Lipoprotein heterogeneity in persons with Spinal Cord Injury: a model of prolonged sitting and restricted physical activity.
Persons with spinal cord injury (SCI) often have low levels of physical activity, which predispose to increased adiposity and decreased high density lipoprotein cholesterol (HDL-C) concentrations, and, generally, normal low density lipoprotein cholesterol (LDL-C) concentrations. In spite of the mixed lipoprotein profile, the SCI population has been reported to have an elevated risk of cardiovascular-related morbidity and mortality. Nuclear magnetic resonance spectroscopy may permit a more precise quantification of lipoprotein particle (P) species, enabling a more accurate inference of risk for cardiovascular disease (CVD) in the SCI population. Fasting blood samples were obtained on 83 persons with chronic SCI and 62 able-bodied (AB) subjects. Fasting plasma insulin (FPI), triglycerides (TG), and P number and size of VLDL (very low density lipoprotein), LDL, and HDL subclasses were determined. AB and SCI subjects were stratified based on HDL-C (i.e., Low <40 and Normal ≥ 40 mg/dl): AB-Normal (n = 48), AB-Low (n = 14), SCI-Normal (n = 49), and SCI-Low (n = 34). Factorial analyses of variance were performed to identify group differences in lipoprotein measurements. Pearson correlations were performed between the number of P by lipoprotein subclass, size, FPI, and TG. The SCI-Normal group was not significantly different from the AB-Normal group for body composition, FPI, TG or LP-IR and had negligible differences in the lipoprotein P profile, except for fewer number and smaller size of HDL-P. The SCI-Low group had a similar lipoprotein profile to that of the AB-Low group, but with a lipid P composition associated with a heightened atherogenic risk and greater tendency toward insulin resistance by the Lipoprotein-Insulin Resistance (LP-IR) score. In the SCI-Low group, the decreased number and reduced size of lipoprotein P were more prevalent and may be associated with increased waist circumference (i.e., abdominal adiposity), relatively elevated TG values (compared to the other subgroups), and an underlying subclinical state of insulin resistance. Prolonged sitting and restricted physical activity in individuals with SCI had the most profound effect on the HDL-C and its lipoprotein P subclasses, but not on LDL-C, however its P subclasses were also unfavorably affected but not to the same degree. The quantification of lipoprotein P characteristics may be a potent tool for the determination of risk for CVD in persons with SCI.


Surgical management of pelvic organ prolapse in women: a short version Cochrane review.
Pelvic organ prolapse may occur in up to 50% of parous women. A variety of urinary, bowel and sexual symptoms may be associated with prolapse. To determine the effects of the many different surgeries in the management of pelvic organ prolapse. We searched the Cochrane Incontinence Group Specialised Trials Register (searched 3 May 2006) and reference lists of relevant articles. We also contacted researchers in the field. Randomised or quasi-randomised controlled trials that included surgical operations for pelvic organ prolapse. Trials were assessed and data extracted independently by two reviewers. Six investigators were contacted for additional information with five responding. Twenty two randomised controlled trials were identified evaluating 2368 women. Abdominal sacral colpopexy was better than vaginal sacrospinous colpopexy in terms of a lower rate of recurrent vault prolapse (RR 0.23, 95% CI 0.07 to 0.77) and less dyspareunia (RR 0.39, 95% CI 0.18 to 0.86), but the trend towards a lower re-operation rate for prolapse following abdominal sacrocolpopexy was not statistically significant (RR 0.46, 95% CI 0.19 to 1.11). However, the vaginal sacrospinous colpopexy was quicker and cheaper to perform and women had an earlier return to activities of daily living. The data were too few to evaluate other clinical outcomes and adverse events. The three trials contributing to this comparison were clinically heterogeneous. For the anterior vaginal wall prolapse, standard anterior repair was associated with more recurrent cystoceles than when supplemented by polyglactin mesh inlay (RR 1.39, 95% CI 1.02 to 1.90) or porcine dermis mesh inlay (RR 2.72, 95% CI 1.20 to 6.14), but data on morbidity, other clinical outcomes and for other mesh or graft materials were too few for reliable comparisons. For posterior vaginal wall prolapse, the vaginal approach was associated with a lower rate of recurrent rectocele and/or enterocele than the transanal approach (RR 0.24, 95% CI 0.09 to 0.64), although there was a higher blood loss and postoperative narcotic use. However, data on the effect of surgery on bowel symptoms and the use of polyglactin mesh inlay or porcine small intestine graft inlay on the risk of recurrent rectocele were insufficient for meta-analysis.Meta-analysis on the impact of pelvic organ prolapse surgery on continence issues was limited and inconclusive, although about 10% of women developed new urinary symptoms after surgery. Although the addition of tension-free vaginal tape to endopelvic fascia plication (RR 5.5, 95% CI 1.36 to 22.32) and Burch colposuspension to abdominal sacrocolpopexy (RR 2.13, 95% CI 1.39 to 3.24) were followed by a lower risk of women developing new postoperative stress incontinence, but other outcomes, particularly economic, remain to be evaluated. Abdominal sacrocolpopexy is associated with a lower rate of recurrent vault prolapse and dyspareunia than the vaginal sacrospinous colpopexy. These benefits must be balanced against a longer operating time, longer time to return to activities of daily living and increased cost of the abdominal approach. The use of mesh or graft inlays at the time of anterior vaginal wall repair may reduce the risk of recurrent cystocele. Posterior vaginal wall repair may be better than transanal repair in the management of rectoceles in terms of recurrence of prolapse. The addition of a continence procedure to a prolapse repair operation may reduce the incidence of postoperative urinary incontinence but this benefit needs to be balanced against possible differences in costs and adverse effects. Adequately powered randomised controlled clinical trials are urgently needed.


Glycyrrhizic acid (GA), a triterpenoid saponin glycoside alleviates ultraviolet-B irradiation-induced photoaging in human dermal fibroblasts.
Glycyrrhizic acid (GA), a triterpenoid saponin glycoside from the roots and rhizomes of licorice is used in traditional and modern medicine for the treatment of numerous medical conditions including skin diseases and beauty care product. In the present study, we investigated the effect of GA against ultraviolet B (UVB) irradiation-induced photoaging in human dermal fibroblasts (HDFs) and its possible mechanism of action. HDFs were subjected to photoaging by sub-toxic dose of UVB (10 mj/cm(2)) irradiation. Cell viability, matrix metalloproteinase 1 (MMP1), pro-collagen 1, cellular and nuclear morphology, cell cycle, intracellular reactive oxygen species (ROS), caspase 3 and hyaluronidase inhibition assays were performed. Western blotting was used to evaluate the expression of NF-kappa B (NF-κB) and cytochrome-C proteins. GA treatment significantly inhibited photoaging. It achieved this by reducing ROS, NF-κB, cytochrome c, caspase 3 levels and inhibiting hyaluronidase enzyme. The main mechanism seems to be, most likely by blocking MMP1 activation by modulating NF-κB signaling. These findings may be useful for development of natural and safe photoprotective agents against UVB irradiation.


Refractory immune thrombocytopenic purpura: current strategies for investigation and management.
There is currently no consensus on how best to manage refractory immune thrombocytopenic purpura (ITP). In part, this reflects the need for individualized treatment due to the wide spectrum of patients' requirements and responsiveness to therapies. The objective of this review is to provide a clinically useful guide to current management strategies. This article suggests investigations to identify factors that may exacerbate thrombocytopenia and underlie poor therapeutic responses, and highlights emerging therapies, including the thrombopoietic agents, which are anticipated to dramatically alter the natural history of "refractory" ITP. Morbidity, mortality and heath-related quality of life are also discussed.


Guided self-help on the Internet for Turkish migrants with depression: the design of a randomized controlled trial.
The Turkish population living in The Netherlands has a high prevalence of psychological complaints and has a high threshold for seeking professional help for these problems. Seeking help through the Internet can overcome these barriers. This project aims to evaluate the effectiveness of a guided self-help problem-solving intervention for depressed Turkish migrants that is culturally adapted and web-based. This study is a randomized controlled trial with two arms: an experimental condition group and a wait list control group. The experimental condition obtains direct access to the guided web-based self-help intervention, which is based on Problem Solving Treatment (PST) and takes 6 weeks to complete. Turkish adults with mild to moderate depressive symptoms will be recruited from the general population and the participants can choose between a Turkish and a Dutch version. The primary outcome measure is the reduction of depressive symptoms, the secondary outcome measures are somatic symptoms, anxiety, acculturation, quality of life and satisfaction. Participants are assessed at baseline, post-test (6 weeks), and 4 months after baseline. Analysis will be conducted on the intention-to-treat sample. This study evaluates the effectiveness of a guided problem-solving intervention for Turkish adults living in The Netherlands that is culturally adapted and web-based. Nederlands Trial Register: NTR2303.


