Ubiquitin metabolism affects cellular response to volatile anesthetics in yeast.

To investigate the mechanism of action of volatile anesthetics, we are studying mutants of the yeast Saccharomyces cerevisiae that have altered sensitivity to isoflurane, a widely used clinical anesthetic. Several lines of evidence from these studies implicate a role for ubiquitin metabolism in cellular response to volatile anesthetics: (i) mutations in the ZZZ1 gene render cells resistant to isoflurane, and the ZZZ1 gene is identical to BUL1 (binds ubiquitin ligase), which appears to be involved in the ubiquitination pathway; (ii) ZZZ4, which we previously found is involved in anesthetic response, is identical to the DOA1/UFD3 gene, which was identified based on altered degradation of ubiquitinated proteins; (iii) analysis of zzz1Delta zzz4Delta double mutants suggests that these genes encode products involved in the same pathway for anesthetic response since the double mutant is no more resistant to anesthetic than either of the single mutant parents; (iv) ubiquitin ligase (MDP1/RSP5) mutants are altered in their response to isoflurane; and (v) mutants with decreased proteasome activity are resistant to isoflurane. The ZZZ1 and MDP1/RSP5 gene products appear to play important roles in determining effective anesthetic dose in yeast since increased levels of either gene increases isoflurane sensitivity whereas decreased activity decreases sensitivity. Like zzz4 strains, zzz1 mutants are resistant to all five volatile anesthetics tested, suggesting there are similarities in the mechanisms of action of a variety of volatile anesthetics in yeast and that ubiquitin metabolism affects response to all the agents examined.

Histological features of nerve fibers and endoneural vessels in a case of Wegener's granulomatosis.

A sural nerve biopsy obtained from a patient with Wegener's granulomatosis and overt clinical signs of polyneuropathy showed degenerative changes of both myelinated and unmyelinated fibers. The pathological aspects were those of an axonopathy. Endoneural vessels were also involved, showing changes either in the endothelial cells, which were thickened and enriched with organelles, or in the basal membrane, which was reduplicated and thicker than in the controls. There were no cellular infiltrates nor was there clear evidence of fibrosis in the vascular wall. We suggest that peripheral neuropathy in Wegener's granulomatosis could be secondary to endoneural vessel changes on the basis of a possible immune complex action.

Vasculitic neuropathy in panarteritis nodosa: clinical and ultrastructural findings.

Clinical involvement of the peripheral nervous system in panarteritis nodosa is common, but the histological aspects are little known. We describe the sural nerve, muscle and skin biopsy findings in a patient with panarteritis nodosa, affected by mononeuritis multiplex. The data are compared to those reported in other types of vasculitis neuropathy.

The importance of quantitative electron microscopy in studying hypertrophic neuropathies. A comparison between a case of Déjérine Sottas disease (HMSN III) and a case of the hypertrophic form of Charcot-Marie-Tooth disease (HMSN I).

The electron microscopic features and quantitative morphometric data of the sural nerve in Déjérine-Sottas disease (HMSN III) and in the hypertrophic form of Charcot-Marie-Tooth disease (HMSN I) are reported. Both forms are characterized by onion bulb formations, but they differ in: a) increased incidence of mucoid connective tissue in DS disease; b) higher incidence of demyelination in DS disease; c) uniformly small size of the remaining myelinated fibers in DS disease; d) larger and more developed onion bulbs in DS disease; e) clusters of 2-4 myelinated fibers in the core of onion bulbs of CMT disease; f) peripheral concentric lamellae with the typical aspects of the denervation bands of the unmyelinated fiber type in the onion bulbs of the CMT disease; g) non-involvement of unmyelinated fibers in DS disease. These differences permit two types of onion bulbs to be distinguished, and suggest a different pathogenesis. Electron microscopy, coupled with quantitative determinations, permits a deeper insight into the formation modalities of onion bulbs and may help in the diagnosis of the different forms of hypertrophic neuropathies.

Substantia gelatinosa Rolandi neurons: ultrastructure of the cellular somata, synapses and intercellular contacts.

The central cells of substantia gelatinosa are small spindle-shaped neurons with an average perimeter of 26.8 micrometers and an average cross-sectional area of 44.9 micrometers2. No difference has been found between neurons of C1 and those of the lower cervical segments. It was calculated that axo-somatic synapses are about 20 per cell and generally occur in small clusters of 3-4 synapses each. Despite their low number they are probably of functional relevance when compared to the small size of the somata of substantia gelatinosa neurons. Most of the synaptic boutons contain pleomorphic electronlucent vesicles and have symmetrical synaptic junctions. Large granular synaptic vesicles also occur intermingled with the electronlucent ones. Sites of somato-dendritic and somato-somatic membrane apposition are fairly extensive: they over about 8% of the cellular perimeter. The possibility of cellular interactions or material interchanges at these sites of direct membrane apposition is suggested. Somatodendritic synapses were occasionally observed. Although the neuropil is indeed the main target of the different inputs to the substantia gelatinosa and the site of most of the local circuits, the somata may too be involved in synaptic transmission and possibly in intercellular coupling.

Trithiozine polyneuropathy: clinical, neurophysiological and histopathological study of three cases.

3 peptic ulcer patients, treated for a few weeks with Trithiozine, developed polyneuropathy. The histopathological patterns in the 2 patients in whom sural nerve biopsy was done presented wallerian degeneration of the axons of the myelinated fibers, especially those of larger caliber. The evidence for a iatrogenic toxic etiology is discussed.