Parallel Colorimetric Quantification of Choline and Phosphocholine as a Method for Studying Choline Kinase Activity in Complex Mixtures.
Choline kinase (Chok) is an enzyme found in eukaryotes and Gram-positive bacteria. Chok catalyzes the production of phosphocholine from choline and ATP. This enzyme has been validated as a drug target in Streptococcus pneumonia, but the role Chok enzymatic activity plays in bacterial cell growth and division is not well understood. Phosphocholine production by Chok and its attenuation by inhibitors in the context of complex samples such as cell extracts can currently be quantified by several methods. These include choline depletion measurements, radioactive methods, mass-spectrometry, and nuclear magnetic resonance. The first does not measure phosphocholine directly, the second requires elaborate safety procedures, and the third and fourth require significant capital investments and technical expertise. For these reasons, a less expensive, higher throughput, more easily accessible assay is needed to facilitate further study in Gram-positive Choks. Here, we present the development of a triiodide/activated charcoal/molybdenum blue system for detecting and quantifying choline and phosphocholine in parallel. We demonstrate that this system can reliably quantify changes in choline and phosphocholine concentrations over time in Chok enzymatic assays using cell extracts as the source of the enzyme. This is an easily accessible, convenient, robust, and economical method for studying Chok activity in complex samples. The triiodide/activated charcoal/molybdenum blue system opens new doors into the study choline kinase in Gram-positive pathogens.


Fibrinolysis resistant fibrin deposits in lymph nodes with Hodgkin's disease.
Extravasal fibrin deposition is frequently observed within and around tumorous tissues and has been implicated in various aspects of tumor growth. However, no adequate information has been available on the mechanism how intratumoral interstitial fibrin deposits escape a prompt elimination by the fibrinolytic system. In this study we provide immunomorphological evidence showing that fibrin deposits in lymph nodes with Hodgkin's disease are stabilized and made resistant to fibrinolysis by factor XIII (FXIII) of blood coagulation. By double immunofluorescent labelling systems fibrin deposits were simultaneously stained for alpha 2-antiplasmin (alpha 2-AP), the main physiological inhibitor of fibrinolysis and in a number of nodular areas they were also labelled for plasmin(ogen). The detection of alpha 2-antiplasmin-plasmin complex-neoantigen (alpha 2-AP-P-Neo) revealed that alpha 2-AP reacted with plasmin, i.e., alpha 2-AP covalently linked to fibrin indeed inhibited intratumoral fibrinolysis. In addition to fibrin deposits FXIII was also found in cellular elements characterized earlier as tumor associated macrophages. These cells were attached to fibrin strands suggesting that they are involved in the intratumoral fibrin formation and might be a source of fibrin stabilizing factor in the tumor stroma.


DNA methylation of TOMM40-APOE-APOC2 in Alzheimer's disease.
The apolipoprotein E (APOE) ε4 allele is the major genetic risk factor for Alzheimer's disease (AD). Multiple regulatory elements, spanning the extended TOMM40-APOE-APOC2 region, regulate gene expression at this locus. Regulatory element DNA methylation changes occur under different environmental conditions, such as disease. Our group and others have described an APOE CpG island as hypomethylated in AD, compared to cognitively normal controls. However, little is known about methylation of the larger TOMM40-APOE-APOC2 region. The hypothesis of this investigation was that regulatory element methylation levels of the larger TOMM40-APOE-APOC2 region are associated with AD. The aim was to determine whether DNA methylation of the TOMM40-APOE-APOC2 region differs in AD compared to cognitively normal controls in post-mortem brain and peripheral blood. DNA was extracted from human brain (n = 12) and peripheral blood (n = 67). A methylation array was used for this analysis. Percent methylation within the TOMM40-APOE-APOC2 region was evaluated for differences according to tissue type, disease state, AD-related biomarkers, and gene expression. Results from this exploratory analysis suggest that regulatory element methylation levels within the larger TOMM40-APOE-APOC2 gene region correlate with AD-related biomarkers and TOMM40 or APOE gene expression in AD.


Ionic Switch Induced by a Rectangular-Hexagonal Phase Transition in Benzenammonium Columnar Liquid Crystals.
We demonstrate switching of ionic conductivities in wedge-shaped liquid-crystalline (LC) ammonium salts. A thermoreversible phase transition between the rectangular columnar (Colr) and hexagonal columnar (Colh) phases is used for the switch. The ionic conductivities in the Colh phase are about four orders of magnitude higher than those in the Colr phase. The switching behavior of conductivity can be ascribed to the structural change of assembled ionic channels. X-ray experiments reveal a highly ordered packing of the ions in the Colr phase, which prevents the ion transport.


Hospital to home: smoothing the journey for the new ostomist.
For most patients, being discharged from hospital is an important milestone in their recovery. Having come through surgery, they have completed their early recovery, are well enough to leave the safe confines of the hospital and have reached the natural end point of what should be a well coordinated episode of care with a satisfactory outcome, where the discharge is as important as the admission. However, although most are naturally pleased to be going home, patients will have many fears and anxieties about how they are actually going to manage. This includes not only coping with their recovery, but also managing their lives, returning to their usual activities and lifestyle and coping with their new stoma. Knowledge information and support, nursing interventions and experiences in hospital are valuable and will be put to good use at home. This article identifies the key issues that may arise during this time, the level of knowledge and skill required for a successful transition home and the support required by the patient to adapt to their changed circumstances.


Association of gamma-glutamyltransferase with plasma lipoprotein and lipid-protein complex in cholestasis.
Distribution of plasma gamma-glutamyltransferase (GGT) activity among lipoproteins was studied by ultracentrifugation and polyacrylamide gradient gel electrophoresis of plasma from 2 normal controls, 7 patients with intrahepatic cholestasis, and 5 patients with biliary obstruction. Half the total plasma activity was associated with lipoproteins, and more than 90 per cent of the residue activity with macromolecular lipid-protein complex. Healthy subjects had the highest GGT activity in HDL, intermediate activity in LDL, and the lowest in VLDL. In cholestasis, GGT activity increased mainly by the following two mechanisms: 1) the appearance of cholestatic lipoproteins carrying GGT, such as lipoprotein X or Slow-Migrating HDL, or increase in concentration of lipid-protein complex with GGT activity and 2) increase in GGT activity per unit weight of HDL.


Congenital Cataracts in Preterm Infants: A Review.
A congenital cataract is one of the most treatable causes of visual impairment during infancy. Preterm infants who are born alive before 37 weeks of pregnancy need special care, including proper age documentation, preoperative assessment, and monitoring postoperatively for at least 24 hours. Management of cataracts in preterm infants is critical as regards the timing of cataract surgery and the challenges associated with cataract surgery and posterior segment management for retinopathy of prematurity (ROP). This narrative review aims to provide comprehensive insight and up-to-date clinical research findings regarding the pathophysiology and management of congenital cataracts in preterm infants.


Peer assisted learning in patient-centred interviewing: the impact on student tutors.
Effective methods for teaching patient-centred interviewing skills are resource intensive. Providing students the opportunity to work in small groups with simulated patients is highly valued and has demonstrable long-term benefits. Expanding cohorts of medical students and diminishing faculty resources led to the implementation of a peer assisted learning (PAL) project in patient-centred interviewing skills. The paper reports the evaluation of a PAL project on student tutors. The methodology included direct and indirect measures of student tutors' skills in facilitation and patient-centred interviewing. The self-report evaluations strongly suggest that participating in a PAL project has substantial benefits for student tutors that included both interviewing and facilitation skills. Objective measures revealed no change in patient-centred interviewing skills after participating in the project. The study concludes that formalizing PAL may tap a valuable resource within the medical school and provide benefits for student tutors. Careful consideration needs to be given to ways in which student tutors are supported before, during and after the project.


Physiological and morphological studies of rat pheochromocytoma cells (PC12) chemically fused and grown in culture.
Cell fusion induced by polyethylene glycol has been used to produce in culture giant multinucleate PC12 cells (up to 300 micron in diameter compared to 10-20 micron for unfused cells). Fused cells, like their unfused counterparts, were found to express various neuronal properties. They contained catecholamines. In the presence of nerve growth factor they extended long processes and expressed Na+, Ca2+, and K+ conductances generally associated with excitable cells. In the absence of nerve growth factor these cells neither grew long processes nor generated Na+-spikes. Other neuronal properties were also observed.


Do oligoclonal bands add information to MRI in first attacks of multiple sclerosis?
To evaluate whether oligoclonal bands (OB) add information to MRI in predicting both a second attack and development of disability in patients with clinically isolated syndromes (CIS). From 1995 to 2006, 572 patients with CIS were included in a prospective study. Patients underwent brain MRI and determination of OB within 3 months of first attack. The number and location of lesions and presence of OB were studied. We analyzed time to second attack and to Expanded Disability Status Scale 3.0 according to number of Barkhof criteria (BC) and the presence or absence of OB. We studied 415 (73%) patients with CIS with both baseline MRI and determination of OB. Patients were followed for a mean of 50 months (SD 31). Compared to the reference group with 0 BC at baseline MRI, patients with one to two BC showed a hazard ratio (HR) for conversion to CDMS of 3.8 (2.0 to 7.2) and patients with three to four BC of 8.9 (4.8 to 16.4). Of the total cohort, OB were positive in 61% of the patients. However, broken down by MRI group, OB were positive in 31% of those with no BC; 69% of those with one to two BC; and 85% of those with three or four BC. The presence of OB increased the risk of a second relapse (HR 1.7; 1.1 to -2.7) independently of baseline MRI but did not modify the development of disability. Presence of oligoclonal bands doubles the risk for having a second attack, independently of MRI, but does not seem to influence the development of disability.


Photorefractive keratectomy with a small spot laser and tracker.
The Autonomous Technologies LADARVision excimer laser system utilizes an eye tracking mechanism and a small spot for photorefractive keratectomy. One hundred and two eyes of 102 patients were treated for -1.50 to -6.25 D of spherical myopia at the spectacle plane using a 6-mm diameter ablation zone. One year follow-up was available for 93 eyes (91%). Uncorrected visual acuity for eyes treated for distance vision was 20/40 or better in 99% (n = 90), and 20/20 or better in 70% (n = 64) of eyes at 12 months. Spectacle-corrected visual acuity was 20/25 or better in all 92 eyes reported; no eye lost more than 2 lines of spectacle-corrected visual acuity, and only 1 eye (1.0%) experienced a loss of 2 lines (20/12.5 to 20/20) at 1 year. The refractive result was within +/- 0.50 D of the desired correction in 75% (n = 70), and within +/- 1.00 D in 93% (n = 86) of eyes at 12 months. Refractive stability was achieved between 3 and 6 months. Corneal haze was graded as trace or less in 100% of the 93 eyes. No significant reductions were noted in contrast sensitivity or endothelial cell density. Patients treated with the Autonomous Technologies LADARVision excimer laser system for -1.50 to -6.25 D of spherical myopia with 1 year follow-up had uncorrected visual acuity of 20/20 or better in 70%, no significant loss of spectacle-corrected visual acuity, no reduction of endothelial cell density or contrast sensitivity, and low levels of corneal haze.


