Spectrum of morphological appearance of amyloid deposits in Alzheimer's disease

Summary Immunocytochemical staining with monoclonal antibodies to the -protein on tissue sections which have been pretreated with formic acid is not only a very specific but also a highly sensitive method for the detection of amyloid deposits in the brains of Alzheimer's disease victims. We report here a spectrum of morphological appearance of the brain amyloid deposits which are one of the main histopathological correlates of this disorder. Deposits of the -protein are not only found in the well-known lesions [congophilic angiopathy and senile (neuritic) plaques] but are also seen under various morphological forms for which the word plaques does not appear an appropriate term: amyloid fibrils are found as large areas of diffuse infiltration of the neuropil, as ribbon-like infiltration in the subpial layer of the cerebral cortex, as granular deposits in the white matter, as diffuse deposits in the molecular layer of the cerebellum and the basal ganglia and as star-shaped deposits in the cerebellar Purkinje cell layer. The morphology of these deposits seems to depend on the cyto-and fibroarchitectonics of the brain region in which they are found, on the amount of amyloid deposited, and also on the type of staining technique used. It is only under specific circumstances that the deposition of amyloid in the neuropil is accompanied by the formation of paired helical filaments in nerve cell processes and their parent perikarya. In conclusion, our studies suggest that the extent of brain amyloidosis in Alzheimer's disease is much wider than so far appreciated.Supported in part by grants 5-AGO-4220-05 and 5-HD-22634-02 from the National Institutes of Heath     

Cutaneous stimulation evokes long-lasting excitation of spinal interneurons in the turtle

1. We demonstrated multisecond increases in the excitability of the rostral-scratch reflex in the turtle by electrically stimulating the shell at sites within the rostral-scratch receptive field. To examine the cellular mechanisms for these multisecond increases in scratch excitability, we recorded from single cutaneous afferents and sensory interneurons that responded to stimulation of the shell within the rostral-scratch receptive field. A single segment of the midbody spinal cord (D4, the 4th postcervical segment) was isolated in situ by transecting the spinal cord at the segment's anterior and posterior borders. The isolated segment was left attached to its peripheral nerve that innervates part of the rostral-scratch receptive field. A microsuction electrode (4-5 microns ID) was used to record extracellularly from the descending axons of cutaneous afferents and interneurons in the spinal white matter at the posterior end of the D4 segment. 2. The turtle shell is innervated by slowly and rapidly adapting cutaneous afferents. All cutaneous afferents responded to a single electrical stimulus to the shell with a single action potential. Maintained mechanical stimulation applied to the receptive field of some slowly adapting afferents produced several seconds of afterdischarge at stimulus offset. We refer to the cutaneous afferent afterdischarge caused by mechanical stimulation of the shell as "peripheral afterdischarge." 3. Within the D4 spinal segment there were some interneurons that responded to a brief mechanical stimulus within their receptive fields on the shell with short afterdischarge and others that responded with long afterdischarge. Short-afterdischarge interneurons responded to a single electrical pulse to a site in their receptive fields either with a brief train of action potentials or with a single action potential. Long-afterdischarge interneurons responded to a single electrical shell stimulus with up to 30 s of afterdischarge. Long-afterdischarge interneurons also exhibited strong temporal summation in response to a pair of electrical shell stimuli delivered up to several seconds apart. Because all cutaneous afferents responded to an electrical shell stimulus with a single action potential, we conclude that electrically evoked afterdischarge in interneurons was produced by neural mechanisms in the spinal cord; we refer to this type of afterdischarge as "central afterdischarge." 4. These results demonstrate that neural mechanisms for long-lasting excitability changes in response to cutaneous stimulation reside in a single segment of the spinal cord. Cutaneous interneurons with long afterdischarge may serve as cellular loci for multise     

Epidemiology of gentamicin-resistant, gram-negative bacillary colonization in a spinal cord injury unit.

A prospective epidemiological survey of a spinal cord injury unit for gentamicin-resistant, gram-negative bacilli was undertaken. The initial survey of the unit suggested a low level of cross-infection involving Pseudomonas aeruginosa and Providencia stuartii. However, a longitudinal study of new admissions revealed that only 13 of 52 nosocomial acquisitions could be considered to be due to cross colonization. Comparison of data on antibiotic use did not suggest selective pressure for resistant endogenous flora. Nosocomial acquisition was directly related to the length of the hospital stay. Antibiotic susceptibility testing of gentamicin-resistant, gram-negative bacilli showed only minor differences between nosocomial isolates and those present during the initial survey. Of the usual antimicrobial agents, amikacin, carbenicillin, and cefoxitin were the most active against all organisms, with the exception of Serratia spp. Of the new beta-lactams, ceftazidime and imipemide (N-formimidoyl thienamycin) were most active.     

