Lack of Amphetamine-Like Effects After Administration of Mefenorex in Normal Young Subjects

Mefenorex is an indirect sympathomimetic amine which acts as an anorectic drug and is used in combination with low diet to treat excess weight. The central nervous system (CNS) effects of mefenorex were assessed in a randomized, double-blind, three-way cross-over, placebo-controlled study involving nine healthy young male volunteers. They received either a single oral dose of mefenorex 80 mg (twice the recommended dose) or d-amphetamine sulfate 18 mg or a placebo at 1-week intervals. CNS pharmacodynamic measurements consisted of subjective evaluation (visual analogue scales and the Addiction Research Centre inventory (ARCI)), EEG, psychomotor performance and attention (tracking, simple and choice reaction times, tapping, continuous performance task, DSST, body sway) and memory (working memory and recall of a word list). d-Amphetamine produced a typical psychostimulant EEG profile (significant decrease in slow delta waves and increase in fast beta activities), significantly increased amphetamine, benzedrine and morphine–benzedrine scores of ARCI and significantly decreased body sway compared to placebo and mefenorex. A trend in favour of a stimulant effect occurred for all other parameters (particularly speed of reaction) and no changes of memory were noticed. In contrast, mefenorex did not produce an amphetamine-like EEG profile, neither significantly changed ARCI scores nor significantly modified psychomotor and memory performance compared to the placebo, although it induced a decrease in body sway. In conclusion, the present results indicate that a single oral dose of mefenorex, at twice the recommended daily dose, does not possess amphetamine-like subjective and EEG stimulant effects or sensations of well-being, often encountered with drugs of abuse liability potential, in a healthy young population.     

Factors that affect the uptake of ammonia by the brain: the blood-brain pH gradient

The brain uptake index (BUI) for [¹³N]ammonia was measured in 7 areas of the rat brain at 8 different pH values ranging from 6.58 to 7.73. When the regional BUI was plotted as a function of the pH of the test bolus, a significant linear correlation was found for each region (P < 0.001). The highest slope was observed in the thalamus-basal ganglia complex (0.392 ± 0.018) (S.D.), and the lowest in the ventral pons (0.143 ± 0.011). These studies indicate that the brain-blood pH gradient plays a major role in determining the forward flux of ammonia from the blood into the brain in the physiological pH range. Regional differences in the slope may be due to metabolic factors. This pH effect may be important in clinical conditions characterized by hyperammonemia such as hepatic encephalopathy, and in the interpretation of [¹³N]ammonia emission tomographic images of the brain.     

Assessment of radiologic progression in rheumatoid arthritis. A randomized, controlled trial

Radiologic assessment of progressive joint destruction in rheumatoid arthritis is generally considered to be the ultimate standard for evaluation of treatment. We compared alternative radiologic techniques by performing a randomized, controlled trial in which hand films of rheumatoid arthritis patients were read by several skilled observes. The number of joints evaluated (34 versus 18) was found to make relatively little difference, but the number of readers and their experience level was critical. Films should be read in pairs. Joint space narrowing and erosion scores were shown to contribute independent information. Use of recommended techniques can reduce the number of patients required and, thus, can reduce the cost of a clinical trial by more than half and can substantially increase the sensitivity and efficiency of a trial. Therefore, critical selection of the method of assessing study endpoint is of great importance.     

Cross-species genetic screens identify transglutaminase 5 as a regulator of polyglutamine-expanded ataxin-1