Popular participation and the state: democratizing the health sector in rural Peru.
Popular participation has been an important component of most primary health care strategies since the Alma Ata Declaration, 1978. This article examines the use of state-sponsored participation in the health sector in Peru and some of the experiences that have accompanied its implementation. Taking the Local Health Administration Committees (CLAS) from the second Fujimori government (1995-2000) as an example, it is shown that for self-motivated rural communities to work in harmony with the state, there must be willingness to adapt to the varying levels of intra-community differences, social integration and social support.


Production of Highly Polarized Positrons Using Polarized Electrons at MeV Energies.
The Polarized Electrons for Polarized Positrons experiment at the injector of the Continuous Electron Beam Accelerator Facility has demonstrated for the first time the efficient transfer of polarization from electrons to positrons produced by the polarized bremsstrahlung radiation induced by a polarized electron beam in a high-Z target. Positron polarization up to 82% have been measured for an initial electron beam momentum of 8.19 MeV/c, limited only by the electron beam polarization. This technique extends polarized positron capabilities from GeV to MeV electron beams, and opens access to polarized positron beam physics to a wide community.


Microfluidic accumulation assay to quantify the attachment of the marine bacterium Cobetia marina on fouling-release coatings.
Testing the adhesion of marine biofilm formers on bioresistant coatings is important to determine their fouling-release and antifouling properties. A dynamic attachment assay for the marine bacterium Cobetia marina (C. marina) was developed to test the adhesion on coatings and bioresistant surfaces. With well-defined culture conditions, the reproducibility of the microfluidic accumulation experiments with C. marina was verified using self-assembling monolayers as model surfaces. The assay discriminated the attachment of C. marina on four different surfaces with different wettability and protein resistances. In addition to these benchmark experiments on self-assembled monolayers, the adhesion of C. marina on polyglycerol coatings with different thicknesses was investigated.


Effect of dystocia on yield, fertility, and cow losses and an economic evaluation of dystocia scores for Holsteins.
Lactation records of US Holstein cows were analyzed with mixed models to determine the effect of dystocia on 305-d milk, fat, and protein yields, days open, number of services, and cow losses and to estimate the economic loss associated with dystocia. The data were 122,715 records of 71,618 cows from 1980 to 1991. The single-trait animal model included herd-year-season, sex of calf, age of dam, and dystocia score as fixed effects and animal and permanent environment as random effects. The effect of dystocia was significant (P < 0.01) on all traits within and across parities. Over multiple parities, the differences between score 5 (extreme difficulty) versus score 1 (no problem) for milk yield, fat yield, protein yield, days open, number of services, and cow deaths were 703.6 kg, 24.1 kg, 20.8 kg, 33 d, 0.2 services, and 4.1%, respectively. The losses associated with traits were priced and summed to determine the total economic loss associated with dystocia. In addition, calf mortality was considered to be a cost. Across parities, estimates of costs were $0.00, $50.45, $96.48, $159.82, and $379.61 for scores 1 to 5, respectively. Cost of dystocia was relatively higher on a per incidence basis than would be expected from the mean of the population. The total cost associated with dystocia (i. e., within-parity sum of costs associated with dystocia scores weighted by the probability of occurrence) was $28.53 for an average heifer and about $10.00 for an average cow for other parities.


Concerning the use of Western medical terms to represent traditional Chinese medical concepts.
This paper strongly rejects the notion that the use of biomedical terms to represent traditional Chinese medical concepts is helpful to the internationalization of Chinese medicine. It further argues that this practice destroys the integrity and independence of Chinese medical concepts. Taking the term fēng huo yan as an example, it shows that the biomedical term "acute conjunctivitis" often suggested as the translation for this term is unsatisfactory, because (1) the clinical reference is not identical, (2) it introduces the concepts of "conjunctiva" and "inflammation" , which are not Chinese medical concepts, and (3) destroys the Chinese medical concepts "wind" and "fire" expressed in the Chinese, which reflect the way the disease is traditionally diagnosed and treated. While for English readers not familiar with Chinese medicine, "acute conjunctivitis" may be immediately intelligible, for those seeking a deep understanding of the subject, the literal translation (loan translation) "wind-fire eye" is much more helpful. This paper supports these arguments with numerous other examples.


Dependence of subthalamic nucleus oscillations on movement and dopamine in Parkinson's disease.
Local field potentials and pairs of neurones in the subthalamic nucleus (STN) of patients with Parkinson's disease show high-frequency oscillations (HFOs) at 15-30 Hz. This study explores how these HFOs are modulated by voluntary movements and by dopaminergic medication. We examined 15 patients undergoing implantation of bilateral deep brain stimulating electrodes using microelectrode recordings of pairs of STN neurones (eight patients) and macroelectrode recordings of local field potentials from the STN (14 patients). Synchronized HFOs between STN neurones were observed in 28 out of 37 pairs in five patients who had tremor in the operating room and none of 45 pairs in three patients who did not. In two of the three non-tremulous patients, HFOs in the frequency spectra of local field potentials were detected but were weaker than in those patients with tremor. Active movement suppressed synchronized HFOs in three out of five pairs of neurones, independent of changes in firing rate. HFOs observed in the local field potentials in nine out of 14 patients were reduced with voluntary movement in six of the eight patients tested. Dopaminergic medication decreased the incidence of synchronized HFOs in STN neurone pairs, reduced HFO synchrony in a pair of tremor cells concurrent with a reduction in firing rate and limb tremor, and decreased HFOs of local field potentials in the STN. These results demonstrate that HFO synchronization in the STN is reduced by voluntary movements and by exogenous dopaminergic medication. A mechanism for neuronal oscillatory synchronization in basal ganglia is proposed. It is suggested that the firing of STN neurones can be synchronized by 15-30 Hz cortical beta oscillatory activity, particularly when dopamine deficiency results in a higher background firing rate of STN neurones, and that this synchronization contributes to parkinsonian pathophysiology.


Disability is the major negative predictor for achievement of Boolean-based remission in patients with rheumatoid arthritis treated with tocilizumab.
To analyze the efficacy of tocilizumab (TCZ) and the factors that influence achievement of Boolean-based remission in patients with rheumatoid arthritis (RA) treated with TCZ in daily clinical practice. The efficacy of TCZ at 24 weeks after initiation of TCZ in 80 patients with RA was analyzed by comparing achievement of "DAS28 remission" with that of "Boolean-based remission". The predictive factors that influence achievement of Boolean-based remission were determined using multiple logistic regression analysis using a step-wise method. DAS28 remission and Boolean-based remission were achieved in 50.0 and 12.5% of patients, respectively. Significant differences in achieving Boolean-based remission were observed when patients were stratified by disease duration in tertiles (p < 0.05) and by physical function in tertiles (p < 0.05); no such differences were observed for achieving DAS28 remission. The least achievable component among the Boolean-based remission criteria was patient's global assessment. The predictive factor for not achieving Boolean-based remission at 24 weeks was having a worse baseline physical function (odds ratio, 3.66; 95 % confidence interval, 1.17-14.48). This study suggests that baseline disability predicts a lack of achievement of Boolean-based remission. Thus, better responses to TCZ may be obtained when TCZ is initiated in RA patients before disability develops.


[Enhancement of the activity of antitubercular agents with other antimicrobial agents].
The experimental studies have provided strong evidence that the efficacy of etiotropic therapy for tuberculosis can be enhanced by applying a number of antimicrobial agents having different mechanism of action, which belong to cephalosporins, macrolides, aminoglycosides, fluoroquinolones. The basis of the mechanism responsible for potentiation of activity of essential tuberculostatic drugs for potentiation of activity of essential tuberculostatic drugs is enhanced inhibition of the viability of a microbacterial population, prevented development of drug resistance in tuberculosis mycobacteria, and increased function of macrophages.


Tailored Extended Bifrontal Craniotomy for Anterior Skull Base Tumors: Anatomic Description of a Modified Surgical Technique and Case Series.
Open transcranial approaches to the anterior skull base remain an integral component of current skull base practice. Evolution of these and other techniques has resulted in revisions of standard, tried-and-true methods in attempts to improve patient outcomes and cosmesis, while still providing the best combination of surgical exposure and ergonomics. To describe a modified approach for midline tumors of the anterior skull base. We describe the anatomy and techniques of a modified extended bifrontal craniotomy for anterior skull base tumors. Case examples and a postoperative 3-dimensional computed tomographic reconstruction of the craniotomy are provided. The technique has been employed with success in 3 tuberculum sellae meningiomas where the anterior limit of the tumor is several centimeters back from the inner table of the frontal bone. The mean distance from the tumor to inner table was 2.8 cm (range 1.3-3.8 cm). Mean tumor dimensions were 3.0 cm (transverse), 3.5 cm (anterior-posterior), and 2.2 cm (craniocaudal). Average operative time was 557 min. No cases had new T2/fluid-attenuated inversion recovery magnetic resonance imaging signal of the inferior frontal lobe to indicate retraction injury. The tailored extended bifrontal craniotomy for anterior skull base tumors provides adequate access to the anterior cranial fossa and has replaced our standard extended bifrontal approach. Keeping the osteotomy cut lines outside of the orbit reduces orbital swelling and mechanical disruption of conjugate eye movements in the early postoperative period, while allowing for minimal frontal lobe retraction and providing sufficient surgical exposure along the anterior skull base.


Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Relieve Inflammatory Bowel Disease in Mice.
Exosomes secreted by mesenchymal stem cells (MSCs) have shown repairing effects on several tissue injury diseases. In this study, we aimed to investigate the effects of exosomes released from human umbilical cord mesenchymal stem cells (hucMSCs) on the treatment of dextran sulfate sodium- (DSS-) induced inflammatory bowel disease (IBD) and to explore the underlying mechanism. We found that indocyanine green (ICG) labeled exosomes homed to colon tissues of IBD mice at 12 hours after injection. Exosomes significantly relieved the severity of IBD in mice as hucMSCs. The expression of IL-10 gene was increased while that of TNF-α, IL-1β, IL-6, iNOS, and IL-7 genes was decreased in the colon tissues and spleens of exosomes-treated mice. Furthermore, the infiltration of macrophages into the colon tissues was decreased by exosome treatment in IBD mice. In addition, we provided evidence that in vitro coculture with exosomes inhibited the expression of iNOS and IL-7 in mouse enterocoelia macrophages. Moreover, we found that the expression of IL-7 was higher in the colon tissues of colitis patients than that of healthy controls. Our findings suggest that exosomes from hucMSCs have profound effects on alleviating DSS-induced IBD and may exert their impact through the modulation of IL-7 expression in macrophages.


Learning disabilities occurring concomitantly with linguistic differences.
This article discusses characteristics of educational environments that facilitate success for culturally and linguistically diverse (CLD) learners, thereby reducing inappropriate referrals to special education, and offers recommendations for adapting referral and assessment processes to better serve CLD students suspected of having learning disabilities. Effective instructional practices are considered, and competencies needed by teachers who serve CLD students with learning disabilities are suggested. Specific attention is given to identifying and serving students with learning disabilities who are also limited English proficient.


The role of cardiac energy metabolism in cardiac hypertrophy and failure.
In mammalian heart, incessant production of cellular energy is vital for maintaining continuous mechanical pumping function providing the body for oxygen and nutrients. To ensure this essential function, cardiac muscle adapt to increased energy demand or compromised energy supply by reprogramming the network of genes whose products are necessary to match the production of energy to consumption. Failure in this regulation leads to severe cardiac dysfunction and has been associated with cardiac pathogenesis including cardiac hypertrophy, failure and diabetes. Metabolic adaptations are induced by network of transcriptional pathways that are activated by a variety of factors such as hormones, nutrients, second messengers and oxygen. The metabolic phenotype of the heart is maintained by pathways controlling transcriptional regulators, which include peroxisome proliferator-activated receptors, estrogen-related receptors and nuclear respiratory factors, as well as their common coactivator protein peroxisome proliferator-activated receptor γ coactivator 1. These central regulators of gene expression are complemented with factors such as hypoxia inducible factor 1, which is activated in insufficient oxygenation of the tissue. Here, we discuss how these pathways relate to the cardiac metabolism and how they interact with pathways controlling the contractile phenotype of the heart.


Unexpected ring-closure products derived from 3-(2-allylanilino)-3-phenylacrylate esters: crystal and molecular structures of 3-acetyl-8-allyl-6-methyl-2-phenylquinolin-4-yl acetate and (2RS)-2,8-dimethyl-4-phenyl-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinolin-6-one.
The reactions of two 3-(2-allylanilino)-3-phenylacrylate esters with acetic anhydride and with strong acids has revealed a richly diverse reactivity providing a number of unexpected products. Thus, acetylation of ethyl 3-(2-allylanilino)-3-phenylacrylate, (Ia), or ethyl 3-(2-allyl-4-methylanilino)-3-phenylacrylate, (Ib), with acetic anhydride yields not only the expected acetylated esters, (II), as the major products but also the unexpected polysubstituted quinolines 3-acetyl-8-allyl-2-phenylquinolin-4-yl acetate, (IIIa), and 3-acetyl-8-allyl-6-methyl-2-phenylquinolin-4-yl acetate, (IIIb), as minor products. Subsequent reaction of the major product ethyl 2-[(2-allyl-4-methylanilino)(phenyl)methylidene]-3-oxobutanoate, (IIb), with concentrated sulfuric acid did not provide the expected 3-acetylquinoline derivative, but instead two unexpected products, namely ethyl 4-ethyl-2-phenyl-1,4-dihydroquinoline-3-carboxylate, (IV), and ethyl 3-acetyl-4-ethyl-2-phenyl-3,4-dihydroquinoline-3-carboxylate, (V), in yields of 39 and 22%, respectively. The reaction of (Ib) with Eaton's reagent gave both the quinoline (Z)-6-methyl-2-phenyl-8-(prop-1-en-1-yl)quinolin-4(1H)-one, (VI), and the unexpected tricyclic product (2RS)-2,8-dimethyl-4-phenyl-1,2-dihydro-6H-pyrrolo[3,2,1-ij]quinolin-6-one, (VII), in yields of 71 and 12%, respectively. The products (II)-(VII) have all been fully characterized spectroscopically and the crystal structures of two of the unexpected products, i.e. (IIIb) (C23H21NO3) and (VII) (C19H17NO), are reported here. The formation of compounds (IV), (V) and (VII) all require an isomerization of the initial allyl substituent, with migration of the C=C double bond from the terminal site to the internal site. In (IIIb), the two acetyl substituents are oriented such that the intramolecular distance between the two carbonyl O atoms is only 3.243 (2) Å, and in (VII), the five-membered ring adopts a twisted half-chair conformation. The molecules of compound (IIIb) are linked by two independent hydrogen bonds to form sheets built from R4(3)(20) rings and the sheets are linked by a π-π stacking interaction to form a three-dimensional framework structure. The molecules of compound (VII) are linked by a single type of C-H...O hydrogen bond to form centrosymmetric R2(2)(14) dimers. The molecules of compound (V), which crystallizes with Z' = 2, are linked by two N-H...O and two C-H...O hydrogen bonds, forming a chain of rings.


Comparative Filtration Performance of Composite Air Filter Materials Synthesized Using Different Impregnated Porous Media.
Indoor environment quality is currently a hot research topic. In this study, composite air filter materials were synthesized using different impregnated porous medium materials, and their filtration performance and structural parameters were analyzed. The results showed that composite filter materials' structures changed at the fibers' surfaces when synthesized using different porous medium material layers. The filtration efficiency of composite filter materials synthesized using different porous media reached a maximum 0.8 m/s filtration velocity, and PM10, PM2.5, and PM1.0 increased by 1.67~26.07, 1.19~26.96, and 1.10~21.98%, respectively. The filtration efficiencies of reduced graphene oxide composite for PM10, PM2.5, and PM1.0 were 21.26, 20.22, and 18.50% higher, respectively, than those of carbon black composite. In addition, the filtration efficiency of the composite material synthesized by reducing graphene oxide improved for 0 to 1.0 μm particulates and was more effective by comparison. Filtration efficiency and resistance were comprehensively considered during air filter use to provide useful values for the selection and preparation of composite filter materials in the future.


Leader-cell-driven epithelial sheet fingering.
Collective cell migration is crucial in many biological processes such as wound healing, tissue morphogenesis, and tumor progression. The leading front of a collective migrating epithelial cell layer often destabilizes into multicellular finger-like protrusions, each of which is guided by a leader cell at the fingertip. Here, we develop a subcellular-element-based model of this fingering instability, which incorporates leader cells and other related properties of a monolayer of epithelial cells. Our model recovers multiple aspects of the dynamics, especially the traction force patterns and velocity fields, observed in experiments on Madin-Darby canine kidney cells. Our model predicts the necessity of the leader cell and its minimal functions for the formation and maintenance of a stable finger pattern. Meanwhile, our model allows for an analysis of the role of supracellular actin cable on the leading front, predicting that while this observed structure helps maintain the shape of the finger, it is not required in order to form a finger. In addition, we also study the driving instability in the context of continuum active fluid model, which justifies some of our assumptions in the computational approach. In particular, we show that in our model no finger protrusions would emerge in a phenotypically homogenous active fluid and hence the role of the leader cell and its followers are often critical.


Autocrine IL-6 drives cell and extracellular matrix anisotropy in scar fibroblasts.
Fibrosis is associated with dramatic changes in extracellular matrix (ECM) architecture of unknown etiology. Here we exploit keloid scars as a paradigm to understand fibrotic ECM organization. We reveal that keloid patient fibroblasts uniquely produce a globally aligned ECM network in 2-D culture as observed in scar tissue. ECM anisotropy develops after rapid initiation of a fibroblast supracellular actin network, suggesting that cell alignment initiates ECM patterning. Keloid fibroblasts produce elevated levels of IL-6, and autocrine IL-6 production is both necessary and sufficient to induce cell and ECM alignment, as evidenced by ligand stimulation of normal dermal fibroblasts and treatment of keloid fibroblasts with the function blocking IL-6 receptor monoclonal antibody, tocilizumab. Downstream of IL-6, supracellular organization of keloid fibroblasts is controlled by activation of cell-cell adhesion. Adhesion formation inhibits contact-induced cellular overlap leading to nematic organization of cells and an alignment of focal adhesions. Keloid fibroblasts placed on isotropic ECM align the pre-existing matrix, suggesting that focal adhesion alignment leads to active anisotropic remodeling. These results show that IL-6-induced fibroblast cooperativity can control the development of a nematic ECM, highlighting both IL-6 signaling and cell-cell adhesions as potential therapeutic targets to inhibit this common feature of fibrosis.


Fluorescence resonance energy transfer detection methods: Sensitized emission and acceptor bleaching.
The present study compared the advantages and disadvantages of fluorescence resonance energy transfer (FRET) determination technologies, namely, sensitized emission (SE) and acceptor bleaching (AB), in order to analyze the applicability of SE and AB for studies investigating particularly interesting new cysteine histidine-rich protein 1 (PINCH1)/integrin-linked kinase (ILK) interaction. HeLa cells were transfected with cyan fluorescent protein (CFP)-PINCH1 and yellow fluorescent protein (YFP)-ILK to establish a PINCH1/ILK interaction examination model. PINCH1/ILK interactions in different parts of the cells were also examined by SE and AB. The FRET determination technologies SE and AB were able to examine PINCH1/ILK interaction. SE was more sensitive for FRET determination and thus had greater reliability. Therefore, SE is highly commended for membrane protein-protein interaction studies.


Electrostatic Interaction-Based Fabrication of Calcium Alginate-Zein Core-Shell Microcapsules of Regulable Shapes and Sizes.
Core-shell microcapsules with combined features of hydrophilicity and hydrophobicity have become much popular. However, the assembly of biocompatible and edible materials in hydrophilic-hydrophobic core-shell microcapsules is not easy. In this work, based on electrostatic interactions, we prepared controllable calcium alginate (ALG)-zein core-shell particles of different shapes and sizes using hydrophilic ALG and hydrophobic zein by a two-step extrusion method. Negatively charged hydrogel beads of spherical, ellipsoidal, or fibrous shape were added into a positively charged zein solution (dissolved in 70% (v/v) aqueous ethanol solution) to achieve different-shaped core-shell particles. Interestingly, the size, shape, and shell thickness of the particles can be regulated by the needle diameter, stirring speed, and zein concentration. Moreover, for simplification, the core-shell particles were also synthesized by a one-step extrusion method, in which an ALG solution was added dropwise into a 70% (v/v) aqueous ethanol solution containing zein and CaCl2. The particles synthesized in this work showed controlled digestion of encapsulated medium-chain triglyceride (MCT) and sustained release of encapsulated thiamine and ethyl maltol. Our preparation method is simplistic and can be extended to fabricate a variety of hydrophilic and hydrophobic core-shell structures to encapsulate a broad spectrum of materials.


