Characterization of a novel bisacridone and comparison with PSC 833 as a potent and poorly reversible modulator of P-glycoprotein

Novel compounds, composed of two acridone moieties connected by a propyl or butyl spacer, were synthesized and tested as potential modulators of P-glycoprotein (P-gp)-mediated multidrug resistance. The propyl derivative 1,3-bis(9-oxoacridin-10-yl)-propane (PBA) was extremely potent and, at a concentration of 1 microM, increased steady state accumulation of vinblastine (VLB) approximately 9-fold in the multidrug-resistant cell line KB8-5. In contrast to the readily reversible effects of VRP and cyclosporin A on VLB uptake and similar to the effects of the cyclosporin analog PSC 833, this modulation by PBA was not fully reversed 6-8 hr after transfer of cells to PBA-free medium. Continuous exposure to 3 microM PBA was nontoxic and could completely reverse VLB resistance in KB8-5 cells. Consistent with its effects on VLB transport, the drug resistance-modulating effect of PSC 833 was significantly more persistent than that of VRP. However, the effect of PBA was, like that of VRP, rapidly reversed once the modulator was removed from the extracellular environment. PBA was able to compete with radiolabeled azidopine for binding to P-gp and to stimulate P-gp ATPase activity. However, both the steady state accumulation of PBA and the rate of efflux of PBA were similar in drug-sensitive KB3-1 and drug-resistant KB8-5 cells, suggesting that this compound is not efficiently transported by P-gp. These results indicate that PBA represents a new class of potent and poorly reversible synthetic modulators of P-gp-mediated VLB transport.     

Radiographic and clinical classification of acquired midtarsus deformities

To develop a classification of midtarsus deformities, clinical examination and weightbearing radiographs were used to evaluate 131 feet in 109 patients (average age, 59+/-11 years) with those deformities. Patients were classified into four types based on anatomic location of the maximum deformity. Type I (N=43) showed deformity at the metatarsocuneiform joints medially and the fourth and fifth metatarsocuboid joints laterally, with plantarmedial and/or medial prominence. Type II (N= 60) had deformity at the naviculocuneiform joint medially and the fourth and fifth metatarsocuboid joints laterally; plantarlateral prominence was characteristic, although one-third had isolated or additional medial prominences. Type III (N=17) had major deformity in the perinavicular region, with a prominence plantarcentrally or plantarlaterally. Type IV (N=11) had deformity at the transverse tarsal joints with variable prominences. Each type was further subdivided into stages A, B, and C based on the severity of the deformity. In stage B, the midtarsus was coplanar with the metatarsocalcaneal plane. In stage A, the midtarsus was above this plane. In stage C, the midtarsus was below this plane. We concluded that midtarsus deformities can be classified as one of four types and one of three stages. Additional study is warranted to correlate this system with prognosis and treatment for this pathologic process.     

Microstructures and mechanical properties of Ni3Al alloyed with iron additions

The alloying behavior of iron in B-doped Ni₃Al was studied using optical and transmission electron microscopy for microstructural analysis and tensile testing for mechanical property evaluation. The aluminide dissolves less than 15 at. pct iron. At iron levels of 15 pct, depending on the aluminum level, formation of both transformed B2 phase (β^′) and disordered fee phase (γ) is observed. The phase relationships in the aluminide containing 10 pct iron were studied in detail by quenching from temperatures below 1370 °C. Tensile properties of nickel-iron aluminides were determined as functions of iron content and test temperature. The tensile results are discussed in terms of solid-solution hardening, atomic size misfit, and precipitation of γ, β^′, and carbides.     

Luria's contributions to clinical and behavioral neuropsychology.

The famous Soviet neuropsychologist and neurologist A. R. Luria made many important contributions to clinical and behavioral neuropsychology including the understanding of human brain functioning, the clinical assessments of higher cortical functioning (especially aphasia), and the development of personal therapy plans for the rehabilitation of individuals with local brain lesions. These contributions are best understood from reviewing certain family intellectual and political considerations, which influenced Luria's remarkable blending of psychology and neurology. Also, the relevance of Luria's contribution to behavior neuropsychology, the use of behavior therapy techniques with brain-damaged individuals, is examined. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The use of indirect memory tests to assess malingered amnesia: A study of metamemory.

