A safer vaccine for Alzheimer's disease?

Recent reports indicate that amyloid-β (Aβ) vaccine-based therapy for Alzheimer’s disease (AD) may be on the horizon. There are, however, concerns about the safety of this approach. Immunization with Aβ1–42 may not be appropriate in humans because it crosses the blood–brain barrier, can seed fibril formation, and is highly fibrillogenic. Aβ1–42 fibrils can in turn cause inflammation and neurotoxicity. This issue is of a particular concern in the elderly who often do not mount an adequate immune response to vaccines. Our findings show that vaccination with nonamyloidogenic/nontoxic Aβ derivative may be a safer therapeutic approach to impede the progression of Aβ-related histopathology in AD. Although the site of action of the anti-Aβ antibodies has been suggested to be within the brain, peripheral clearance of Aβ may have a greater role in reducing cerebral amyloid plaques in these animals and eventually in AD patients. Antibodies in general are predominantly found outside the central nervous system (CNS) and will, therefore, primarily clear systemic Aβ compared to brain Aβ. This disruption of the equilibrium between central and peripheral Aβ should then result in efflux of Aβ out of the brain, and subsequent removal of plaques. Aβ therapy can be targeted to the periphery, which may result in fewer CNS side effects, such as inflammation. Future Aβ derived vaccines should include T_h epitopes, carriers and/or lipid moieties to enhance antibody production in the elderly, the population predominantly affected by AD.     

The incidence and management of priapism in Western Australia: a 16 year audit

The objective of the study was to conduct a retrospective audit of patients who presented with priapism in Western Australia during the years 1985-2000. We searched the records of the teaching hospitals in metropolitan Perth and those of the Keogh Institute for Medical Research for the diagnostic code for priapism. A total of 82 episodes of priapism in 63 patients occurred over this 16 year period. In all, 62 episodes occurred after intracavernosal injections (ICI) and 20 were due to other causes. Treatment of priapism included simple aspiration of blood, intracavernosal injection of alpha-adrenergic agents and surgical shunt procedures. Priapism occurring outside the setting of ICI was more likely to require surgery; seven of 20 episodes. After ICI therapy, eight of 62 episodes required shunts. The use of prostaglandin E1 as the drug of choice in ICI therapy in 1989 led to a fall in the incidence of ICI-induced priapism. Priapism is a major side effect of ICI therapy and an uncommon, although important, side effect of other conditions. The incidence of priapism has fallen with the introduction of prostaglandin E1 monotherapy as the favoured drug for ICI therapy of erectile failure.     

Fibrillar amyloid-beta affects neurofibrillary changes but only in neurons already involved in neurofibrillary degeneration

The aim of this study of the cerebral cortex of 8 non-demented elderly subjects and of 17 subjects in the severe stage of Alzheimer's disease (AD) (Global Deterioration Scale stage 7/Functional Assessment Staging procedure stage 7a-f) was to examine the relationships between amyloid-beta (Abeta) deposits and neurofibrillary degeneration. The study shows that neuronal processes with neurofibrillary changes are detectable in only a minority of fibrillar plaques: from 31% to 49% of fibrillar plaques within frontal, temporal, parietal, limbic, occipital, and insular cortices. The correlations observed between the numerical densities of neurons with neurofibrillary tangles (NFTs) and the densities of Thioflavin-S-positive fibrillar plaques with neurofibrillary changes (r=0.61; P<0.01) indicate that neurofibrillary pathology in neocortical plaques reflects the topography and rate of neurofibrillary changes in neocortical neurons. The accumulation of abnormally phosphorylated tau in only some plaques indicates that fibrillar Abeta enhances paired helical filament accumulation locally only in dystrophic neurites already involved in neurofibrillary degeneration. The lack of correlation between the number of neurons with neurofibrillary changes and the number of all Thioflavin-S-positive fibrillar plaques (with and without neurofibrillary changes) suggests that beta-amyloidosis does not contribute to initiation of neurofibrillary degeneration in neurons.     

The effect of the nitric oxide synthase inhibitor, L-NMMA, on sodium metabisulphite-induced bronchoconstriction and refractoriness in asthma.

