Current applications of Multivariate Curve Resolution- Alternating Least Squares (MCR-ALS) in pharmaceutical analysis: Review.
The present review encompasses various applications of multivariate curve resolution- alternating least squares (MCR-ALS) as a promising data handling, which is issued by analytical techniques in pharmaceutics. It involves different sections starting from a concise theory of MCR-ALS and four detailed applications in drugs analysis. Dissolution, stability, polymorphism, and quantification are the main four detailed applications. The data generated by analytical techniques associated with MCR-ALS deals accurately with different challenges compared to other chemometric tools. For each reviewed purpose, it was explained how MCR-ALS was applied and detailed information was given. Different approaches were introduced to overcome challenges that limit the use of MCR-ALS efficiently in pharmaceutical mixture were also discussed.


Core-shell-structured nonstoichiometric bioceramic spheres for improving osteogenic capability.
A rational design of fully interconnected porous constructs of biomaterials with controlled pore-wall bioactivity and biodegradation is of importance in the advancement of bone regenerative medicine. We hypothesize that the layered structure of hybrid bioceramics produces time-dependent biological performances to tune osteogenic responses. We thereby developed core-shell-structured nonstoichiometric Ca silicate (nCSi) spheres and evaluated the effect of spatiotemporal distribution of bi-component nCSi on osteogenic capability. The alginate-based 4% Sr-, 6% Mg-, or 10% Mg-doped nCaSi (i.e. CSi-Sr4, CSi-Mg6, CSi-Mg10) slurries were extruded into a Ca2+-rich solution through the core or shell layer of a coaxial bilayer nozzle, and after drying and sintering treatments, the core-shell nCSi ceramic spheres were prepared. The improved sintering property and denser structure of CSi-Mg6 and CSi-Mg10 shells readily retarded bioactive ion release and biodegradation of CSi-Sr4@CSi-Mg6 and CSi-Sr4@CSi-Mg10 spheres compared with those of CSi-Sr4@CSi-Sr4. When the spheres were implanted into the femoral bone defect in rabbits, the differences in biodegradation and bone regeneration rate in relation to microsphere scaffolds were measured at 6-18 weeks post-implantation. CSi-Sr4@CSi-Mg10 showed slow biodegradation and new bone regeneration, whereas CaSi-Sr4@CSi-Sr4 showed a much faster degradation such that a low osteogenic capacity was observed with prolongation of time. However, CSi-Sr4@CSi-Mg6 spheres displayed expected biodegradation and osteogenic activity with time. These results confirmed the slight tailoring in both doping ions and that component distribution of nCSi is beneficial for adjusting osteogenesis of core-shell spheres. By rationally choosing foreign ion doping, this concept may represent a versatile strategy for the production of a variety of core-shell bioactive ceramics for bone regeneration and repair applications.


Changes in cell spreading and cytoskeletal organization are induced by adhesion to a fibronectin-fibrin matrix.
Plasma fibronectin (pFN) cross-linked to fibrin during the injury response provides a provisional matrix required for cells to begin tissue repair. Using a synthetic matrix of pFN and fibrin as a substrate for cell adhesion and spreading, we have determined that pFN covalently cross-linked to fibrin into a complex multimer is functionally distinct from pFN immobilized onto a plastic surface. NIH-3T3 cells on a FN-fibrin matrix reach 50% of the maximal cell area of cells spread on FN-coated plastic. They neither attach nor spread on cross-linked fibrin alone. Cells on pFN-fibrin matrices form few prominent stress fibers and exhibit clear differences in membrane ruffling and filopodial extension when stained with rhodamine-labeled phalloidin. Interestingly, these differences are enhanced by upregulation of protein kinase C. These data suggest that cell-FN interactions can be modified by the molecular context of the protein within the extracellular matrix resulting in distinct cell morphology and cytoskeletal organization.


Exposure to Ultraviolet Radiation in the Modulation of Human Diseases.
This review focuses primarily on the beneficial effects for human health of exposure to ultraviolet radiation (UVR). UVR stimulates anti-inflammatory and immunosuppressive pathways in skin that modulate psoriasis, atopic dermatitis, and vitiligo; suppresses cutaneous lesions of graft-versus-host disease; and regulates some infection and vaccination outcomes. While polymorphic light eruption and the cutaneous photosensitivity of systemic lupus erythematosus are triggered by UVR, polymorphic light eruption also frequently benefits from UVR-induced immunomodulation. For systemic diseases such as multiple sclerosis, type 1 diabetes, asthma, schizophrenia, autism, and cardiovascular disease, any positive consequences of UVR exposure are more speculative, but could occur through the actions of UVR-induced regulatory cells and mediators, including 1,25-dihydroxy vitamin D3, interleukin-10, and nitric oxide. Reduced UVR exposure is a risk factor for the development of several inflammatory, allergic, and autoimmune conditions, including diseases initiated in early life. This suggests that UVR-induced molecules can regulate cell maturation in developing organs.


Disarming Cellular Alarm Systems-Manipulation of Stress-Induced NKG2D Ligands by Human Herpesviruses.
The coevolution of viruses and their hosts led to the repeated emergence of cellular alert signals and viral strategies to counteract them. The herpesvirus family of viruses displays the most sophisticated repertoire of immune escape mechanisms enabling infected cells to evade immune recognition and thereby maintain infection. The herpesvirus family consists of nine viruses that are capable of infecting humans: herpes simplex virus 1 and 2 (HSV-1, HSV-2), varicella zoster virus (VZV), Epstein-Barr virus (EBV), human cytomegalovirus (HCMV), roseoloviruses (HHV-6A, HHV-6B, and HHV-7), and Kaposi's-sarcoma-associated herpesvirus (KSHV). Most of these viruses are highly prevalent and infect a vast majority of the human population worldwide. Notably, research over the past 15 years has revealed that cellular ligands for the activating receptor natural-killer group 2, member D (NKG2D)-which is primarily expressed on natural killer (NK) cells-are common targets suppressed during viral infection, i.e., their surface expression is reduced in virtually all lytic herpesvirus infections by diverse mechanisms. Here, we review the viral mechanisms by which all herpesviruses known to date to downmodulate the expression of the NKG2D ligands. Also, in light of recent findings, we speculate about the importance of the emergence of eight different NKG2D ligands in humans and further allelic diversification during host and virus coevolution.


Dynamics of interacting edge defects in copolymer lamellae.
It is known that terraces at the air-polymer interface of lamella-forming diblock copolymers do not make discontinuous jumps in height. Despite the underlying discretized structure, the height profiles are smoothly varying. The width of a transition region of a terrace edge in isolation is typically several hundreds of nanometres, resulting from a balance between surface tension, chain stretching penalties, and the enthalpy of mixing. What is less well known in these systems is what happens when two transition regions interact with one another. In this study, we investigate the dynamics of the interactions between copolymer lamellar edges. We find that the data can be well described by a model that assumes a repulsion between adjacent edges. While the model is simplistic, and does not include molecular level details, its agreement with the data suggests that some of the the underlying assumptions provide insight into the complex interplay between defects.


Prevalence of MRI-defined recent silent ischemia and associated bleeding risk with thrombolysis.
Uncertainties about the frequency and the associated bleeding risk of recent silent ischemia (RSI), incidentally found on pretreatment MRI, in candidates for thrombolysis require clarification because exclusion from therapy is a serious consequence for patients with such MRI findings. We retrospectively analyzed the fluid-attenuated inversion recovery (FLAIR)/diffusion-weighted imaging (DWI) obtained before IV thrombolysis in 115 patients to search for MRI-defined RSI; these corresponded to well-developed FLAIR/DWI brain hyperintensities (RSI+), as distinct from the acute index ischemia, which typically lacked FLAIR changes. Patients without such findings were assigned to the RSI- group. Groups were compared for baseline characteristics and for rates of symptomatic and asymptomatic hemorrhagic transformation (HT) using odds ratios (OR) and their 95%confidence intervals (CI). We observed RSI in 21 patients (18.3%). The mean (SD) volume of RSI was 6.5 (12) mL (interquartile range 0.6-9). None of the baseline parameters differed between groups. There was no significant difference in rates of any type of HT between groups. Parenchymal hemorrhage type 1 or type 2 according to European Cooperative Acute Stroke Study criteria occurred in 2 (10%) RSI+ patients and in 10 (11%) RSI- patients (OR 0.88; 95% CI 0.18-4.37). Symptomatic HT, defined according to National Institute of Neurological Disorders and Stroke criteria, occurred in 1 (5%) RSI+ patient and in 10 (11%) RSI- patients (OR 0.42; 95% CI 0.05-3.47). We found that 18.3% of patients with acute stroke treated by IV thrombolysis in a stroke unit had RSI on pretreatment MRI. However, the presence of RSI was not associated with an increased risk of asymptomatic or symptomatic HT.


olf413, a putative octopamine biosynthesis pathway gene is required for negative geotactic motor function in Drosophila melanogaster.
Olf413 gene annotated as CG12673 in the genome of Drosophila melanogaster has been predicted to code for a protein with putative function in octopamine biosynthesis. The expression pattern and the biological function of the gene awaits investigation. The present study is the first report where we describe its expression in the late pupal brain as depicted by enhancer-driven green fluorescent protein (GFP) expression. With experiments using loss of function olf413 mutant flies, we have demonstrated that olf413 function is essential for motor activity, gravity sensing and spatial balancing of the body against gravity during climbing.


Bacteriophage mv4 site-specific recombination: the central role of the P2 mv4Int-binding site.
The contributions of the five (mv4)Int- and two (mv4)Xis arm-binding sites to the spatial intasome organization of bacteriophage mv4 were found not to be equivalent. The 8-bp overlap region was mapped to the left extremity of the core region and is directly flanked by the P2 Int arm-binding site. These results and the absence of characteristic Int core-binding sites suggest that the P2 site is the determinant for integrase positioning and recognition of the core region.


