Cellular and humoral immune response in progressive multifocal leukoencephalopathy

Progressive multifocal leukoencephalopathy (PML) is a fatal, demyelinating disease caused by JC virus (JCV) in patients with severe immunosuppression. We studied the JCV-specific cellular and humoral immune response in 7 healthy donors (HD), 6 human immunodeficiency virus-1 (HIV-1)-infected patients without PML (HIV), 4 HIV-1-negative patients with PML (PML), and 8 HIV-1-positive patients with PML (HIV/PML). As antigens, recombinant virus-like particles of the major structural protein VP1 (VP1-VLP) of JCV, tetanus toxoid (TT), or the mitogen phytohemagglutinin (PHA) were used. Proliferation of peripheral blood mononuclear cells (PBMC) after stimulation with the VP1-VLP was significantly suppressed in PML and HIV/PML patients compared to HD. After antigen stimulation the production of interferon-gamma (IFN-gamma) was reduced in PML, in HIV/PML, and in HIV patients. The production of interleukin-10 (IL-10), however, was elevated in HIV/PML patients. Neither proliferation nor cytokine production correlated with the presence of JCV DNA in PBMC. The immunoglobulin G serum antibody titer to the VP1-VLP was slightly elevated in HIV, elevated in PML, and highly elevated in HIV/PML patients compared to HD. The development of PML appears to coincide with a general impairment of the Th1-type T-helper cell function of cell-mediated immunity.     

Anti-myelin-associated glycoprotein antibodies and endoneurial cryoglobulin deposits responsible for a severe neuropathy

A 73-year-old man was investigated for a peripheral neuropathy which occurred in the course of a Waldenstrom's macroglobulinemia. Serum immuno-fixation electrophoresis demonstrated two IgM monoclonal gammopathies of the kappa and lambda chain isotypes, and one had the physical characteristics of cryoglobulin. Immunoblot studies on the patient's serum revealed antibodies which reacted with peripheral nervous system proteins of different molecular weights including the myelin-associated glycoprotein (MAG). An immunofluorescence study of a superficial peroneal nerve biopsy revealed not only a binding of IgM and kappa light chain on several myelin sheaths but also the presence of IgM and kappa light chain deposits in the endoneurium. On electron microscopic examination, numerous fibres presented a widely spaced myelin and the endoneurial deposits had the ultrastructure of cryoglobulin. This is the first case presenting features of widely spaced myelin related to serum anti-MAG activity associated with monoclonal cryoglobulin deposits in the endoneurium.     

Multiple-regression hospitalization-cost model for pharmacy cost analysis

A multiple-regression model that used hospital data for a single diagnosis-related group (DRG) was developed and tested as a tool for measuring the effect of pharmaceutical services on costs. Computer-generated data from one university teaching hospital for fiscal year 1983 were used to develop a model for identifying patient-specific and treatment-specific factors that correlated with total hospital costs and adjusted total costs (total costs minus room and board). Costs were analyzed for patients hospitalized for cardiothoracic procedures (DRG 108). Data for 100 patients were included. The demographic, severity, treatment-intensity, and drug-use factors included in the model accounted for 95.6% of the variation in adjusted total cost. Length of stay, number of secondary surgical procedures, quantity of supplies or drugs used in the operating room, and several drug therapies--tobramycin, i.v. electrolytes, and i.v. fluids--had significant effects on adjusted total cost. This regression model was useful for assessing the effects of the choice of drug therapy or specific services on the costs for one DRG; it should be tested for other DRGs in other institutions. The usefulness of the model for planning cost-effective services is limited by the need for better billing information, cost-estimation techniques, and records of clinical services provided.     

Modulation of monocrotaline-induced hepatic genotoxicity in rats

Monocrotaline (MCT), a hepatotoxic/hepatocarcinogenic pyr-rolizidinealkaloid (PA) induced DNA-DNA interstrand crosslinks in a dose-dependentmanner through 30 mg/kg. Hepatic cytochrome P-450 has been shownto bioactivate MCT to pyrrole derivatives which are thoughtto be respons-ible for these genotoxic lesions. We have hypothesizedthese lesions to be related to the adverse hepatic actions ofMCT and other PAs. Studies reported here investigated the effectof phenobarbital, a P450 inducer, 2-dimethylaminoethyl-2,2-diphenylvalerate, a P450 inhibitor and butylated hydroxy anisole,a dietary antioxidant, on hepatic DNA-DNA interstrand cross-linksinduced by a single dose of MCT (15 mg/kg i.p.) administeredto male Sprague-Dawley rats. DNA damage was assessed by alkalineelution. The effects of these pretreatment regimens on MCT-inducedDNA-DNA interstrand cross-linking was qualitatively similarto their reported effects on the hepatotoxicity of MCT. Theeffects of these pretreatments on hepatic cytochrome P-450 content,hepatic non-protein sulfliydryl levels and hepatic glutathioneS-transferase activities were similarly investigated in attemptsto explain the observed effects on DNA cross-link induction.These data provide further support for the association betweenDNA damage and the adverse hepatic effects of MCT.     

Properties of a recombinant human secretin receptor: a comparison with the rat and rabbit receptors.