RBM3 expression is upregulated by NF-κB p65 activity, protecting cells from apoptosis, during mild hypothermia.
The RNA-binding protein RBM3, a cold shock protein whose expression is elevated under hypothermic conditions, plays an important role in cell survival; however, little is known about the mechanism underlying the mild hypothermia-mediated regulation of RBM3 expression and apoptosis. Here we show that the transcription factor NF-κB p65 is phosphorylated at Ser276 and activates RBM3 gene transcription via binding to a particular element within the promoter region in response to induced hypothermia, elevating the protein expression, and suppressing apoptosis. Treatment with caffeic acid phenethyl ester (CAPE), a potent and specific inhibitor that suppresses the translocation of NF-κB p65 from the cytoplasm to the nucleus, resulted in decreased levels of RBM3 mRNA and protein and increased incidence of apoptosis despite cells were cultured under hypothermic conditions. Overexpression of RBM3 abolished the induction of apoptosis in cells treated with CAPE, indicating that NF-κB p65-upregulated RBM3 expression is necessary for the suppression of apoptosis. In addition, experiments with cells overexpressing RBM3 supported the finding demonstrating that the mild hypothermia-mediated higher expression of RBM3 suppressed the induction of apoptosis. Conversely, experiments with cells deficient in RBM3 supported the finding demonstrating that the CAPE-mediated loss of RBM3 induced apoptosis. These results suggest that NF-κB p65 is a critical mediator of mild hypothermia, to which cells are exposed as an extracellular environment, and a central inducer of RBM3 expression, which is responsible for preventing cells from apoptosis. Moreover, CAPE may have a potential for the application to a therapeutic agent for the treatment of cancers.


Putative resistance genes of cereals: structure and expected function.
Sequences of two recently cloned genes playing a role in resistance against wheat pathogens (receptor-like kinase Lrk10 and Cre3 genes) were used to search for similarity of cereal clones included in the NCBI database. We found 23 clones with similarity to the Cre3 gene with predicted NBS and LRR domains, and 50 clones with serine/threonine kinase function and similarity to the new receptor-like kinase gene Lrk10 from wheat. In those two groups of clones some conservative nucleotide sequences were identified. Two sequences are identical between the majority of resistance gene candidate clones with a high similarity to Lrk10, and two sequences are identical between the majority of resistance gene candidate clones with similarity to the Cre3 gene.


Business continuity 2014: From traditional to integrated Business Continuity Management.
As global change continues to generate new challenges and potential threats to businesses, traditional business continuity management (BCM) slowly reveals its limitations and weak points to ensuring 'business resiliency' today. Consequently, BCM professionals also face the challenge of re-evaluating traditional concepts and introducing new strategies and industry best practices. This paper points to why traditional BCM is no longer sufficient in terms of enabling businesses to survive in today's high-risk environment. It also looks into some of the misconceptions about BCM and other stumbling blocks to establishing effective BCM today. Most importantly, however, this paper provides tips based on the Business Continuity Institute's (BCI) Good Practices Guideline (GPG) and the latest international BCM standard ISO 22301 on how to overcome the issues and challenges presented.


[Cytotoxic molecules, perforin and serine esterase in cytotoxic T lymphocyte].
Cytotoxic T lymphocyte (CTL) contains two cytotoxic molecules, perforin and serine esterase, in its cytoplasmic granules. These molecules play a key role in CTL-mediated cell lysis, but the precise mechanism has not been fully understood. The author has discovered some of the biochemical characteristics of these cytotoxic molecules. The molecular weight of purified perforin was 66 kd under reducing conditions. Its activity was absolutely dependent on the Ca2+ concentration. The highest activity was seen at 0.2 mM Ca2+ concentration. The Zn2+ ion inhibited the perforin activity in the presence of Ca2+ ion. Heparin increased the pore-forming activity of perforin with highest stimulation at 400 ng/ml. The perforin inhibitor protein, having a molecular weight of 500 kd, was isolated from human serum. This inhibitor suppressed the membrane-binding activity of perforin. The CTL-specific serine esterase detected with the substrate BLT had a molecular weight of 66 kd determined by HPLC gel filtration. The author found that the localization of BLT serine esterase was distinct from that of perforin in CTL. A study into the significance of the difference in the localization of the two molecules is now in progress.


Evidence report on the occurrence, assessment, and treatment of fatigue in cancer patients.
To determine the occurrence of cancer-related fatigue, the methods used to assess it, and the efficacy of the available treatments, we performed literature searches that identified English-language publications on these topics. Twenty-seven studies were identified in which the quantitative estimation of the occurrence of cancer-related fatigue was an end point. Fifty-six were judged to be relevant to the assessment of fatigue, and 10 randomized controlled clinical trials of treatments of cancer-related fatigue were retrieved. The occurrence of cancer-related fatigue was found to range from 4% to 91%, depending on the population studied and the methods of assessment. Few population-based studies and no longitudinal studies of cancer-related fatigue have been performed. The methods of fatigue assessment were highly variable. Exercise programs show promise to prevent or treat fatigue in some subsets of cancer patients, and the use of epoetin alfa for correction of anemia has been shown to ameliorate fatigue. The number of subjects in the treatment trials was small and their methodologic quality was inconsistent.


[Promoting effect of hyperhomocysteinemia on vascular calcification in rats].
To explore the effect of hyperhomocysteinemia on vascular calcification and the underlying mechanism of it. Arterial calcification of Sprague-Dawley rats was induced by vitamin D3 plus nicotine. Hyperhomocysteinemia was established by feeding high methionine diet for six weeks and was assessed b y plasma total homocysteine (tHcy) level detected by HPLC method. Calcification was confirmed by von Kossa staining, measurement of calcium content, alkaline phosphatases (ALP) activity and osteocalcin (OC) concentration of vascular tissue. Lipid conjugated dienes formation were determined to reflecting the production of lipid peroxide. The results showed that there were mass black granules deposited in aortic wall of the calcified rats by von Kossa staining. Calcium content, ALP activity, OC concentration in calcified rats increased by 8.09-fold, 45.57% and 2.81-fold compared with those of the control group (P < 0.01). Calcium content in calcified rats with high methionine diet increased by 34.29% compared with that of the calcified rats, while ALP activity and OC content decreased by 29.13% and 74.69% compared with that of the calcified rats. Lipid conjugated dienes formation in plasma of the rat with high methionine diet and of calcified rats with high methionine diet increased by 1.93 and 2.89-fold compared with those of the control group, respectively (P < 0.01), and in calcified rats with high methionine diet group was increased by 32.90% compared with that of high methionine diet group (P < 0.01). Hyperhomocysteinemia could promote vascular calcification, which might be mediated through the production of lipid peroxide.


Microcantilevers bend to the pressure of clustered redox centers.
The redox-activated deflection of microcantilevers has attracted interest for nanoactuation and chemical sensing. Microcantilever sensors are devices that transduce (bio)chemical reactions into a quantifiable nanomechanical motion via surface stress changes. Despite promising applications in analytical science, poor signal-to-noise ratios and a limited understanding of the molecular origins of the surface stress changes that cause the observed deflections remain obstacles to cantilever-based sensing becoming an established (bio)detection method, such as surface plasmon resonance and electrochemistry. We use phase-separated, binary self-assembled monolayers (SAMs) of ferrocenyldodecanethiolate and n-undecanethiolate as a model system to study the effect of the steric crowding of the redox centers on the surface stress change and cantilever deflection produced by the electrochemical oxidation of the surface-tethered ferrocene to ferrocenium. We correlate the measured surface stress change to the fraction of the clustered ferrocenyldodecanethiolate phase in the binary SAMs. The pairing of anions with the sterically crowded clustered ferroceniums induces a collective molecular reorientation which drives the cantilever deflection. The results provide fundamental insights into the response mechanism of microcantilever-based actuating and sensing technologies.


A Leishmania secretion system for the expression of major ampullate spidroin mimics.
Spider major ampullate silk fibers have been shown to display a unique combination of relatively high fracture strength and toughness compared to other fibers and show potential for tissue engineering scaffolds. While it is not possible to mass produce native spider silks, the potential ability to produce fibers from recombinant spider silk fibers could allow for an increased innovation rate within tissue engineering and regenerative medicine. In this pilot study, we improved upon a prior fabrication route by both changing the expression host and additives to the fiber pulling precursor solution to improve the performance of fibers. The new expression host for producing spidroin protein mimics, protozoan parasite Leishmania tarentolae, has numerous advantages including a relatively low cost of culture, rapid growth rate and a tractable secretion pathway. Tensile testing of hand pulled fibers produced from these spidroin-like proteins demonstrated that additives could significantly modify the fiber's mechanical and/or antimicrobial properties. Cross-linking the proteins with glutaraldehyde before fiber pulling resulted in a relative increase in tensile strength and decrease in ductility. The addition of ampicillin into the spinning solution resulted in the fibers being able to inhibit bacterial growth.


Communications Between the Endoplasmic Reticulum and Other Organelles During Abiotic Stress Response in Plants.
To adapt to constantly changing environmental conditions, plants have evolved sophisticated tolerance mechanisms to integrate various stress signals and to coordinate plant growth and development. It is well known that inter-organellar communications play important roles in maintaining cellular homeostasis in response to environmental stresses. The endoplasmic reticulum (ER), extending throughout the cytoplasm of eukaryotic cells, is a central organelle involved in lipid metabolism, Ca2+ homeostasis, and synthesis and folding of secretory and transmembrane proteins crucial to perceive and transduce environmental signals. The ER communicates with the nucleus via the highly conserved unfolded protein response pathway to mitigate ER stress. Importantly, recent studies have revealed that the dynamic ER network physically interacts with other intracellular organelles and endomembrane compartments, such as the Golgi complex, mitochondria, chloroplast, peroxisome, vacuole, and the plasma membrane, through multiple membrane contact sites between closely apposed organelles. In this review, we will discuss the signaling and metabolite exchanges between the ER and other organelles during abiotic stress responses in plants as well as the ER-organelle membrane contact sites and their associated tethering complexes.


