The aminoglycoside antibiotics have been a mainstay in the systemic therapy for serious Gram-negative infections for nearly five decades. The adverse effects of ototoxicity and nephrotoxicity, first recognized after the introduction of streptomycin in the 1940s [l, 21, still pose many unresolved basic questions and continue to complicate the clinical application of these drugs. It has been well-documented that aminoglycoside-induct hearing loss is related to the progressive and irreversible destruction of cochlear outer hair cells from the inner ear [3]. A variety of biochemical effects have been described and mechanisms of toxicity advanced 141, but no cellular event has yet been causally linked to cytotoxicity or cell death.

We have demonstrated recently that incubation of the aminoglycoside gentamicin with an hepatic post-mitochondrial fraction produces a compound toxic to sensory cells from the inner ear in short-term culture; in contrast, the parent aminoglycoside was non-toxic in vitro (Huang MY and Schacht J, Biochem Pharmacol 40: R11-R14, 1990). In the present study, we investigated the subcellular distribution of the enzymatic activity and the nature of the metabolite. Isolated outer hair cells from the guinea pig cochlea were used to assay for cytotoxicity. The enzyme(s) responsible for this novel reaction of aminoglycosides was exclusively localized to the cytosolic fraction of guinea pig liver. No activity was detected in nuclear, lysosomal/mitochondrial or microsomal preparations. Furthermore, the toxin-forming enzymatic activity was associated with the high molecular weight fraction of the cytosol and did not require low molecular weight components. Filtration of the toxin through molecular weight cut-off membranes showed a molecular size of approximately 500. This evidence is consistent with the toxin being a gentamicin derivative.

The role of [F]fluorodeoxyglucose (FDG) positron-emission tomography (PET) in mucosa-associated lymphoid tissue (MALT) of marginal zone lymphoma remains poorly defined. We correlated initial PET with pathology, clinical factors, and outcome. From January 2001 to July 2012, 173 MALT lymphoma patients with a biopsied lesion identified on PET within 90 days of tissue biopsy were analyzed. PET positivity and intensity of FDG uptake were correlated with clinical factors and patient outcome. Among 173 accrued cases, biopsied site was PET avid in 123 patients (71%); median standardized uptake value (SUV) was 6.0 (range: 0.7-28.0), and SUV >10.0 in 20 patients (16%). PET avidity varied by organ sites. PET positivity correlated with higher International Prognostic Index, but not with 5-year overall survival (OS; 96% vs 88%, PET negative vs positive, = .229) or 5-year progression-free survival (67% vs 56%, = .493). SUV was an independent prognostic factor of OS, and an increased SUV was associated with a decreasing 5-year OS. Patients who presented with SUV ≥10 had a higher rate of subsequent large cell transformation (20% vs 5%, = .035) and inferior OS (78% vs 92%, = .008). The exact role of FDG PET in the management of MALT lymphoma, beyond initial staging, remains to be defined.

Abstract:We develop an analytical model to predict the collapse conformation for a single semiflexible polymer chain in solution, given its length, diameter, stiffness, and self-attractiveness. We construct conformational phase diagrams containing three collapsed states, namely torus, bundle, and globule over a range of dimensionless ratios of the three energy parameters, namely solvent-water surface energy (γ s ), energy of bundle end folds (γ e ), and bending energy per unit length in a torus (γ b ). Our phase diagram captures the general phase behavior of a single long chain (>10 Kuhn lengths) at moderately high (order unity) dimensionless temperature, which is the ratio of thermal energy to the attractive interaction between neighboring monomers. We find that the phase behavior approaches an asymptotic limit when the dimensionless chain length to diameter ratio (L*) exceeds 300. We successfully validate our analytical results with Brownian Dynamics (BD) simulations, using a mapping of the simulation parameters to those used in the phase diagram. We evaluate the effect of three different bending potentials in the range of moderately high dimensionless temperature, a regime not been previously explored by simulations, and find qualitative agreement between the model and simulation results. We, thus, demonstrate that a rather simplified analytical model can be used to qualitatively predict the final collapsed state of a given polymer chain.

We find using dissipative particle dynamics (DPD) simulations that a deformable droplet sheared in a narrow microchannel migrates to steady-state position that depends upon the dimensionless particle capillary number , which controls the droplet deformability (with V the centerline velocity, μ the fluid viscosity, Γ the surface tension, R the droplet radius, and H the gap), the droplet (particle) Reynolds number , which controls inertia, where ρ is the fluid density, as well as on the viscosity ratio of the droplet to the suspending fluid κ = μ/μ. We find that when the Ohnesorge number is around 0.06, so that inertia is stronger than capillarity, at small capillary number Ca < 0.1, the droplet migrates to a position close to that observed for hard spheres by Segre and Silberberg, around 60% of the distance from the centerline to the wall, while for increasing Ca the droplet steady-state position moves smoothly towards the centerline, reaching around 20% of the distance from centerline to the wall when Ca reaches 0.5 or so. For higher Oh, the droplet position is much less sensitive to Ca, and remains at around 30% of the distance from centerline to the wall over the whole accessible range of Ca. The results are insensitive to viscosity ratios from unity to the highest value studied here, around 13, and the drift towards the centerline for increasing Ca is observed for ratios of droplet diameter to gap size ranging from 0.1 to 0.3. We also find consistency between our predictions and existing perturbation theory for small droplet or particle size, as well as with experimental data. Additionally, we assess the accuracy of the DPD method and conclude that with current computer resources and methods DPD is not readily able to predict cross-stream-line drift for small particle Reynolds number (much less than unity), or for droplets that are less than one tenth the gap size, owing to excessive noise and inadequate numbers of DPD particles per droplet.