Luteolin inhibits viral-induced inflammatory response in RAW264.7 cells via suppression of STAT1/3 dependent NF-κB and activation of HO-1.
Luteolin is a common dietary flavonoid present in Chinese herbal medicines that has been reported to have important anti-inflammatory properties. Previous studies have shown that luteolin is an anti-inflammatory and anti-oxidative agent. In this study, the anti-virus inflammatory capacity of luteolin and its molecular mechanisms of action were analyzed. The cytotoxic effects of luteolin were assessed in the presence or absence of pseudorabies virus (PRV) via LDH and MTT assays. The results showed that luteolin (<10μM) had no toxic effects and there were tendencies toward higher cell survival. In PRV-infected RAW264.7 cells, luteolin potently inhibited the production of NO, iNOS, COX-2 and inflammatory cytokine production. Luteolin did not inhibit the phosphorylation of ERK 1/2, p38, and JNK 1/2 either. We found that PRV-induced NF-κB activation is regulated through inhibition of STAT1and STAT3 phosphorylation in response to luteolin. Additionally, luteolin caused the induction of HO-1 via upregulation of Nrf2, both of which are involved in the secretion of proinflammatory mediators. The blockade of HO-1 expression with SnPP, a HO-1 inhibitor, attenuated HO-1 induction by luteolin and thus mitigated its anti-inflammatory effects during PRV-infected RAW264.7 cells. Taken together, our data indicate that luteolin diminishes the proinflammatory mediators NO, inflammatory cytokines and the expression of their regulatory genes, iNOS and COX-2, in PRV-infected RAW264.7 cells by inhibiting STAT1/3 dependent NF-κB activation and inducing Nrf2mediated HO-1 expression.


Analytical characterisation of nanoscale zero-valent iron: A methodological review.
Zero-valent iron nanoparticles (nZVI) have been widely tested as they are showing significant promise for environmental remediation. However, many recent studies have demonstrated that their mobility and reactivity in subsurface environments are significantly affected by their tendency to aggregate. Both the mobility and reactivity of nZVI mainly depends on properties such as particle size, surface chemistry and bulk composition. In order to ensure efficient remediation, it is crucial to accurately assess and understand the implications of these properties before deploying these materials into contaminated environments. Many analytical techniques are now available to determine these parameters and this paper provides a critical review of their usefulness and limitations for nZVI characterisation. These analytical techniques include microscopy and light scattering techniques for the determination of particle size, size distribution and aggregation state, and X-ray techniques for the characterisation of surface chemistry and bulk composition. Example characterisation data derived from commercial nZVI materials is used to further illustrate method strengths and limitations. Finally, some important challenges with respect to the characterisation of nZVI in groundwater samples are discussed.


Neurologic complications of inferior petrosal sinus sampling.
Inferior petrosal sinus sampling (IPSS) is a useful diagnostic technique in adrenocorticotropic hormone (ACTH)-dependent hypercortisolism with normal or equivocal MR imaging. The procedure is believed to be safe, with mostly minor complications. However, there are rare, but severe, neurologic complications that need to be considered. We performed an institutional review board-approved retrospective review of our institutional IPSS experience from July 2001 to January 2007. IPSS was performed for the evaluation of Cushing disease. The end points of particular interest were the indications for IPSS and the incidence of associated complications. During the study period of 5(1/2) years, 44 patients underwent IPSS for evaluation of Cushing disease. There were 33 women and 11 men with a mean age of 43.1 years. Because of equivocal imaging and endocrine testing, 36 of 44 patients underwent IPSS, and 8 of 44 underwent IPSS after failed transsphenoidal exploration. The only complication was injury to the brain stem that occurred after an unremarkable procedure in a 42-year-old woman. She developed clinical evidence of pontomedullary dysfunction with MR imaging consistent with brain stem infarction. The cause of this injury is unclear, but a venous variant leading to transient venous hypertension or thrombosis is suspected. Neurologic injury is a rare but serious complication associated with IPSS. Despite this, if performed under a strict paradigm, IPSS is both accurate and safe and can be very useful in the management of Cushing disease.


[Denaturation and enzymatic proteolysis in vitro of protein fractions of soya flour].
Soya, in spite of its high nutritional value and moderate cost, possesses certain undesirable qualities which limit its use in animal and human nutrition. The amendment of these qualities has resulted in much work. In this study the effects of technological treatments on the properties of certain protein fractions capable of being produced industrially were observed. Three fractions were prepared from defatted soybean flour of the "Harosoy 63" variety: an acid-precipitated fraction, a cold-insoluble fraction at 0-3 degrees C, and a water-soluble fraction. The properties of the fractions were studied both before denaturation and after denaturation by either heat or alcohol. The degree of proteolysis of each fraction by two digestive enzymes, pepsin and trypsin, was measured by the increase of non-protein nitrogen as a function of time. Several methods were used for electrophoretic analysis. The results showed that the thermal treatment at 100 degrees C and the treatment with varying concentrations of ethanol (from 10 to 100 p. 100) modified electrophoretic diagrams and the solubility of the proteins in trichloracetic acid. Moderate, moist heating of the protein fractions (100 degrees C, 20 mn) before proteolysis by pepsin and trypsin, in general, favored proteolysis. The most marked effect observed was in the acid-precipitated fraction (in which Kunitz inhibitor was concentrated treated by trypsin. Heating the fractions beyond thirty minutes had a negative effect on proteolysis: the level of proteolysis was the same, or in some cases, lower than before denaturation, especially on subsequent treatment with pepsin. The effects of the ethanol treatment were different from that of heat: the proteolysis was accelerated only with the acid-precipitated fraction.


Electrochemical deposition of highly hydrophobic perfluorinated polyaniline film for biosensor applications.
Highly hydrophobic perfluorinated polyaniline thin films with water contact angle of ∼140° and low internal resistance properties are prepared through electrochemical polymerization. UV-visible spectroscopy demonstrates a gradual evolution of the polaron band which indicates the electronic conductive properties of the polymers. Simultaneous possession of the water-repelling property and electron conductivity for superhydrophobic perfluorinated polyaniline leads to a unique polymer that is suitable as a solid contact in ion-selective electrodes for in situ monitoring of pH changes during early stages of inflammation and septic shock. The superhydrophobic properties should suppress interactions with interfering salts and proteins, and the sensitivity towards protons could be monitored by measuring the phase boundary potential, which depends on the H+ concentration. The potentiometric measurements demonstrate a fast response with a slope of 44.4 ± 0.2 mV per unit pH. The presence of interfering ions and/or human serum albumin does not have any significant effect on the performance of the perfluorinated film. Moreover, it is demonstrated that the response of the perfluorinated film is reversible within the biomedically relevant pH range from 4.0 to 8.5, and stable over time.


Severe mycobacterial and Salmonella infections in interleukin-12 receptor-deficient patients.
Interleukin-12 (IL-12) is a cytokine that promotes cell-mediated immunity to intracellular pathogens by inducing type 1 helper T cell (TH1) responses and interferon-gamma (IFN-gamma) production. IL-12 binds to high-affinity beta1/beta2 heterodimeric IL-12 receptor (IL-12R) complexes on T cell and natural killer cells. Three unrelated individuals with severe, idiopathic mycobacterial and Salmonella infections were found to lack IL-12Rbeta1 chain expression. Their cells were deficient in IL-12R signaling and IFN-gamma production, and their remaining T cell responses were independent of endogenous IL-12. IL-12Rbeta1 sequence analysis revealed genetic mutations that resulted in premature stop codons in the extracellular domain. The lack of IL-12Rbeta1 expression results in a human immunodeficiency and shows the essential role of IL-12 in resistance to infections due to intracellular bacteria.


[Effects of open or closed suctioning on lung dynamics and hypoxemia in mechanically ventilated patients].
This study was conducted to compare effects of open and closed suctioning methods on lung dynamics (dynamic compliance, tidal volume, and airway resistance) and hypoxemia (oxygen saturation and heart rate) in mechanically ventilated patients. This study was a cross-over repeated design. Participants were 21 adult patients being treated with endotracheal intubation using a pressure-controlled ventilator below Fraction of Inspired Oxygen (FiO₂) 60% and PEEP 8 cmH₂O. Data were collected at baseline and 1, 2, 3, 4, 5, and 10 minutes after suctioning. Data were analyzed using two-factor ANOVA with repeated measures on time and suctioning type. Effects of the interaction between suction type and time were significant for oxygen saturation and heart rate but not significant for dynamic compliance, tidal volume, or airway resistance. Prior to performance of suctioning, tidal volume and oxygen saturation were significantly lower, but airway pressure and heart rate were significantly higher using the closed suctioning method as compared with the open suctioning method. For patients on ventilator therapy below FiO₂ 60% and PEEP 8cmH₂O, open suctioning performed after delivery of 100% FiO₂ using a mechanical ventilator may not have as much negative impact on lung dynamics and hypoxemia as closed suctioning.


Cost-effectiveness of Weight Watchers and the Lighten Up to a Healthy Lifestyle program.
Intensive weight loss programs that incorporate dietary counselling and exercise advice are popular and are supported by evidence of immediate weight loss benefits. We evaluate the cost-effectiveness of two weight loss programs, Lighten Up to a Healthy Lifestyle and Weight Watchers. Health gains from prevention of chronic disease are modelled over the lifetime of the Australian population. These results are combined with estimates of intervention costs and cost offsets (due to reduced rates of lifestyle-related diseases) to determine the dollars per disability-adjusted life year (DALY) averted by each intervention program, from an Australian health sector perspective. Both weight loss programs produced small improvements in population health compared to current practice. The time and travel associated with attending group-counselling sessions, however, was costly for patients, and overall the cost-effectiveness ratios for Lighten Up ($130,000/DALY) and Weight Watchers ($140,000/DALY) were high. Based on current evidence, these intensive behavioural counselling interventions are not very cost-effective strategies for reducing obesity, and the potential benefits for population health are small. It will be critical to consider other strategies (e.g. changing the 'obesogenic' environment) or explore alternative methods of intervention delivery (e.g. Internet) to see if they offer a more cost-effective approach by effectively reaching a high number of people at a low cost.