Safe Medication Management at Ambulatory Surgery Centers.
Safe medication management is an important aspect of preventing patient harm. Medication management in the ambulatory setting can be complicated because of state and federal regulations and requirements imposed by accrediting organizations. Ambulatory surgery center leaders should review their medication management programs internally to assess their comprehensiveness in terms of efficiency, meeting regulatory requirements, and keeping patients safe. Partnering with a pharmacist or pharmacy consultant can be a useful way to address challenges with proper medication management. Perioperative medication use and administration, postoperative pain management, medication disposal, staff member and physician education, proper documentation in the medical record by all disciplines, pharmacoeconomics, pharmacy compounding needs, and controlled medication management and oversight are all important components of this segment of care. Ensuring that medication management programs at ambulatory surgery centers meet all regulatory and patient safety requirements is essential.


Characterization of polyalphaolefins using halogen anion attachment in atmospheric pressure photoionization coupled with ion mobility spectrometry-mass spectrometry.
Polyalphaolefins (PAOs) are saturated alpha olefin oligomers used as a base stock oil for synthetic lubricants. The synthetic base stocks are manufactured from linear alpha olefins by catalytic oligomerization processes. The aim of this work was the characterization of different PAO grades, synthesized from different linear alpha olefins using two oligomerization processes, acid and metallocene catalyses. Negative ion atmospheric pressure photoionization (APPI) coupled with ion mobility spectrometry-mass spectrometry (IMS-MS) permitted the detection of intact PAO adducts with either chloride, bromide or iodide ions using halogenated solvents (e.g. dichloromethane, dibromomethane and diiodomethane) and toluene as the dopant. The best signal-to-noise ratio was obtained with dichloromethane. The APPI mass spectra displayed characteristic ion distributions for high viscosity PAO grades. The mass shift between two adjacent ions permitted the identification of repeating units and consequently the monomers of alpha olefins used to manufacture the PAO. For low PAO grades, the halide anion adducts were not detected as they are less stable. The IMS-MS data, as well as the correlated variables, i.e. the drift time and full width at half maximum (FWHM) of the IMS peaks, can be used to differentiate polyalphaolefins of the same grade but differently synthesized.


Toward Personalized Tinnitus Treatment: An Exploratory Study Based on Internet Crowdsensing.
Introduction: Chronic tinnitus is a condition estimated to affect 10-15% of the population. No treatment has shown efficacy in randomized clinical trials to reliably and effectively suppress the phantom perceptions, and little is known why patients react differently to the same treatments. Tinnitus heterogeneity may play a central role in treatment response, but no study has tried to capture tinnitus heterogeneity in terms of treatment response. Research Goals: To test if the individualized treatment response can be predicted using personal, tinnitus, and treatment characteristics. Methods: A survey conducted by the web platform Tinnitus Hub collected data of 5017 tinnitus bearers. The participants reported which treatments they tried and the outcome of the given treatment. Demographic and tinnitus characteristics, alongside with treatment duration were used as predictors of treatment outcomes in both an univariate as well as a multivariate regression setup. First, simple linear regressions were used with each of the 13 predictors on all of 25 treatment outcomes to predict how much variance could be explained by each predictor individually. Then, all 13 predictors were added together in the elastic net regression to predict treatment outcomes. Results: Individual predictors from the linear regression models explained on average 2% of the variance of treatment outcome. "Duration of treatment" was the predictor that explained, on average, most of the variance, 6.8%. When combining all the predictors in the elastic net, the model could explain on average 16% of the deviance of treatment outcomes. Discussion: By demonstrating that different aspects predict response to various treatments, our results support the notion that tinnitus heterogeneity influences the observed variability in treatment response. Moreover, the data suggest the potential of personalized tinnitus treatment based on demographic and clinical characteristics.


The dynamics of unentangled polymers during capillary rise infiltration into a nanoparticle packing.
Although highly packed polymer nanocomposites (PNCs) are important for a wide array of applications, preparing them remains difficult because of the poor dispersion of NPs at high loading fractions. One method to successfully prepare PNCs with high loadings is through capillary rise infiltration, as previously shown by Huang et al., although the mechanism of polymer infiltration remains largely unknown. We use molecular dynamics simulations to directly simulate the process of capillary rise infiltration, and we show that the polymers follow Lucas-Washburn dynamics. We observe a wetting front that precedes bulk infiltration, and chains belonging to this front are highly adsorbed to NPs. We also investigate the viscosity of the model polymers both globally and locally in supported and free-standing films, and we find reduced viscosity near the surface of the films and increased viscosity near the supporting substrate, similar to the results of local relaxation times. The reduction in the viscosity at the free surface for short, oligomeric polymers is smaller than for higher molecular weight polymers, and the ratio of the surface viscosities is most consistent with the predictions of the Lucas-Washburn equation. Our results introduce the mechanism by which polymers infiltrate a highly packed NP film, which may shed light on better ways to prepare these materials for energy storage applications and protective coatings.


Dosage, Efficacy and Safety of Cannabidiol Administration in Adults: A Systematic Review of Human Trials.
Considering data from in vitro and in vivo studies, cannabidiol (CBD) seems to be a promising candidate for the treatment of both somatic and psychiatric disorders. The aim of this review was to collect dose(s), dosage schemes, efficacy and safety reports of CBD use in adults from clinical studies. A systematic search was performed in PubMed, Embase and Cochrane library for articles published in English between January 1, 2000 and October 25, 2019. The search terms used were related to cannabis and CBD in adults. We identified 25 studies (927 patients; 538 men and 389 women), of which 22 studies were controlled clinical trials (833 patients) and three were observational designs (94 patients) from five countries. Formulations, dose and dosage schemes varied significantly between studies. Varying effects were identified from the randomized controlled trials (RCTs), more apparent effects from non-RCTs and minor safety issues in general. From the controlled trials, we identified anxiolytic effects with acute CBD administration, and therapeutic effects for social anxiety disorder, psychotic disorder and substance use disorders. In general, studies were heterogeneous and showed substantial risks of bias. Although promising results have been identified, considerable variation in dosage schemes and route of administration were employed across studies. There was evidence to support single dose positive effect on social anxiety disorder, short medium-term effects on symptomatic improvement in schizophrenia and lack of effect in the short medium-term on cognitive functioning in psychotic disorders. Overall, the administration was well tolerated with mild side effects.


Reduced graphene oxide wrapped core-shell metal nanowires as promising flexible transparent conductive electrodes with enhanced stability.
Transparent conductive electrodes (TCEs) are widely used in a wide range of optical-electronic devices. Recently, metal nanowires (NWs), e.g. Ag and Cu, have drawn attention as promising flexible materials for TCEs. Although the study of core-shell metal NWs, and the encapsulation/overcoating of the surface of single-metal NWs have separately been an object of focus in the literature, herein for the first time we simultaneously applied both strategies in the fabrication of highly stable Ag-Cu NW-based TCEs by the utilization of Ag nanoparticles covered with reduced graphene oxide (rGO). The incorporation of Ag nanoparticles by galvanic displacement reaction was shown to significantly increase the long term stability of the electrode. Upon comparison with a CuNW reference, our novel rGO/Cu-AgNW-based TCEs unveiled remarkable opto-electrical properties, with a 3-fold sheet resistance decrease (from 29.8 Ω sq-1 to 10.0 Ω sq-1) and an impressive FOM value (139.4). No detrimental effect was noticed in the relatively high transmittance value (T = 77.6% at 550 nm) characteristic of CuNWs. In addition, our rGO/Cu-AgNW-based TCEs exhibited outstanding thermal stability up to 20 days at 80 °C in air, as well as improved mechanical flexibility. The superior performance herein reported compared with both CuNWs and AgNWs, and with a current conventional ITO reference, is believed to highlight the great potential of these novel materials as promising alternatives in optical-electronic devices.


An in vitro deletion in ribE encoding lumazine synthase contributes to nitrofurantoin resistance in Escherichia coli.
Nitrofurantoin has been used for decades for the treatment of urinary tract infections (UTIs), but clinically significant resistance in Escherichia coli is uncommon. Nitrofurantoin concentrations in the gastrointestinal tract tend to be low, which might facilitate selection of nitrofurantoin-resistant (NIT-R) strains in the gut flora. We subjected two nitrofurantoin-susceptible intestinal E. coli strains (ST540-p and ST2747-p) to increasing nitrofurantoin concentrations under aerobic and anaerobic conditions. Whole-genome sequencing was performed for both susceptible isolates and selected mutants that exhibited the highest nitrofurantoin resistance levels aerobically (ST540-a and ST2747-a) and anaerobically (ST540-an and ST2747-an). ST540-a/ST540-an and ST2747-a (aerobic MICs of >64 μg/ml) harbored mutations in the known nitrofurantoin resistance determinants nfsA and/or nfsB, which encode oxygen-insensitive nitroreductases. ST2747-an showed reduced nitrofurantoin susceptibility (aerobic MIC of 32 μg/ml) and exhibited remarkable growth deficits but did not harbor nfsA/nfsB mutations. We identified a 12-nucleotide deletion in ribE, encoding lumazine synthase, an essential enzyme involved in the biosynthesis of flavin mononucleotide (FMN), which is an important cofactor for NfsA and NfsB. Complementing ST2747-an with a functional wild-type lumazine synthase restored nitrofurantoin susceptibility. Six NIT-R E. coli isolates (NRCI-1 to NRCI-6) from stools of UTI patients treated with nitrofurantoin, cefuroxime, or a fluoroquinolone harbored mutations in nfsA and/or nfsB but not ribE. Sequencing of the ribE gene in six intestinal and three urinary E. coli strains showing reduced nitrofurantoin susceptibility (MICs of 16 to 48 μg/ml) also did not identify any relevant mutations. NRCI-1, NRCI-2, and NRCI-5 exhibited up to 4-fold higher anaerobic MICs, compared to the mutants generated in vitro, presumably because of additional mutations in oxygen-sensitive nitroreductases.


