Formation of the nicotinic acetylcholine receptor binding sites

Nicotinic acetylcholine receptors (AChRs) are activated by ACh binding to two sites located on different alpha subunits. The two alpha subunits, alpha gamma and alpha delta, are distinguished by their interface with gamma and delta subunits. We have characterized the formation of the ACh binding sites and found, contrary to the current model, that the sites form at different times and in a set order. The first site forms on alpha gamma subunits during the process of subunit assembly. Our data are consistent with the appearance of this site on alpha beta gamma delta subunit tetramers soon after the site for the competitive antagonist alpha-bungarotoxin has formed and delta subunits have assembled with alpha beta gamma trimers. The second site is located on alpha delta subunits and forms after AChR subunits have assembled into alpha2 beta gamma delta pentamers. By determining the order in which the ACh binding sites form, we have also identified the sites in which the delta and second alpha subunits associate during subunit assembly.     

Treatment of Goodpasture syndrome with cyclophosphamide, prednisone and plasma exchange transfusions

Repeated plasm exchanges were performed in a 44-year-old man with Goodpasture syndrome, also treated with cyclophosphamide and prednisone. Improvement was observed within 3 weeks of starting the protocol, and by the 76th week, endogenous creatinine clearance had increased from 30 to 56 ml/min/1.73 M2 and serum albumin from 2.7 to 3.7 g/dl. Prior treatment with immunosuppressive drugs had not significantly influenced circulating antibody levels. But sustained suppression of antibody was achieved after the plasma exchanges were begun, suggesting that physical removal of circulating antibody combined with antiproliferative drug treatment may be a useful way to control undesirable humoral immune responses.     

Acute renal failure: a study of the course and prognosis of 104 patients and of the role of furosemide

Cortisone, aldosterone or nialamide was administered to adrenalectomized or sham-operated rats for 7 days, and methamphetamine was injected 24 hrs after the last injection of these compounds. Stereotyped head movement and licking activity were scored 5 min, 30 min and 60 min after methamphetamine injection and, in parallel brain methamphetamine levels in similarly treated rats were measured 5 min, 30 min and 60 min after the methamphetamine injection. Adrenalectomy depressed stereotyped head movements but enhanced the brain amphetamine accumulation. Nialamide but not the hormones further increased the amphetamine accumulation in adrenalectomized rats. No drugs had any effect on the amphetamine-induced head movement suppressed by adrenalectomy.     

Intra-oral shape recognition by 138 mentally retarded subjects

Among Ss with normal intelligence, oral shape-recognition tests have shown a relationship between articulatory ability and oral sensory integrity. This investigation explored oral sensory impairment as a possible contributory cause of the articulatory difficulties exhibited by the mentally retarded. The Florida Oral-form Recognition Measure (FORM), a task requiring the intra-oral identification of 10 geometric shapes, was administered to 138 mentally retarded Ss. Twenty Ss were retested to establish reliability. Ss were placed in groups according to etiological categories (AAMD classification) and were assigned speech ratings by a speech pathologist. Of the total sample, 86% had varying degrees of defective speech or language. Mean FORM score was 3.5, and preliminary analysis yielded significant correlations between FORM score and IQ and between speech and language rating. Further multivariate analysis with IQ held as a co-variant indicated no significant relationship between FORM score and communicative ability. This suggests caution in inferring that intra-oral shape-recognition scores reflect degree of oral sensory integrity. Perhaps a battery of oral perceptual tasks might more validly assess oral sensation-perception and aid in clarifying its relationship to speech.     

Altered calcium channel currents in Purkinje cells of the neurological mutant mouse leaner

Mutations of the alpha1A calcium channel subunit have been shown to cause such human neurological diseases as familial hemiplegic migraine, episodic ataxia-2, and spinocerebellar ataxia 6 and also to cause the murine neurological phenotypes of tottering and leaner. The leaner phenotype is recessive and characterized by ataxia with cortical spike and wave discharges (similar to absence epilepsy in humans) and a gradual degeneration of cerebellar Purkinje and granule cells. The mutation responsible is a single-base substitution that produces truncation of the normal open reading frame beyond repeat IV and expression of a novel C-terminal sequence. Here, we have used whole-cell recordings to determine whether the leaner mutation alters calcium channel currents in cerebellar Purkinje cells, both because these cells are profoundly affected in leaner mice and because they normally express high levels of alpha1A. In Purkinje cells from normal mice, 82% of the whole-cell current was blocked by 100 nM omega-agatoxin-IVA. In Purkinje cells from homozygous leaner mice, this omega-agatoxin-IVA-sensitive current was 65% smaller than in control cells. Although attenuated, the omega-agatoxin-IVA-sensitive current in homozygous leaner cells had properties indistinguishable from that of normal Purkinje neurons. Additionally, the omega-agatoxin-IVA-insensitive current was unaffected in homozygous leaner mice. Thus, the leaner mutation selectively reduces P-type currents in Purkinje cells, and the alpha1A subunit and P-type current appear to be essential for normal cerebellar function.     

Evaluation of cefaclor in acute otitis media caused by ampicillin-resistant H. influenzae

Cefaclor was used to treat 13 children with acute otitis media caused by ampicillin-resistant strains of Hemophilus influenzae. The children were re-examined on days 4, 10, and 28. Pharmacologic compliance was assessed by means of a bioinhibition assay on a urine specimen obtained on days 4, 7, and 10. Nine of the 13 children had evidence by tympanogram of residual otitis media with effusion (secretory otitis media). Of these, three were noted to have a bulging, yellow or grey eardrum, which suggested an ongoing acute process. A second middle ear culture was obtained from two of the 3 children, but no pathogens were recovered. Two others had recurrence of otitis shortly after cessation of therapy. Cefaclor is an acceptable antibiotic for the treatment of ampicillin-resistant acute otitis media; but, after cefaclor therapy, some children continued to have a bulging eardrum and sterile pus in the middle ear or had recurrences of otitis soon after cessation of therapy.     

An improved approach to delivery of enteral nutrition in the intensive care unit

Using immunohistochemistry, vasoactive intestinal peptide (VIP) was visualized in taste bud cells of the carp, Cyprinus carpio, and the European catfish, Silurus glanis, by means of light and electron microscopy. Intracellular membrane systems, presumably smooth endoplasmic reticulum, of light (sensory) cells, but not of dark (supporting) cells and basal cells, were densely labelled with antibody. In the frog (four species: Rana temporaria, R. ridibunda, R. arvalis, R. pipiens), taste bud cells did not label. However, the dense basal nerve fibre plexus, some subepithelial ganglionic cells, but no ascending intragemmal fibres, were immunoreactive. In fish, the results support evidence that VIP is involved in the modulation of taste transduction at the level of receptor cells. In the frog, an indirect, possibly vasodilatatory effect on taste perception may be considered.