Laccase mediator systems for eco-friendly production of medium-density fiberboard (MDF) on a pilot scale: physicochemical analysis of the reaction mechanism.
Increasing prices of petrochemical resins and possible harmful formaldehyde emissions from conventionally produced wood composites have resulted in increased interest in enzymatic binder systems as environmentally friendly alternatives for gluing lignocellulosic products. In this study, laccase mediator systems (LMSs) were used to activate lignin on wood fiber surfaces in the pilot-scale production of medium-density fiberboard (MDF) using a dry process. Three different mediators were applied: 4-hydroxybenzoic acid (HBA), 1-hydroxybenzotriazole (HBT), and acetosyringone (AS) of which HBA performed best. The mechanical properties of the manufactured boards produced with thermomechanical pulp (TMP) fibers, laccase, and HBA fulfilled all required European standards for wood-based panels. Oxygen consumption rates of the different LMSs and (13)C NMR spectroscopy results for treated TMP fibers were obtained for qualitative and quantitative analysis of lignin activation. The results show that reactions were most effective within the first 30 min of incubation. Oxygen consumption was fastest and highest for the LMS using HBA. (13)C NMR spectroscopy indicated the highest decrease of aromatic groups in the wood fiber lignin with this LMS. The data correlated well with the quality of the MDF. The required enzymatic reaction times allowed direct integration of the LMS into standard MDF production techniques. The results indicate that application of LMSs has a high potential for environmentally friendly MDF production.


ENHANCING EFFECT OF FECES ON ISOLATION OF SALMONELLAE FROM SELENITE BROTH.
The addition of feces to selenite broth significantly enhanced the ability of this medium to select for salmonellae in an environment initially containing overwhelming numbers of coliform bacteria. Either heat-sterilized or Seitz-filtered feces produced this effect. In most experiments, the selectivity of selenite broth was unaffected by unsterile feces. Human blood and plasma markedly reduced selenite efficiency. In a base medium supporting both coliform and Shigella growth, heat-sterilized feces imposed a measure of selectivity for Shigella.


Peripheral nerve reconstruction with collagen tubes filled with denatured autologous muscle tissue in the rat model.
Conventional nerve conduits lack cellular and extracellular guidance structures critical for bridging larger defects. In this study, an exogenous matrix for axonal regeneration was provided by pretreated muscle tissue. In 24 rats, 14-mm sciatic nerve segments were resected and surgically reconstructed using one of the following methods: autograft (AG); bovine type I collagen conduit; (MDM) collagen tube filled with modified denatured autologous muscle tissue. For 8 weeks, functional regeneration was evaluated by footprint and video gait analysis. Evaluation was complemented by electrophysiology, as well as qualitative and quantitative structural assessment of nerves and target muscles. Group AG was superior both structurally and functionally, showing higher axon counts, a more normal gait pattern, and less severe muscle atrophy. Fiber quality (fiber size and myelin thickness) was highest in group MDM, possibly related to the myelin-producing effect of muscular laminin. However, axon count was lowest in this group, and ultrastructural analysis of the denatured muscle tissue showed areas of incomplete denaturation that had acted as a mechanical barrier for regenerating axons. In light of these results, the often advocated use of muscular exogenous matrix for peripheral nerve reconstruction is reviewed in the literature, and its clinical application is critically discussed. In conclusion, combined muscle tubes may have a positive influence on nerve fiber maturation. However, muscle pretreatment is not without risks, and denaturation processes need to be further refined.


The glucose transporter (GLUT-4) and vesicle-associated membrane protein-2 (VAMP-2) are segregated from recycling endosomes in insulin-sensitive cells.
Insulin stimulates glucose transport in adipocytes by translocation of the glucose transporter (GLUT-4) from an intracellular site to the cell surface. We have characterized different synaptobrevin/vesicle-associated membrane protein (VAMP) homologues in adipocytes and studied their intracellular distribution with respect to GLUT-4. VAMP-1, VAMP-2, and cellubrevin cDNAs were isolated from a 3T3-L1 adipocyte expression library. VAMP-2 and cellubrevin were: (a) the most abundant isoforms in adipocytes, (b) detectable in all insulin responsive tissues, (c) translocated to the cell surface in response to insulin, and (d) found in immunoadsorbed GLUT-4 vesicles. To further define their intracellular distribution, 3T3-L1 adipocytes were incubated with a transferrin/HRP conjugate (Tf/HRP) and endosomes ablated following addition of DAB and H2O2. While this resulted in ablation of > 90% of the transferrin receptor (TfR) and cellubrevin found in intracellular membranes, 60% of GLUT-4 and 90% of VAMP-2 was not ablated. Immuno-EM on intracellular vesicles from adipocytes revealed that VAMP-2 was colocalized with GLUT-4, whereas only partial colocalization was observed between GLUT-4 and cellubrevin. These studies show that two different v-SNAREs, cellubrevin and VAMP-2, are partially segregated in different intracellular compartments in adipocytes, implying that they may define separate classes of secretory vesicles in these cells. We conclude that a proportion of GLUT-4 is found in recycling endosomes in nonstimulated adipocytes together with cellubrevin and the transferrin receptor. In addition, GLUT-4 and VAMP-2 are selectively enriched in a postendocytic compartment. Further study is required to elucidate the function of this latter compartment in insulin-responsive cells.


SLC25A23 augments mitochondrial Ca²⁺ uptake, interacts with MCU, and induces oxidative stress-mediated cell death.
Emerging findings suggest that two lineages of mitochondrial Ca(2+) uptake participate during active and resting states: 1) the major eukaryotic membrane potential-dependent mitochondrial Ca(2+) uniporter and 2) the evolutionarily conserved exchangers and solute carriers, which are also involved in ion transport. Although the influx of Ca(2+) across the inner mitochondrial membrane maintains metabolic functions and cell death signal transduction, the mechanisms that regulate mitochondrial Ca(2+) accumulation are unclear. Solute carriers--solute carrier 25A23 (SLC25A23), SLC25A24, and SLC25A25--represent a family of EF-hand-containing mitochondrial proteins that transport Mg-ATP/Pi across the inner membrane. RNA interference-mediated knockdown of SLC25A23 but not SLC25A24 and SLC25A25 decreases mitochondrial Ca(2+) uptake and reduces cytosolic Ca(2+) clearance after histamine stimulation. Ectopic expression of SLC25A23 EF-hand-domain mutants exhibits a dominant-negative phenotype of reduced mitochondrial Ca(2+) uptake. In addition, SLC25A23 interacts with mitochondrial Ca(2+) uniporter (MCU; CCDC109A) and MICU1 (CBARA1) while also increasing IMCU. In addition, SLC25A23 knockdown lowers basal mROS accumulation, attenuates oxidant-induced ATP decline, and reduces cell death. Further, reconstitution with short hairpin RNA-insensitive SLC25A23 cDNA restores mitochondrial Ca(2+) uptake and superoxide production. These findings indicate that SLC25A23 plays an important role in mitochondrial matrix Ca(2+) influx.


[Modern approaches for the choice of open-access method of plastic surgery for recurrent inguinal hernia].
Retrospective analysis of the treatment results concerning 272 patients, who have suffered recurrent inguinal hernia and were operated on in the clinic for the period of 1999-2009 yrs, was done. The need for preperitoneal plasty of inguinal canal performance for recurrent inguinal hernia, using extrainguinial access to hernia defect, was noted. This procedure lowers therisk of iatrogenic injury occurrence of anatomic structures of inguinal canal.


Influence of Maternal Immune Activation on Autism-like Symptoms and Coping Strategies in Male Offspring.
Maternal immune activation (MIA) caused by exposure to pathogens or inflammation during critical periods of gestation increased susceptibility to neurodevelopmental disorders, including autism, in the offspring. In the present work, we aimed to provide characterization of the long-term consequences on anxiety-like behavior and cardiovascular stress response of MIA in the offspring. This study aimed to evaluate the effect of MIA by lipopolysaccharide (LPS) in adult male offspring. In our study, the animals were subjected to a range of behavioral and physiological tests, including the elevated plus maze, social interaction, cat odor response, open field behavior, contextual fear conditioning, and cardiovascular responses during restraint stress. In the offspring of MIA, our study unveiled distinct anxious behaviors. This was evident by fewer entries into the open arms of the maze, diminished anti-thigmotaxis in the open field, and a decrease in social interaction time. Moreover, these rats showed heightened sensitivity to cat odor, exhibited prolonged freezing during fear conditioning, and presented elevated 22Hz ultrasonic vocalizations. Notably, during restraint stress, these animals manifested an augmented blood pressure response, and this was associated with an increase in c-fos expression in the locus coeruleus compared to the control group. These findings collectively underline the extensive behavioral and physiological alterations stemming from MIA. This study deepens our understanding of the significance of maternal health in predisposing offspring to neurobehavioral deficits and psychiatric disorders.


Psychological assessment of gestational carrier candidates: current approaches, challenges, and future considerations.
The role of a mental health professional (MHP) in the psychological assessment of gestational carrier (GC) candidates has evolved over time, with clinical practices well established in the United States. Current ASRM guidelines recommend that all GC candidates undergo a psychosocial consultation and psychological testing (where deemed appropriate). Practice standards are relatively consistent among mental health disciplines, with assessments typically involving a clinical interview and the administration of a single, objective, self-report personality inventory. Although recent studies have established normative data for GCs, there has been little research into which assessment protocols are best suited to answer the referral questions of interest. Current challenges for MHPs placed in a gate-keeping role include providing a thorough screening using measures that typically yield defensive profiles that make them difficult to interpret. Research is emerging that suggests that using a multimethod approach in the psychological assessment of GCs may yield a more comprehensive psychological profile of GC candidates. This could allow MHPs to determine psychological appropriateness with more confidence and contribute additional data to be used in pre-surrogacy counseling. Assessing the psychological appropriateness of a woman to serve as a GC is a complex process, and there are a multitude of factors that must be considered, not the least of which are the psychological well-being of a potential GC, her partner, and her children throughout the process and beyond.


