Synthesis and biological properties of cylindramide derivatives: evidence for calcium-dependent cytotoxicity of tetramic acid lactams

To gain insight into the biological properties of tetramic acid lactam cylindramide 1, the analogues 4 a-d bearing a cyclopentane ring instead of the pentalene unit were prepared by tandem conjugate addition/enolate trapping of cyclopentenone 10; a Sonogashira or Stille coupling, followed by a Julia-Kocienski olefination, macrolactamisation and Lacey-Dieckmann cyclisation were the key steps. The previous NMR structure of cylindramide 1, which was based on NOE and J coupling restraints, could be refined by including residual dipolar coupling data measured for a sample of cylindramide that was aligned in polyacrylonitrile (18 %). Biological screening of cylindramide 1 and its analogues 2-epi-1, 20 and 4 revealed promising antiproliferative activity against several tumour cell lines. It turned out that the activity is strongly correlated to the functionalised pentalene system. The configuration of the cyclopentane ring and an intact tetramic acid lactam with the correct configuration seem to play an equal role in the cytotoxicity. The antiproliferative activity was found to be calcium dependent. Phenotypic characterisation of the mode of action showed vacuolisation and vesicle formation in the endoplasmic reticulum.     

Application of Seismic Refraction Tomography in Karst Terrane

Seismic refraction tomography field data were collected on several bridge foundation sites in Pennsylvania, in close proximity to geotechnical boring locations. Profiles determined from these field measurements were plotted against drilling data, and these comparisons revealed the ability of seismic wave velocities to differentiate overburden soil from rock. In addition, foundation construction data were collected at each of the sites and compared with refraction test results determined prior to construction. In particular, top of rock revealed by an excavation, and pile tip elevations at driving refusal, were compared with refraction test results. From these data it appears that seismic wave tomograms can characterize the soil/rock interface, and that it is possible to predict expected design pile lengths based upon a measured P-wave velocity tomogram. It can be concluded from these site comparisons that geophysical techniques such as seismic refraction tomography can provide important additional information to site characterization for bridge foundations in karst terrane. However, these techniques should not be viewed as a replacement, but should be conducted during design stage site investigation to aid selection of borehole locations and other testing needs.     

Third party presence during criminal forensic evaluations: Psychologists' opinions, attitudes, and practices.

If you are a psychologist who conducts forensic evaluations, how would you respond to an attorney's or family member's request to be present or to videotape the evaluation? Your answer may be impacted by legal, professional, ethical, and practical issues as addressed in legal and mental health publications. However, there is a dearth of empirical attention, and even the opinions and practices of psychologists in this arena are unclear. The present article addresses the need for empirical data on third party presence by surveying forensic clinicians' perspectives on the topic. A total of 160 forensic practitioners (41% response rate) provided information on their attitudes and practices pertaining to third parties in an evaluation. Overall, most clinicians believe third party presence can negatively impact an evaluation, yet most have conducted examinations under such conditions. The article concludes with speculation as to the impact of third party presence, a call for research and professional standards, and specific guidelines for psychologists who may struggle with these complex issues. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Synthesis of stable isotope labeled 3-acetyldeoxynivalenol

Stable isotope labeled 3-acetyldeoxynivalenol (3-AcDON) was synthesized in excellent yield from deoxynivalenol as starting material. This is the first synthesis of a stable isotope labeled type-B trichothecene suitable as internal standard for HPLC-MS/MS or GC-MS analysis of trichothecene mycotoxins. The isotopic purity of the 3-d(3)-AcDON was determined to be 94.9%.     

Antihemolytic and antiproteolytic properties of substituted thiosemicarbazidophenothiazines and thiazolidonylphenothiazines

Antihemolytic and antiproteolytic properties of several 10-(1-acetyl-4-arylthiosemicarbazido) phenothiazines and their corresponding cyclized 10-(2-arylimino-3-acetylamino-4-thiazolidonyl) phenothiazines were investigated. In vitro protection of hypoosmotic hemolysis of human red blood cells by substituted thiosemicarbazidophenothiazines and substituted thiazolidonyl-phenothiazines was concentration dependent; the degree of protection ranged from 19 to 32 and 26 to 42%, respectively, at a final concentration of 0.1 mM. All phenothiazines exhibited antiproteolytic activity. The in vitro inhibition of trypsin-induced hydrolysis of bovine serum albumin by these phenothiazines was concentration dependent and competitive in nature; the degree of inhibition ranged from 30 to 50 and 32 to 79% for substituted thiosemicarbazidophenothiazines and substituted thiazolidonlyphenothiazines, respectively, at a concentration of 1mM. Cyclization of substituted thiosemicarbazidophenothiazines into the corresponding cyclized substitited thiazolidonlyphenothiazines increased the antihemolytic and antiproteolytic effectiveness of these phenothiazines.     