Electromagnetic scattering from multiple sub-wavelength apertures in metallic screens using the surface integral equation method.
This work presents a novel finite-element solution to the problem of scattering from multiple two-dimensional holes with side grating in infinite metallic walls. The formulation is based on using the surface integral equation with free-space Green's function as the boundary constraint. The solution region is divided into interior regions containing each hole or cavity as a side grating and exterior region. The finite-element formulation is applied inside the interior regions to derive a linear system of equations associated with nodal field values. The surface integral equation is then applied at the opening of the holes as a boundary constraint to connect nodes on the boundaries to interior nodes. The technique presented here is highly efficient in terms of computing resources, versatile and accurate in comparison with previously published methods. The near and far fields are generated for different single and multiple hole examples.


Gain control with A-type potassium current: IA as a switch between divisive and subtractive inhibition.
Neurons process and convey information by transforming barrages of synaptic inputs into spiking activity. Synaptic inhibition typically suppresses the output firing activity of a neuron, and is commonly classified as having a subtractive or divisive effect on a neuron's output firing activity. Subtractive inhibition can narrow the range of inputs that evoke spiking activity by eliminating responses to non-preferred inputs. Divisive inhibition is a form of gain control: it modifies firing rates while preserving the range of inputs that evoke firing activity. Since these two "modes" of inhibition have distinct impacts on neural coding, it is important to understand the biophysical mechanisms that distinguish these response profiles. In this study, we use simulations and mathematical analysis of a neuron model to find the specific conditions (parameter sets) for which inhibitory inputs have subtractive or divisive effects. Significantly, we identify a novel role for the A-type Potassium current (IA). In our model, this fast-activating, slowly-inactivating outward current acts as a switch between subtractive and divisive inhibition. In particular, if IA is strong (large maximal conductance) and fast (activates on a time-scale similar to spike initiation), then inhibition has a subtractive effect on neural firing. In contrast, if IA is weak or insufficiently fast-activating, then inhibition has a divisive effect on neural firing. We explain these findings using dynamical systems methods (plane analysis and fast-slow dissection) to define how a spike threshold condition depends on synaptic inputs and IA. Our findings suggest that neurons can "self-regulate" the gain control effects of inhibition via combinations of synaptic plasticity and/or modulation of the conductance and kinetics of A-type Potassium channels. This novel role for IA would add flexibility to neurons and networks, and may relate to recent observations of divisive inhibitory effects on neurons in the nucleus of the solitary tract.


[Allocation of health care resources in the state of Santa Catarina, Brazil: a contribution to a discussion on health financing].
To describe the health situation in municipalities in the state of Santa Catarina, Brazil, in 1996, and to investigate how that correlated with federal health spending in 1997. Multiple regression analysis was used to investigate the association between federal health care funding and proportional mortality, supply of health services (hospitals and outpatient clinics), and the municipality's population (number of inhabitants). Also investigated was the association between mortality from broad groups of causes and socioeconomic structure, supply of health services, and the municipality's population. The multiple regression analysis showed an association between proportional mortality due to: 1) infectious diseases and: infant mortality, number of non-doctor medical professionals per 10,000 inhabitants, and number of physicians per 10,000 inhabitants (negative association); 2) chronic degenerative diseases and: percentage of individuals 60 years and older, infant mortality (negative association), and number of non-doctor medical professionals per 10,000 inhabitants (negative association); and 3) external causes of death and: the municipality's population, number of hospitals per 10,000 inhabitants (negative association), and percentage of children younger than 1 year. Health spending per inhabitant in 1997 was mainly associated with the municipality's population, number of outpatient clinics per 10,000 inhabitants, Swaroop and Uemura mortality rate, and deaths due to chronic degenerative diseases in 1996. Municipalities with a better morbidity and mortality profile and a better health services structure received more federal health care resources. To improve this situation, special strategies should be considered in order to ensure additional resources for municipalities that have poorer health indicators.


Impact of chronic sexual abuse and depression on inflammation and wound healing in the female reproductive tract of HIV-uninfected and HIV-infected women.
Sexual violence is associated with increased risk of HIV acquisition/transmission in women. Forced sex can result in physical trauma to the reproductive tract as well as severe psychological distress. However, immuno-biological mechanisms linking sexual violence and HIV susceptibility are incompletely understood. Using the Women's Interagency HIV Study repository, a total of 77 women were selected to form 4 groups, stratified by HIV serostatus, in the following categories: 1) no sexual abuse history and low depressive symptom score (below clinically significant cut-off, scores <16) (Control); 2) no sexual abuse history but high depressive symptom score, ≥16 (Depression); 3) chronic sexual abuse exposure and low depressive symptom score (Abuse); 4) chronic sexual abuse exposure and high depressive symptom score (Abuse+Depression). Inflammation-associated cytokines/chemokines/proteases (TNF-α, IL-6, IL-1α, IL-1β, TGF-β MIP-3α, IP-10, MCP-1, Cathepsin B), anti-inflammatory/anti-HIV mediators (Secretory leukocyte protease inhibitor (SLPI), Elafin, beta defensin 2 (HBD2), alpha defensins (HNP 1-3), Thrombospondin (TSP-1), Serpin A1, A5, Cystatin A, B), and wound-healing mediators (Gro-α, VEGF, PDGF, EGF, FGF, IGF), were measured in cervical-vaginal lavage (CVL) using ELISA. Linear regression was used to model association of biomarkers with depression and abuse as predictor variables; the interaction between depression and abuse was also tested. Anti-HIV activity in CVL was tested using TZM-bl indicator cell line. In HIV-uninfected women, median levels of IL-6 (p = 0.04), IL-1α (p<0.01), TGF-β (p = 0.01), IP-10 (p = <0.01), PDGF (p<0.01) and FGF (p<0.01), differed significantly between groups. Specifically, an association was found between chronic sexual abuse and increased IL-1α (p<0.01), MIP-3α (p = 0.04), IP-10 (p<0.01), Serpin B1 (p = 0.01), FGF (p = 0.04) and decreased TGF-β (p<0.01), MCP-1 (p = 0.02), PDGF (p<0.01). Further, there was evidence of significant interactions between chronic sexual abuse and current depression for IL-1α, IP-10, Serpin A1, Cystatin B, and FGF. In HIV-infected women, median levels of TNF-α (p<0.01), IL-6 (p = 0.05), MIP-3α (p<0.01), and MCP-1 (p = 0.01), differed significantly between groups. Specifically, an association was found between chronic sexual abuse and increased MCP-1 (p = 0.03), Gro-α (p = 0.01) and decreased TNF-α (p<0.01), IL-1α (p = 0.02), MIP-3α (p<0.01) and Cathepsin B (p = 0.03). Current depressive symptoms were associated with significantly decreased MIP-3α (p<0.01). There was evidence of significant interactions between chronic sexual abuse and current depression for MCP-1 and FGF. No significant differences were observed in anti-HIV activity among all eight groups. Heat-map analyses revealed distinct immune network patterns, particularly in the Abuse groups for both HIV-infected and uninfected women. Our data indicates a complex relationship between chronic sexual abuse exposure, depressive symptoms, and FRT immune mediators that are also affected by HIV status. Association of chronic sexual abuse with increase in inflammation-associated cytokine/chemokine expression, along with impaired wound-healing associated growth-factors can create a microenvironment that can facilitate HIV infection. Evaluation of longitudinal changes in exposures and biomarkers are needed to untangle the immuno-biological mechanisms that may put women who endure life-long sexual abuse at increased risk for HIV.


Acute toxicity and repeated dose 28-day oral toxicity study of metriviv syrup in female rats.
Metriviv syrup is a poly-herbal formulation used as uterine tonic and for treating gynecological ailments such as infertility, leucorrhea, and menstrual disorders. There is no scientific data on the safety of this formulation available, therefore, its detail toxicity study in female albino rats was conducted. Acute toxicity and repeated dose 28 days oral toxicity study of metriviv syrup in female rats. In oral acute toxicity study, syrup metriviv was administered orally once only at the dose of 2000mg/kg in rats in a sequential manner. For repeated dose toxicity study, Metriviv syrup was administered orally for 28 consecutive days in albino rats at three dose levels, i.e., TED, TEDx5 and TEDx10 dose levels (1.35, 0.75, 13.5 ml/kg, twice a day respectively). Results of acute toxicity study showed that drug did not produce any behavioral changes, signs of toxicity and mortality up to the dose of 2000 mg/kg in rats. In repeated dose 28-day oral toxicity study, Metriviv did not produce any signs of toxicity and changes in behavioral parameters. Metriviv did not affect cellular as well as non-cellular elements of the blood to significant extent. Serum biochemical profile and histological study clearly indicated that the test formulation is not likely to produce any serious changes at lower dose level while produced mild-to-moderate changes at TEDx10 dose level and same was reverted in recovery study after discontinuation of the drug. The study concluded that metriviv syrup is safe to administer up to dose of 2000 mg/kg in female rats during acute toxicity. In repeated dose 28-day oral toxicity study, test drug at TEDx10 has only mild-to-moderate adverse potential for liver and kidney while did not have any major toxic effects at therapeutic dose level in female albino rats.