Refractoriness to indirect bronchoconstrictor stimuli, is a feature of asthma but the mechanism is poorly understood. This study tested the hypothesis that endogenous nitric oxide (NO) produced during a first bronchoconstrictor challenge protects against subsequent challenge and therefore has a role in the refractory process. The effect of an NO synthase inhibitor, N(G)-mono-methyl-L-arginine (L-NMMA), on refractoriness to sodium metabisulphite (MBS) was investigated in 20 subjects with mild asthma. On visit one, the dose of MBS which caused a 20% fall in forced expiratory volume in one second (FEV1) (PD20) was determined. On visit two, the refractory index (RI) to MBS was determined by challenging the subjects twice with their PD20 of MBS, the second challenge proceeding after recovery from the first. Those showing a refractory index of approximately 30% (10 subjects) inhaled either L-NMMA or placebo followed 5 min later by two challenges with their PD20 of MBS in a double-blind cross over study at two further visits. The dose of L-NMMA used was shown to reduce exhaled NO for a duration sufficient to cover the second MBS challenge However, no significant difference was found between L-NMMA and placebo in maximum fall in FEV1% and area under the curve (AUC) during first or second MBS challenges or in RI on the two study days. It is concluded that subjects with mild asthma show refractoriness to sodium metabisulphite, but that endogenous nitric oxide is unlikely to be involved either in the refractory process or in the response to sodium metabisulphite per se.     

A profile of cognitive deficit in females from fragile X families

Fragile X, a recently discovered X-linked syndrome, is usually associated with mental retardation in affected males. Less consistent findings have been described for females. neuropsychological evaluation of seven nonretarded females from fragile X families suggested a characteristic profile: on Wechsler IQ tests, a positive Verbal-Performance score difference and lower subtest scaled scores on Arithmetic, Digit Span, Block Design, and Object Assembly; on the Wide Range Achievement Test, a lower score on Arithmetic than on Reading or Spelling; and on the Benton Visual Retention Test, defective recall. These results suggest the existence of X-linked learning disability in females.     

Phenotype variability in the Miller acrofacial dysostosis syndrome. Report of two further patients

In this report we present two unrelated patients with the postaxial dysostosis syndrome (Miller syndrome) and document further the phenotypic variability of the craniofacial stigmata and of the postaxial (and preaxial) upper and lower limb reduction anomalies.     

The spatio-temporal pattern of Wallerian degeneration in the Rhesus monkey optic nerve

Summary Three patterns of degeneration were distinguished in the Rhesus monkey optic nerve following eye enucleation. (1) A traumatic zone, extending for 1 to 2 mm from the site of transection and characterized by a rapid infiltration of haematogenous macrophages, the rapid degeneration and removal of all neural elements and the formation of astrocytic scar tissue within 35 days. (2) A conical zone, closely associated with the central retinal blood vessels, in which the pattern of degeneration was similar to the traumatic zone except that the onset was delayed and the removal of debris was slower. There was extensive vesiculation of myelin sheaths in these two zones which was indicative of haematogenous cell infiltration. (3) The remainder of the nerve underwent classical Wallerian degeneration in which endogenous cells slowly phagocytosed the degenerating nerve fibres. These observations are considered relevant to the controversy concerning the identification of the macrophage involved in Wallerian degeneration; many studies have described the macrophage within the area of trauma rather than the macrophage involved at some distance from the site of trauma.Supported by Grants 692-B-2 from the National Multiple Sclerosis Society; NS 02255 and NS 08180 from the National Institutes of Health and a grant from the Alfred P. Sloan Foundation     

Disruption of temporo-entorhinal connections abolishes the facilitatory effect of angiotensins on memory in rats.

It has been found in our laboratory that the positive influence of angiotensin II (AII) and its 3-7 fragment [AII(3-7)] on learning and memory processes is mediated by the excitatory amino acids, since it was abolished by NMDA receptor antagonists. The purpose of the present study was to investigate whether bilateral disruption of glutamatergic temporo- entorhinal connections may have an influence on the facilitatory effect of both angiotensin peptides on memory motivated affectively. The bilateral transections of temporo-entorhinal connections were made in 27 male rats 10 days before testing the influence of intracerebroventricular AII and AII(3-7) injection on retrieval of a passive avoidance response. Twenty-seven additional rats served as sham-operated controls. Twenty-five lesioned and 25 sham-operated animals were accepted to the final analysis. AII and its 3-7 fragment significantly improved the retrieval process in sham-operated groups of rats. Bilateral disruption of temporo-entorhinal connections totally abolished the facilitatory effect of both angiotensins on recall of information in a passive avoidance situation. Moreover, bilateral disruption of temporo-entorhinal connections markedly but not significantly attenuated crossings of squares, evaluated in an open field test, without an influence on rearings and bar approaches. These results may suggest that in the facilitatory effect of AII and AII(3-7) on memory motivated affectively involves reciprocal glutamatergic connection between lateral entorhinal cortex and temporal cortex.