Autoradiographic comparison of thallium-201 diethyldithiocarbamate, isopropyliodoamphetamine and iodoantipyrine as cerebral blood flow tracers.
We investigated [201Tl]diethyldithiocarbamate (DDC) as a tracer for local cerebral blood flow (LCBF). Awake male rats were given intravenous infusions of a mixture of DDC and reference tracer(s): [123I]isopropyliodoamphetamine (IMP) and/or [14C]iodoantipyrine (IAP). LCBF values for DDC, IMP, and IAP were measured using simultaneous multiple radionuclide autoradiography and quantitative digital image analysis. Patterns of local cerebral blood flow (LCBF) obtained with DDC were intermediate compared to IMP and IAP, although they were more similar to those of IMP. DDC and IMP underestimated LCBF in some white matter and adjacent structures, while IAP underestimated LCBF values in high flow regions. We conclude that DDC uptake generally reflects local cerebral blood flow and that it can therefore be used as a cerebral perfusion tracer in humans using SPECT imaging.


Endothelial microparticles prevent lipid-induced endothelial damage via Akt/eNOS signaling and reduced oxidative stress.
Endothelial microparticles (EMPs) are endothelium-derived submicron vesicles that are released in response to diverse stimuli and are elevated in cardiovascular disease, which is correlated with risk factors. This study investigates the effect of EMPs on endothelial cell function and dysfunction in a model of free fatty acid (FFA) palmitate-induced oxidative stress. EMPs were generated from TNF-α-stimulated HUVECs and quantified by using flow cytometry. HUVECs were treated with and without palmitate in the presence or absence of EMPs. EMPs were found to carry functional eNOS and to protect against oxidative stress by positively regulating eNOS/Akt signaling, which restored NO production, increased superoxide dismutase and catalase, and suppressed NADPH oxidase and reactive oxygen species (ROS) production, with the involvement of NF-erythroid 2-related factor 2 and heme oxygenase-1. Conversely, under normal conditions, EMPs reduced NO release and increased ROS and redox-sensitive marker expression. In addition, functional assays using EMP-treated mouse aortic rings that were performed under homeostatic conditions demonstrated a decline in endothelium-dependent vasodilatation, but restored the functional response under lipid-induced oxidative stress. These data indicate that EMPs harbor functional eNOS and potentially play a role in the feedback loop of damage and repair during homeostasis, but are also effective in protecting against FFA-induced oxidative stress; thus, EMP function is reflected by the microenvironment.-Mahmoud, A. M., Wilkinson, F. L., McCarthy, E. M., Moreno-Martinez, D., Langford-Smith, A., Romero, M., Duarte, J., Alexander, M. Y. Endothelial microparticles prevent lipid-induced endothelial damage via Akt/eNOS signaling and reduced oxidative stress.


Relugolix: a novel androgen deprivation therapy for management of patients with advanced prostate cancer.
Androgen deprivation therapy (ADT) is the foundation of treatment for patients with locally advanced, recurrent and metastatic prostate cancer, most commonly using luteinizing releasing hormone (LHRH) agonists. More recently, a new approach to ADT has emerged with the development of gonadotropin-releasing hormone (GnRH) antagonists, which aim to overcome some of the potential adverse physiologic effects of LHRH agonists. This article focuses on the newest GnRH antagonist, relugolix - a once-daily treatment and the only oral GnRH antagonist that has now been approved for the treatment of advanced prostate cancer. In phase II and III studies, relugolix achieved rapid and sustained castration without the testosterone surge associated with LHRH agonists, thus avoiding the potential clinical consequences of tumor flare and the necessity for concomitant anti-androgen therapy. Relugolix also achieved rapid testosterone recovery, which may potentially reduce ADT-related adverse events and offer opportunities for combination and intermittent therapy strategies. Cardiovascular safety is a particular concern in men with prostate cancer and ADT further increases cardiovascular risk: indeed, LHRH agonists are required to have a drug label warning about an increased risk of cardiovascular disease. Data from the phase III HERO study demonstrate an improved cardiac safety profile for the GnRH antagonist relugolix compared with the LHRH agonist leuprolide, including a significantly reduced risk for a major adverse cardiovascular event. Taken together, the data indicate that relugolix may mitigate some of the cardiovascular concerns surrounding ADT and has the potential to become a new standard of care for men with prostate cancer. In summary, relugolix represents a novel and recently available prostate cancer management strategy, incorporating the mechanistic advantages of GnRH antagonists and the potential benefits of oral administration.


The effects of drugs used in anaesthesia on platelet membrane receptors and on platelet function.
Platelet dysfunctions are known origins of perioperative bleeding disorders which are a major concern in the management of surgical patients. Among multiple factors, interactions of drugs used in anaesthesia with platelets have been implicated to aggravate the risk of haemorrhagic complications. This paper reviews in vitro and in vivo studies which have examined the effects of inhalational, intravenous, and local anaesthetics, opioids, and muscle relaxants on platelets. A brief summary of platelet physiology, function tests, and flow cytometric assessment of membrane receptors is included. Although the results of many studies have been conflicting, it appears that halothane, sevoflurane, and propofol inhibit platelet function in a reversible and dose-related manner at concentrations used clinically. Ilalothane affects the intracellular activating second messenger inositol triphosphate, platelet calcium homeostasis, thromboxane A2 formation, and the inhibiting signal transduction pathway including cyclic adenosine monophosphate. The proposed platelet inhibiting mechanism of sevoflurane involves the suppression of thromboxane A2 formation. Propofol appears to cause platelet dysfunctions by inhibiting calcium mobilisation upon agonist stimulation. Nitrous oxide causes a modest suppression of calcium mobilisation. An interaction of local anaesthetics with components in the platelet membrane appears to account for their inhibiting effect, but only at concentrations far higher than that found during clinical use. A clinically relevant antithrombotic effect of regional anaesthesia has been observed, though. Isoflurane, enflurane, desflurane, barbiturates, etomidate, opioids, and muscle relaxants seem to have negligible effects on platelets at therapeutic concentrations. Anaesthetists should be aware of the potential impairment of the coagulation profile by anaesthetic agents.


Islets of meningioma in an acoustic schwannoma in a patient with neurofibromatosis-2: pathology and magnetic resonance imaging findings.
Mixed tumors of the cerebellopontine angle, composed of meningioma and schwannoma components, are extremely rare; so far, only 12 cases have been reported in the literature. They are thought to be exclusively associated with neurofibromatosis-2. We present a mixed tumor of schwannoma and meningioma in a patient with neurofibromatosis-2 and discuss the pathology and magnetic resonance imaging (MRI) findings in relation to the literature. Review of the literature shows that a typical MRI pattern has not been established for mixed tumors and it seems unlikely that a meningioma component can be differentiated within a schwannoma preoperatively.


Temporomandibular joint "open lock" versus condylar dislocation: signs and symptoms, imaging, treatment, and pathogenesis.
In the temporomandibular joint (TMJ) "open-lock" condition the condyle is entrapped in front of the lagging disc and cannot slide back under the fossa. The aim of this retrospective study was to describe the signs and symptoms and imaging of TMJ "open lock" versus condylar dislocation and clarify its pathogenesis. The study stresses the efficacy of arthrocentesis in restoring the functional capacity of the joint, while obviating the need for surgical intervention. The study included 5 patients (3 females and 2 males; ages ranging from 11 to 26 years) presenting 6 open-lock joints that did not respond to conservative treatment. The TMJs postarthrocentesis status in 5 joints (follow-up period, 6 to 32 months) was determined by patient self-assessment and clinical examination. Five TMJs had recurrent open lock and were treated by arthrocentesis. They reacted favorably to the treatment and the open-lock events were eliminated. The first case was apparently misdiagnosed as condylar dislocation, and unnecessary surgical intervention was performed. Arthrocentesis is a safe and rapid procedure that prevents recurrence of open-lock conditions. This disorder should be distinguished from recurrent condylar dislocation, which requires surgical intervention.


Robust femtosecond-written chirped and tilted fiber Bragg gratings for Raman filtering in multi-kW fiber lasers.
We present a robust chirped and tilted fiber Bragg grating (CTFBG) in a large-mode-area double-cladding fiber (LMA-DCF) written by a femtosecond (fs) laser. By implementing the fs-CTFBG into the output end of a high-power fiber laser for Raman filtering, a power handling capability of 4 kW is achieved with a Raman filtering ratio of ∼13 dB. To the best of our knowledge, this is the maximum handling power of a CTFBG for Raman filtering. The signal loss of the fs-CTFBG is 0.03 dB, which has little effect on the output laser beam quality. The air-cooled fs-CTFBG has a minimum temperature slope of 7.8°C/kW due to a self-annealing effect. This work proves the excellent performance of the fs-CTFBG, promoting the development of high-power CTFBGs.


Meeting report - Cell size and growth: from single cells to the tree of life.
In April 2022, The Company of Biologists hosted their first post-pandemic in-person Workshop at Buxted Park Country House in the Sussex countryside. The Workshop, entitled 'Cell size and growth: from single cells to the tree of life', gathered a small group of early-career and senior researchers with expertise in cell size spanning a broad range of organisms, including bacteria, yeast, animal cells, embryos and plants, and working in fields from cell biology to ecology and evolutionary biology. The programme made ample room for fruitful discussions and provided a much-needed opportunity to discuss the most recent findings relating to the regulation of cell size and growth, identify the emerging challenges for the field, and build a community after the pandemic.


Kidney Discard Rates in the United States During American Transplant Congress Meetings.
Deceased-donor kidney discard rates vary by region, but it is unknown whether discard rates and transplant outcomes vary during the American Transplant Congress (ATC) each year. Using national registry data, we determined rates of kidney discard, delayed graft function, graft failure, and mortality from December 31, 1999, through December 30, 2015, during ATC dates and compared these rates with those on the same days of the week during the 2 weeks before and after the ATC (non-ATC). We used multivariable regression to determine associations between ATC and these outcomes. From 7902 donors (1575 ATC; 6327 non-ATC), 12 588 recipients received kidney transplants (2455 ATC; 10 133 non-ATC), and 2666 kidneys were discarded (582 ATC; 2084 non-ATC). Kidneys were more often discarded during ATC (19% vs 17%, P = 0.006; adjusted odds ratio, 1.21; 95% confidence interval, 1.05-1.40). There were no significant differences in donor, transplant, or recipient characteristics by ATC/non-ATC dates or by ATC/non-ATC transplant dates for delayed graft function, graft failure, or mortality. On the basis of a 21% increased odds of discard, the ATC itself may result in 5 additional kidney discards during this important conference every year, which suggests the need for innovative staffing or other logistic solutions during these planned meetings.


