Synthesis and characterization of cyclic pseudopeptide libraries containing thiomethylene and thiomethylene-sulfoxide amide bond surrogates

Resistance-modifying agents (RMAs) such as Verapamil have been proved to be effective in reversing multi-drug resistance (MDR) in many in vitro assays. In this study we have investigated the efficacy of Dex-Verapamil, the R-isomer of Verapamil, as a chemosensitizer in a murine leukemia cell line (P388) and in its resistant counterpart (P388/Dx) expressing a typical MDR phenotype. We have examined in vivo the effect of the co-administration of Dex-Verapamil and Doxorubicin in mice transplanted with P388 or P388/Dx cells. Mice treated with the combination of Doxorubicin plus RMA had a significant increase in survival rate as compared to controls; however, the effect was modest. On the contrary, in vitro Dex-Verapamil can enhance Doxorubicin cytotoxicity in P388/Dx cells with a much greater effect depending on the treatment scheme used, by increasing the intracellular content of drug. Taken together our data indicate that Dex-Verapamil can indeed increase the sensitivity to Doxorubicin in resistant cells, but the limited efficacy shown in vivo demonstrates that this phenomenon is strongly dependent on the treatment scheme used and on the maintenance of constantly elevated serum levels.     

Unpredication, unscheduling, unspeculation: reverse engineering Itanium executables

EPIC (explicitly parallel instruction computing) architectures, exemplified by the Intel Itanium, support a number of advanced architectural features, such as explicit instruction-level parallelism, instruction predication, and speculative loads from memory. However, compiler optimizations that take advantage of these features can profoundly restructure the program's code, making it potentially difficult to reconstruct the original program logic from an optimized Itanium executable. This paper describes techniques to undo some of the effects of such optimizations and thereby improve the quality of reverse engineering such executables.     

Cytoskeletal changes during neurogenesis in cultures of avain neural crest cells

Neural crest cells are motile and mitotic, whereas their neuronal derivatives are terminally post-mitotic and consist of stationary cell body from which processes grow. The present study documents changes in the cytoskeleton that occur during neurogenesis in cultures of avain neural crest cells. The undifferentiated neural crest cells contain dense bundles of actin filaments throughout their cytoplasm, and a splayed array of microtubules attached to the centrosome. In newly differentiating neurons, the actin bundles are disrupted and most of the remaining actin filaments are reorganized into a cortical layer underlying the plasma membrane of the cell body and processes. Microtubules are more abundant in newly-differentiating neurons than in the undifferentiated cells, and individual microtubules can be seen dissociated from the centrosome. Neuron-specific beta-III tubulin appears in some crest cells prior to cessation of motility and cell division, and expression increases with total microtubule levels during neurogenesis. To investigate how these early cytoskeletal changes might contribute to alterations in morphology during neurogenesis, we have disrupted the cytoskeleton with pharmacologic agents. Microfilament disruption by cytochalasin immediately arrests the movement of neural crest cells and causes them to round-up, but does not significantly change the morphology of the immature neurons. Microtubule depolymerization by nocodazole slows the movement of undifferentiated cells and causes retraction of processes extended by the immature neurons. These results suggest that changes in the actin and microtubule arrays within neural crest cells govern distinct aspects of their morphogenesis into neurons.     

Delta opioid peptide [D-Ala2,D-leu5]enkephalin blocks the long-term loss of dopamine transporters induced by multiple administrations of methamphetamine: involvement of opioid receptors and reactive oxygen species