Lightweight application for generating clinical research information systems: MAGIC.
Our purpose was to build and test a lightweight solution for generating clinical research information systems (CRIS) that would allow non-IT professionals with basic knowledge of computer usage to quickly define and build a ready-to-use, safe and secure web-based clinical research system for data management. We use the acronym MAGIC (Medical Application Generator InteraCtive) for the system. The generated CRIS should be very easy to build and use, so a common LAMP (Linux Apache MySQL Perl) platform was used, which also enables short development cycles. The application was built and tested using eXtreme Programming (XP) principles by a small development team consisting of one informatics specialist, one physician and one graphical designer/programmer. The parameter and graphical user interface (GUI) definitions for the CRIS can be made by non-IT professionals using an intuitive English-language-like formalism called application definition language (ADL). From these definitions, the MAGIC builds an end-user CRIS that can be used on a wide variety of platforms (from standard workstations to hand-held devices). A working example of a national health-care-quality assessment program is presented to illustrate this process. The lightweight application for generating CRIS (MAGIC) has proven to be useful for both clinical and analytical users in real working environment. To achieve better performance and interoperability, we are planning to recompile the application using XML schemas (XSD) in HL7 CDA or openEHR archetypes formats used for parameters definition and for data interchange between different information systems.


Eliashberg analysis of tunneling experiments: support for the pairing glue hypothesis in cuprate superconductors.
Evidence for the validity of the pairing glue interpretation of high temperature superconductivity is presented using a modified Eliashberg analysis of experimental superconductor-insulator-superconductor (SIS) tunneling data in B2Sr2CaCu2O8 (Bi2212) over a wide range of doping. This is accomplished by extracting detailed information on the diagonal and anomalous contributions to the quasiparticle self-energy. In particular, a comparison of the imaginary part of the anomalous self-energy ImΦ(ω) and the pairing glue spectral function α2F(ω) used in the model is consistent with Hubbard model simulations in the literature. In addition, the real part of the diagonal self-energy for optimal doped Bi2212 bears a strong resemblance to that obtained from photoemission experiments.


Large-Scale, Ion-Current-Based Proteomic Investigation of the Rat Striatal Proteome in a Model of Short- and Long-Term Cocaine Withdrawal.
Given the tremendous detriments of cocaine dependence, effective diagnosis and patient stratification are critical for successful intervention yet difficult to achieve due to the largely unknown molecular mechanisms involved. To obtain new insights into cocaine dependence and withdrawal, we employed a reproducible, reliable, and large-scale proteomics approach to investigate the striatal proteomes of rats (n = 40, 10 per group) subjected to chronic cocaine exposure, followed by either short- (WD1) or long- (WD22) term withdrawal. By implementing a surfactant-aided precipitation/on-pellet digestion procedure, a reproducible and sensitive nanoLC-Orbitrap MS analysis, and an optimized ion-current-based MS1 quantification pipeline, >2000 nonredundant proteins were quantified confidently without missing data in any replicate. Although cocaine was cleared from the body, 129/37 altered proteins were observed in WD1/WD22 that are implicated in several biological processes related closely to drug-induced neuroplasticity. Although many of these changes recapitulate the findings from independent studies reported over the last two decades, some novel insights were obtained and further validated by immunoassays. For example, significantly elevated striatal protein kinase C activity persisted over the 22 day cocaine withdrawal. Cofilin-1 activity was up-regulated in WD1 and down-regulated in WD22. These discoveries suggest potentially distinct structural plasticity after short- and long-term cocaine withdrawal. In addition, this study provides compelling evidence that blood vessel narrowing, a long-known effect of cocaine use, occurred after long-term but not short-term withdrawal. In summary, this work developed a well-optimized paradigm for ion-current-based quantitative proteomics in brain tissues and obtained novel insights into molecular alterations in the striatum following cocaine exposure and withdrawal.


Improved calcium sulfate recovery from a reverse osmosis retentate using eutectic freeze crystallization.
A novel low temperature crystallization process called eutectic freeze crystallization (EFC) can produce both salt(s) and ice from a reverse osmosis (RO) stream by operating at the eutectic temperature of a solution. The EFC reject stream, which is de-supersaturated with respect to the scaling component, can subsequently be recycled back to the RO process for increased water recovery. This paper looks at the feasibility of using EFC to remove calcium sulfate from an RO retentate stream and compares the results to recovery rates at 0 and 20 °C. The results showed that there was a greater yield of calcium sulfate obtained at 0 °C as compared with 20 °C. Operation under eutectic conditions, with only a 20% ice recovery, resulted in an even greater yield of calcium sulfate (48%) when compared with yields obtained at operating temperatures of 0 and 20 °C (15% at 0 °C and 13% at 20 °C). The theoretical calcium recoveries were found to be 75 and 70% at 0 and 20 °C respectively which was higher than the experimentally determined values. The EFC process has the added advantage of producing water along with a salt.


Safety and efficacy of normalizing fasting glucose with bedtime NPH insulin alone in NIDDM.
To examine the safety and overall clinical effects of normalizing the fasting plasma glucose (FPG) level with bedtime NPH insulin alone in patients with non-insulin-dependent diabetes mellitus (NIDDM) that is poorly controlled with maximal doses of sulfonylureas. Twelve obese male NIDDM subjects were treated for 16 weeks with bedtime insulin after a 4-week sulfonylurea washout. The insulin dosage was increased until the FPG level was normalized. The 24-h plasma glucose profiles and lipid and HbA1c levels were measured at the beginning and end of the study, and the incidence and severity of hypoglycemic episodes were closely monitored. In addition, hyperglycemic clamp studies were performed to assess insulin secretion and provide an indirect measurement of insulin sensitivity. FPG (14.6 +/- 0.9 mmol/l at week 0) was normalized ( < 6.4 mmol/l) within 6 weeks (5.9 +/- 0.6 mmol/l) and remained at target levels until the end of the study (4.0 +/- 0.03 mmol/l at week 16, P < 0.001). The insulin dose was 80 +/- 9 U/day (0.86 +/- 0.10 U/kg). Improved glycemic control was confirmed by a reduction in HbA1c (10.9 +/- 0.05 vs. 7.2 +/- 0.2%, P < 0.001) and mean 24-h glucose (17.2 +/- 0.2 vs. 7.4 +/- 0.2 mmol/l, P < 0.001). The incidence of mild or moderate hypoglycemic episodes was 3.4 +/- 1/patient for the entire 16-week study, and no patient experienced severe hypoglycemia. Bedtime insulin significantly improved total cholesterol, low-density lipoprotein cholesterol, very-low-density lipoprotein cholesterol, and triglyceride levels (P < 0.01). Weight gain was 2.4 +/- 0.7 kg, and blood pressure was unchanged. During the hyperglycemic clamp, there was an improvement in the first phase (P < 0.001) and in the second phase (P < 0.01) of insulin secretion. There also was an increase in the rate of exogenous glucose infused (M) (P < 0.01) and in the M/C-peptide ratio (P < 0.02), suggesting enhanced insulin sensitivity. NPH insulin given at bedtime in amounts sufficient to achieve a normal FPG level does not cause excessive or severe hypoglycemia and does lead to good glycemic and lipid control in NIDDM. Bedtime insulin therapy also is accompanied by improved insulin secretion and insulin sensitivity. We conclude that a single dose of insulin alone at bedtime merits consideration as a therapeutic strategy in patients with poorly controlled NIDDM.


Considerations for initial therapy in the treatment of acute heart failure.
The diagnosis of patients presenting to the emergency department with acute heart failure (AHF) is challenging due to the similarity of AHF symptoms to other conditions such as chronic obstructive pulmonary disease and pneumonia. Additionally, because AHF is most common in an older population, the presentation of coexistent pathologies further increases the challenge of making an accurate diagnosis and selecting the most appropriate treatment. Delays in the diagnosis and treatment of AHF can result in worse outcomes and higher healthcare costs. Rapid initiation of treatment is thus necessary for optimal disease management. Early treatment decisions for patients with AHF can be guided by risk-stratification models based on initial clinical data, including blood pressure, levels of troponin, blood urea nitrogen, serum creatinine, B-type natriuretic peptide, and ultrasound. In this review, we discuss methods for differentiating high-risk and low-risk patients and provide guidance on how treatment decisions can be informed by risk-level assessment. Through the use of these approaches, emergency physicians can play an important role in improving patient management, preventing unnecessary hospitalizations, and lowering healthcare costs. This review differs from others published recently on the topic of treating AHF by providing a detailed examination of the clinical utility of diagnostic tools for the differentiation of dyspneic patients such as bedside ultrasound, hemodynamic changes, and interrogation of implantable cardiac devices. In addition, our clinical guidance on considerations for initial pharmacologic therapy in the undifferentiated patient is provided. It is crucial for emergency physicians to achieve an early diagnosis of AHF and initiate therapy in order to reduce morbidity, mortality, and healthcare costs.