Binding and inhibition of the ternary complex factor Elk-4/Sap1 by the adapter protein Dok-4.
The adapter protein Dok-4 (downstream of kinase-4) has been reported as both an activator and inhibitor of Erk and Elk-1, but lack of knowledge about the identity of its partner molecules has precluded any mechanistic insight into these seemingly conflicting properties. We report that Dok-4 interacts with the transactivation domain of Elk-4 through an atypical phosphotyrosine-binding domain-mediated interaction. Dok-4 possesses a nuclear export signal and can relocalize Elk-4 from nucleus to cytosol, whereas Elk-4 possesses two nuclear localization signals that restrict interaction with Dok-4. The Elk-4 protein, unlike Elk-1, is highly unstable in the presence of Dok-4, through both an interaction-dependent mechanism and a pleckstrin homology domain-dependent but interaction-independent mechanism. This is reversed by proteasome inhibition, depletion of endogenous Dok-4 or lysine-to-arginine mutation of putative Elk-4 ubiquitination sites. Finally, Elk-4 transactivation is potently inhibited by Dok-4 overexpression but enhanced by Dok-4 knockdown in MDCK renal tubular cells, which correlates with increased basal and EGF-induced expression of Egr-1, Fos and cylcinD1 mRNA, and cell proliferation despite reduced Erk activation. Thus, Dok-4 can target Elk-4 activity through multiple mechanisms, including binding of the transactivation domain, nuclear exclusion and protein destabilization, without a requirement for inhibition of Erk.


Novel tetrahydrocurcumin integrated mucoadhesive nanocomposite κ-carrageenan/xanthan gum sponges: a strategy for effective local treatment of oral cancerous and precancerous lesions.
Oral cancer is one of the leading causes of death worldwide. Oral precancerous lesions (OPL) are the precursors of oral cancer, with varying degrees of progression. Tetrahydrocurcumin (THC) is a major metabolite of curcumin with superior anticancer properties against various types of cancer. However, THC's clinical outcome is limited by its poor aqueous solubility. Herein, we developed novel mucoadhesive biopolymer-based composite sponges for buccal delivery of THC, exploiting nanotechnology and mucoadhesion for efficient prevention and treatment of oral cancer. Firstly, THC-nanocrystals (THC-NC) were formulated and characterized for subsequent loading into mucoadhesive composite sponges. The anticancer activity of THC-NC was assessed on a human tongue squamous carcinoma cell line (SCC-4). Finally, the chemopreventive activity of THC-NC loaded sponges (THC-NC-S) was examined in DMBA-induced hamster OPL. The selected THC-NC exhibited a particle size of 532.68 ± 13.20 nm and a zeta potential of -46.08 ± 1.12 mV. Moreover, THC-NC enhanced the anticancer effect against SCC-4 with an IC50 value of 80 µg/mL. THC-NC-S exhibited good mucoadhesion properties (0.24 ± 0.02 N) with sustained drug release, where 90% of THC was released over 4 days. Furthermore, THC-NC-S had a magnificent potential for maintaining high chemopreventive activity, as demonstrated by significant regression in the dysplasia degree and a decline in cyclin D1 (control: 40.4 ± 12.5, THC-NC-S: 12.07 ± 5.2), culminating in significant amelioration after 25 days of treatment. Conclusively, novel THC-NC-S represent a promising platform for local therapy of OPL, preventing their malignant transformation into cancer.


Zoon's balanitis treated by circumcision.
Zoon's balanitis is a chronic balanitis affecting parts of the glans penis and prepuce, usually considered refractory to treatment. This article reports the study of seven cases successfully treated by circumcision.


Response of the lysosomal system of the corneal epithelium to tyrosine-induced cell injury.
Rats fed excess tyrosine develop corneal epithelial disease which parallels that found in humans with tyrosine aminotransferase deficiency (tyrosinosis). In the rat, focal lesions develop within the central epithelium and contain crystals (presumably tyrosine) that disrupt cells. We have studied these lesions and localized acid phosphatase and aryl sulfatase at the electron microscope level. Within 60 hr after initiation of diet, cells within the lesions showed an increase in lysosomal enzyme activity. This activity was localized inside some of the crystal ghosts and in numerous lysosomes, including autophagic vacuoles and multivesicular bodies. After 84 hr on diet the entire central corneal epithelium was disrupted and polymorphonuclear leukocytes had infiltrated the area. Crystals were phagocytosed by or developed within polymorphonuclear leukocytes. We hypothesize that crystals form within epithelial cells, disrupt first their lysosomes, and then cells, leading to externalization of lysosomal enzymes. This extracellular lysosomal enzyme release may be responsible for the acute inflammatory response that ensues.


Targeting Hispanic adolescents with outdoor food & beverage advertising around schools.
Although some research has focused on the food environment and food marketing, little has examined outdoor food and beverage (FB) advertising, particularly its relationship to the Hispanic composition in schools. Therefore, the purpose of this study was to determine if the prevalence of outdoor FB advertising was greater around middle and high schools with a majority Hispanic population as compared to schools with a lower Hispanic population. All FB advertisements located within a half-mile of 47 schools in Central Texas were documented. Advertisements were coded as free standing or on establishments. Advertisements were coded for theme including price (emphasizing price) and deals/value meals (promoting discounted price/meal deals). These two themes were combined to create an overall price promotion variable. In order to determine if the prevalence of FB advertising varied by the Hispanic composition of the students in the school, data from the Texas Education Agency was used to create a variable which dichotomized the schools into two groups: schools that reported ≥60% Hispanic students or 'Hispanic schools' (n = 21) and schools that reported <60% Hispanic students or 'non-Hispanic schools' (n = 26). Linear regression analyses were conducted to determine if the prevalence of outdoor FB advertising was greater around Hispanic schools as compared to non-Hispanic schools. Hispanic schools had more overall outdoor FB advertisements as compared to non-Hispanic schools (p = 0.02). Similarly, we found significantly more outdoor FB establishment (p = 0.02) and price promotion (p = 0.05) around Hispanic schools as compared to non-Hispanic schools. Differences in freestanding advertisements by school type approached significance (p = 0.07) with Hispanic schools having more freestanding FB advertisements on average. Further research is needed that documents the content of these advertisements and determines the extent to which these advertisements affect Hispanic and other racial/ethnic minority youth's attitudes and behaviors toward the consumption of these products.


Ultrastructure of the intact surface zone of white spot and brown spot carious lesions in human enamel.
Electron microscopy of the intact surface zone of white spot and brown spot carious lesions showed that in general their ultrastructure was similar. Their outermost crystalline surface consisted of small crystals similar to those in healthy enamel, crystals with central core dissolution, and rounded crystals. Below this, surface demineralization of enamel was observed as the enlargement of micropores, the central core dissolution of crystals, the formation of channels and the enlargement of spaces at prism boundaries. Remineralization of enamel was observed as the partial occlusion of voids, the rounding and enlargement of crystals, and some new needle-shaped crystals. Some other features indicated combined demineralization and remineralization. The occlusion of spaces at prism boundaries was a more common feature in brown spot lesions, whereas the pockets of rounded crystals were more common in white spot lesions. A relatively uniform distribution of needle-shaped crystals throughout the intact surface zone was a feature of some brown spot lesions only.


Physiological transition of a coliphage lambda DNA replication.
The "rolling-circle" replicative intermediate (sigma-type molecules) which is normally produced in the late stage of coliphage lambda DNA replication can be found during the first round of lambda DNA replication if cells infected with lambda replication mutant Ots28 are incubated at the nonpermissive temperature until the late stage of the latent period of lambda infection. After shifting to the permissive temperature, the vast majority of replicating forms are sigma-type rolling circle even during the first round of DNA replication. Concatemeric lambda DNA molecules, produced from these sigma-type intermediates, are efficiently packaged into progeny phage, indicating that in the first round of lambda DNA replication, double-branched theta-type molecules are not required for production of viable progeny phage.


Effective Suppression of HIV-1 Replication by Cytotoxic T Lymphocytes Specific for Pol Epitopes in Conserved Mosaic Vaccine Immunogens.
Cytotoxic T lymphocytes (CTLs) with strong abilities to suppress HIV-1 replication and recognize circulating HIV-1 could be key for both HIV-1 cure and prophylaxis. We recently designed conserved mosaic T-cell vaccine immunogens (tHIVconsvX) composed of 6 Gag and Pol regions. Since the tHIVconsvX vaccine targets conserved regions common to most global HIV-1 variants and employs a bivalent mosaic design, it is expected that it could be universal if the vaccine works. Although we recently demonstrated that CTLs specific for 5 Gag epitopes in the vaccine immunogens had strong ability to suppress HIV-1 replication in vitro and in vivo, it remains unknown whether the Pol region-specific CTLs are equally efficient. In this study, we investigated CTLs specific for Pol epitopes in the immunogens in treatment-naive Japanese patients infected with HIV-1 clade B. Overall, we mapped 20 reported and 5 novel Pol conserved epitopes in tHIVconsvX. Responses to 6 Pol epitopes were significantly associated with good clinical outcome, suggesting that CTLs specific for these 6 Pol epitopes had a strong ability to suppress HIV-1 replication in HIV-1-infected individuals. In vitro T-cell analyses further confirmed that the Pol-specific CTLs could effectively suppress HIV-1 replication. The present study thus demonstrated that the Pol regions of the vaccine contained protective epitopes. T-cell responses to the previous 5 Gag and present 6 Pol protective epitopes together also showed a strong correlation with better clinical outcome. These findings support the testing of the conserved mosaic vaccine in HIV-1 cure and prevention in humans.IMPORTANCE It is likely necessary for an effective AIDS vaccine to elicit CD8+ T cells with the ability to recognize circulating HIV-1 and suppress its replication. We recently developed novel bivalent mosaic T-cell vaccine immunogens composed of conserved regions of the Gag and Pol proteins matched to at least 80% globally circulating HIV-1 isolates. Nevertheless, it remains to be proven if vaccination with these immunogens can elicit T cells with the ability to suppress HIV-1 replication. It is well known that Gag-specific T cells can suppress HIV-1 replication more effectively than T cells specific for epitopes in other proteins. We recently identified 5 protective Gag epitopes in the vaccine immunogens. In this study, we identified T cells specific for 6 Pol epitopes present in the immunogens with strong abilities to suppress HIV-1 in vivo and in vitro This study further encourages clinical testing of the conserved mosaic T-cell vaccine in HIV-1 prevention and cure.