Delta opioid peptide [D-Ala2,D-leu5]enkephalin (DADLE) can prolong organ preservation and increases myocardial tolerance to ischemia. Our study examined the protective property of DADLE against methamphetamine- (METH) induced dopaminergic terminal damage in the central nervous system. Because the neurotoxicity of METH involves reactive oxygen species, we also examined if DADLE might be an antioxidative agent in vitro. DADLE at 2 and 4 mg/kg (i.p.), given 30 min before each METH administration (5 or 10 mg/kg, i.p., four injections in a day at 2-hr intervals), dose-dependently blocked the METH-induced long-term dopamine transporter loss. The opioid antagonist naltrexone blocked this action of DADLE in both aspects of striata but tends not to affect the effects of DADLE in the nucleus accumbens. DADLE did not alter changes in body temperature induced by METH. The reduction of striatal dopaminergic content and tyrosine hydroxylase activity caused by METH, however, were not blocked by DADLE. In vitro, DADLE was approximately equipotent to glutathione in inhibiting both superoxide anion formation induced by xanthine oxidase and hydroxyl radical formation evoked by ferrous/citrate complex. DADLE was only slightly less potent than glutathione in inhibiting the iron/ascorbate-induced brain lipid peroxidation. These results suggest that DADLE can protect the terminal membranes of dopaminergic neurons against METH-induced insult but not the loss of dopaminergic content and tyrosine hydroxylase activity and that this action of DADLE might involve opioid receptors as well as the sequestration of free radical.     

Muscle mass and fat mass in relation to bone mineral density in very old men and women: the Framingham Heart Study

Aim of the study was investigate the cross-sectional relationship between body composition and bone mineral density (BMD) in very old men and women. The study sample consisted of 504 women and 285 men, aged 72-93 yr, participating in examination 22 (1992-1993) of the Framingham Heart Study. Total body BMD, regional BMD, and soft-tissue body composition was measured by dual-energy X-ray absorptiometry. Both muscle mass and percentage body fat were positively associated with total body BMD in women. After adjustment for age, physical activity, smoking status, estrogen use, and thiazide use, BMD increased with increasing tertile of muscle mass (p = 0.007) and with increasing tertile of percentage body fat (p = 0.0001) in women. In men muscle mass, not percentage body fat, was positively associated with BMD. After adjustment for potential confounders, BMD remained associated with muscle mass only (p = 0.02). These results were similar for leg BMD and arm BMD. The study suggests that the influence of muscle and fat mass on bone mineral density is different between very old men and women.     

Impaired interleukin-12 production is associated with a defective anti-tumor response in colorectal cancer

OBJECTIVE: Spontaneous spinal epidural hematoma (SSEH) is an idiopathic accumulation of blood in the vertebral epidural space without identifiable predisposing factors. First reported in 1869, the clinical outcome in children younger than 18 years old has not been clearly delineated. DESIGN: A comprehensive review of the English language literature revealed 26 patients younger than 18 years old with reported clinical outcomes. The 27th case is presented. RESULTS: Complete neurologic recovery occurred in 14 of 27 (52%) patients, partial recovery in 12 of 27 (44%) patients, and death in 1 of 27 (4%) patients. CONCLUSION: There is an overall good prognosis for neurologic recovery in children who experience SSEH.     

Fluctuations in visual neglect after stroke?

Clinical experience suggests that the visual neglect in stroke patients fluctuates over short periods of time. This fluctuation has been variously attributed to fatigue, time of day, previous activities, patient learning and compensation. Such fluctuations have clinical implications for the assessment and rehabilitation of visual neglect but do date no formal study has evaluated the extent of such fluctuation over the course of a day. Twenty-two patients with an acute stroke and 19 patients with convalescent stroke were examined for visual neglect twice on the same day using the Visual Neglect Recovery Index (VNRI), a valid and sensitive measure of the severity of neglect, which could be used to select acute patients for trials of treatment of neglect. The inter-test reliability was extremely high. In contrast to past clinical accounts most patients failed to show significant fluctuation. Although preliminary, this finding suggests that a single assessment of visual neglect, using the VNRI, could help select patients for treatment trials.     

Adhesion to skin

The failure energy of an adhesive bond can be factorized into two terms, one of which is a dimensionless loss function and the other, the true interfacial bonding energy, ₀. Experimental techniques have been developed to effect a separation of these two terms and thus measure ₀, but they are unsuitable for the pressure-sensitive adhesives used in surgical tapes and dressings. This is because these adhesives flow readily under load. This paper describes an extrapolation technique by which this problem can be resolved. Adhesive peel data are extrapolated both to zero peel velocity and zero load, to give a true threshold value for peeling energy which is independent of temperature. Values of ₀ are given for a natural-rubber based adhesive and substrates of glass and human skinin vivo. For glass ₀ = 28J m^–2 and for normal skin ₀ 14J m-2.