Genotoxicity and toxicity of the potential cancer-preventive agent polyphenon E

The potential health benefits of green tea continue to attract public and scientific interests and are attributed in part to polyphenolic catechin constituents. Polyphenon E (Poly E) is a decaffeinated green tea catechin mixture containing about 50% epigallocatechin gallate and 30% other catechins. We evaluated the toxicity and genotoxicity of Poly E by using two in vitro assays: bacterial mutagenesis in a Salmonella typhimurium-E. coli assay and the L5178Y mouse lymphoma cell thymidine kinase (Tk) gene mutation assay. In addition, we used two in vivo genotoxicity assays: the mouse micronucleus assay and the Big Blue cII transgenic mouse mutation assay. Repeat-dose toxicity evaluations were performed in mice in parallel with the Big Blue transgenic mutation assays. No significant increases in the revertant colonies were found in the bacterial mutagenesis assay, but a significant increase in the mutant frequency (MF) at the Tk locus was observed in the mouse lymphoma test system. We observed toxicity in mice when Poly E was administered at doses of 2,000 mg/kg/day. Lower doses produced no significant increases in micronucleated erythrocytes in the bone marrow of Swiss-Webster mice and no significant increases in cII transgene MF in the liver, lung, or spleen compared with controls. These results indicate that Poly E, although toxic at high doses (2,000 mg/kg/day), poses minimal genotoxic concern. In addition, these studies highlight the importance of using both in vitro and in vivo systems in genetic toxicity screening of pharmaceuticals before they are administered to humans.     

Neural timescales or lack thereof

This article aims at making readers, experimentalists and theorists, more aware of the abstractions made by an observer when measuring and reporting behavioral and neural timescales. These abstractions stow away the fact that, above lower boundaries that reflect fairly well understood physical constraints, observed and reported timescales are often not intrinsic to the biological system; rather, in most cases they reflect conditions that are imposed by the observer through the measuring procedure. This is true at practically every level of organization, from behavior down to molecules. I analyze the impacts of the resulting temporal manifold in behavioral and brain sciences on experimental designs and mathematical modeling.     

Towards optimization in digital chest radiography using Monte Carlo modelling

A Monte Carlo based computer model of the x-ray imaging system was used to investigate how various image quality parameters of interest in chest PA radiography and the effective dose E vary with tube voltage (90-150 kV), additional copper filtration (0-0.5 mm), anti-scatter method (grid ratios 8-16 and air gap lengths 20-40 cm) and patient thickness (20-28 cm) in a computed radiography (CR) system. Calculated quantities were normalized to a fixed value of air kerma (5.0 microGy) at the automatic exposure control chambers. Soft-tissue nodules were positioned at different locations in the anatomy and calcifications in the apical region. The signal-to-noise ratio, SNR, of the nodules and the nodule contrast relative to the contrast of bone (C/C(B)) as well as relative to the dynamic range in the image (C(rel)) were used as image quality measures. In all anatomical regions, except in the densest regions in the thickest patients, the air gap technique provides higher SNR and contrast ratios than the grid technique and at a lower effective dose E. Choice of tube voltage depends on whether quantum noise (SNR) or the contrast ratios are most relevant for the diagnostic task. SNR increases with decreasing tube voltage while C/C(B) increases with increasing tube voltage.     

Anisotropic Photomechanical Response of Stretched Blend Film Made of Polycaprolactone‐Polyvinyl Ether with Azobenzene Group as Side Chain

A rapid and reversible anisotropic photomechanical response of polymer film was achieved by using uniaxially stretched blend film composed of polycaprolactone and poly(vinyl ether) with azobenzene moiety (Azo‐PVE) as a side chain. The photomechanical response behavior of the film was studied under a constant tensile stress. The deformation or recovery was rapidly completed within at most 0.1 min of UV + Vis light irradiation being switched on or off, respectively. The anisotropy of deformation was confirmed on a stretched film subjected to light irradiation. The deformation was observed as a contraction in a direction parallel to the stretching direction and as an elongation in the perpendicular direction. The anisotropy of the photoresponse was remarkably observed with increase in the stretching ratio, reflecting the binding between amorphous areas by Azo‐PVE long chains.

