Potential roles of protease inhibitors in Alzheimer's disease

Recently, protease inhibitors have been recognized as potential contributors to the pathogenesis of Alzheimer's disease. In this role, they could mediate an exaggerated regenerative response in the brain, participate as acute phase reactants, or be involved in the aberrant proteolytic processing of the amyloid proteins. Protease inhibitors are, therefore, attractive targets for drug intervention in Alzheimer's disease.     

Cytoskeletal rearrangement by oxidative stress

The cytoskeleton is susceptible to oxidative stress and this occurs prior to membrane blebbing and cell lysis. Vimentin intermediary filaments in rheumatoid synoviocytes are more susceptible than in normal synoviocytes and this may have pathological significance. They are however no more susceptible to heat shock than other cell types.     

TRH-induced reflex changes in patients with ALS

A trial of Thyrotropin Releasing Hormone (TRH) 5.0 mg/kg body weight subcutaneously every other day for two weeks produced transient increased tone in muscles, along with other (side-) effects in patients with Amyotrophic Lateral Sclerosis (ALS). One patient's extensor plantar transiently changed to a flexor plantar reflex after injection, probably due to disproportionate increase in tone of the calf muscles. No significant changes in F-waves or H-reflexes were seen. No increase in useful voluntary strength, or in strength measured by Medical Research Council (MRC) testing or strain gauge isometric strength testing was seen. However, dyspnea was seen within 10 minutes of TRH injection.     

Structural modeling of functional neural pathways mapped with 2-deoxyglucose: effects of acoustic startle habituation on the auditory system

This paper describes the first application of structural modeling to neuroscience. Structural modeling (also known as path analysis) is a method to assess the relative impact of directional links in a system and how these interrelations may change under different conditions. The objective was to demonstrate how structural modeling can be used to determine the functional interrelationships between brain structures that form the auditory system. Using structural modeling, changes in auditory system 2-DG uptake were examined during long- and short-term habituation of the acoustic startle reflex. Models were based on the anatomical connections between central auditory system structures. Using functional 2-DG data, the correlations between these structures were calculated and numerical weights were computed for each anatomical link. The analysis revealed that the lemniscal path was dominant during short-term habituation, while during long-term habituation this influence was modified through extra-lemniscal pathways. The models are discussed in the context of previous findings to demonstrate how structural modeling can not only complement, but also extract more information from 2-DG mapping experiments.     

A phase I-II trial of 4'-deoxydoxorubicin (esorubicin) in refractory or relapsed acute leukemia

In a phase I-II study, 21 patients with relapsed or refractory acute leukemia were treated with 4'-deoxydoxorubicin (esorubicin), the 4'-deoxy derivative of doxorubicin. Four of 14 evaluable patients with acute nonlymphocytic leukemia (ANLL) in relapse or refractory to other anthracyclines achieved partial response (28.5%). Pharmacokinetics were similar to those of the parent compound, doxorubicin. Esorubicin has activity in ANLL and has pharmacologic properties comparable to those of other anthracyclines. Dose-limiting toxicity occurs in the form of mucositis, which may limit its use in combination with other antileukemic drugs.     

Isolation and characterization of a distinct immunoregulatory isoform of alpha-fetoprotein produced by the normal fetus

In this report, we examine the functional significance of the molecular microheterogeneity of alpha-fetoprotein (AFP). In doing so, we have taken the direct approach of purifying the naturally occurring isomeric forms of fetal-derived AFP using a preparative anion exchange column linked to an automated fast protein liquid chromatography (FPLC) system followed by parallel testing of each isolated molecular variant for in vitro immunoregulatory activity. The data obtained demonstrate the presence of seven distinct variants of AFP as defined by their retention volumes on FPLC elution profiles, by their pIs on analytical IEF gels, and by Western blot analysis. Molecular mass determination by SDS-PAGE showed each isomer to be equivalent in size to 69,000-dalton native unfractionated AFP molecules. All the immunosuppressive activity of AFP was localized to a single variant representing only 6% of the total composition of native AFP. The immunoregulating isomer termed AFP-1 was the least acidic of the seven isolated variants with a pI of 5.1 and displayed a sialic acid content of 1 mol/mol of protein. The inhibitory activity of AFP-1 could be readily measured on T cell-dependent antibody synthesis, Con A-induced stimulation of Lyt-1+23- thymocyte DNA synthesis, and lymphokine-activated NK cell activity. All other isomers were without effect in these test systems. The immunosuppressive AFP-1 isomer also displayed the strongest growth-promoting influence on cultured bone marrow lymphocytes. There was no correlation between functional activity and degree of expression of sialic acid residues on the AFP molecules. These findings demonstrate that the immunoregulating function of AFP is confined to a distinct and relatively small subpopulation of native AFP molecules and should therefore contribute to the resolution of outstanding questions regarding the structure/function relationship of this onco-fetal glycoprotein.