Ethanol-induced elevation of 3 alpha-hydroxy-5 alpha-pregnan-20-one does not modulate motor incoordination in rats.
Ethanol administration elevates the levels of GABAergic neuroactive steroids in brain and contributes to some of its behavioral actions. In the present study, we investigated whether such elevation of GABAergic neuroactive steroids contributes to the motor incoordinating effects of ethanol. Sprague-Dawley rats were administered ethanol (2 g/kg intraperitoneally) or saline, and the level of 3alpha-hydroxy-5alpha-pregnan-20-one (3alpha,5alpha-THP) was measured across time in cerebral cortex and in various brain regions at the peak time by radioimmunoassay. To study whether increases in GABAergic neuroactive steroids are responsible for the motor incoordinating actions of ethanol, rats were subjected to chemical (5alpha-reductase inhibitor, finasteride) and surgical (adrenalectomy) manipulations before receiving ethanol (2 g/kg intraperitoneally) injections. The rats were then subjected to different paradigms to evaluate motor impairment including the Majchrowicz motor intoxication rating scale, Rotarod test, and aerial righting reflex task at different time points. The radioimmunoassay of 3alpha,5alpha-THP in different brain regions showed that ethanol increases 3alpha,5alpha-THP levels by 3- and 9-fold in cerebral cortex and hippocampus, respectively. There was no change in 3alpha,5alpha-THP levels in cerebellum and midbrain. The time course of 3alpha,5alpha-THP elevations in the cerebral cortex showed significant increases 20-min after ethanol injection with a peak at 60 min. In contrast, motor toxicity peaked between 5 and 10 min after ethanol injections and gradually decreased over time. Furthermore, adrenalectomy or pretreatment with finasteride (2 x 50 mg/kg, subcutaneously) did not reduce motor incoordinating effects of ethanol as assessed by the Majchrowicz intoxication rating score, Rotarod test, or aerial righting reflex task. Ethanol increases GABAergic neuroactive steroids in a time- and brain region-selective manner. The role of neuroactive steroids in alcohol action is specific for certain behaviors. Alcohol-induced deficits in motor coordination are not mediated by elevated neuroactive steroid biosynthesis.


Changes in bone resorption markers among Japanese patients with postmenopausal osteoporosis treated with alendronate and risedronate.
We compared the abilities of alendronate and risedronate to reduce levels of urinary cross-linked N-telopeptides of type I collagen (NTX) in Japanese postmenopausal women. The patients were randomly divided into two groups (alendronate, 5 mg/day, n = 61; risedronate, 2.5 mg/day, n = 60). All patients had taken all medication prescribed for the first month and at least 90% of that prescribed for each of the following 6 months. Urinary NTX was measured at baseline, as well as at 1 and 6 months after starting treatment. According to the guidelines of the Japan Osteoporosis Society, the minimum significant change (MSC) for urinary NTX is defined as a 35% decrease from baseline and the cutoff level for a high risk of future fracture is 54.3 nmol bone collagen equivalent (BCE)/mmol.Cr. The NTX reduction rates at 1 and 6 months were greater with alendronate than with risedronate, but the difference was not significant. The rate of patients with a reduction in the MSC at 1 month was greater with alendronate than with risedronate, but the difference did not reach significance. Alendronate reduced NTX at 1 month significantly more in patients with a high risk of fracture than risedronate, but the difference was no longer significant at 6 months. The rate of MSC did not significantly differ between the two groups. In conclusion, alendronate decreases bone resorption markers more obviously and rapidly than risedronate, especially in high risk for fracture, but not significantly according to the guidelines of the Japan Osteoporosis Society.


Effects of sample attrition in a longitudinal study of the association between alcohol intake and all-cause mortality.
Longitudinal studies show higher mortality among abstainers and heavy drinkers than among light and moderate alcohol consumers. The influence on this association of missing information on alcohol intake due to attrition (dropout) has not been examined previously. The aims of this study were to characterize participants who dropped out and to evaluate whether the missing information influenced the association between alcohol intake and all-cause mortality. Data on the 18 974 participants in the Copenhagen City Heart Study, with four measures of alcohol intake and other life-style factors during 28 years of follow-up, were linked with nation-wide registers on socio-economic covariates, mortality and disease incidence. Logistic regression was used to describe life-style and socio-economic determinants of attrition, and Poisson regression was used to evaluate how attrition affected the association between alcohol intake and mortality. The statistical methods used for dealing with missing values were complete case analysis, carry last observation forward, simple imputations, multiple imputation and weighting. Abstinence and high alcohol intake, current smoking, physical inactivity and high body mass index increased the odds of dropping out, whereas being married, more years of education, skilled occupation, high income and large residential area decreased the odds. Attrition was associated with increased mortality and incidence rates of heart disease, lung and upper digestive tract cancers and alcoholic liver diseases. Increased mortality among abstainers and heavy drinkers was observed with all methods used for handling missing data on alcohol intake. Attrition was non-random, and the observed association between alcohol intake and all-cause mortality did not differ by statistical method for handling missing data.


Maternal obesity and diabetes during pregnancy and early autism screening score at well-child visits in standard clinical practice.
Early intervention and treatment can help reduce disability in children diagnosed with autism spectrum disorder. Screening for autism spectrum disorder in young children identifies those at increased likelihood of diagnosis who may need further support. Previous research has reported that exposure to maternal obesity and diabetes during pregnancy is associated with higher likelihood of autism spectrum disorder diagnosis in children. However, little is known about whether these maternal conditions are associated with how very young children score on autism spectrum disorder screening tools. This study examined associations between exposure to maternal obesity and diabetes during pregnancy and offspring scores on the Quantitative Checklist for Autism in Toddlers, an autism spectrum disorder screening questionnaire administered between 18-24 months at well-child visits. A higher score on the Quantitative Checklist for Autism in Toddlers suggests a higher likelihood of autism spectrum disorder; children with scores 3 or greater are referred to developmental pediatricians for evaluation. Our study found that children of mothers with obesity or diabetes during pregnancy had higher scores than children whose mothers did not have these conditions. Associations with maternal obesity and gestational diabetes diagnosed at or before 26 weeks of pregnancy were also present in children who did not have later autism spectrum disorder diagnoses, suggesting that exposure to these conditions during early pregnancy may be associated with a broad range of social and behavioral abilities. Identifying associations between maternal health conditions and early Quantitative Checklist for Autism in Toddlers screening scores could influence future screening and provision of support for children of mothers with these conditions.


A real-time articulated human motion tracking using tri-axis inertial/magnetic sensors package.
A basic requirement in virtual environments is the tracking of objects, especially humans. A real time motion-tracking system was presented and evaluated in this paper. System sensors were built using tri-axis microelectromechanical accelerometers, rate gyros, and magnetometers. A Kalman-based fusion algorithm was applied to obtain dynamic orientations and further positions of segments of the subject's body. The system with the proposed algorithm was evaluated via dynamically measuring Euler orientation and comparing with other two conventional methods. An arm motion experiment was demonstrated using the developed system and algorithm. The results validated the effectiveness of the proposed method.


Appropriate Management of Acute Diarrhea in Children Among Public and Private Providers in Gujarat, India: A Cross-Sectional Survey.
Diarrhea remains a leading cause of morbidity and mortality among children under 5 years of age in low- and middle-income countries. In 2006, the Indian government formally endorsed the World Health Organization guidelines that introduced zinc supplementation and low-osmolarity oral rehydration salts (ORS) for the treatment of diarrhea. Despite this, zinc is rarely prescribed and has not been available in the public sector in India until very recently. The Diarrhea Alleviation Through Zinc and ORS Treatment (DAZT) project was implemented in Gujarat between 2011 and 2013 to accelerate the uptake of zinc and ORS among public and private providers in 6 rural districts. As part of an external evaluation of DAZT, we interviewed 619 randomly selected facility- and community-based public and private providers 2-3 months after a 1-day training event had been completed (or, in the case of private providers, after at least 1 drug-detailing visit by a pharmaceutical representative had occurred) and supplies were in place. The purpose of the interviews was to assess providers' knowledge of appropriate treatment for diarrhea in children, reported treatment practices, and availability of drugs in stock. More than 80% of all providers interviewed reported they had received training or a drug-detailing visit on diarrheal treatment in the past 6 months. Most providers in all cadres (range, 68% to 100%) correctly described how to prepare ORS and nearly all (range, 90% to 100%) reported routinely prescribing it to treat diarrhea in children. Reported routine prescription of zinc was lower, ranging from 62% among private providers to 96% among auxiliary nurse-midwives. Among providers who reported ever not recommending zinc (n = 242), the 2 most frequently reported reasons for not doing so were not completely understanding zinc for diarrhea treatment and not having zinc in stock at the time of contact with the patient. In a multiple logistic regression analysis, recent training or drug-detailing visits and having zinc in stock were associated with reported zinc prescribing (P<.05). Recent training among public providers was significantly associated with having correct knowledge of zinc treatment duration and dosage, but the same was not true of drug-detailing visits among private providers. Treating diarrhea with zinc and low-osmolarity ORS is new for public and private providers in India and other low- and middle-income countries. Sufficient training and logistics support to ensure consistent supplies are critical if providers are to begin routinely treating all diarrhea episodes with zinc and ORS.


Changing the general factor of personality and the c-fos gene expression with methylphenidate and self-regulation therapy.
A deepening in the biological nature of the general factor of personality (GFP) is suggested: the activation level of the stress system is here represented by the gene expression of c-fos. The results of a single case experimental design are reported. A model of four coupled differential equations that explains the human personality dynamics as a consequence of a single stimulant drug intake has been fitted to psychological and biological experimental data. The stimulant-drug conditioning and its adaptation to the considered mathematical model is also studied for both kinds of measures. The dynamics of the c-fos expression presents a similar pattern to the dynamics of the psychological measures of personality assessed by the GFP-FAS (Five-Adjective Scale of the General Factor of Personality) as a consequence of a single dose of stimulant drug (methylphenidate). The model predicts similar dynamic patterns for both psychological and biological measures. This study proves that describing mathematically the dynamics of the effects of a stimulant drug as well as the effects of a conditioning method on psychological or subjective variables and on gene expression is possible. It verifies the existence of biological mechanisms underlying the dynamics of the General Factor of Personality (GFP).


Integration of sensory and reward information during perceptual decision-making in lateral intraparietal cortex (LIP) of the macaque monkey.
Single neurons in cortical area LIP are known to carry information relevant to both sensory and value-based decisions that are reported by eye movements. It is not known, however, how sensory and value information are combined in LIP when individual decisions must be based on a combination of these variables. To investigate this issue, we conducted behavioral and electrophysiological experiments in rhesus monkeys during performance of a two-alternative, forced-choice discrimination of motion direction (sensory component). Monkeys reported each decision by making an eye movement to one of two visual targets associated with the two possible directions of motion. We introduced choice biases to the monkeys' decision process (value component) by randomly interleaving balanced reward conditions (equal reward value for the two choices) with unbalanced conditions (one alternative worth twice as much as the other). The monkeys' behavior, as well as that of most LIP neurons, reflected the influence of all relevant variables: the strength of the sensory information, the value of the target in the neuron's response field, and the value of the target outside the response field. Overall, detailed analysis and computer simulation reveal that our data are consistent with a two-stage drift diffusion model proposed by Diederich and Bussmeyer for the effect of payoffs in the context of sensory discrimination tasks. Initial processing of payoff information strongly influences the starting point for the accumulation of sensory evidence, while exerting little if any effect on the rate of accumulation of sensory evidence.


