Widespread serum amyloid P immunoreactivity in cortical amyloid deposits and the neurofibrillary pathology of Alzheimer's disease and other degenerative disorders

Amyloid P (AP) component is present in all types of systemic amyloid deposits. Recently, it has been shown to be also present in cerebral amyloid lesions of Alzheimer's disease (AD). In this study, we used immunocytochemical methods to extend these findings at the electron microscope level and characterize the spectrum of AP immunoreactivity in neurofibrillary pathology (NFP) of AD and other neurodegenerative disorders including Down's syndrome (DS), Creutzfeldt-Jakob, Parkinson's, Pick's and diffuse Lewy body diseases and progressive supranuclear palsy. In AD and DS, AP immunoreaction product was evident in all the classical amyloid lesions and NFP in a large sample of all cortical areas examined. The distribution and relative intensity of immunostaining was similar to that of thioflavin S staining in serial sections. In many cases, however, plaques and vessels stained by anti-AP serum were not apparent with thioflavin S. Serial sections immunostained with antiserum to amyloid A, C-reactive protein or to other proteins involved in systemic amyloidoses and the acute phase response showed no evidence of staining in any of the cerebral lesions. Electron microscopy confirmed that AP immunoreactivity was associated with the abnormal filaments characteristic of NFP as well as amyloid fibrils found in plaques and vessels showing congophilic amyloid angiopathy. Plaques of Creutzfeldt-Jakob disease, Pick bodies of Pick's disease, tangles and Lewy bodies in Parkinson's disease and a subpopulation of Lewy bodies in the diffuse Lewy body disease coexistent with AD were also stained. With the exception of vessels in two of the five cases, AP was not detected in age-matched controls. Our observations indicate AP to be a consistent feature of cerebral NFP and amyloid deposits.     

Differences in the abilities of human tau isoforms to promote microtubule assembly.

Three isoforms of human tau protein were compared for their abilities to induce microtubule assembly. The three isoforms, tau 3 (tau containing three microtubule-binding domains), tau 4 (tau containing four microtubule-binding domains) and tau 4L (tau containing four microtubule binding domains plus a 58-amino-acid insert near the N-terminus) were expressed in E. coli and purified using ammonium sulfate precipitation, ion exchange, and size exclusion chromatography. All three isoforms induced microtubule assembly at micromolar concentrations and showed similar critical concentrations for assembly of 0.4-0.45 microM. However, tau 4 induced microtubule formation at a rate five- to tenfold faster than either tau 3 or tau 4L. The rate of microtubule elongation seen with tau 4 was twofold greater than with tau 3 or tau 4L, suggesting that the faster rate of microtubule assembly seen with tau 4 was due, at least in part, to faster elongation. Tau 4 induced a greater number of microtubules to form at steady state than did tau 3 or tau 4L. The microtubules generated with each tau isoform had similar steady-state length distributions and were equally susceptible to cold-induced disassembly. These results indicate that the additional microtubule-binding domain in tau 4 enhances microtubule assembly, while the 58-amino-acid insert negates the stimulatory effect of the fourth microtubule-binding domain.     

A role for GABAB receptors in excitation and inhibition of thalamocortical cells.

Gamma-aminobutyric acid (GABA) in the thalamus has mainly been associated with the inhibitory modulation of the sensory and cortical flow of information via a 'classical', chloride-dependent, GABAA receptor-mediated action. However, the discovery of a late, long-lasting potassium-dependent inhibitory postsynaptic potential (IPSP) mediated by GABAB receptors present on thalamocortical cells, has allowed new insights into our understanding of the physiological role of this neurotransmitter. In particular, work on the dorsal lateral geniculate nucleus indicates that together with a relatively weak inhibition, GABAB receptor-mediated IPSPs 'prepare' thalamocortical cells for burst firing by activating low-threshold calcium potentials. Thus, GABA in the thalamus can no longer be viewed only as a 'classical' inhibitory transmitter but also as a neuromodulator with a 'priming' role for burst firing excitation. This dual role of GABAB receptors in inhibition and excitation of thalamocortical cells might allow different interpretations of earlier findings in animals and humans, both in healthy and pathological conditions. It will also help to identify new functions for postsynaptic GABAB receptors in other parts of the central nervous system.     

Isolation of a rat S100 alpha cDNA and distribution of its mRNA in rat tissues.

In order to clarify the reported discrepancies in S100 alpha protein and mRNA distribution in rat tissues, a rat S100 alpha cDNA has been isolated and this species homologous probe along with a rat S100 beta cDNA probe has been used to examine S100 mRNA expression in rat tissues. Although the rat S100 alpha cDNA was missing approximately 30 nucleotides of coding sequence, only 4 conservative changes in amino acid sequence were observed when the deduced amino acid sequence was compared to the bovine S100 alpha amino acid sequence. Thus, S100 alpha proteins, like S100 beta proteins, are highly conserved among species. All nineteen of the tissues examined (including cerebrum and cerebellum) contained S100 alpha mRNA. In addition, S100 beta mRNA was detected in thirteen of the nineteen tissues examined. These results are in agreement with previous protein distribution studies and further demonstrate that S100 proteins are not brain-specific and are expressed in a large number of tissues. Although S100 alpha and S100 beta mRNAs were detected in rat tissues which had previously been reported to contain S100 alpha and S100 beta protein, a direct correlation between the protein and mRNA levels were not observed, suggesting that different mechanisms regulate S100 expression in various tissues. S100 alpha exhibited a single similar size mRNA species (0.5 Kb) in all tissues examined, as did S100 beta (1.5 Kb), suggesting that the individual S100 proteins are expressed as single mRNA and protein products in rat tissues.     

Treatment of acne vulgaris. Guidelines for primary care physicians.

The spectrum of acne vulgaris is wide, ranging from minor comedones to devastating nodules and cysts. Appropriate therapy requires an understanding of the various types of lesions, their pathophysiology, and the rationale for treatment. Good patient rapport and communication are important, and close follow-up is necessary until the treatment regimen has stabilized. Timely referral to a dermatologist is essential when therapy is not effective. With effort, the treatment of acne can be quite rewarding for both patient and physician.     

Temporomandibular joint eminence augmentation by down-fracture and inter-positional cartilage graft. A new surgical technique.

A new surgical technique for the treatment of recurrent temporomandibular joint subluxation or dislocation is described. Following a horizontal osteotomy and down-fracture of the articular eminence an inter-positional bovine cartilage xenograft is inserted in order to augment the vertical height of the eminence. The procedure combines simplicity with minimal post-operative morbidity. The increase in eminence height is both predictable and stable.