A secretin receptor was cloned from a commercial human pancreatic complementary DNA (cDNA) bank. The amino acid sequence deduced from the nucleotide sequence differed slightly from the three different sequences previously published, suggesting a genetic polymorphism of the human receptor. The binding properties of the receptor were evaluated by testing natural secretin, related peptides, and synthetic analogs or fragments on membranes of Chinese hamster ovary (CHO) cells expressing the receptor after transfection. The second-messenger coupling was evaluated by adenylate cyclase measurement. The human secretin receptor was compared with the rat and the rabbit receptors. In the three animals species, rat and human secretin were equipotent; rabbit secretin was equipotent on human and rabbit secretin receptors and less potent on the rat receptor. Similar data were obtained for the [Arg16]-secretin analog. Deletion of histidine 1 and replacement of aspartate 3 reduced the affinity of the peptides for the three receptors; however, the reduction was more pronounced on rat than on human and rabbit secretin receptors. Finally, the low affinity of the rat and human receptors for vasoactive intestinal peptide (VIP) was identical; the rabbit receptor, however, had a 20-fold higher affinity. Thus the human secretin receptor shows properties of both rat and rabbit receptors. Evaluation of the properties of chimeric receptors will be useful to fit the ligand on the receptors.     

Retinal projections in the ground squirrel (Citellus tridecemlineatus)

The retinal projections of the thirteen-lined ground squirrel were determined by tracing anterograde transport of intravitreally injected horseradish peroxidase (HRP) or wheat-germ conjugated horseradish peroxidase (WGA-HRP). Label was seen in the suprachiasmatic nucleus and adjacent anterior hypothalamic area, the accessory optic system (the medial, dorsal, and lateral terminal nuclei), the dorsal and ventral lateral geniculate nuclei, the intergeniculate leaflet, the pretectal nuclei (the anterior, posterior, and olivary pretectal nuclei and the nucleus of optic tract), and the superior colliculus. Most of these structures were labeled bilaterally, with dense contralateral label and sparse ipsilateral label, a pattern typical for animals with laterally placed eyes. However, the suprachiasmatic nucleus and the nucleus of the optic tract received input only from the contralateral eye. In contrast to previous degeneration studies, the sensitive HRP tracers (in conjunction with cytochrome-oxidase reactivity) revealed an elaborate organization within the lateral geniculate nucleus (dorsal LGN, ventral LGN, and intergeniculate leaflet) that is consistent with existing organizational schemes for other mammalian species.     

Behavioural profile of partial D2 dopamine receptor agonists

The effects of partial D2 dopamine (DA) receptor agonists on the behavioural activation produced by 1.5 and 8.0 mg/kgd-amphetamine were compared with the changes produced by the classical DA antagonist haloperidol. Alterations in behaviour were assessed in standard activity monitoring cages by direct observation of the rats using a rapid time sampling procedure. Haloperidol blockedd-amphetamine (1.5 mg/kg)-induced increases in photocell counts, ambulation, rearing and sniffing up, and after the highest dose of the DA antagonist the animals were mainly inactive. The partial D2 DA agonist SDZ 208–911 was equipotent to haloperidol in blocking the increase in photocell counts and rearing produced byd-amphetamine. However, even high doses of the drug did not reduce the incidence of sniffing or induce inactivity, but qualitative changes in the form of sniffing did occur. Although considerably less potent, preclamol exerted similar effects to SDZ 208–911. The profiles of SDZ 208–912 and terguride were intermediary to those of SDZ 208–911 and haloperidol. All compounds blocked the repetitive sniffing down produced by 8.0 mg/kgd-amphetamine. After a low dose of haloperidol, these stereotyped behaviours were replaced by a behavioural syndrome similar to that observed with low dosed-amphetamine, but inactivity was observed following a further small increase in antagonist dose. The blockade of stereotypy by SDZ 208–911, preclamol and terguride was accompanied only by the low dosed-amphetamine behavioural syndrome; no inhibition of sniffing or induction of inactivity occurred. SDZ 208–912 exhibited a profile with features very similar to that noted with haloperidol. These findings suggest that partial D2 agonists exert similar, but not identical, behavioural effects to classical DA antagonists when dopaminergic function in increased byd-amphetamine. The differences in behavioural profile are discussed in relation to variations in the intrinsic efficacy of the dopaminergic compounds and to differences in the response capability of D2 receptor populations underlying the different behaviours produced byd-amphetamine.     

PSYCHOLOGICAL EFFECTS OF AN EPIDEMIOLOGICAL STUDY OF BENIGN PROSTATIC HYPERTROPHY

SUMMARY The psychological impact of an epidemiological study of benign prostatic hypertrophy (BPH) was assessed in a representative sample of practice list patients. Of the 889 men completing a general health self-report questionnaire previously validated in a screening programme, 75% knew nothing of problems of the prostate, and 84.5% were not at all worried about prostate problems prior to commencement of the study. Receiving the letter of invitation and the procedures neither increased nor reduced anxiety levels for 69% and 70% respectively. In the 227 men referred to hospital for further investigation the procedure increased anxiety in 28%, decreased anxiety in 20%, and had no effect on the remainder. The sample of 137 (16%) men who, prior to interview, were in some way worried about problems of the prostate had significantly more urinary tract symptoms than those who were not at all worried about prostatic problems. Despite being worried about prostatic problems and having significant urinary symptoms, this group was no more likely to have attended a GP for investigation and/or treatment. Results are discussed in relation to the possible psychological effects of general health screening and the reluctance of men to attend for consultation despite awareness and concern regarding urinary symptomatology.