Interleukin-8 induction and adhesion of the coccoid form of Helicobacter pylori.
To determine the pathological significance of the coccoid form of Helicobacter pylori, its adhesion to and induction of secretion of interleukin-8 (IL-8) by gastric epithelial (MKN45) cells were studied. By flow cytometry, the adhesion of the coccoid form to MKN45 cells was significantly lower than that of the helical form. The monoclonal antibody A20 recognising lipopolysaccharide of H. pylori inhibited the adhesion of the coccoid form to MKN45 cells as much as that of the helical form. There was significantly lower induction of IL-8 secretion by MKN45 cells exposed to the coccoid form (two of four strains) as compared with the helical form.


Apolipoprotein A-I mimetic peptide L-4F prevents myocardial and coronary dysfunction in diabetic mice.
Diabetes is a major health problem associated with adverse cardiovascular outcomes. The apolipoprotein A-I mimetic peptide L-4F is a putative anti-diabetic drug, has antioxidant and anti-inflammatory proprieties and improves endothelial function. In obese mice L-4F increases adiponectin levels, improving insulin sensitivity, and reducing visceral adiposity. We hypothesized that the pleiotropic actions of L-4F can prevent heart and coronary dysfunction in a mouse model of genetically induced Type II diabetes. We treated db/db mice with either L-4F or vehicle for 8 weeks. Trans-thoracic echocardiography was performed; thereafter, isolated hearts were subjected to ischemia/reperfusion (IR). Glucose, insulin, adiponectin, and pro-inflammatory cytokines (IL-1β, TNF-α, MCP-1) were measured in plasma and HO-1, pAMPK, peNOS, iNOS, adiponectin, and superoxide in cardiac tissue. In db/db mice L-4F decreased accumulation of subcutaneous and total fat, and increased insulin sensitivity and adiponectin levels while lowering inflammatory cytokines (P < 0.05). L-4F normalized in vivo left ventricular (LV) function of db/db mice, increasing (P < 0.05) fractional shortening and decreasing (P < 0.05) LV dimensions. In I/R experiments, L-4F prevented coronary microvascular resistance from increasing and LV function from deteriorating in the db/db mice. These changes were associated with increased cardiac expression of HO-1, pAMPK, peNOS, and adiponectin and decreased levels of superoxide and iNOS (P < 0.01). In the present study we showed that L-4F prevented myocardial and coronary functional abnormalities in db/db mice. These effects were associated with stimulation of HO-1 resulting in increased levels of anti-inflammatory, anti-oxidative, and vasodilatatory action through a mechanism involving increased levels of adiponectin, pAMPK, and peNOS.


[Molecular diagnosis of food allergy--do we know more?].
Component-resolved diagnostics (CRD) is the research method that allows to determine the concentrations of specific immunoglobulin E against a particular allergenic components. The paper discusses the importance of CRD in the food allergy diagnosis to common animal and vegetable allergens. The capabilities of the method and its limitations in the application are presented. One of the main advantages of the CRD is to obtain information on the potential allergen cross-reactivity regarding inhalant allergens and food, which are exhibiting structural similarity within the epitopes. CRD explains on the molecular level allergens cross-reactivity. It allows to distinguish cross-reactions occurring after ingestion of food in patients with hypersensitivity that occurs primarily to pollen from the coexistence of inhaled and food allergies. It is also possible to use the method of the CRD for selected allergens to predict the severity of allergic reactions after ingestion of allergic food in patients with symptoms of food allergy. In addition, in small children component-resolved diagnostics can be helpful in predicting achieve in food tolerance to certain allergens. Due to the present limitations, practical conclusions and guidance should be drawn with a caution. This method does not replace clinical observation and double-blind placebo-controlled food challenge, which is still the gold standard in the diagnosis of food allergy. Due to the geographic diversity resulting in different exposure to pollen and dietary factors researches on allergen components in populations living in different climatic zones give different results. This allows to observe that the diagnostic and prognostic inference based on the analysis of CRD results is limited and should always be considered in the clinical context. Especially in situations of estimating the risk of severe allergic reactions. Despite these limitations, the CRD method is a modern tool to the current diagnosis of allergy deserving of its popularisation. It provides information on allergenic components at the molecular level, allowing better understanding of symptoms and patient adjusted procedures.


Expression and purification of correctly processed, active human TACE catalytic domain in Saccharomyces cerevisiae.
Human tumor necrosis factor-alpha (TNF alpha) converting enzyme (TACE) releases soluble TNF alpha from cells. It is a member of the adamalysin family of metalloproteases. A truncated form of TACE cDNA was expressed in Saccharomyces cerevisiae and purified to homogeneity in order to study TACE structure and function. Recombinant TACE was expressed as a preproprotein including the pro- and catalytic (PROCAT) domains fused to the yeast alpha-factor leader. A C-terminal immunoreactive FLAG peptide was added for Western blot detection and anti-FLAG antibody column purification. We constructed two glycosylation mutant PROCAT TACE isoforms to facilitate purification. A PROCAT isoform, mutated to eliminate two N-linked glycosylation sites, was buffer exchanged and purified to homogeneity by ion exchange chromatography and an anti-FLAG antibody affinity step. N-terminal sequence analysis showed that the mutant preproprotein was processed in yeast at the furin protease cleavage site and yielded an active catalytic domain which has TNF alpha peptide-specific protease activity. Mass spectrometry of the purified catalytic domain showed that removal of both N-linked sites results in a homogeneous sized polypeptide lacking further posttranslational modifications.


Sublingual epidermoid cyst.
Dermoid and epidermoid cysts are developmental pathologies that occur in the head and neck with an incidence ranging from 1.6 to 6.9%, and they represent less than 0.01% of all oral cavity cysts. Our purpose is to report a case of sublingual epidermoid cyst of the floor of the mouth. We studied and operated on an 18-year-old white male patient showing a large swelling of oral floor. His main symptoms were difficulty breathing, swallowing, and speaking. At his birth the patient's tongue was adherent to the floor of the mouth. His father had the same problem at birth. Both father and son underwent surgical separation of tongue, during the post-neonatal period. After the surgical removal of the swelling, under general anesthesia, all the patient's symptoms were missed. Histological examination of the mass confirmed the diagnosis of an epidermoid cyst. No relapse of the lesion was present in ten months of follow-up. Many theories are proposed on the etiology of the epidermoid and dermoid cyst. In this case a traumatic event can be found, such as an operation of the tongue in neonatal age. However a multifactorial origin must be assumed for justifying the fact that the patient's father did not develop a dermoid cyst although he had the same problem of an adherent tongue and was operated on.


A randomized controlled trial of the therapeutic workplace for community methadone patients: a partial failure to engage.
The Therapeutic Workplace is an employment-based treatment for drug addiction that uses wages for work to reinforce drug abstinence. The Therapeutic Workplace has promoted abstinence from heroin and cocaine in treatment-resistant mothers in methadone treatment. This study attempted to replicate that effect in crack cocaine users recruited from community-based methadone programs. Participants were randomly assigned to a Therapeutic Workplace (n=22) or usual care control (n=25) group. Therapeutic Workplace participants were invited to work in the workplace and earn vouchers every weekday for 9 months contingent on documented opiate and cocaine abstinence. The two groups did not differ significantly on measures of cocaine or opiate use collected during study participation. Daily attendance and urinalysis results of the Therapeutic Workplace group were analyzed, and only 7 of the 22 participants initiated consistent periods of abstinence and workplace attendance. Two individuals gained access to the workplace on a few days, and 9 participants attempted to gain access to the workplace but never provided a drug-negative urine sample. Possible reasons for differences between the current study and the previous Therapeutic Workplace study are considered. Procedures that increase participant contact with the Therapeutic Workplace and its reinforcement contingencies might increase the likelihood of these individuals being successful in the treatment program.


Determining medical staffing requirements for humanitarian assistance missions.
The primary mission of hospital ships is to provide acute medical and surgical services to U.S. forces during military operations. Hospital ships also provide a hospital asset in support of disaster relief and humanitarian assistance (HA) operations. HA missions afford medical care to populations with vastly different sets of medical conditions from combat casualty care, which affects staffing requirements. Information from a variety of sources was reviewed to better understand hospital ship HA missions. Factors such as time on-site and location shape the mission and underlying goals. Patient encounter data from previous HA missions were used to determine expected patient conditions encountered in various HA operations. These data points were used to project the medical staffing required for future missions. Further data collection, along with goal setting, must be performed to accomplish successful future HA missions. Refining staffing requirements allows deployments to accomplish needed HA and effectively reach underserved areas.


Evaluation of a novel rapid genomic test including polygenic risk scores for the diagnosis and management of familial hypercholesterolaemia.
Introduction: Familial hypercholesterolaemia (FH) is a common autosomal dominant genetic condition, characterised by elevated LDL cholesterol (LDL-C), leading to premature cardiovascular disease (CVD). Early and accurate diagnosis, with implementation of preventative therapies, has a major impact on reducing premature CVD, morbidity and mortality. Genetic testing is recommended to confirm clinical diagnosis in the proband and enable cascade testing in relatives. There is growing evidence that the risk of CVD conferred by hypercholesterolaemia depends not only on monogenic causes but also on polygenic factors. GENinCode has developed a novel genomic testing system (Lipid inCode®) which we have assessed against an accredited National Health Service (NHS UK) genetic screening service in order to validate its diagnostic and clinical utility. Methods: DNA samples from 40 index cases who had been referred for FH testing in an ISO15189-accredited NHS genetic screening service, were retrospectively tested using the Lipid inCode® assay. The results were compared with those from NHS testing. Results: There was absolute concordance in variant detection between both diagnostic tests for monogenic and polygenic FH, the only difference being in the interpretation and classification of DNA variants based on ACMG guidelines, which did not differ by more than one classification class. The Lipid inCode® test was equivalent to the NHS test in providing comprehensive genetic analysis that included the assessment of both monogenic (FH) and polygenic determinants of blood cholesterol and including a pharmacogenomic assessment of predisposition to statin-related myopathy. Conclusion: The Lipid inCode® diagnostic test can be undertaken with rapid turnaround and gave the same results as those reported by standard NHS genetic laboratory testing. In addition to assessment of monogenic FH, the Lipid inCode® assay provides additional genetic data, such as polygenic factors contributing to hypercholesterolaemia, a polygenic risk score (PRS) for coronary artery disease (CAD), pharmacogenomic testing for statin myopathy, and genetic predisposition to raised Lp(a).