Incorporation and washout of n-3 polyunsaturated fatty acids after diet supplementation in clinical studies.
Current evidence suggests that at least part of the cardioprotective benefits of consumption of long-chain n-3 polyunsaturated fatty acids (PUFAs) relates to their incorporation into the phospholipids of cardiac cell membranes. Dietary supplementation with purified extracts of n-3 PUFAs derived from fish oil rapidly alters the composition of fatty acids in blood cell membranes and in other tissues. The present review summarises the time-course and dose-dependent incorporation and washout of n-3 PUFAs in the clinical setting and discusses the implications of these pharmacokinetic data in terms of biological effects.


[A new PCR-primer for specific amplification of human DNA fragments selected on the basis of computer analysis of the nucleotide sequences of MER1 dispersed repeats in man].
The possibility of using oligonucleotides from MER1 family repeats as PCR primers for the amplification of human genome DNA fragments was studied. The recommended oligonucleotide primers were chosen by computer analysis of the data base of the EMBL (release 37.0) nucleotide sequences. Use of one of the oligonucleotides was shown to allow specific human DNA amplification to be carried out.


Evaluation of skin graft take following post-burn raw area in normovolaemic anaemia.
Traditional wisdom is that wound healing is directly related to haemoglobin level in the blood; therefore blood transfusion is given in anaemic patients to raise the haemoglobin level for better wound healing. Evaluation of wound healing in the form of split thickness skin graft take was done in 35 normovolaemic anaemic patients (haemoglobin level of < 10 gm/ dl) and compared with control group (patients with haemoglobin level of 10 or > 10 gm/ dl). There was no statistically significant difference in mean graft take between the two groups. It is not mandatory to keep haemoglobin level at or >10 g/dL or PCV value at or >30% for skin graft take, as mild to moderate anaemia per se does not cause any deleterious effect on wound healing; provided perfusion is maintained by adequate circulatory volume. Prophylactic transfusion to increase the oxygen carrying capacity of the blood for the purpose of wound healing is not indicated in asymptomatic normovolemic anaemic patients (with haemoglobin levels greater than 6g/dL) without significant cardiovascular or pulmonary disease.


Neurophysiological function in farm workers exposed to organophosphate pesticides.
To investigate neurophysiological effects of low-level exposure to foliar organophosphate residues during one season among agricultural workers, the authors performed a cross-sectional study of 67 Hispanic farm workers and 68 age-, gender-, ethnicity-, and education-matched reference subjects. The neurophysiological examination included sensory and motor nerve conduction and neuromuscular junction testing. Erythrocyte cholinesterase activity was measured at the time of examination. No statistically significant neurophysiological differences between the exposed and reference groups were observed. Farm workers and reference subjects had similar sensory nerve latency and amplitude (sural), motor nerve conduction velocity (ulnar), and neuromuscular junction function (ulnar). No relationship between duration of exposure during the season and electrophysiological measures of nerve function was found. Exposure of farm workers to the low levels of organophosphate pesticides during one season experienced by farm workers in this study was not associated with impaired peripheral neurophysiological function.


Polymorphisms of survivin -31 G/C gene are associated with risk of urothelial carcinoma in Serbian population.
Survivin is thought to play an important role in carcinogenesis and is found to be associated with poor clinical outcome in various malignancies. Gene -31 G/C polymorphism has been identified as a risk factor for the development of several types of tumors. The purpose of this study was to investigate the association between survivin gene promoter -31C/G polymorphism and urothelial carcinoma (UC) risk in Serbian population and to compare the different expressions of survivin in UC of different disease stages, histological grades and tumor location in the upper or lower urinary tract. DNA from 94 patients with primary UC and from 82 healthy subjects was subjected to PCR restriction fragment length polymorphism analysis (PCR-RFLP) to identify individual genotypes. UC samples were subjected to immunohistochemical analysis to assess survivin expression in these lesions. It was observed that the frequency of G/G genotype was greater in patients with UC (58.7%) than in controls (32%). Compared with study subjects carrying the C/G or C/C genotypes, significantly increased UC risk was found for individuals carrying the G/G genotype. Those carrying the G/G genotype had a significantly increased UC risk compared with those with C/G or C/C genotypes. Patients with UC carrying the G/G genotype had a greater prevalence of muscle-invading (stage T2-T4), high-grade (G2) tumor and immunohistochemicaly overexpressed survivin compared with those carrying the C/G or C/C genotypes. G/G genotype of the -31C/G polymorphism might be a risk factor for UC development.


[Interleukin-2 production and receptor expression of alveolar lymphocytes stimulated by Propionibacterium acnes in sarcoidosis].
We previously reported that alveolar lymphocytes in patients with active sarcoidosis are sensitized to Propionibacterium acnes (P. acnes) which may play a significant role in the induction of alveolitis in these patients. However, the mechanism of lymphocyte activation is not fully understood. In this study, we further investigated the production of Interleukin-2 (IL-2), and the responsiveness to IL-2 of alveolar lymphocytes obtained from sarcoidosis patients and stimulated by P. acnes in vitro. In 21 untreated sarcoidosis patients, 7 treated patients and 13 control subjects, the mean IL-2 activity of fluid released from cultured alveolar lymphocytes was 9.8 +/- 15.7 u/ml (M +/- SD), 1.9 +/- 4.7 u/ml and 0.2 +/- 0.8 u/ml respectively. The IL-2 activity of lymphocytes from untreated patients was significantly higher than that of control subjects (p less than 0.02). The responsiveness of alveolar lymphocytes to recombinant IL-2 was evaluated by 3H-thymidine uptake in the presence and absence of P. acnes. Lymphocytes stimulated by P. acnes showed a significantly increased uptake (3766 +/- 3929 dpm) compared to unstimulated lymphocytes (1123 +/- 968 dpm) obtained from 11 untreated sarcoidosis patients (p less than 0.02). On the other hand, the responsiveness of lymphocytes obtained from 6 control subjects was low, regardless of stimulation by P. acnes. There was a significant correlation (p less than 0.05) between the P. acnes-induced production of IL-2 by alveolar lymphocytes and the blastogenesis of alveolar lymphocytes in untreated sarcoidosis patients. Our data indicate that P. acnes stimulates IL-2 production and IL-2 receptor induction in alveolar lymphocytes from patients with active sarcoidosis.


The chemotherapy of rodent malaria. XLVIII. The activities of some synthetic 1,2,4-trioxanes against chloroquine-sensitive and chloroquine-resistant parasites. Part 1: Studies leading to the development of novel cis-fused cyclopenteno derivatives.
The new Chinese antimalarial blood schizontocide, artemisinin, derived from the plant Artemisia annua, displays a high level of activity against polyresistant Plasmodium falciparum. Several synthetic 1,2,4-trioxanes were examined in a search for compounds that exhibit a similar type of action against drug-resistant parasites. This paper, the first of a series, describes the examination of these trioxanes against drug-sensitive and drug-resistant malaria parasites in a rodent model, using artemisinin and arteether as comparison standards. Cis-fused cyclohexeno-1,2,4-trioxanes (10-17) substituted with various side-chains revealed for the most part variable but weak antimalarial activity. On the other hand, cis-fused cyclopenteno-1,2,4-trioxanes (18-19) showed greater activity, 19 showing about 1/30th of the activity of arteether against drug-sensitive Plasmodium berghei in vivo, thereby providing a clue to the structure-activity relationship.


The Relationship Between Serum Bilirubin Concentration and Atrial Fibrillation.
Several studies have demonstrated that higher serum bilirubin inhibits the inflammation and proliferation of vascular smooth muscle cells; also there is a relationship between serum bilirubin and cardiovascular disease. However, the relationship between bilirubin and atrial fibrillation (AF) is still unknown. In our study, we compared serum bilirubin, between nonvalvular AF patients and controls. One hundred and two patients with nonvalvular chronic AF without any other cardiovascular disease (mean age 62.51 ± 5.88) were included in our study. One hundred age-matched healthy people with sinus rhythm were accepted as control groups (mean age 61.35 ± 5.44). Routine biochemical parameters and serum bilirubin levels were performed. No statistically significant difference was found between two groups in terms of basic characteristics. Total, direct and indirect serum bilirubin levels were significantly lower among persons with AF compared to controls (0.82 ± 0.8 vs. 0.48 ± 0.5, 0.30 ± 0.2 vs. 0.19 ± 0.1 and 0.52 ± 0.5 vs. 0.29 ± 0.3 mg/dL; all P < 0.001, respectively). As a result, our study revealed a relationship between serum bilirubin and nonvalvular AF.


Shape tunability of copper nanocrystals deposited on nanorods.
The significant role of metal particle geometry in dictating catalytic activity, selectivity, and stability is well established in heterocatalysis. However, this topic is rarely explored in semiconductor-metal hybrid photocatalytic systems, primarily due to the lack of synthetic control over this feature. Herein, we present a new synthetic route for the deposition of metallic Cu nanoparticles with spherical, elliptic, or cubic geometrical shapes, which are selectively grown on one side of the well-established CdSe@CdS nanorod photocatalytic system. An additional multipod morphology in which several nanorod branches are combined on a single Cu domain is presented as well. Cu is an earth-abundant low-cost catalyst known to promote a diverse gallery of organic transformations and is an excellent thermal and electrical conductor with interesting plasmonic properties. Its deposition on cadmium chalcogenide nanostructures is enabled here via mitigation of the reaction kinetics such that the cation exchange reaction is prevented. The structural diversity of these sophisticated nanoscale hybrid systems lays the foundations for shape-activity correlation studies and employment in various applications.


Endocytic regulation of Notch activation and down-regulation (review).
Notch receptor signalling plays a central role in development and its misfunction has been linked to a number of diseases. In the cannonical Notch signalling pathway, ligand binding to Notch activates a series of proteolytic cleavages that release the Notch intracellular domain for trafficking to the nucleus, where it activates the transcription factor, Suppressor of Hairless (Su(H)). A number of recent papers have demonstrated the importance of endocytic trafficking of Notch and its ligands for both the activation and the down-regulation of the Notch receptor. These reports highlight uncertainty regarding the whereabouts in the cell where Notch activation occurs, and the form of the ligand that can induce signalling. In this review we speculate that, decision points between alternative trafficking pathways represent important regulatory nodes that may allow Notch signalling levels to be modulated by other developmental signals, providing context-dependency to Notch activation. We also review data that suggest that key proteolytic events, associated with Notch activation, may occur within the endocytic pathway or require prior endocytosis and recycling of Notch and its ligands to the cell surface. Sorting within the endocytic pathway, regulated by several different ubiquitin ligase proteins, may be involved in ensuring whether ligand and receptor are competent to signal. Furthermore, the utilisation of an alternative mechanism of Notch signalling, independent of Su(H), may depend on driving endocytic Notch into a specific compartment, in response to the activity of the ring finger domain protein, Deltex.


