstrated that stresses and strains were closer to normal for uncemented stems than for cemented stems. The values were affected by relative tightness of fit in the proximal and distal regions and by the presence or absence of a collar. For designing an optimal fit-stem, the average femoral geometry was first determined. The stem was used in a photoelastic coating study that showed a continuous strain field over the bone surface. The average proximomedial bone strains for intact, press-fit, loose press-fit with collar, and proximally cemented (to simulate ingrowth) designs were 100%, 65%, 101%, and 54%, respectively. Localized patches of high strain were seen on the proximal bone surface and beneath a collar, indicative of localized stem-bone contact points.     

Nafenopin, a hypolipidemic and non-genotoxic hepatocarcinogen increases intracellular calcium and transiently decreases intracellular pH in hepatocytes without generation of inositol phosphates

Addition of nafenopin (30-300 microM to 45Ca2+ preloaded cultured hepatocytes caused a rapid and concentration-dependent increase in 45Ca2+ efflux in a manner similar to vasopressin, as evidenced by the loss of radioactivity from the cells. In contrast to vasopressin, addition of nafenopin to [3H]inositol prelabelled hepatocytes in culture did not increase [3H]inositol phosphate production. When added simultaneously with vasopressin, nafenopin inhibited the vasopressin-stimulated [3H]inositol phosphate production. In hepatocyte suspensions isolated from rats treated for 1 week with a carcinogenic dose of nafenopin (1000 ppm in their daily food) the incorporation of [3H]inositol into the phosphoinositide fraction, particularly phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate, was much less than that in hepatocytes isolated from untreated rats. The vasopressin-stimulated [3H]inositol phosphate production was also decreased. Experiments with hepatocyte suspensions preloaded with Ca2+ or pH sensitive fluorescent indicators demonstrated that addition of nafenopin caused an increase in intracellular free Ca2+ and transient acidification of the cells. The increase in [Ca2+]i was decreased by only about 25% when extracellular calcium was removed indicating that nafenopin mainly mobilizes Ca2+ from intracellular stores. The recovery to basal pH was amiloride-sensitive indicating the importance of Na+/H+ exchange in pH recovery after intracellular acidification. Amiloride also inhibited DNA synthesis induced by nafenopin and by epidermal growth factor in cultured hepatocytes; but this effect occurred concomitantly with inhibition of basal DNA synthesis. We suggest that hepatic Ca2+ mobilization induced by nafenopin may play an important role in the mechanism by which nafenopin exerts its physiological as well as its tumour promotive activity upon chronic treatment with carcinogenic doses.     

Primary carcinoid tumor of the urinary bladder.

A 62-year-old woman who presented with urinary frequency and microscopic hematuria was found to have a 1.2 x 1.0 x 0.6-cm polypoid carcinoid tumor of the urinary bladder. The tissue resected from the base after removal of the polypoid lesion disclosed a small focus of residual carcinoid tumor, associated with Brunn's epithelial nests, cystitis cystica, and cystitis glandularis. Tumor cells exhibited strong argyrophilia and weak argentaffinity. Immunohistochemical staining reactions were strongly positive for chromogranin and serotonin, and electron microscopy revealed characteristic dense-core granules. Flow cytometric evaluation revealed an aneuploid cell population with a DNA index of 1.20.     

Role of topical lignocaine during carotid endarterectomy.

Forty carotid endarterectomies were undertaken in 34 patients. Operations were prospectively randomized to periarterial application of either 1 per cent lignocaine (n = 19) or normal saline (n = 21), and detailed measurements taken of intraoperative pulse rate and blood pressure. Patients receiving lignocaine demonstrated a lower pulse rate, and lower systolic and mean blood pressures than those receiving placebo, with significance in relation to clamp application and shunt removal (P < 0.05). It was particularly noticeable that patients receiving lignocaine demonstrated less intraoperative variation in pulse rate and blood pressure. Topical lignocaine stabilizes pulse rate and blood pressure during carotid endarterectomy.