Mathematical modeling and parameter estimation of levodopa motor response in patients with parkinson disease.
Parkinson disease (PD) is characterized by a clear beneficial motor response to levodopa (LD) treatment. However, with disease progression and longer LD exposure, drug-related motor fluctuations usually occur. Recognition of the individual relationship between LD concentration and its effect may be difficult, due to the complexity and variability of the mechanisms involved. This work proposes an innovative procedure for the automatic estimation of LD pharmacokinetics and pharmacodynamics parameters, by a biologically-inspired mathematical model. An original issue, compared with previous similar studies, is that the model comprises not only a compartmental description of LD pharmacokinetics in plasma and its effect on the striatal neurons, but also a neurocomputational model of basal ganglia action selection. Parameter estimation was achieved on 26 patients (13 with stable and 13 with fluctuating LD response) to mimic plasma LD concentration and alternate finger tapping frequency along four hours after LD administration, automatically minimizing a cost function of the difference between simulated and clinical data points. Results show that individual data can be satisfactorily simulated in all patients and that significant differences exist in the estimated parameters between the two groups. Specifically, the drug removal rate from the effect compartment, and the Hill coefficient of the concentration-effect relationship were significantly higher in the fluctuating than in the stable group. The model, with individualized parameters, may be used to reach a deeper comprehension of the PD mechanisms, mimic the effect of medication, and, based on the predicted neural responses, plan the correct management and design innovative therapeutic procedures.


Survey of Practice Pattern in Patients With Heparin-Induced Thrombocytopenia Requiring Cardiopulmonary Bypass.
Heparin-induced thrombocytopenia (HIT) is an immune-mediated adverse reaction to heparin. Patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) are routinely anticoagulated with heparin before the initiation of bypass. Heparin is contraindicated, however, in patients with acute HIT, and alternatives to routine practice are often used. While guidelines have recently been published addressing this topic 10, there remains variance between institutions in how these cases are treated. Our goal was to better delineate practice trends in the diagnosis and management of HIT patients requiring CPB. We surveyed members of the Society of Cardiovascular Anesthesiologists (SCA) and the American Society for Extracorporeal Technology (AmSECT) using an online survey tool. We received 304 completed surveys (5.8% response rate), 75% completed by an anesthesiologist, and 24% by a perfusionist. The majority of respondents used clinical history and/or antibody testing (71% and 63%, respectively) to diagnose HIT. Seventy-five percent of respondents reported using an institutional protocol for HIT-CPB cases. Most respondents (89%) reported having at least 1 case in the last 3 years, with a total case experience of at least 785 cases (785 = the minimum number of cases in each case volume category × the number of respondents choosing that category). The strategy recommended in published guidelines, bivalirudin, was the most commonly reported alternative anticoagulation strategy (75%) used by respondents in HIT cases, with most (83%) using the activated clotting time (ACT) to monitor anticoagulation. Most responding SCA and AmSECT members reported that their institution used a protocol or guideline for HIT/CPB cases, and most guidelines directed the use of bivalirudin as an alternative anticoagulant. Various other methods such as plasmapheresis are also being used with success in this patient population. Further research, including comparison studies of alternative anticoagulant strategies, is required to elucidate the best approach to these difficult cases.


Awareness and assessment of periodontal problems among dentists and the public.
Awareness of periodontal problems by the public and their assessment by the practising dentist affect the levels of periodontal health. Many people do not recognize the symptoms of periodontal disease nor do they associate existing symptoms with the disease. Thus they do not perceive a need for professional or self-care. Most people in industrialized nations clean their teeth daily and visit the dentist at least once every 2 years. Yet, evidence suggests that levels of plaque and the incidence of bleeding gums are higher than expected either because people have not received individual instruction or they are not complying with appropriate regimens. Further, evidence suggests that many general dentists have low interest in the aetiology, prevention and treatment of periodontal diseases. It appears that such dentists have not retained their skills in the early recognition and diagnosis of periodontal diseases, nor in oral hygiene education or skill transfer. Likewise, only a small proportion of the general dentist's time is spent on prevention and periodontal care. To improve periodontal health, recommendations for the dental profession to pursue at the community, professional and individual levels are offered.


"We're Just Not Prepared for Eating Over Our Whole Life": A Mixed Methods Approach to Understanding Dietary Behaviors Among Longer Term Cancer Survivors.
In many countries, there are growing numbers of persons living with a prior diagnosis of cancer, due to the aging population and more successful strategies for treatment. There is also growing evidence of the importance of healthful diet and weight management for survivorship, yet many long-term cancer survivors are not successfully following recommendations. We explored this issue in a mixed methods study with 53 adult survivors of 3 cancers (breast, prostate, and non-Hodgkin's lymphoma), living in Maryland. Participants provided three 24-hour dietary recalls, and results were used to classify respondents on 2 metrics of healthful eating (the Healthy Eating Index 2010, and a 9-item index based on current dietary recommendations). Recalls were also used to guide in-depth qualitative discussions with participants regarding self-assessment of dietary behaviors, healthful eating, and diet's importance in cancer prevention and survivorship. Survivors following a more healthful diet were more likely to be female, have greater socioeconomic resources, more years since diagnosis, normal weight, and no smoking history. Qualitative discussions revealed a more nuanced understanding of dietary strategies among healthful eaters, as well as the importance of household members in dietary decision making. Most survivors had received little nutrition counseling as part of their cancer care, highlighting the importance of holistic, household-oriented nutrition education for maintaining health among long-term cancer survivors.


Tensor framelet based iterative image reconstruction algorithm for low-dose multislice helical CT.
In this study, we investigate the feasibility of improving the imaging quality for low-dose multislice helical computed tomography (CT) via iterative reconstruction with tensor framelet (TF) regularization. TF based algorithm is a high-order generalization of isotropic total variation regularization. It is implemented on a GPU platform for a fast parallel algorithm of X-ray forward band backward projections, with the flying focal spot into account. The solution algorithm for image reconstruction is based on the alternating direction method of multipliers or the so-called split Bregman method. The proposed method is validated using the experimental data from a Siemens SOMATOM Definition 64-slice helical CT scanner, in comparison with FDK, the Katsevich and the total variation (TV) algorithm. To test the algorithm performance with low-dose data, ACR and Rando phantoms were scanned with different dosages and the data was equally undersampled with various factors. The proposed method is robust for the low-dose data with 25% undersampling factor. Quantitative metrics have demonstrated that the proposed algorithm achieves superior results over other existing methods.


Granular and lattice deposits in corneal dystrophy caused by R124C mutation of TGFBIp.
Both granular and lattice deposits are present in Avellino corneal dystrophy (ACD), primarily associated with the R124H mutation of transforming growth factor-β-induced (TGFBIp). We investigated the presence of these deposits in other TGFBI mutations and the use of Thioflavin-T (ThT), a fluorescent amyloid stain for characterizing corneal amyloid deposits. Surgical corneal specimens of 3 unrelated patients clinically diagnosed with ACD were studied. Corneal sections from normal individuals and patients with prior lattice corneal dystrophy (LCD) were used as controls. Histochemical studies were performed with Congo red and Masson trichrome stains, and fluorescent imaging with scanning laser confocal microscopy was performed for ThT and anti-TGFBIp antibody staining. Clinical and histopathological findings supported the diagnoses of ACD in these 3 cases in whom granular deposits stained with Masson trichrome and lattice deposits stained with ThT and Congo red showed birefringence and dichroism as expected. However, genotyping revealed a heterozygous R124C mutation in each case. In addition to classical stromal deposits, unique subepithelial TGFBIp aggregates, which stain with neither ThT nor trichrome, were observed. In control LCD sections, stromal deposits were stained with ThT but not with trichrome, confirming lack of granular deposits. Our results demonstrate that both granular and lattice corneal deposits can be associated with R124C mutation in addition to the more common R124H mutation. An additional feature of nonhyaline, nonamyloid, TGFBIp subepithelial deposits might substantiate the categorization of such cases as a variant form of ACD. This study further validates ThT staining for detection of amyloid TGFBIp deposits.


Chondrogenic Gene Expression Differences between Chondrocytes from Osteoarthritic and Non-OA Trauma Joints in a 3D Collagen Type I Hydrogel.
Objective The purpose of the current study was to compare the donor age variation of chondrocytes from non-OA (osteoarthritic) trauma joints in patients of young to middle age (20.5 ± 3.7, 31.8 ± 1.9, 41.9 ± 4.1 years) embedded in matrix-associated autologous chondrocyte transplantation (MACT) grafts (CaReS). The chondrocyte-specific gene expression of CaReS grafts were then compared to chondrocytes from OA joints (in patients aged 63.8 ± 10 years) embedded in a collagen type I hydrogel. Design OA chondrocytes and articular chondrocyte-laden grafts were cultured over 14 days in chondrogenic growth medium. We performed reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) to evaluate the mRNA expression levels of chondrocyte-specific and hypertrophic markers. Results Gene expression analysis with RT-qPCR revealed no significant difference in chondrocyte-specific genes ( COL2A1, ACAN, SOX9, SOX5, SOX6) among 3 different age group of patients with CaReS grafts. In a comparative analysis of OA chondrocytes to articular chondrocytes, chondrogenic markers ( COL2A1, SOX6) exhibited higher expression in OA chondrocytes ( P < 0.05). Hypertrophic or OA cartilage pathogenesis marker ( MMP3, MMP13) expression was higher and COL1A1 had significantly lower expression ( P < 0.05) in OA chondrocytes than articular chondrocytes when cultivated in collagen type I hydrogels. Conclusion In summary, we identify that donor age variation does not influence the chondrogenic gene expression of the CaReS system. We also identified that freshly isolated OA chondrocytes embedded in collagen type I hydrogels can exhibit chondrogenic gene expression as observed in articular chondrocytes on the CaReS grafts. Transforming OA chondrocytes to articular chondrocytes can be regarded as an alternative option in the MACT technique.