Many neurodegenerative disorders are caused by abnormal accumulation of misfolded proteins. In spinocerebellar ataxia type 1 (SCA1), accumulation of polyglutamine-expanded (polyQ-expanded) ataxin-1 (ATXN1) causes neuronal toxicity. Lowering total ATXN1, especially the polyQ-expanded form, alleviates disease phenotypes in mice, but the molecular mechanism by which the mutant ATXN1 is specifically modulated is not understood. Here, we identified 22 mutant ATXN1 regulators by performing a cross-species screen of 7787 and 2144 genes in human cells and Drosophila eyes, respectively. Among them, transglutaminase 5 (TG5) preferentially regulated mutant ATXN1 over the WT protein. TG enzymes catalyzed cross-linking of ATXN1 in a polyQ-length–dependent manner, thereby preferentially modulating mutant ATXN1 stability and oligomerization. Perturbing Tg in Drosophila SCA1 models modulated mutant ATXN1 toxicity. Moreover, TG5 was enriched in the nuclei of SCA1-affected neurons and colocalized with nuclear ATXN1 inclusions in brain tissue from patients with SCA1. Our work provides a molecular insight into SCA1 pathogenesis and an opportunity for allele-specific targeting for neurodegenerative disorders.     

An endogenous glycosylphosphatidylinositol-specific phospholipase D releases basic fibroblast growth factor-heparan sulfate proteoglycan complexes from human bone marrow cultures

Basic fibroblast growth factor (bFGF) is a hematopoietic cytokine that stimulates stromal and stem cell growth. It binds to a glycosylphosphatidylinositol (GPI)-anchored heparan sulfate proteoglycan on human bone marrow (BM) stromal cells. The bFGF- proteoglycan complex is biologically active and is released by addition of exogenous phosphatidylinositol-specific phospholipase C. In this study, we show the presence of an endogenous GPI-specific phospholipase D (GPI-PLD) that releases the bFGF-binding heparan sulfate proteoglycan and the variant surface glycoprotein (a model GPI-anchored protein) from BM cultures. An involvement of proteases in this process is unlikely, because released proteoglycan contained the GPI anchor component, ethanol-amine, and protease inhibitors did not diminish the release. The mechanism of release is likely to involve a GPI-PLD and not a GPI-specific phospholipase C, because the release of variant surface glycoprotein did not reveal an epitope called the cross- reacting determinant that is exposed by phospholipase C-catalyzed GPI anchor cleavage. In addition, phosphatidic acid (which is specifically a product of GPI-PLD-catalyzed anchor cleavage) was generated during the spontaneous release of the GPI-anchored variant surface glycoprotein. We also detected GPI-PLD-specific enzyme activity and mRNA in BM cells. Therefore, we conclude that an endogenous GPI-PLD releases bFGF-heparan sulfate proteoglycan complexes from human BM cultures. This mechanism of GPI anchor cleavage could be relevant for mobilizing biologically active bFGF in BM. An endogenous GPI-PLD could also release other GPI-anchored proteins important for hematopoiesis and other physiologic processes.     

Antibody to a synthetic oligopeptide in subjects at risk for human immunodeficiency virus infection.

Detection of antibodies to human immunodeficiency virus (HIV) by enzyme-linked immunosorbent assay (ELISA) is the accepted method to screen blood products at risk to transmit infection. The presence of antibodies to HIV in 565 serum specimens from 274 patients with acquired immunodeficiency syndrome (AIDS) or AIDS-related complex, symptomatic and asymptomatic subjects at risk for AIDS, and controls was determined with an ELISA that incorporates synthetic peptides (designated E32/E34) representing sequences in the envelope glycoprotein gp41. Of 105 specimens from patients with AIDS or AIDS-related complex, 3 specimens that were negative by commercially licensed ELISA and immunoblot test were similarly unreactive in the E32/E34 ELISA. For homosexual men with generalized lymphadenopathy, 186 specimens were positive by the E32/E34 ELISA and 63 specimens were negative. In comparison, with the licensed ELISA, 184 of these samples were positive and 65 samples were negative. The two samples that were positive in the E32/E34 ELISA but not the commercial kit were also positive by immunoblotting. Sequential sera from one individual who apparently underwent seroconversion according to the commercial assays were all positive by E32/E34 ELISA and immunoblotting. Thus, the ELISA with synthetic peptides is an extremely sensitive and specific test of antibody response to HIV and has not yet yielded a negative result with a Western blot (immunoblot)-confirmed antibody-positive serum.