Localization of a gene for otosclerosis to chromosome 15q25-q26

Among white adults otosclerosis is the single most common cause of hearing impairment. Although the genetics of this disease are controversial, the majority of studies indicate autosomal dominant inheritance with reduced penetrance. We studied a large multi- generational family in which otosclerosis has been inherited in an autosomal dominant pattern. Five of16 affected persons have surgically confirmed otosclerosis; the remaining nine have a conductive hearing loss but have not undergone corrective surgery. To locate the disease- causing gene we completed genetic linkage analysis using short tandem repeat polymorphisms (STRPs) distributed over the entire genome. Multipoint linkage analysis showed that only one genomic region, on chromosome 15q, generated a lod score >2.0. Additional STRPs were typed in this area, resulting in a lod score of 3.4. STRPs FES (centromeric) and D15S657 (telomeric) flank the 14. 5 cM region that contains an otosclerosis gene.      

Induced luteolysis in the primate: rapid loss of luteinizing hormone receptors

The molecular mechanisms involved in luteolysis are still unclear in the primate. This study aimed to investigate the effect of induced luteolysis on the ovarian luteinizing hormone (LH) receptor and the steroidogenic enzyme, 3beta-hydroxysteroid dehydrogenase (3beta-HSD) in the marmoset monkey. Luteolysis was induced in the mid-luteal phase either directly by systemic prostaglandin F2alpha (PGF2alpha), or indirectly by LH withdrawal using systemic gonadotrophin releasing hormone antagonist (GnRHant) treatment. The LH receptor was studied by isotopic mRNA in-situ hybridization and in-situ ligand binding and 3beta-HSD expression was studied using isotopic mRNA in-situ hybridization and immunohistochemistry. Induced luteolysis was associated with a reduction in the expression of LH receptor (P < 0.0001) and 3beta-HSD mRNA, closely followed by a reduction in the LH receptor (P < 0.05) and 3beta-HSD protein concentrations within 24 h. There were no differences in the findings whether luteolysis was induced with PGF2alpha or GnRHant. This study shows that disparate mechanisms to induce luteolysis in the primate result in an identical rapid loss of the LH receptor and 3beta-HSD. In conclusion, induced luteolysis leads to rapid loss of the steroidogenic pathway in luteal cells.      

X-linked liver glycogenosis type II (XLG II) is caused by mutations in PHKA2, the gene encoding the liver alpha subunit of phosphorylase kinase

X-linked liver glycogenosis type II (XLG II) is a recently described X- linked liver glycogen storage disease, mainly characterized by enlarged liver and growth retardation. These clinical symptoms are very similar to those of XLG I. In contrast to XLG I patients, however, XLG II patients do not show an in vitro enzymatic deficiency of phosphorylase kinase (PHK). Recently, mutations were identified in the gene encoding the liver alpha subunit of PHK (PHKA2) in XLG I patients. We have now studied the PHKA2 gene of four unrelated XLG II patients and identified four different mutations in the open reading frame, including a deletion of three nucleotides, an insertion of six nucleotides and two missense mutations. These results indicate that XLG II is due to mutations in PHKA2. In contrast to XLG I, XLG II is caused by mutations that lead to minor structural abnormalities in the primary structure of the liver alpha subunit of PHK. These mutations are found in a conserved RXX(X)T motif, resembling known phosphorylation sites that might be involved in the regulation of PHK. These findings might explain why the in vitro PHK enzymatic activity is not deficient in XLG II, whereas it is in XLG I.      

Post-marketing surveillance of enalapril: experience in 11 710 hypertensive patients in general practice

Post-marketing surveillance in general practice represents an important part of the monitoring of adverse events associated with newly introduced drugs. Such a study of the angiotensin-converting enzyme inhibitor enalapril maleate has been undertaken in 11 710 patients with essential hypertension. Serious adverse events occurred in 1.7% of patients, though most of these were not thought to be related to the treatment. The incidence rates of death (0.09%), stroke (0.11%) and myocardial infarction (0.15%) were compatible with rates predicted from age, sex and blood pressure considerations. Other events reported were hypotension (0.3%), angioneurotic oedema (0.03%), rash (0.5%), taste disturbance (0.2%) and cough (1.0%). The degree of blood pressure reduction attained was similar to that previously reported from pre-marketing development studies, as was the overall nature and frequency of both serious and non-serious adverse events. The most frequently reported event during enalapril therapy was of an improvement in well-being (19.8%).