trans-3-Benzyl-4-hydroxy-7-chromanylbenzoic acid derivatives as antagonists of the leukotriene B4 (LTB4) receptor

The SAR of a series of 2-(7-chromanyl)benzoic acids has been investigated with the aim of identifying potent and selective LTB4 receptor antagonists that maintain potency in complex biological fluids. We found optimal activity in derivatives with electron-withdrawing groups in the benzoic acid ring and with an unsubstituted C-3 benzyl group on the chromanol nucleus. While compounds containing a 3-(4-phenyl)benzyl chromanol substituent were potent LTB4 receptor antagonists, the increased lipophilicity imparted by the additional phenyl substituent led to decreased potency in the presence of plasma proteins. From among the potent compounds identified, CP-195543, the 5'-trifluoromethyl 3-benzyl chromanol, was selected for development.     

Characterization of the three-dimensional solution structure of human profilin: 1H, 13C, and 15N NMR assignments and global folding pattern

Human profilin is a 15-kDa protein that plays a major role in the signaling pathway leading to cytoskeletal rearrangement. Essentially complete assignment of the 1H, 13C, and 15N resonances of human profilin have been made by analysis of multidimensional, double- and triple-resonance nuclear magnetic resonance (NMR) experiments. The deviation of the 13C alpha and 13C beta chemical shifts from their respective random coil values were analyzed and correlate well with the secondary structure determined from the NMR data. Twenty structures of human profilin were refined in the program X-PLOR using a total of 1186 experimentally derived conformational restraints. The structures converged to a root mean squared distance deviation of 1.5 A for the backbone atoms. The resultant conformational ensemble indicates that human profilin is an alpha/beta protein comprised of a seven-stranded, antiparallel beta-sheet and three helices. The secondary structure elements for human profilin are quite similar to those found in Acanthamoeba profilin I [Archer, S. J., Vinson, V. K., Pollard, T. D., & Torchia, D. A. (1993), Biochemistry 32, 6680-6687], suggesting that the three-dimensional structure of Acanthamoeba profilin I should be analogous to that determined here for human profilin. The structure determination of human profilin has facilitated the sequence alignment of lower eukaryotic and human profilins and provides a framework upon which the various functionalities of profilin can be explored. At least one element of the actin-binding region of human profilin is an alpha-helix. Two mechanisms by which phosphatidylinositol 4,5-bisphosphate can interfere with actin-binding by human profilin are proposed.     

Ultrasonographic characteristics of first-trimester gestations in recurrent spontaneous aborters

OBJECTIVE: To compile, for the first time, serial ultrasonographic findings during the first trimester of pregnancy in women with a history of primary recurrent spontaneous abortion so as to define the dynamics of early normal and abnormal gestations in this category of gravidas. STUDY DESIGN: Transvaginal ultrasonograms were obtained weekly from 5 to 12 weeks' gestational age in 40 women, 10 each of four groups: recurrent spontaneous aborters and primiparas (controls), with both successful and failed gestations. RESULTS: Embryonic heart motion was detected in 40-50% of successful pregnancies during the fifth week of gestation and in the balance by the sixth week, while heart motion was detected in no more than 50% of pregnancies that later failed. Of the failed pregnancies, all were evident by the eighth week of gestation, including those with previously documented viability. The gestational sac size and crown-rump length were smaller than expected in both failed groups, with the sac size difference evident as early as week 5 and the crown-rump length difference apparent by week 7. CONCLUSION: Appropriate timing of the initial ultrasonogram in recurrent aborters (i.e., 8 weeks' gestational age) can identify, by means of heart motion and gestational sac features, all pregnancies that will ultimately fail.     

Aspirative lipectomy in patients with alimentary-constitutional obesity

The results of aspirative lipectomy in patients with 2nd and 3rd stage of alimentary-constitutional obesity are analysed. The effectiveness of lipectomy with surgical creation of a small ventricle and without previous surgery, has been demonstrated. The criteria of patients selection, based on their somatic and psychic features, are formulated. Aspirative lipectomy has certain advantages over other types of plastic surgery as it has the minimal rate of postoperative complications.     

Seroepidemiologic studies of hantavirus infection among wild rodents in California

To assess the functional significance of putative proteins encoded by alternately spliced mRNA of the sheep testicular FSH receptor, a short form cDNA comprising of the first four exons (117 residues mature protein) was engineered for expression in Escherichia coli. The expressed protein of molecular mass 15 kDa was purified to homogeneity and verified by reaction with an antibody against a synthetic peptide sequence unique to the amino (N)-terminal region FSH receptor. The purified FSH receptor domain protein bound 125I-labeled hFSH in a ligand blot on polyvinylidine difluoride membranes. Further analyses by slot blot revealed high affinity of the immobilized protein with significant reaction at 10 pmol. As the immobilized receptor protein also reacted with structurally related hormones (125I-labeled LH/125I-labeled human chorionic gonadotropin), we confirmed that interaction most probably occurred via the common alpha-subunit of these glycoprotein hormones. Our results reveal that this N-terminal portion of the FSH receptor contain(s) major site(s) for hormone recognition that could be mediated via the alpha-subunit. A rabbit antibody to the receptor inhibited FSH action in receptor bearing cells, revealing the utility of such recombinant FSH receptor protein(s) for modulation of hormone action.     