Many techniques have been suggested for identifying criminal suspects who are simulating amnesia for events surrounding a crime. The present research focuses on indirect memory tests as a potential means of discriminating between those who genuinely suffer from amnesia and those who are simulating. Ss studied a list of words and subsequently performed either a word completion or a fragment completion task. Under normal indirect test instructions, typical priming effects were observed. When Ss were motivated to simulate amnesia for the list, target completion rates were consistently, and sometimes reliably, below baseline completion rates. This finding is contrary to the performance of genuine amnesics, whose performance on indirect tests typically mirrors that of normal Ss. Indirect tests may prove useful in discriminating genuine and simulating amnesics. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

An examination of five preferred orientation functions

Five functions for describing the preferred orientation of graphite-like materials were examined. Their relative behavior for various degrees of orientation were compared, particularly with respect to the ease of discriminating among them experimentally. The results obtained when data were fitted by a non-linear least squares method were used for a practical comparison. It was found that a constant term is required to allow for base line effects and some unoriented material. For careful evaluation of functions it is necessary to assume that the angle for maximum X-ray reflection intensity was set with some error. Among the five functions compared, the Bragg function fitted the comparison data best. However, if zero slope is required 90° away from the reference axis, this function is ineligible. In that case the Bacon and Ergun functions were equally good. Systematic trends in some of the data were related to sample preparation. The standard deviation for measuring the orientation parameter by fitting a function in this manner was from 0.4 to 3%.     

Expression of IL-5 in thymocytes/T cells leads to the development of a massive eosinophilia, extramedullary eosinophilopoiesis, and unique histopathologies

Transgenic mice were generated using regulatory elements from the CD3delta gene to drive T cell expression of IL-5. Expression of this cytokine resulted in white blood cell counts that expand virtually unabated (approximately 400,000 cells/mm3). This expansion is characterized by a profound eosinophilia (>60%) and commensurate increases in the absolute numbers of all other white blood cell types. In particular, circulating B220+ B lymphocyte populations increased >30-fold over wild-type (+/+) levels. Cell differentials and expression studies using a marker for eosinophil precursor cells (major basic protein gene expression) suggest that the peripheral eosinophilia is induced primarily through the establishment of extramedullary sites of eosinophilopoiesis. These mice display a massive peritoneal cavity cell exudate (1-2 x 10(8) cells) dominated by eosinophils (approximately 50%) and the infiltration of eosinophils in nearly all organ systems. Sudden unexplained death occurs in 70% of all transgenic animals by 12 mo of age. Surviving transgenic animals display severe inflammatory pathologies that include ulcerating skin lesions as well as lower bowel inflammation. These pathologies parallel clinical observations of patients with a profound eosinophilia and imply that IL-5 effector functions during some inflammatory responses may be contingent upon peripheral lymphohemopoietic expression.     

Pattern of ocular dominance columns in human striate cortex in strabismic amblyopia

Previous experiments in animals have shown that early unilateral eyelid suture, a model of amblyopia induced by cataract, causes shrinkage of ocular dominance columns serving the deprived eye in the striate cortex. It is unknown whether the ocular dominance columns are affected in amblyopia produced by strabismus. We examined specimens of striate cortex obtained postmortem from a 79-year-old woman with a history of amblyopia in her left eye (20/800) since age 2 from accommodative esotropia. Four years prior to her death, she suffered an ischemic infarct of the left optic disc. This injury to the left optic disc made it possible to label the ocular dominance columns using cytochrome oxidase histochemistry. The pattern of ocular dominance columns was reconstructed throughout most of the right striate cortex. No shrinkage of columns was found. In the left cortex only half the column mosaic was labelled, because the patient had some residual vision in the temporal retina of her left eye. The columns within the labelled portion of the overall mosaic appeared normal. These findings indicate that shrinkage of ocular dominance columns does not occur in humans with amblyopia caused by accommodative esotropia. The ocular dominance columns are probably no longer susceptible to shrinkage at the age when most children with this condition begin to develop amblyopia.