Plasmacytic differentiation of circulating Epstein-Barr virus-infected B lymphocytes during acute infectious mononucleosis.
During the acute phase (1 wk of symptoms or less) of infectious mononucleosis (IM), 70--80% of circulating Epstein-Barr virus nuclear antigen (EBNA)-positive cells have differentiated toward plasma cells. Thus the characteristics of the infected cells in the majority of IM patients during early disease are indistinguishable from EBNA-positive tumor cells of a previously reported child who developed lymphoma during IM. IgA and IgG were the most frequent and IgM the least frequent immunoglobulin isotypes detected in EBNA-positive cells. In acute disease EBNA was present in 5.5--20% of T cell-depleted blood lymphocytes but in the 2nd or 3rd wk of illness the number of EBNA-positive cells sharply decreased to 0.4--1.4%. At the same time the fraction of antigen-positive cells containing cytoplasmic immunoglobulins also diminished, suggesting either that differentiation of infected cells was altered during the disease or that nondifferentiated antigen-positive cells had a survival advantage. Both the high proportion of plasmacytic EBNA-positive cells seen during acute disease and the apparent loss of differentiation by these cells later in disease may be regulated by host immunologic factors. Immunoglobulin-producing EBNA-positive cells may be the source of heterophile antibodies and other seemingly inappropriate antibodies usually found in serum during IM; however, increased numbers of noninfected plasma cells were present in some patients and may also be a potential source of these unusual antibodies.


The development of an integrated platform to identify breast cancer glycoproteome changes in human serum.
Protein glycosylation represents one of the major post-translational modifications and can have significant effects on protein function. Moreover, changes in the carbohydrate structure are increasingly being recognized as an important modification associated with cancer etiology. In this report, we describe the development of a proteomics approach to identify breast cancer related changes in either concentration and/or the carbohydrate structures of glycoprotein(s) present in blood samples. Diseased and healthy serum samples were processed by an optimized sample preparation protocol using multiple lectin affinity chromatography (M-LAC) that partitions serum proteins based on glycan characteristics. Subsequently, three separate procedures, 1D SDS-PAGE, isoelectric focusing and an antibody microarray, were applied to identify potential candidate markers for future study. The combination of these three platforms is illustrated in this report with the analysis of control and cancer glycoproteomic fractions. Firstly, a molecular weight based separation of glycoproteins by 1D SDS-PAGE was performed, followed by protein, glycoprotein staining, lectin blotting and LC-MS analysis. To refine or confirm the list of interesting glycoproteins, isoelectric focusing (targeting sialic acid changes) and an antibody microarray (used to detect neutral glycan shifts) were selected as the orthogonal methods. As a result, several glycoproteins including alpha-1B-glycoprotein, complement C3, alpha-1-antitrypsin and transferrin were identified as potential candidates for further study.


Histone H3 lysine 9 methylation is an epigenetic imprint of facultative heterochromatin.
Post-translational modifications of histone amino termini are an important regulatory mechanism that induce transitions in chromatin structure, thereby contributing to epigenetic gene control and the assembly of specialized chromosomal subdomains. Methylation of histone H3 at lysine 9 (H3-Lys9) by site-specific histone methyltransferases (Suv39h HMTases) marks constitutive heterochromatin. Here, we show that H3-Lys9 methylation also occurs in facultative heterochromatin of the inactive X chromosome (Xi) in female mammals. H3-Lys9 methylation is retained through mitosis, indicating that it might provide an epigenetic imprint for the maintenance of the inactive state. Disruption of the two mouse Suv39h HMTases abolishes H3-Lys9 methylation of constitutive heterochromatin but not that of the Xi. In addition, HP1 proteins, which normally associate with heterochromatin, do not accumulate with the Xi. These observations suggest the existence of an Suv39h-HP1-independent pathway regulating H3-Lys9 methylation of facultative heterochromatin.


Costs of dying: alternatives to rationing.
In western industrialised countries, about 30% of health-care expenditure of retired people is incurred by individuals in their last year of life. The corresponding high costs of dying have led medical philosophers to ask for a rationing of health-care services according to age. By contrast, this paper pursues an individualistic approach. High costs of dying are identified as a consequence of moral hazard on both the demand and supply side of the health-care sector. Health insurance prevents demand for health-care services from decreasing when an individual's residual life expectancy shrinks. Age-related moral hazard can be limited by a coinsurance scheme with a deductible that increases with the age of the insured. Given the high costs of dying, the optimal insurance policy links the coinsurance rate to the age-specific mortality risk.


Association of traumatic brain injury with subsequent neurological and psychiatric disease: a meta-analysis.
Mild traumatic brain injury (TBI) has been proposed as a risk factor for the development of Alzheimer's disease, Parkinson's disease, depression, and other illnesses. This study's objective was to determine the association of prior mild TBI with the subsequent diagnosis (that is, at least 1 year postinjury) of neurological or psychiatric disease. All studies from January 1995 to February 2012 reporting TBI as a risk factor for diagnoses of interest were identified by searching PubMed, study references, and review articles. Reviewers abstracted the data and assessed study designs and characteristics. Fifty-seven studies met the inclusion criteria. A random effects meta-analysis revealed a significant association of prior TBI with subsequent neurological and psychiatric diagnoses. The pooled odds ratio (OR) for the development of any illness subsequent to prior TBI was 1.67 (95% CI 1.44-1.93, p < 0.0001). Prior TBI was independently associated with both neurological (OR 1.55, 95% CI 1.31-1.83, p < 0.0001) and psychiatric (OR 2.00, 95% CI 1.50-2.66, p < 0.0001) outcomes. Analyses of individual diagnoses revealed higher odds of Alzheimer's disease, Parkinson's disease, mild cognitive impairment, depression, mixed affective disorders, and bipolar disorder in individuals with previous TBI as compared to those without TBI. This association was present when examining only studies of mild TBI and when considering the influence of study design and characteristics. Analysis of a subset of studies demonstrated no evidence that multiple TBIs were associated with higher odds of disease than a single TBI. History of TBI, including mild TBI, is associated with the development of neurological and psychiatric illness. This finding indicates that either TBI is a risk factor for heterogeneous pathological processes or that TBI may contribute to a common pathological mechanism.


Acetaminophen-induced hepatotoxicity in mice is dependent on Tlr9 and the Nalp3 inflammasome.
Hepatocyte death results in a sterile inflammatory response that amplifies the initial insult and increases overall tissue injury. One important example of this type of injury is acetaminophen-induced liver injury, in which the initial toxic injury is followed by innate immune activation. Using mice deficient in Tlr9 and the inflammasome components Nalp3 (NACHT, LRR, and pyrin domain-containing protein 3), ASC (apoptosis-associated speck-like protein containing a CARD), and caspase-1, we have identified a nonredundant role for Tlr9 and the Nalp3 inflammasome in acetaminophen-induced liver injury. We have shown that acetaminophen treatment results in hepatocyte death and that free DNA released from apoptotic hepatocytes activates Tlr9. This triggers a signaling cascade that increases transcription of the genes encoding pro-IL-1beta and pro-IL-18 in sinusoidal endothelial cells. By activating caspase-1, the enzyme responsible for generating mature IL-1beta and IL-18 from pro-IL-1beta and pro-IL-18, respectively, the Nalp3 inflammasome plays a crucial role in the second step of proinflammatory cytokine activation following acetaminophen-induced liver injury. Tlr9 antagonists and aspirin reduced mortality from acetaminophen hepatotoxicity. The protective effect of aspirin on acetaminophen-induced liver injury was due to downregulation of proinflammatory cytokines, rather than inhibition of platelet degranulation or COX-1 inhibition. In summary, we have identified a 2-signal requirement (Tlr9 and the Nalp3 inflammasome) for acetaminophen-induced hepatotoxicity and some potential therapeutic approaches.


Fenretinide inhibits macrophage inflammatory mediators and controls hypertension in spontaneously hypertensive rats via the peroxisome proliferator-activated receptor gamma pathway.
Fenretinide is a novel anticancer agent reported to exhibit anti-invasive and antimetastatic activities. It has also been shown to improve obesity and diabetes, although the effects of fenretinide on hypertension are still unknown, and the detailed mechanisms remain unclear. In this study, we have shown that treatment with lipopolysaccharide (LPS) decreased the expression of peroxisome proliferator-activated receptor γ (PPARγ) in RAW264.7 macrophages, and pretreatment with fenretinide reversed the effect of LPS on PPARγ expression. In addition, LPS-induced pro-inflammatory cytokine production, including tumor necrosis factor-α, interleukin 6, and monocyte chemoattractant protein 1 were dose-dependently reversed by fenretinide, and the effects of fenretinide on LPS-induced pro-inflammatory cytokine production were blocked by treatment with PPARγ antagonist. Moreover, fenretinide decreased LPS-induced inducible nitric oxide synthase expression and nitrogen oxide production. These effects were blocked by the pretreatment with PPARγ antagonist in a dose-dependent manner, indicating fenretinide activated PPARγ to exert anti-inflammation activity. In view of the role of inflammation in hypertension and the anti-inflammatory action of fenretinide, we found that administration of fenretinide in spontaneously hypertensive rats significantly decreased blood pressure. Taken together, these results indicate that fenretinide might be a potent antihypertensive agent that works by suppressing inflammation via activating PPARγ.