Derivatives of apomorphine and of other N-substituted norapomorphines

Derivatives of apomorphine and of N-n-propylnorapomorphine were prepared to obtain modified pharmacological activity and enhanced chemical stability. Mouse profile and dog emesis screens were performed, and the activity of various N-substituted derivatives and their esters was evaluated and compared to the parent compounds. The N-n-propyl diacetate derivative and N-methyl and N-n-propyl ascorbate salts were remarkably stable to air: apomorphine etherate was no more stable than the free base. The dimers, the major products formed during the acid-catalyzed rearrangement of morphines to apomorphines, were all potent emetics. Additionally, two showed a significant antagonism to morphine in mice and dogs.     

Reproducibility of the histologic diagnosis of pneumonia among a panel of four pathologists: analysis of a gold standard

STUDY OBJECTIVE: To establish a histologic diagnosis of pneumonia by consensus of a panel of pathologists, to test the interobserver and intraobserver variation in the histologic diagnosis of pneumonia, to compare the diagnostic accuracy of diagnosing pneumonia with and without preselected histologic criteria, and to establish more specific histologic criteria for the diagnosis of pneumonia. METHODS: The study group consisted of 39 patients who died after a mean of 14 days of mechanical ventilation. A postmortem open lung biopsy was performed on all patients. The tissue was reviewed independently by four pathologists who categorized the slides from each patient as showing or not showing pneumonia. Interobserver variation was calculated using the kappa statistic. Six months following the initial evaluation, the same slides were resubmitted to one of the pathologists for reevaluation to look for intraobserver error. Finally, the slides were reviewed and categorized by the criteria of Johanson et al into no pneumonia, mild, moderate, or severe bronchopneumonia. A comparison was made of the patients selected as demonstrating histologic pneumonia by each of the examinations. RESULTS: The reliability coefficient (kappa) measuring agreement among the four pathologists was good at 0.916. However, the prevalence of pneumonia as determined by each of the four pathologists varied; pathologist A, 15 of 39 (38%); pathologist B, 12 of 39 (31%); pathologist C, 9 of 39 (23%); and pathologist D, 7 of 39 (18%). Resubmitting the same slides to the same pathologist 6 months later resulted in reclassification of 2 of 39 patients. Using the histologic criteria of Johanson and colleagues, 14 patients were selected as having pneumonia compared with only nine patients selected by consensus of three of four pathologists. CONCLUSIONS: Recognition of histologic pneumonia varies among pathologists. The preselected criteria of Johanson and colleagues detected histologic pneumonia in eight of nine patients picked by consensus of pathologists, but six additional patients classified as "no histologic pneumonia" by the consensus of pathologists were judged to have histologic pneumonia by these criteria. The results established the necessity for standardization of histologic criteria for studies using biopsy as the gold standard for bacterial pneumonia. An atlas showing the criteria used in our selection was developed.     

Mechanistic insights derived from retardation and peak broadening of particles up to 200 nm in diameter in electrophoresis in semidilute polyacrylamide solutions

Rigid spherical particles in the size range of 5-200 nm diameter were subjected to capillary zone electrophoresis (CZE) in semidilute solutions of uncross-linked polyacrylamide of M(r) 5, 7 and 18 x 10(6) (PA-5, -7 and -18, respectively) of varying concentrations up to 1.6% and at field strengths varying from 68 to 270 V/cm. For all particles under study, the experimental Ferguson plots, log(mobility) vs. polymer concentration, permit a linear approximation. Their slope, the retardation coefficient KR = delta log (mobility)/delta (concentration), for particles smaller than 30 nm in diameter increased with particle size in PA-5 and -7 independently of electric field strength and polymer M(r). The KR of particles of 30 nm in diameter or more was found to be independent of particle size at the lowest field strength used but to decrease with it at the higher values of field strength. The decrease was parallel but shifted to higher values of retardation when the polymer M(r) increased from 5 to 7 x 10(6). With a decreasing ratio of average mesh size of the polymer network, zeta, to particle radius, R, the approach to "continuity" of the polymeric medium (zeta/R < 1) with both increasing particle size and polymer concentration does not result in the retardation behavior expected according to the macroscopic (bulk) viscosity of the solution. These experimental observations were hypothetically interpreted in terms of a transition to a retardation mechanism comprising the formation of a polymer depletion layer near the particle surface--polymer solution interface. Peak width exhibited an overall increase with PA-7 concentration for all particles studied. For particles of 30 nm in diameter or less, the increase was steepest when the radius of the particle was approximately commensurate with zeta at a given polymer concentration. For the largest particle, 205 nm in diameter, peak broadening with polymer concentration was found to correlate linearly with peak asymmetry. CZE of the particles in PA-18 solutions revealed abnormal behavior, with both mobility and peak width remaining near-constant up to a concentration of 0.08% and sharply declining at higher concentrations. The decline of relative mobility is the same-for the entire particle size range used, while peak width declines in direct relation to particle size.