Selective Retina Therapy with Real-Time Feedback-Controlled Dosimetry for Treating Acute Idiopathic Central Serous Chorioretinopathy in Korean Patients.
To evaluate short-term treatment outcomes following selective retina therapy (SRT) with real-time feedback-controlled dosimetry in Korean patients with acute idiopathic central serous chorioretinopathy (CSC). Sixteen eyes (16 patients) with acute idiopathic CSC (symptom duration < 3 months) were included in this retrospective study. All patients underwent a single session of SRT with real-time feedback-controlled dosimetry. Best-corrected visual acuity (BCVA) and central foveal thickness (CFT) before and 3 months after treatment were examined and compared. The logarithm of minimal angle of resolution BCVA was significantly better 3 months after treatment (0.16 ± 0.18) than at the time of diagnosis (0.27 ± 0.18, P = 0.002). Additionally, subretinal fluid had resolved in all 16 eyes 3 months after treatment and CFT was significantly lower 3 months after treatment (215.6 ± 17.9 μm) than at baseline (441.4 ± 124.8 μm, P < 0.001). No notable SRT-related complications were observed during the study period. The results of the present study suggest that SRT is a useful therapeutic option for patients with acute idiopathic CSC. Further studies are required to better understand the long-term efficacy of this treatment. This trial is registered with clinical trial registration number NCT03339856.


Investigation of Sub-100 nm Gold Nanoparticles for Laser-Induced Thermotherapy of Cancer.
Specialized gold nanostructures are of interest for the development of alternative treatment methods in medicine. Photothermal therapy combined with gene therapy that supports hyperthermia is proposed as a novel multimodal treatment method for prostate cancer. In this work, photothermal therapy using small (<100 nm) gold nanoparticles and near-infrared (NIR) laser irradiation combined with gene therapy targeting heat shock protein (HSP) 27 was investigated. A series of nanoparticles: nanoshells, nanorods, core-corona nanoparticles and hollow nanoshells, were synthesized and examined to compare their properties and suitability as photothermal agents. In vitro cellular uptake studies of the nanoparticles into prostate cancer cell lines were performed using light scattering microscopy to provide three-dimensional (3D) imaging. Small gold nanoshells (40 nm) displayed the greatest cellular uptake of the nanoparticles studied and were used in photothermal studies. Photothermal treatment of the cancer cell lines with laser irradiation at 800 nm at 4 W on a spot size of 4 mm (FWHM) for 6 or 10 min resulted in an increase in temperature of ~12 °C and decrease in cell viability of up to 70%. However, in vitro studies combining photothermal therapy with gene therapy targeting HSP27 did not result in additional sensitization of the prostate cancer cells to hyperthermia.


Distinct roles of TRF1 in the regulation of telomere structure and lengthening.
The telomere is a functional chromatin structure that consists of G-rich repetitive sequences and various associated proteins. Telomeres protect chromosomal ends from degradation, provide escape from the DNA damage response, and regulate telomere lengthening by telomerase. Multiple proteins that localize at telomeres form a complex called shelterin/telosome. One component, TRF1, is a double-stranded telomeric DNA binding protein. Inactivation of TRF1 disrupts telomeric localization of other shelterin components and induces chromosomal instability. Here, we examined how the telomeric localization of shelterin components is crucial for TRF1-mediated telomere-associated functions. We found that many of the mTRF1 deficient phenotypes, including chromosomal instability, growth defects, and dysfunctional telomere damage response, were suppressed by the telomere localization of shelterin components in the absence of functional mTRF1. However, abnormal telomere signals and telomere elongation phenotypes were either not rescued or only partially rescued, respectively. These data suggest that TRF1 regulates telomere length and function by at least two mechanisms; in one TRF1 acts through the recruiting/tethering of other shelterin components to telomeres, and in the other TRF1 seems to play a more direct role.


[Antiarrhythmic properties of lidoflazine in the therapy of auricular fibrillation and flutter (clinical studies of 26 patients)].
Successful conversion to sinus rhythm was achieved in 20 out of 26 patients (77%) with chronic atrial fibrillation or flutter of various origin, that had existed for about 40 +/- 13 months. There was a significant relation between the converting dose of Lidoflazine and the duration of atrial fibrillation. In those patients with atrial fibrillation, that preexisted no longer than two years, restoration of sinus rhythm was achieved in 12 of 14 cases (86%) with an average dose of 109 +/- 67 mg Lidoflazine a day, whereas in the group with atrial fibrillation known for more than two years therapeutical success was obtained only in 8 of 12 cases (67%). The dose of conversion was 382 +/- 150 mg/day in this group and produced in a few patients toxic side effects. Two patients relapsed to atrial fibrillation. On this reasons conversion with Lidoflazine should only be done in patients with atrial fibrillation within two years. There were no significant changes related to: heart rate, myocardial function and intraventricular conduction process. In the presence of underlying hypokalaemic disturbances and/or additional therapy with digitalis preparations Lidoflazine may be the cause of developing premature beats. Lidoflazine may be regarded as a relatively safe drug even in large doses, if monitoring of heart rhythm and QTc-interval is available.


Problems of combination drug therapy in children.
Despite the current trend toward monotherapy, polytherapy in children with epilepsy is still common. A drug combination is advantageous only if it achieves a higher efficacy:toxicity ratio (therapeutic index) or if its antiepileptic spectrum is wider. Studies of brain concentrations of antiepileptic drugs have so far shown that a higher efficacy:toxicity ratio is not achieved by most combinations. Problems are associated with drug combinations. First, numerous pharmacokinetic interactions are documented. These interactions, which can be associated with significant changes in blood levels at a given dose, make frequent measurements and dosage readjustments necessary. They can also alter the concentration of active metabolites or the free fraction of a drug. Second, toxicity can be assumed to be at least partially cumulative, since reduction in polytherapy has been shown to be associated with a reduction in side effects. Third, the therapeutic range appears to depend on whether a drug is taken alone or in combination, so that polytherapy confuses the interpretation of serum drug measurements. Fourth, the presence of more than one drug will add to the difficulty in evaluating the efficacy or side effects of any single drug. Finally, a pharmacodynamic interaction between valproate and several other antiepileptics, particularly the barbiturates, can lead to a stuporous state. Transition from polytherapy to monotherapy is much more difficult to achieve than the opposite.


Central nervous system leukemia.
With one exception, the risk and severity of neurotoxicity is directly proportional to the number of therapeutic modalities used. Three are worse than two, and two are worse than one. Combinations of therapeutic modalities which include CNS RT appear to be the most neurotoxic. The least neurotoxic combination of two modalities appears to be the IT MTX with high-dose intravenous MTX. Thus far, high-dose MTX appear to be the safest single modality, in terms of acute, subacute, and delayed neurotoxicity. The improved outcome in intellectual and academic performance in the NCI-191/CCG-134P conjoint trial of the CCSG and the Pediatric Branch described above (see section of Presymptomatic CNS Therapy) appears to confirm this observation. Whether triple IT chemotherapy will have the same result remains to be established. If CNS RT must be combined with MTX therapy, the least neurotoxic approach appears to be to administer these modalities in sequence, IT MTX, or high-dose intravenous MTX followed by CNS RT. MTX given during or after CNS RT appears from the clinical data to be more likely to produce severe neurologic sequelae. An ultimate goal would be to avoid both ionizing RT and IT chemotherapy. To this end, the NCI/CCSG study has demonstrated that this may be possible, except for those patients who are at the highest risk for CNS relapse despite conventional CNS prophylaxis. Meanwhile, for presymptomatic therapy, either cranial RT (18 Gy total dose at 120-180 cGy per day) in conjunction with IT MTX, or frequent IT chemotherapy with MTX, cytarabine, and hydrocortisone combined and administered throughout induction, consolidation, and maintenance is eminently justified in the majority of children with ALL. On a worldwide basis, chemoradiotherapy with cranial RT and IT MTX remains the established method of preventing overt CNS leukemia. The benefits of this intervention, in terms of prevention of symptomatic CNS leukemia, prolongation of complete remission, and increased cure rates, are clearly worth the risks.


Enhancement of local tumour control by misonidazole and hyperthermia.
Combination treatment of a C3H mammary carcinoma with misonidazole, hyperthermia and radiation resulted in greater local tumour control than with any of these agents singly or in pairs. Dose modification factors for the 3-fold combinations were 3.28 when tumours were immersed in a 42.5 degree C waterbath for 1h after irradiation, and 5.03 at 43.0 degrees C. Cytotoxicity of misonidazole alone was slight, as reflected histologically and in tumour growth. Hyperthermia had a marked effect on these two parameters. Foot damage by hyperthermia was greatest when feet were taped.


Rheological and structural properties of aqueous alginate during gelation via the Ugi multicomponent condensation reaction.
Turbidity, structure, and rheological features during gelation via the Ugi multicomponent condensation reaction of semidilute solutions of alginate have been investigated at different polymer and cross-linker concentrations and reaction temperatures. The gelation time of the system decreased with increasing polymer and cross-linker concentrations, and a temperature rise resulted in a faster gelation. At the gel point, a power law frequency dependence of the dynamic storage modulus (G' proportional, variant omega(n)(')) and loss modulus (G' ' proportional, variant omega(n)(' ')) was observed for all gelling systems with n' = n' ' = n. By varying the cross-linker density at a fixed polymer concentration (2.2 wt %), the power law exponent is consistent with that predicted (0.7) from the percolation model. The value of n decreases with increasing polymer concentration, whereas higher temperatures give rise to higher values of n. The elastic properties of the gels continue to grow over a long time in the postgel region, and at later stages in the gelation process, a solidlike response is observed. The turbidity of the gelling system increases as the gel evolves, and this effect is more pronounced at higher cross-linker concentration. The small-angle neutron scattering results reveal large-scale inhomogeneities of the gels, and this effect is enhanced as the cross-linker density increases. The structural, turbidity, and rheological features were found to change over an extended time after the formation of the incipient gel. It was demonstrated that temperature, polymer, and cross-linker concentrations could be utilized to tune the physical properties of the Ugi gels such as structure, transparency, and viscoelasticity.