     

A computational model of perceptual fill-in following retinal degeneration

The ablation of afferent input results in the reorganization of sensory and motor cortices. In the primary visual cortex (V1), binocular retinal lesions deprive a corresponding cortical region [lesion projection zone (LPZ)] of visual input. Nevertheless, neurons in the LPZ regain responsiveness by shifting their receptive fields (RFs) outside the retinal lesions; this re-emergence of neural activity is paralleled by the perceptual completion of disrupted visual input in human subjects with retinal damage. To determine whether V1 reorganization can account for perceptual fill-in, we developed a neural network model that simulates the cortical remapping in V1. The model shows that RF shifts mediated by the plexus of spatial- and orientation-dependent horizontal connections in V1 can engender filling-in that is both robust and consistent with psychophysical reports of perceptual completion. Our model suggests that V1 reorganization may underlie perceptual fill-in, and it predicts spatial relationships between the original and remapped RFs that can be tested experimentally. More generally, it provides a general explanation for adaptive functional changes following CNS lesions, based on the recruitment of existing cortical connections that are involved in normal integrative mechanisms.     

Morbidity of DSM-IV Axis I disorders in patients with noncardiac chest pain: Psychiatric morbidity linked with increased pain and health care utilization

The present study examined current and lifetime psychiatric morbidity, chest pain, and health care utilization in 229 patients with noncardiac chest pain (NCCP), angina-like pain in the absence of cardiac etiology. Diagnostic interview findings based on the Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV; American Psychiatric Association, 1994) revealed a psychiatrically heterogeneous sample of whom 44% had a current Axis I psychiatric disorder. A total of 41% were diagnosed with a current anxiety disorder, and 13% were diagnosed with a mood disorder. Overall, 75% of patients had an Axis I clinical or subclinical disorder. Lifetime diagnoses of anxiety (55%) and mood disorders (44%) were also prevalent, including major depressive disorder (41%), social phobia (25%), and panic disorder (22%). Patients with an Axis I disorder reported more frequent and more painful chest pain compared with those without an Axis I disorder. Presence of an Axis I disorder was associated with increased life interference and health care utilization. Findings reveal that varied DSM-IV Axis I psychiatric disorders are prevalent among patients with NCCP, and this psychiatric morbidity is associated with a less favorable NCCP presentation. Implications for early identification of psychiatric disorders are discussed.     

CD28 signals the differential control of regulatory T cells and effector T cells

One possible means of driving antigen‐specific immune suppression is to expand or induce antigen‐specific FoxP3‐expressing Treg cells. One way of activating and expanding these specialized cells, both in vitro and in vivo, is by strong costimulation via CD28 with an agonistic anti‐CD28 monoclonal antibody, called anti‐CD28 superagonist (CD28SA). However, CD28SA also strongly activates conventional T (Tconv) cells to secrete proinflammatory cytokines and, under certain conditions, causes serious cytokine release syndrome. In this issue of European Journal of Immunology, Tabares et al. [Eur. J. Immunol. 2014. 44: 1225–1236] address how CD28SA can be used for the differential control of human Treg and Tconv cells to suppress immune responses without serious adverse effects. They show that, depending on the dose of the antibody or by comedication of cortico‐steroid, the selective expansion of Treg cells can be achieved without significantly activating Tconv cells to produce inflammatory cytokines. This difference in CD28 signal sensitivity between the two populations can be exploited for better control of immune responses.     