Kallikreins on steroids: structure, function, and hormonal regulation of prostate-specific antigen and the extended kallikrein locus.
The 15 members of the kallikrein-related serine peptidase (KLK) family have diverse tissue-specific expression profiles and putative proteolytic functions. The kallikrein family is also emerging as a rich source of disease biomarkers with KLK3, commonly known as prostate-specific antigen, being the current serum biomarker for prostate cancer. The kallikrein locus is also notable because it is extraordinarily responsive to steroids and other hormones. Indeed, at least 14 functional hormone response elements have been identified in the kallikrein locus. A more comprehensive understanding of the transcriptional regulation of kallikreins may help the field make more informed hypotheses about the physiological functions of kallikreins and their effectiveness as biomarkers. In this review, we describe the organization of the kallikrein locus and the structure of kallikrein genes and proteins. We also focus on the transcriptional regulation of kallikreins by androgens, progestins, glucocorticoids, mineralocorticoids, estrogens, and other hormones in animal models and human prostate, breast, and reproductive tract tissues. The interaction of the androgen receptor with androgen response elements in the promoter and enhancer of KLK2 and KLK3 is also summarized in detail. There is evidence that all kallikreins are regulated by multiple nuclear receptors. Yet, apart from KLK2 and KLK3, it is not clear whether all kallikreins are direct transcriptional targets. Therefore, we argue that gaining more detailed information about the mechanisms that regulate kallikrein expression should be a priority of future studies and that the kallikrein locus will continue to be an important model in the era of genome-wide analyses.


Genome-wide association studies for agronomical traits in a world wide spring barley collection.
Genome-wide association studies (GWAS) based on linkage disequilibrium (LD) provide a promising tool for the detection and fine mapping of quantitative trait loci (QTL) underlying complex agronomic traits. In this study we explored the genetic basis of variation for the traits heading date, plant height, thousand grain weight, starch content and crude protein content in a diverse collection of 224 spring barleys of worldwide origin. The whole panel was genotyped with a customized oligonucleotide pool assay containing 1536 SNPs using Illumina's GoldenGate technology resulting in 957 successful SNPs covering all chromosomes. The morphological trait "row type" (two-rowed spike vs. six-rowed spike) was used to confirm the high level of selectivity and sensitivity of the approach. This study describes the detection of QTL for the above mentioned agronomic traits by GWAS. Population structure in the panel was investigated by various methods and six subgroups that are mainly based on their spike morphology and region of origin. We explored the patterns of linkage disequilibrium (LD) among the whole panel for all seven barley chromosomes. Average LD was observed to decay below a critical level (r2-value 0.2) within a map distance of 5-10 cM. Phenotypic variation within the panel was reasonably large for all the traits. The heritabilities calculated for each trait over multi-environment experiments ranged between 0.90-0.95. Different statistical models were tested to control spurious LD caused by population structure and to calculate the P-value of marker-trait associations. Using a mixed linear model with kinship for controlling spurious LD effects, we found a total of 171 significant marker trait associations, which delineate into 107 QTL regions. Across all traits these can be grouped into 57 novel QTL and 50 QTL that are congruent with previously mapped QTL positions. Our results demonstrate that the described diverse barley panel can be efficiently used for GWAS of various quantitative traits, provided that population structure is appropriately taken into account. The observed significant marker trait associations provide a refined insight into the genetic architecture of important agronomic traits in barley. However, individual QTL account only for a small portion of phenotypic variation, which may be due to insufficient marker coverage and/or the elimination of rare alleles prior to analysis. The fact that the combined SNP effects fall short of explaining the complete phenotypic variance may support the hypothesis that the expression of a quantitative trait is caused by a large number of very small effects that escape detection. Notwithstanding these limitations, the integration of GWAS with biparental linkage mapping and an ever increasing body of genomic sequence information will facilitate the systematic isolation of agronomically important genes and subsequent analysis of their allelic diversity.


Modulation of TLR signaling by multiple MyD88-interacting partners including leucine-rich repeat Fli-I-interacting proteins.
Emerging evidences suggest TLR-mediated signaling is tightly regulated by a specific chain of intracellular protein-protein interactions, some of which are yet to be identified. Previously we utilized a dual-tagging quantitative proteomics approach to uncover MyD88 interactions in LPS-stimulated cells and described the function of Fliih, a leucine-rich repeat (LRR) protein that negatively regulates NF-kappaB activity. Here we characterize two distinct LRR-binding MyD88 interactors, LRRFIP2 and Flap-1, and found that both are positive regulators of NF-kappaB activity. Upon LPS stimulation, LRRFIP2 was also found to positively regulate cytokine production in macrophages, suggesting a functional role in TLR4-mediated inflammatory response. Furthermore, we observed that immediately following LPS stimulation both LRRFIP2 and Flap-1 compete with Fliih for interacting with MyD88 to activate the signaling. By using a novel multiplex quantitative proteomic approach, we found that at endogenous levels these positive and negative regulators interact with MyD88 in a timely and orderly manner to differentially mediate the NF-kappaB activity through the course of signaling from initiation to prolongation, and to repression. Based on these data, we describe a mechanistic model in which selective modulation of TLR signaling is achieved by temporal and dynamic interactions of MyD88 with its regulators.


Domestication, genomics and the future for banana.
Cultivated bananas and plantains are giant herbaceous plants within the genus Musa. They are both sterile and parthenocarpic so the fruit develops without seed. The cultivated hybrids and species are mostly triploid (2n = 3x = 33; a few are diploid or tetraploid), and most have been propagated from mutants found in the wild. With a production of 100 million tons annually, banana is a staple food across the Asian, African and American tropics, with the 15 % that is exported being important to many economies. There are well over a thousand domesticated Musa cultivars and their genetic diversity is high, indicating multiple origins from different wild hybrids between two principle ancestral species. However, the difficulty of genetics and sterility of the crop has meant that the development of new varieties through hybridization, mutation or transformation was not very successful in the 20th century. Knowledge of structural and functional genomics and genes, reproductive physiology, cytogenetics, and comparative genomics with rice, Arabidopsis and other model species has increased our understanding of Musa and its diversity enormously. There are major challenges to banana production from virulent diseases, abiotic stresses and new demands for sustainability, quality, transport and yield. Within the genepool of cultivars and wild species there are genetic resistances to many stresses. Genomic approaches are now rapidly advancing in Musa and have the prospect of helping enable banana to maintain and increase its importance as a staple food and cash crop through integration of genetical, evolutionary and structural data, allowing targeted breeding, transformation and efficient use of Musa biodiversity in the future.


Distinctive Regulation of Emotional Behaviors and Fear-Related Gene Expression Responses in Two Extended Amygdala Subnuclei With Similar Molecular Profiles.
The central nucleus of the amygdala (CeA) and the lateral division of the bed nucleus of the stria terminalis (BNST) are the two major nuclei of the central extended amygdala that plays essential roles in threat processing, responsible for emotional states such as fear and anxiety. While some studies suggested functional differences between these nuclei, others showed anatomical and neurochemical similarities. Despite their complex subnuclear organization, subnuclei-specific functional impact on behavior and their underlying molecular profiles remain obscure. We here constitutively inhibited neurotransmission of protein kinase C-δ-positive (PKCδ+) neurons-a major cell type of the lateral subdivision of the CeA (CeL) and the oval nucleus of the BNST (BNSTov)-and found striking subnuclei-specific effects on fear- and anxiety-related behaviors, respectively. To obtain molecular clues for this dissociation, we conducted RNA sequencing in subnuclei-targeted micropunch samples. The CeL and the BNSTov displayed similar gene expression profiles at the basal level; however, both displayed differential gene expression when animals were exposed to fear-related stimuli, with a more robust expression change in the CeL. These findings provide novel insights into the molecular makeup and differential engagement of distinct subnuclei of the extended amygdala, critical for regulation of threat processing.


Structurally characterised vanadium(V)-substituted Keggin-type heteropolysulfates [SVM11O40]3- (M = Mo, W): voltammetric and spectroscopic studies related to the V(V)/V(IV) redox couple.
Structures of the n-tetrabutylammonium salts of [SVM11O40](3-) (M = Mo, W) have been determined by X-ray crystallography and exhibit 3D networks with the V atom disordered over several sites. The cyclic voltammetric behavior of SVM11 in neutral and acidified acetonitrile solutions also has been investigated with respect to the V(V)/V(IV) couple. Results have been interpreted in conjunction with data provided by (51)V NMR spectroscopy on the oxidized V(V) form and by EPR spectroscopy on the reduced V(IV) form. Based on mechanistic details inferred from these studies, simulations of the cyclic voltammograms have been undertaken and results compared with experimental data in acidic media (two protonated forms) in order to provide estimates of equilibrium and kinetic parameters. For the V(V)/V(IV) couple in the series [XVM11O40](n-) (X = Si,Ge,P,As,S; M = Mo,W), the reversible potentials in neutral acetonitrile linearly depend on the total charge of the vanadium-substituted polyoxometalates, similar to the dependence previously reported for the non-substituted parent Keggin polyoxometalates [XM12O40](m-).


