Increased MPTP neurotoxicity in vesicular monoamine transporter 2 heterozygote knockout mice

The neurotoxic action of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been proposed to be attenuated by sequestration into intracellular vesicles by the vesicular monoamine transporter (VMAT2). The purpose of this study was to determine if mice with genetically reduced levels of VMAT2 (heterozygote knockout; VMAT2 +/-) were more vulnerable to MPTP. Striatal dopamine (DA) content, the levels of DA transporter (DAT) protein, and the expression of glial fibrillary acidic protein (GFAP) mRNA, a marker of gliosis, were assessed as markers of MPTP neurotoxicity. In all parameters measured VMAT2 +/- mice were more sensitive than their wild-type littermates (VMAT2 +/+). Administration of MPTP (7.5, 15, or 30 mg/kg, b.i.d.) resulted in dose-dependent reductions in striatal DA levels in both VMAT2 +/- and VMAT2 +/+ animals, but the neurotoxic potency of MPTP was approximately doubled in the VMAT2 +/- mice: 59 versus 23% DA loss 7 days after 7.5 mg/kg dose for VMAT2 +/- and VMAT2 +/+ mice, respectively. Dopaminergic nerve terminal integrity, as assessed by DAT protein expression, also revealed more drastic reductions in the VMAT2 +/- mice: 59 versus 35% loss at 7.5 mg/kg and 95 versus 58% loss at 15 mg/kg for VMAT2 +/- and VMAT2 +/+ mice, respectively. Expression of GFAP mRNA 2 days after MPTP was higher in the VMAT2 +/- mice than in the wild-type: 15.8- versus 7.8-fold increase at 7.5 mg/kg and 20.1- versus 9.6-fold at 15 mg/kg for VMAT2 +/- and VMAT2 +/+ mice, respectively. These observations clearly demonstrate that VMAT2 +/- mice are more susceptible to the neurotoxic effects of MPTP, suggesting that VMAT2-mediated sequestration of the neurotoxin into vesicles may play an important role in attenuating MPTP toxicity in vivo.     

Cycloalkylpyranones and cycloalkyldihydropyrones as HIV protease inhibitors: exploring the impact of ring size on structure-activity relationships

Previously, 3-substituted cycloalkylpyranones, such as 2d, have proven to be effective inhibitors of HIV protease. In an initial series of 3-(1-phenylpropyl) derivatives with various cycloalkyl ring sizes, the cyclooctyl analog was the most potent. We became interested in exploring the influence of other structural changes, such as substitution on the phenyl ring and saturation of the 5,6-double bond, on the cycloalkyl ring size structure-activity relationship (SAR). Saturation of the 5,6-double bond in the pyrone ring significantly impacts the SAR, altering the optimal ring size from eight to six. Substitution of a sulfonamide at the meta position of the phenyl ring dramatically increases the potency of these inhibitors, but it does not change the optimal ring size in either the cycloalkylpyranone or the cycloalkyldihydropyrone series. This work has led to the identification of compounds with superb binding affinity for the HIV protease (Ki values in the 10-50 pM range). In addition, the cycloalkyldihydropyrones showed excellent antiviral activity in cell culture, with ED50 values as low as 1 microM.     

Two linear acetogenins from Goniothalamus gardneri

Two new acetogenins, gardnerilins A and B, have been isolated from the roots of Goniothalamus gardneri. Both are C35 acetogenins containing non-tetrahydrofuran rings. Their structures have been established on the basis of spectral evidence.     

Anemia increases gastric blood flow in noncirrhotic and cirrhotic patients

BACKGROUND: Previous studies in rats have demonstrated that anemia induces a significant increment in gastric mucosal blood flow. In the present study, we investigated whether chronic anemia induces similar changes in gastric blood perfusion in humans, and if this effect is also present in cirrhotic patients in whom gastric blood flow is usually increased in basal conditions. METHODS: Gastric mucosal blood perfusion was assessed by means of laser-Doppler flowmetry and reflectance spectrophotometry applied through the endoscope. RESULTS: Anemia significantly increases laser-Doppler signal in cirrhotic (2.3 +/- 0.11 vs 2.9 +/- 0.22 volts, p < 0.05) and noncirrhotic patients (1.71 +/- 0.15 vs 2.24 +/- 0.17, p < 0.05). In anemic patients the index of hemoglobin concentration of the gastric mucosa, assessed by reflectance spectrophotometry, was significantly decreased in cirrhotic patients (107.6 +/- 4.7 vs 95.5 +/- 3.3, p < 0.05) and noncirrhotic patients (93.9 +/- 4.1 vs 76.1 +/- 4.2, p < 0.01), whereas the index of oxygen saturation was increased (36.7 +/- 0.7 vs 40.4 +/- 1.4, p = 0.05; and 36.4 +/- 1.1 vs 43.2 +/- 1.9, p < 0.01, respectively). CONCLUSIONS: In conclusion, chronic anemia is associated with an enhanced gastric blood perfusion reflected by an increased laser-doppler signal and gastric mucosal oxygen index despite a decrease in gastric hemoglobin concentration. In cirrhotic patients, anemia promotes a further increment in its basal gastric hyperemia.     

Phase studies of a liquid crystalline polymer: hydroxypropyl cellulose

Phase diagrams for the isotropic-anisotropic phase transition in solutions of a thermotropic cellulose derivative, hydroxypropyl cellulose are presented. The effect of the molecular weight is demonstrated. A comparison to the theory of semi-rigid liquid crystalline polymers is given.     

An electron-microscopic study of Herpetomonase sp. (Leptomonas pessoai)

The fine structure of the promastigotes of Herpetomonas sp. (Leptomonas pessoai) kept in a defined medium at 28 degrees C is described. This portozoon reveals several features in common with other trypanosomatids. A membrane-bounded organelle measuring 0.2 to 0.8 mum in diameter, similar to that described as peroxisome in Crithidia fasciculata, was also observed. A large cavity, located between the nucleus and the kinetoplast and containing vesicles and small particulate material is discussed in this paper.     

High flux hemofiltration

Experiments were performed using a new hollow fiber hemofilter. Ultrafiltration rates and whole blood urea clearances were measured in post-dilution hemofiltration. High ultrafiltration rates were obtained with the new hemofilter. No adverse effects were detected despite filtration fractions above 45%. These experiments suggest that it is possible in post-dilution hemofiltration to obtain small solute clearances comparable to those of hemodialysis without apparent deleterious effects.     

Bleaching of vegetable oils: I. Conversions in soybean oil,triolein and trilinolein

Soybean oil, triolein and trilinolein were treated with acid-activated earth (2–15%) at 25–120 C. With low initial peroxides and in the absence of air, little additional conjugation was found. With high initial peroxides or in the presence of air, conjugated dienes and trienes were formed particularly with high amounts of earth. At higher temperatures and longer bleaching times the amount of conjugated compounds also increased. It can be concluded from the bleaching experiments with triolein and trilinolein that conjugated dienes, trienes and tetraenes are formed much more easily with linoleate than with oleate.