[Quantitative microscopic characteristics of cardial glands in in the human esophagus in postnatal ontogenesis].
Microscopical investigation of oesophagus, obtained from corpses of 33 men and 33 women has been carried out (staining with hematoxylin and eosin, van Gieson). The cardial glands have been revealed in 92.4% of cases in the inferior and in 4.6% of cases in the superior third of the oesophageal wall. They have not been revealed in the superior third of the oesophageal wall. They have not been revealed in its medial third. Amount of acini in the section is essentially changeable. In elderly and old persons the ducts of the glands often form ampullar dilatations. The acinar areas on the section remain stable during the greatest++ period of the postnatal ontogenesis and only during old age they decrease slightly. The proper plate of the mucous membrane in the inferior part of the oesophagus in the zone, where the cardial glands are situated, is always thicker than in the area free from the acini. Close interrelations have been revealed between the cardial glands and lymphoid tissue of the oesophageal wall. The intensity of the glandular-lymphoid interrelations is insignificant in newborns and in children of suckling age. It is maximal in persons of mature and elderly age. Remaining at a sufficiently high level, the glandular-lymphoid associations in old persons are manifested in a less degree than in the previous age groups. No difference in organization of the cardial glands has been revealed in the superior and inferior parts of the oesophageal wall, as well as any sex peculiarities.


Adipose-derived stem cells significantly increases collagen level and fiber maturity in patient-specific biological engineered blood vessels.
Tissue engineering has driven significant research in the strive to create a supply of tissues for patient treatment. Cell integration into engineered tissues maximizes functional capabilities, however, issues of rejection remain. Autologous cell sources able to solve this issue are difficult to identify for tissue engineering purposes. Here, we present the efficacy of patient-sourced cells derived from adipose (adipose-derived stem cells, ASCs) and skin tissue (dermal fibroblasts, PtFibs) to build a combined engineered tunica media and adventitia graft, respectively. Patient cells were integrated into our lab's vascular tissue engineering technique of forming vascular rings that are stacked into a tubular structure to create the vascular graft. For the media layer, ASCs were successfully differentiated into the smooth muscle phenotype using angiotensin II followed by culture in smooth muscle growth factors, evidenced by significantly increased expression of αSMA and myosin light chain kinase. Engineered media vessels composed of differentiated ASCs (ASC-SMCs) exhibited an elastic modulus (45.2 ± 18.9 kPa) between that of vessels of undifferentiated ASCs (71.8 ± 35.3 kPa) and control human aortic smooth muscle cells (HASMCs; 18.7 ± 5.49 kPa) (p<0.5). Tensile strength of vessels composed of ASCs (41.3 ± 15.7 kPa) and ASC-SMCs (37.3 ± 17.0 kPa) were higher compared to vessels of HASMCs (28.4 ± 11.2 kPa). ASC-based tissues exhibited a significant increase in collagen content and fiber maturity- both factors contribute to tissue strength and stability. Furthermore, vessels gained stability and a more-uniform single-tubular shape with longer-term 1-month culture. This work demonstrates efficacy of ASCs and PtFibs to create patient-specific vessels.


Probing the π→π* photoisomerization mechanism of cis-azobenzene by multi-state ab initio on-the-fly trajectory dynamics simulation.
Based on a newly developed algorithm to compute global nonadiabatic switching probability by using only electronic adiabatic potential energy surfaces and gradients, we performed on-the-fly, trajectory-surface hopping simulations at the 5SA-CASSCF(6,6)/6-31G quantum level to probe the π→π* photoisomerization mechanism of the azobenzene within four singlet low-lying electronic states (S0, S1, S2, and S3) coupled with a complicated conical intersection network. We found that four conical intersections between the S1 and S2 states (one is near the cis-isomer region, another near the trans-isomer region, and two others between cis and trans) play the most important roles for understanding the photoisomerization mechanism of azobenzene upon S2 and S3ππ* excitation. We studied six cases to demonstrate the photoisomerization mechanism in detail by choosing eight (six) typical reactive (nonreactive) trajectories, namely, two-step fast-fast processes having lifetimes of several tenths to one hundred femtoseconds and two-step, fast-slow and slow-slow processes having lifetimes of several hundred to one thousand femtoseconds. We found for the first time from simulation that once a trajectory visits the conical intersection near the trans-isomer after ππ* excitation, it could rapidly go through the inversion pathway to trans-azobenzene, and confirms the most recent experimental observations. We performed 536 sampling trajectories (336 from S2 and 200 from S3), initially starting from the Franck-Condon region of cis-azobenzene, and obtained a total reactive quantum yield of 0.3-0.45 in very good agreement with recent experimental results of 0.24-0.50. Moreover, the current method can estimate overall nonadiabatic transition probability for each sampling trajectory from beginning to end. This can greatly accelerate convergence of nonadiabatic molecular dynamic simulation, and, for instance, results in a quantum yield of 0.53 estimated from only eight typical reactive trajectories.


Motion vector quantization for video coding.
A new algorithm is developed for the vector quantization of motion vectors. This algorithm, called motion vector quantization (MVQ), simultaneously estimates and vector quantizes the motion vectors by reinterpreting the block matching algorithm as a type of vector quantization. An iterative design algorithm, based on this concept, is developed. In addition to reducing rate for fixed length encoding, the algorithm also reduces the computation considerably. We include coding simulation results on the Flower Garden sequence.


INVERTED INTERNAL LIMITING MEMBRANE FLAP TECHNIQUE FOR MACULAR HOLE SURGERY WITHOUT EXTRA MANIPULATION OF THE FLAP.
To determine whether surgical manipulation steps of the internal limiting membrane (ILM) flap, such as ILM trimmed, ILM tuck inside the hole, ILM massage, are mandatory to obtain satisfactory outcomes for the repair of large stage IV idiopathic macular hole using the inverted ILM flap technique. In this interventional comparative prospective single-masked study, 81 eyes were randomized into 2 treatments groups. In Group 1 (41 eyes), the classic inverted ILM flap technique was performed. In Group 2 (40 eyes), a modified procedure was used: after ILM peeling, no extra flap manipulation was performed. The macular hole was covered by the inverted ILM flap because of the air pressure at the time of the fluid-air exchange. At 12 months, macular hole closure was observed in 40 eyes (97.6%) in Group 1 and in 39 eyes in Group 2 (97.5%). U-shape closure rate, ellipsoid zone defects, and external limiting membrane defects were similar in both groups. The results indicate no statistical difference in anatomical and functional success between both groups. The macular hole closure rate, improved visual acuity, and no extra complications indicate noninferiority of the modified inverted ILM technique. Internal limiting membrane finishing, tucking, and massage may not be required to obtain surgical success.


One hundred ways to process time, frequency, rate and scale in the central auditory system: a pattern-recognition meta-analysis.
The mammalian auditory system extracts features from the acoustic environment based on the responses of spatially distributed sets of neurons in the subcortical and cortical auditory structures. The characteristic responses of these neurons (linearly approximated by their spectro-temporal receptive fields, or STRFs) suggest that auditory representations are formed, as early as in the inferior colliculi, on the basis of a time, frequency, rate (temporal modulations) and scale (spectral modulations) analysis of sound. However, how these four dimensions are integrated and processed in subsequent neural networks remains unclear. In this work, we present a new methodology to generate computational insights into the functional organization of such processes. We first propose a systematic framework to explore more than a hundred different computational strategies proposed in the literature to process the output of a generic STRF model. We then evaluate these strategies on their ability to compute perceptual distances between pairs of environmental sounds. Finally, we conduct a meta-analysis of the dataset of all these algorithms' accuracies to examine whether certain combinations of dimensions and certain ways to treat such dimensions are, on the whole, more computationally effective than others. We present an application of this methodology to a dataset of ten environmental sound categories, in which the analysis reveals that (1) models are most effective when they organize STRF data into frequency groupings-which is consistent with the known tonotopic organization of receptive fields in auditory structures -, and that (2) models that treat STRF data as time series are no more effective than models that rely only on summary statistics along time-which corroborates recent experimental evidence on texture discrimination by summary statistics.


Which sociodemographic factors are important on smoking behaviour of high school students? The contribution of classification and regression tree methodology in a broad epidemiological survey.
The purpose of this study is to evaluate the most important sociodemographic factors on smoking status of high school students using a broad randomised epidemiological survey. Using in-class, self administered questionnaire about their sociodemographic variables and smoking behaviour, a representative sample of total 3304 students of preparatory, 9th, 10th, and 11th grades, from 22 randomly selected schools of Mersin, were evaluated and discriminative factors have been determined using appropriate statistics. In addition to binary logistic regression analysis, the study evaluated combined effects of these factors using classification and regression tree methodology, as a new statistical method. The data showed that 38% of the students reported lifetime smoking and 16.9% of them reported current smoking with a male predominancy and increasing prevalence by age. Second hand smoking was reported at a 74.3% frequency with father predominance (56.6%). The significantly important factors that affect current smoking in these age groups were increased by household size, late birth rank, certain school types, low academic performance, increased second hand smoking, and stress (especially reported as separation from a close friend or because of violence at home). Classification and regression tree methodology showed the importance of some neglected sociodemographic factors with a good classification capacity. It was concluded that, as closely related with sociocultural factors, smoking was a common problem in this young population, generating important academic and social burden in youth life and with increasing data about this behaviour and using new statistical methods, effective coping strategies could be composed.