Monodispersed bioactive glass submicron particles and their effect on bone marrow and adipose tissue-derived stem cells.
Spherical monodispersed bioactive particles are potential candidates for nanocomposite synthesis or as injectable particles that could be internalized by cells for the local sustained delivery of inorganic therapeutic ions (e.g., calcium or strontium). Particles are also likely to be released from porous bioactive glass and sol-gel hybrid scaffolds as they degrade; thus, it is vital to investigate their interaction with cells. Spherical monodispersed bioactive glass particles (mono-SMBG), with diameters of 215 ± 20 nm are synthesized using a modified Stöber process. Confocal and transmission electron microscopy demonstrate that mono-SMBGs are internalized by human bone marrow (MSCs) and adipose-derived stem cells (ADSCs) and located within cell vesicles and in the cytoplasm. Particle dissolution inside the cells is observed. Alamar Blue, MTT and Cyquant assays demonstrate that 50 μg mL(-1) of mono-SMBGs did not inhibit significantly MSC or ADSC metabolic activity. However, at higher concentrations (100 and 200 μg mL(-1)) small decrease in metabolic activity and total DNA is observed. Mono-SMBG did not induce ALPase activity, an early marker of osteogenic differentiation, without osteogenic supplements; however, in their presence osteogenic differentiation is achieved. Additionally, large numbers of particles are internalized by the cells but have little effect on cell behavior.


Mental Healthcare Act, 2017, and addiction treatment: Potential pitfalls and trepidations.
The Mental Healthcare Act (MHCA), 2017, is enacted with an aim to promote and protect the rights of and improve the care and treatment for people affected by mental illness in India. The Act purportedly includes substance use disorder (SUD) specifically in the definition of mental illness itself. However, some of the phrases used in the definition such as "abuse" are not clear, as the current classificatory systems of mental illnesses do not have any diagnostic category termed "abuse." Another important issue is the lack of clarity on which categories of SUD would be covered under MHCA. Simple reading of the text of the Act seems to suggest that SUD is a single entity for the purpose of this law. In such case, many provisions of the act such as supported admission that are meant for the treatment of people with severe mental illnesses with gross impairment may become applicable to all types of SUD. This can create potential problems for addiction treatment providers. On the other hand, certain other provisions of the Act are good news for patients suffering from SUD. The Act lays down various rights that include, among others, protection from cruel, inhuman, or degrading treatment in any mental health establishment. This is very important from the perspective of treatment of SUD in the context of India, where human rights violations in the name of addiction treatment are often reported. The inclusion of SUD in MHCA, 2017, slots SUD as a health issue, rather than a law-and-order issue alone. This displays the intent of policymakers toward SUD, which, in itself, is laudable. There are certain ways in which the potential pitfalls mentioned earlier can be addressed, which is discussed in the article.


Ligand-Field-Dependent Behavior of Meta-GGA Exchange in Transition-Metal Complex Spin-State Ordering.
Prediction of spin-state ordering in transition metal complexes is essential for understanding catalytic activity and designing functional materials. Semilocal approximations in density functional theory, such as the generalized-gradient approximation (GGA), suffer from several errors including delocalization error that give rise to systematic bias for more covalently bound low-spin electronic states. Incorporation of exact exchange is known to counteract this bias, instead favoring high-spin states, in a manner that has recently been identified to be strongly ligand-field dependent. In this work, we introduce a tuning strategy to identify the effect of incorporating the Laplacian of the density (i.e., a meta-GGA) in exchange on spin-state ordering. We employ a diverse test set of M(II) and M(III) first-row transition metal ions from Ti to Cu as well as octahedral complexes of these ions with ligands of increasing field strength (i.e., H2O, NH3, and CO). We show that the sensitivity of spin-state ordering to meta-GGA exchange is highly ligand-field dependent, stabilizing high-spin states in strong-field (i.e., CO) cases and stabilizing low-spin states in weak-field (i.e., H2O, NH3, and isolated ions) cases. This diverging behavior leads to generally improved treatment of isolated ions and strong field complexes over a standard GGA but worsened treatment for the hexa-aqua or hexa-ammine complexes. These observations highlight the sensitivity of functional performance to subtle changes in chemical bonding.


Tireless surveillance by exhausted T cells.
T cell exhaustion is an evocative concept that results in attenuated function in the face of chronic antigen exposure and is critical to avoid immunopathology. However, tumors often exploit this dampened T cell function to escape the antitumor immune response. In this issue of the JCI, You et al. investigated a different aspect of T cell exhaustion in the setting of tumor immunity by characterizing the capacity of T cells for tireless migration. The dynamic nature of normal T cells was first made famous by intravital microscopy studies in explanted tissues. You et al. used a similar imaging strategy with reanimated human tumors, in which exhausted T cells displayed an enhanced capacity for intratumoral motility. These results suggest that exhausted T cells may be able to teach T cell engineers lessons about navigating within the tumor microenvironment.


Exploring self-rated health among adolescents: a think-aloud study.
Despite extensive use of self-rated health questions in youth studies, little is known about what such questions capture among adolescents. Hence, the aim of this study was to explore how adolescents interpret and reason when answering a question about self-rated health. A qualitative study using think-aloud interviews explored the question, "How do you feel most of the time?", using five response options ("Very good", "Rather good", "Neither good, nor bad", "Rather bad", and "Very bad"). The study involved 58 adolescents (29 boys and 29 girls) in lower secondary school (7th grade) and upper secondary school (12th grade) in Sweden. Respondents' interpretations of the question about how they felt included social, mental, and physical aspects. Gender differences were found primarily in that girls emphasized stressors, while age differences were reflected mainly in the older respondents' inclusion of a wider variety of influences on their assessments. The five response options all demonstrated differences in self-rated health, and the respondents' understanding of the middle option, "Neither good, nor bad", varied widely. In the answering of potential sensitive survey questions, rationales for providing honest or biased answers were described. The use of a self-rated health question including the word 'feel' captured a holistic view of health among adolescents. Differences amongst response options should be acknowledged when analyzing self-rated health questions. If anonymity is not feasible when answering questions on self-rated health, a high level of privacy is recommended to increase the likelihood of reliability.


Carcinomas ex pleomorphic adenoma and malignant mixed tumors. Histomorphologic indexes.
Clinical and pathologic differences exist between the several neoplasms encompassed by the term malignant mixed tumors of salivary glands. The majority of the neoplasms are carcinomas ex pleomorphic adenoma. True malignant mixed tumors (carcinosarcomas) are rare, and even more rare are the benign metastasizing mixed tumors. This study of 40 malignant mixed tumors indicates that two previously unreported variables, measured invasion in millimeters and histologic subclassifications of the malignant neoplasm, are valuable guides to prognosis and biologic behavior. All patients whose malignant neoplasm extended for more than 8 mm beyond residual capsule or benign residual tumor died of their disease. The extent of invasion also correlated with perineurial invasion, involvement of bone, and metastases to lymph nodes. Histologic subclassification points out that there is no prototypical carcinoma ex pleomorphic adenoma and that high- and low-grade carcinomas can be found. Only one of the patients with low-grade (terminal duct) carcinomas died of his disease during follow-up periods extending to over 20 years.


Progress in TiO2 nanotube coatings for biomedical applications: a review.
Titanium dioxide nanotubes (TNTs) have drawn wide attention and been extensively applied in the field of biomedicine, due to their large specific surface area, good corrosion resistance, excellent biocompatibility, and enhanced bioactivity. This review describes the preparation of TNTs and the surface modification that entrust the nanotubes with better antibacterial property and enhanced osteoblast adhesion, proliferation, and differentiation. Considering the contact between TNTs' surface and surrounding tissues after implantation, the interactions between TNTs (with properties including their diameter, length, wettability, and crystalline phase) and proteins, platelets, bacteria, and cells are illustrated. The state of the art in the applications of TNTs in dentistry, orthopedic implants, and cardiovascular stents are introduced. In particular, the application of TNTs in biosensing has attracted much attention due to its ability for the rapid diagnosis of diseases. Finally, the difficulties and challenges in the practical application of TNTs are also discussed.