Cytocompatibility of novel extracellular matrix protein analogs of biodegradable polyester polymers derived from α-hydroxy amino acids

One of the challenges in regenerative medicine is the development of novel biodegradable materials to build scaffolds that will support multiple cell types for tissue engineering. Here we describe the preparation, characterization, and cytocompatibility of homo- and hetero-polyesters of α-hydroxy amino acid derivatives with or without lactic acid conjugation. The polymers were prepared by a direct condensation method and characterized using gel permeation chromatography, ¹H-nuclear magnetic resonance spectroscopy, Fourier transform infrared spectroscopy, differential scanning calorimetry, optical activity, and solubility. The surface charge of the polymers was evaluated using zeta potential measurements. The polymers were coated onto glass cover slips followed by characterization using nano-surface profiler, thin film reflectometry, and atomic force microscopy (AFM). Their interaction with endothelial and neuronal cells was assessed using adhesion, proliferation, and differentiation assays. Of the characterized polymers, Poly-HOVal-LA, but not Poly-(D)HOPhe, significantly augmented nerve growth factor (NGF)-induced neuronal differentiation of the PC12 pheochromcytoma cells. In contrast, Poly-HOLeu increased by 20% the adhesion of endothelial cells, but did not affect PC12 cell differentiation. NGF-induced Erk1/2 phosphorylation in PC12 cells grown on the different polymers was similar to the effect observed for cells cultured on collagen type I. While no significant association could be established between charge and the differentiative/proliferative properties of the polymers, AFM analysis indicated augmentation of NGF-induced neuronal differentiation on smooth polymer surfaces. We conclude that overall selective cytocompatibility and bioactivity might render α-hydroxy amino acid polymers useful as extracellular matrix-mimicking materials for tissue engineering.     

Comparison of positive allergy skin tests among asthmatic children from rural and urban areas living within small geographic area.

BACKGROUND: Evidence of increased asthma and allergic response among urban versus rural residents has been reported. OBJECTIVE: To evaluate the prevalence of allergic response among asthmatic children from urban and rural areas living within close proximity. METHODS: In all, 448 asthmatic children from urban (363) and rural (85) areas were studied. The study group consisted of 234 9-year-olds and 214 12-year-olds. A health questionnaire was completed on each child who subsequently underwent allergic skin prick tests (SPTs). RESULTS: There was significantly more positive SPT response to house-dust mite, mold, cat, and cypress among asthmatic children from urban areas compared with children living in rural areas: 58.3% versus 37.6%, 46.1% versus 31.8%, 17.45 versus 5.9%, and 26.2% versus 15.3%, respectively. Positive SPT for indoor allergens were significantly greater among asthmatic urban residents than asthmatic rural residents: 63.3% versus 45.5%, respectively (P < 0.02). Positive SPT response to all the allergens checked was higher among the 12-year-old age group when compared with the 9-year-olds, 34.6% versus 22.7%, respectively (P = 0.05). CONCLUSIONS: Allergic response measured by SPT is significantly more common among asthmatic children from urban areas as opposed to rural, even though both areas are within small distance of one another. Further, asthmatic children living in urban areas demonstrated more allergic response to both indoor and outdoor allergens. The allergic response tends to increase with increased age in both urban and rural asthmatic children.     

Transplantation of hematopoietic stem cells for induction of unresponsiveness to organ allografts

Although it has been recognized since the early days of Owen and Medawar that engraftment of donor stem cells, induced in utero spontaneously or intentionally neonatally, results in life-long unresponsiveness to donor alloantigens. However, successful induction of transplantation tolerance in adult life still represents an unsolved problem. Engraftment of donor stem cells using conventional modalities involves intensive myeloablative or lymphoablative immunosuppression, which is associated with toxicity and mortality and such methods are not suitable for organ allograft recipients. In this chapter, we present an innovative approach for induction of donor-specific unresponsiveness to bone marrow and organ allografts without myeloablative conditioning. Our methods is based on cyclophosphamide-induced, alloantigen-primed lymphocyte depletion. Cyclophosphamide is administered 1 day following infusion of donor hematopoietic cells, thus eliminating predominantly host T lymphocytes reacting against donor cell challenge, and resulting in relative unresponsiveness to donor alloantigens. Subsequently, life-long tolerance to fully mismatched donor skin allografts can be accomplished by a second infusion of stem cells from the same donor, with donor T cells displacing residual alloreactive host cells that may have escaped deletion. Taken together, we believe that induction of true permanent and specific tolerance to organ allografts using donor hematopoietic cells could become a clinical reality in the foreseeable future.