Injuries in Collegiate Ladies Gaelic Footballers: A 2-Season Prospective Cohort Study.
Although Ladies Gaelic football is one of the most popular female sports in Ireland, just 2 previous injury surveillance studies have been completed, and both were retrospective in nature. To prospectively examine the injury incidence and injury profile in collegiate Ladies Gaelic football over 2 seasons. Prospective cohort study. College. Patients (or Other Participants): Adult Ladies Gaelic footballers from one collegiate institution (season 1: n = 50, season 2: n = 82). All time-loss injuries that occurred were recorded by certified athletic therapists and student-athletic therapists and trainers over 2 seasons. A standardized injury report form was used to record the injury onset, mechanism, location, nature, and outcome. Injury incidence proportion, repeat incidence proportion and total, match and training injury rates, and their 95% confidence intervals were calculated. The frequencies and proportions were also calculated. The match and training injury rates were 42.48 and 7.93 injuries per 1000 hours, respectively. A low repeat incidence proportion per season was noted (11.7% and 0.0%). The injuries were predominantly acute (74.68%) and noncontact (66.25%), with hamstring injuries (21.52%) and strains (36.71%) the most frequent location and nature of injuries noted. Strains (104.92 d absent per 1000 h) and knee injuries (106.46 d absent per 1000 h) led to the greatest injury burden. Further investigations were not frequently required, with an X-ray and magnetic resonance imaging ordered in 8.00% and 6.67% of the cases, respectively. Surgery was completed following one injury. This is the first study to provide prospective injury data on Ladies Gaelic football. Priority needs to be given to preventing hamstring and knee injuries due to their occurrence and negative impact on player availability to play. Collegiate Ladies Gaelic football teams should be encouraged to implement an injury-prevention warm-up, such as the GAA15+, at training and matches.


Rapid Detection of Legionella pneumophila in Drinking Water, Based on Filter Immunoassay and Chronoamperometric Measurement.
Legionella is a pathogenic bacterium, ubiquitous in freshwater environments and able to colonise man-made water systems from which it can be transmitted to humans during outbreaks. The prevention of such outbreaks requires a fast, low cost, automated and often portable detection system. In this work, we present a combination of sample concentration, immunoassay detection, and measurement by chronoamperometry. A nitrocellulose microfiltration membrane is used as support for both the water sample concentration and the Legionella immunodetection. The horseradish peroxidase enzymatic label of the antibodies permits using the redox substrate 3,3',5,5'-Tetramethylbenzidine to generate current changes proportional to the bacterial concentration present in drinking water. Carbon screen-printed electrodes are employed in the chronoamperometric measurements. Our system reduces the detection time: from the 10 days required by the conventional culture-based methods, to 2-3 h, which could be crucial to avoid outbreaks. Additionally, the system shows a linear response (R2 value of 0.99), being able to detect a range of Legionella concentrations between 101 and 104 cfu·mL-1 with a detection limit (LoD) of 4 cfu·mL-1.


To refer or not to refer: a qualitative study of reasons for referral from Role 1.
There are currently over 9000 British soldiers serving in Afghanistan. The Defence Medical Services provide primary health care to soldiers at forward locations using Regimental Medical Officers (RMOs) and General Duties Medical Officers (GDMOs). If required, GDMOs can refer patients to senior colleagues. Currently, little is known about the reasons for referrals by GDMOs. This study aims to identify the main factors affecting why GDMOs refer from forward locations. Nine GDMOs, who deployed on Operation HERRICK 13, were invited to join the study. They maintained a log of their referrals for two 14 day periods, one in each half of their tour. In addition, a semi-structured interview was performed with each GDMO in order to elicit the common themes surrounding referrals. The mean referral rate was 0.9 referrals/GDMO/week. The main reasons for referral were dental problems, musculoskeletal injuries, abdominal pain of unknown cause, and ano-genital problems. Factors that influenced referrals included availability of forwardly projected services (dentist and physiotherapist), manpower availability at the locations, the availability of flights (affected by weather, enemy action, and schedule of routine flights), and the timing of the tour in relation to leave. Referrals from GDMOs were due to doctor inexperience in the treatment of a particular condition, lack of access to investigations and the potential for deterioration in a location without adequate support. The referral decision process was affected by the patient's importance with regards to the mission, the weather and access to safe transportation. The introduction of clinical guidelines for common conditions in conjunction with minor alterations to GDMO training could help reduce referrals from Role 1, preserving manpower, reducing costs, and minimising risk to evacuation aircraft.


In vitro antigen challenge of human antibody libraries for vaccine evaluation: the human immunodeficiency virus type 1 envelope.
Human antibody responses, or versions thereof, can be cloned as phage display libraries. In vaccine evaluation, the possibility therefore exists of challenging the human response in vitro, rather than in vivo, in order to assist in establishing the most promising vaccine leads. The characteristics of the antibodies retrieved directly indicate the strengths and weaknesses of the vaccine at the molecular level. We applied this approach to compare recombinant and native human immunodeficiency virus type 1 envelope preparations. We conclude that recombinant gp160, gp140, and, to a lesser extent, gp120 present epitopes around the CD4 binding site in a conformation different from that of the native multimer and contrary to expected vaccine requirements. Antibodies to the potently neutralizing b12 epitope were selected preferentially from an immune library by purified human immunodeficiency virus type 1 virions. This suggests that b12 is a major epitope on the virions, in contrast to recombinant envelope preparations, in which related, weakly neutralizing epitopes predominate. Although the majority of virions in the preparation used are expected to be noninfective, it appears that they predominantly express a native envelope configuration and would be able to elicit potent neutralizing antibodies.


Neutrophils contribute to ischemia/reperfusion injury in rat liver in vivo.
To determine the role of neutrophils in the pathogenesis of hepatic ischemia/reperfusion injury, livers from male Fischer rats were subjected to 45 min of no-flow ischemia followed by reperfusion for up to 24 h. Two phases of liver injury were identified, an initial phase during the first hour of reperfusion and a later progression phase with 80 +/- 3% hepatocyte necrosis and an 80-fold increase of neutrophil infiltration in the liver after 24 h. Pretreatment with a monoclonal antibody against neutrophils, which caused consistent neutropenia, protected the liver from reperfusion injury as indicated by 28 +/- 10% necrosis, and 84% reduction of hepatic neutrophil accumulation and a complete recovery of the hepatic ATP content. Our data suggest that the later progression phase of reperfusion injury after hepatic no-flow ischemia is mediated mainly by neutrophils.


Evaluation of the quality consistency of powdered poppy capsule extractive by an averagely linear-quantified fingerprint method in combination with antioxidant activities and two compounds analyses.
A novel averagely linear-quantified fingerprint method was proposed and successfully applied to monitor the quality consistency of alkaloids in powdered poppy capsule extractive. Averagely linear-quantified fingerprint method provided accurate qualitative and quantitative similarities for chromatographic fingerprints of Chinese herbal medicines. The stability and operability of the averagely linear-quantified fingerprint method were verified by the parameter r. The average linear qualitative similarity SL (improved based on conventional qualitative "Similarity") was used as a qualitative criterion in the averagely linear-quantified fingerprint method, and the average linear quantitative similarity PL was introduced as a quantitative one. PL was able to identify the difference in the content of all the chemical components. In addition, PL was found to be highly correlated to the contents of two alkaloid compounds (morphine and codeine). A simple flow injection analysis was developed for the determination of antioxidant capacity in Chinese Herbal Medicines, which was based on the scavenging of 2,2-diphenyl-1-picrylhydrazyl radical by antioxidants. The fingerprint-efficacy relationship linking chromatographic fingerprints and antioxidant activities was investigated utilizing orthogonal projection to latent structures method, which provided important pharmacodynamic information for Chinese herbal medicines quality control. In summary, quantitative fingerprinting based on averagely linear-quantified fingerprint method can be applied for monitoring the quality consistency of Chinese herbal medicines, and the constructed orthogonal projection to latent structures model is particularly suitable for investigating the fingerprint-efficacy relationship.


Baboons' response speed is biased by their moods.
The affect-as-information hypothesis (e.g., Schwarz & Clore, 2003), predicts that the positive or negative valence of our mood differentially affects our processing of the details of the environment. However, this hypothesis has only been tested with mood induction procedures and fairly complex cognitive tasks in humans. Here, six baboons (Papio papio) living in a social group had free access to a computerized visual search task on which they were over-trained. Trials that immediately followed a spontaneously expressed emotional behavior were analyzed, ruling out possible biases due to induction procedures. RTs following negatively valenced behaviors are slower than those following neutral and positively valenced behaviors, respectively. Thus, moods affect the performance of nonhuman primates tested in highly automatized tasks, as it does in humans during tasks with much higher cognitive demands. These findings reveal a presumably universal and adaptive mechanism by which moods influence performance in various ecological contexts.


Improved Semantic Image Inpainting Method with Deep Convolution Generative Adversarial Networks.
With the development of generative adversarial networks (GANs), more and more researchers apply them to image inpainting technologies. However, many existing approaches caused some inpainting images to be unclear or even restore failures due to a failure to keep the consistency of the inpainted content and structures in line with the surroundings. In this article, we propose the Improved Semantic Image Inpainting Method with Deep Convolution GANs, which can resolve this inconsistency. In the proposed method, we design a patch discriminator and contextual loss to jointly perform the accuracy and effectiveness for image inpainting. In addition, we also designed a consistency loss based on deep convolutional neural networks to constrain the difference between the generated image and the original image in the feature space. Our proposed method improves the details and authenticity effectively for the inpainting images. We evaluate our proposed method on two different datasets, and the result shows that our proposed method achieves state-of-the-art results.


Addictive behaviors related to opioid use for chronic pain: a population-based study.
The growing body of research showing increased opioid use in patients with chronic pain coupled with concerns regarding addiction encouraged the development of this population-based study. The goal of the study was to investigate the co-occurrence of indicators of addictive behaviors in patients with chronic non-cancer pain in long-term opioid treatment. The study combined data from the individual-based Danish Health Survey in 2010 and the official Danish health and socio-economic, individual-based registers. From a simple random sample of 25,000 adults (16 years or older) living in Denmark, 13,281 individuals were analyzed through multiple logistic regression analyses to assess the association between chronic pain (lasting ≥6 months), opioid use, health behavior, and body mass index. Six potential addictive behaviors were identified: daily smoking; high alcohol intake; illicit drug use in the past year; obesity; long-term use of benzodiazepines; and long-term use of benzodiazepine-related drugs. At least 2 of the 6 addictive behaviors were observed in 22.6% of the long-term opioid users with chronic pain compared with 11.5% of the non-opioid users with chronic pain and 8.9% of the individuals without chronic pain. Thus, a strong association was demonstrated between long-term opioid use and the clustering of addictive behaviors. An intricate relationship between chronic pain, opioid use, and addictive behaviors was observed in this study, which deserves both clinical attention and further research.