Effect of altered vision on constant load exercise performance while wearing a respirator

Previous testing has shown that visual acuity greatly influences task performance at light work rate levels. At moderate to heavy work rates, however, the Performance Rating Table (PRT) predicts almost no visual acuity effect. This experiment was performed to determine if the PRT value is realistic. Ten subjects walked on a treadmill at 75-80% of their maximum heart rates until their voluntary end points. Subjects wore various masks of the same kind, each with a different set of clouded lenses. Visual acuities, as measured on the Snellen eye chart, were measured before, during, and after exercise. It was found that visual acuity did not influence performance time, and that an average value for a performance rating of 91 must have been influenced by other mask factors besides visual acuity. These other factors are most likely respiratory stress, thermal stress, and other vision elements. The full-facepiece masks used in this study adversely affected visual acuity by about three-quarters of a Snellen line during exercise. Postexercise visual acuities were found to first decrease below pre-exercise values, then become better than pre-exercise values, then decline asymptotically to pre-exercise values.     

Research and treatment strategies in first-episode psychoses. The Pittsburgh experience

BACKGROUND: Studies of first-episode patients allow investigation of the biological basis of psychotic disorders without the potential confounds of prior treatment and illness chronicity. Prospective studies of this population can clarify the impact of illness course and treatment on neurobiology. METHOD: We summarise preliminary findings from our ongoing magnetic resonance imaging and spectroscopy studies of first-episode schizophrenia patients being conducted prospectively from index evaluations through a period of two years; during this period, patients were treated with either a conventional antipsychotic such as haloperidol, or the atypical risperidone. RESULTS: Baseline neurobiological evaluations in first-episode schizophrenia patients have revealed evidence for structural and functional brain abnormalities consistent with a neurodevelopmental model of this illness. Our preliminary data support the value of risperidone as an antipsychotic drug of first choice among patients with early schizophrenic illness. CONCLUSIONS: Focused studies of first-episode patients have the potential to unravel pathophysiology of schizophrenic illness. Such knowledge is critical for more effective early detection, intervention and even prevention of this enigmatic disorder.     

DNA-damaging steroidal alkaloids from Eclipta alba from the suriname rainforest1

Bioassay-guided fractionation of the MeOH extract of Eclipta alba using three yeast strains (1138, 1140, and 1353) resulted in the isolation of eight bioactive steroidal alkaloids (1-8), six of which are reported for the first time from nature. The major alkaloid was identified as (20S)(25S)-22,26-imino-cholesta-5,22(N)-dien-3beta-ol (verazine, 3), while the new alkaloids were identified as 20-epi-3-dehydroxy-3-oxo-5,6-dihydro-4,5-dehydroverazine (1), ecliptalbine [(20R)-20-pyridyl-cholesta-5-ene-3beta,23-diol] (4), (20R)-4beta-hydroxyverazine (5), 4beta-hydroxyverazine (6), (20R)-25beta-hydroxyverazine (7), and 25beta-hydroxyverazine (8). Ecliptalbine (4), in which the 22,26-imino ring of verazine was replaced by a 3-hydroxypyridine moiety, had comparable bioactivity to verazine in these assays, while a second alkaloid (8) showed good activity against Candida albicans. All the alkaloids showed weak cytotoxicity against the M-109 cell line.     

DNA minor groove recognition by a tetrahydropyrimidinium analogue of hoechst 33258: NMR and molecular dynamics studies of the complex with d(GGTAATTACC)2

Hoechst 43254 (H43254), a 2,3,4,5-tetrahydropyrimidin-1-ium analogue of the bis-benzimidazole minor groove binding agent Hoechst 33258 (H33258), has been studied by NMR and restrained molecular dynamics in its complex with d(GGTAATTACC)2. We investigate the origin of the enhanced complex stability afforded by the replacement of the N-methylpiperazine ring of H33258 with the tetrahydropyrimidinium ring of H43254, the latter presenting the opportunity for specific minor groove-directed recognition through a pyrimidinium NH. A set of 25 drug-DNA NOEs define the binding site with some precision and are used as part of the structural analysis using restrained molecular dynamics simulations considering explicit solvation and the treatment of electrostatic interactions using the particle mesh Ewald method within AMBER 4.1. Starting with three different initial structures with the drug located at different sites in the groove (pairwise RMSD 4.3-12.6 A) we arrive at three very similar structures (pairwise RMSD 0.80-1.34 A) representing one converged binding site at the centre of the AATT tract. Two of the three structures show the tetrahydropyrimidinium ring to be suitably positioned for an -NH to adenine N3 hydrogen bond suggesting that electrostatic interactions may play an important role in the enhanced affinity as well as imparting additional A-T specificity. The NMR data show that the pyrimidinium NH interaction is dynamic since signal averaging from the two sides of the ring indicate rapid rotations in the bound form.