Diabetes: how to manage chronic kidney disease.
Chronic kidney disease (CKD) is a prevalent and progressive condition worldwide, and diabetes is a leading risk factor of this renal disorder. People with diabetes and CKD are at high risk of complications such as cardiovascular events and death. CKD is often unrecognized and undiagnosed amongst people with diabetes. To manage CKD, multiple existing and newer agents have been studied in trials and recommended in clinical practice guidelines. A narrative review of primary and/or secondary renal outcomes from randomized, controlled trials is summarized in this article. The main objective was to provide the most up-to-date information regarding existing and new pharmacotherapy for the management of CKD amongst people with diabetes, specifically type 2 diabetes (T2D). Traditional agents, such as angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, have been used for 20 years to preserve kidney function. Other existing agents have received approval by the FDA for the management of CKD such as dapagliflozin, with a role in reducing intraglomerular pressure. Evidence with sodium-glucose cotransporter 2 inhibitors show a potential class effect on improving renal outcomes, independent on their effect on glycaemic parameters. Recently, finerenone was approved for people with T2D and CKD based on clinical evidence as a non-steroidal mineralocorticoid receptor antagonist. Overall, primary and secondary prevention trials have influenced changes in clinical practice guidelines regarding the use of existing and new pharmacotherapy for CKD. Additional considerations include lifestyle modifications, blood pressure management and achievement of glycaemic targets for people with diabetes and CKD, following adequate screening of glomerular filtration rate and/or severity of albuminuria. Due to more robust evidence, clinical practice guidelines have been modified to reflect high-level recommendations for the management of CKD in people with diabetes, specifically T2D. Additional evidence is needed amongst people with lower glomerular filtration rates and in comparison with the standard of care.


Serum sialic acid changes in non-insulin-dependant diabetes mellitus (NIDDM) patients following bitter melon (Momordica charantia) and rosiglitazone (Avandia) treatment.
Diabetes mellitus is associated with an increase in sialic acid concentration along with other complications. Sialic acid changes in NIDDM patients were investigated following bitter melon (55 ml/24h) and rosiglitazone (4 mg/24h) treatment. A total of 25 patients of both sexes were used in each experimental group. Patients following bitter melon treatment showed no significant difference of serum sialic acid (57.95+/-4.90 vs. 57.6+/-5.56 mg/dl, p=0.17) and serum glucose concentration (93.7+/-9.63 vs. 88.35+/-6.31 mg/dl, p=0.78) as compared to control subjects. However, the concentration of total cholesterol was significantly high in these patients as compared to control subjects (192+/-14.23 vs. 170.6+/-15.1mg/dl, p<0.03) but within normal range (160-200mg/dl), suggesting the significant hypoglycemic and lipid-lowering properties of bitter melon. The patients following rosiglitazone treatment showed a significant increase of serum sialic acid concentration (60.2+/-5.80 vs. 57.6+/-5.56 mg/dl, p=0.01) along with glucose (112+/-6.2 vs. 88.35+/-6.31 mg/dl, p<0.04) and total cholesterol concentration (216.45+/-20.2 vs. 170.6+/-15.1mg/dl, p<0.01) as compared to control subjects. In addition six of the patients had retinopathy, two of whom were suffering also from myocardial infarction and they still had a higher serum sialic acid (61.05+/-1.20mg/dl), glucose (187+/-2.11 mg/dl), total cholesterol (239.10+/-5.04 mg/dl) and triglyceride (183+/-4.14 mg/dl) concentration, indicating a poor response of these patients to rosiglitazone. Comparison of serum sialic acid concentration of patients, following bitter melon and rosiglitazone treatment revealed no significant difference but the study showed that bitter melon could be more effective in the management of diabetes and its related complications as compared to rosiglitazone.


Benefits and Harms of Omalizumab Treatment in Adolescent and Adult Patients With Chronic Idiopathic (Spontaneous) Urticaria: A Meta-analysis of "Real-world" Evidence.
Omalizumab is indicated for the management of chronic idiopathic urticaria (CIU) (also known as chronic spontaneous urticaria) in adolescents and adults with persistent hives not controlled with antihistamines. The effectiveness of omalizumab in the real-world management of CIU is largely unknown. To quantitatively synthesize what is known about the benefits and harms of omalizumab in the real-world clinical management of CIU regarding urticaria activity, treatment response, and adverse events. Published observational studies (January 1, 2006, to January 1, 2018) and scientific abstracts on the effectiveness of omalizumab in CIU were identified using PubMed, Embase, Web of Science, and Cochrane search engines; references were searched to identify additional studies. Included studies were observational in design and included at least 1 outcome in common with other studies and at a concurrent time point of exposure to omalizumab. A total of 67 articles (35.2% of those screened) were included in the analysis. PRISMA and MOOSE guidelines were followed; independent selection and data extraction were completed by 2 observers. Random-effects meta-analyses were performed. Main outcomes were change in weekly Urticaria Activity Score (UAS7; range, 0-42), change in Urticaria Activity Score (UAS; range 0-6) (higher score indicating worse outcome in both scales), complete and partial response rates (percentages), and adverse event rate (percentage). Omalizumab therapy was associated with an improvement in UAS7 scores (-25.6 points, 95% CI, -28.2 to -23.0; P < .001; 15 studies, 294 patients), an improvement in UAS scores (-4.7 points, 95% CI, -5.0 to -4.4, P < .001; 10 studies, 1158 patients), an average complete response rate of 72.2% (95% CI, 66.1%-78.3%; P < .001; 45 studies, 1158 patients) with an additional average partial response rate of 17.8% (95% CI, 11.7%-23.9%; P < .001; 37 studies, 908 patients), and an average adverse event rate of 4.0% (95% CI, 1.0%-7.0%; P < .001; any level of severity, 47 studies, 1314 patients). Benefits and safety of omalizumab in the real-world treatment of CIU meet or exceed results gleaned from clinical trials. These real-world data on omalizumab in CIU may help inform both clinical treatment expectations and policy decision making.


Cross-border reproductive care in North America: a pilot study testing a prospective data collection program for in vitro fertilization clinics in Canada and the United States.
To develop and test a nonidentifying prospective data collection system for cross-border reproductive care (CBRC) in Canada and the United States (U.S.). Survey and cross-sectional study. Fertility clinics. Women traveling to and from Canada and the U.S. for reproductive care. None. Patients' home country, reason for crossing borders, and type of care received. Of 32 Canadian and 440 U.S. clinics contacted, seven and 46, respectively, responded to the initial questionnaire. Three out of seven Canadian and 44 out of 46 U.S. clinics reported providing CBRC. Seventy five percent agreed that nonidentifying data on country of origin and reason for travel should be collected. However, only one of seven Canadian and none of 46 U.S. clinics that expressed initial interest actually collected data, despite multiple communications. Although CBRC is a major component of assisted reproductive technology in North America (3%-10% of IVF cycles are provided to out-of-country patients in Canada and the U.S.), clinicians are not motivated to collect the simplest of data regarding CBRC patients. Despite this, reliable data are needed to help better understand the reasons for and impact of CBRC.


Interdisciplinary Relationship Models for Complementary and Integrative Health: Perspectives of Chinese Medicine Practitioners in the United States.
The combination of biomedicine and traditional and complementary medicine (T&CM) is often referred to as integrative medicine. However, the degree to which the medical disciplines are integrated varies between medical settings, and it is believed by some to be impossible due to epistemological and paradigmatic differences. Clinicians' perspectives are important determinants of how different medical disciplines are used together. This study explores the perspectives of experienced Chinese medicine practitioners when asked about the most ethical model (opposition, integration, or pluralism) for the relationship between biomedicine and T&CM. Thirty-one Chinese medicine practitioners, undertaking a doctoral upgrade program at the Pacific College of Oriental Medicine, participated in this study. Participants were asked to read a publication discussing three models (opposition, integration, and pluralism) for the relationship between biomedicine and T&CM and then discuss, via an online forum within Moodle learning management system, the most ethical model. An inductive content analysis of the forum posts was undertaken to identify common themes, followed by member checking. The data were found to contain six major and six minor themes. There was a clear preference for pluralism. The Chinese medicine practitioners expressed reservations about the integrative model, and, above all, cared about the quality of patient care. Much dialogue occurred around issues related to a power imbalance within health care, and possible cooptation issues. Paradigmatic differences and a lack of compatibility between biomedical research models and the practice of Chinese medicine were seen as problematic to the validity of research findings. Interprofessional education was viewed as critical for the development of respect, shared patient care, and referrals between clinicians from different disciplines. This study provides insight into the issues associated with combining biomedicine and T&CM that are perceived by Chinese medicine practitioners. Such insights are important for the development and management of clinical settings that provide complementary and integrative health care, especially as the provision of insurance coverage for T&CM increases.


Effect of prior cancer on outcomes in advanced lung cancer: implications for clinical trial eligibility and accrual.
Prior cancer is a common exclusion criterion in lung cancer trials. This practice reflects concerns that prior cancer may affect trial conduct or outcomes. However, the impact of prior cancer on survival in lung cancer is not known. We identified patients older than age 65 years with stage IV lung cancer diagnosed between 1992 and 2009 in the Surveillance, Epidemiology, and End Results-Medicare linked registry. Prior cancer was characterized by type, stage, and timing. All-cause and lung cancer-specific survival were compared between patients with and without prior cancer using propensity score-adjusted Cox regression. Overall, 102 929 patients with stage IV lung cancer were identified, of whom 14.7% had a history of prior cancer. More than two-thirds (76.0%) of prior cancers were localized or regional stage; most were diagnosed five or fewer years prior to the lung cancer diagnosis. In propensity score-adjusted analysis, patients with prior cancer had better all-cause (hazard ratio [HR] = 0.93, 95% confidence interval [CI] = 0.91 to 0.94) and lung cancer-specific (HR = 0.81, 95% CI = 0.79 to 0.82) survival. In a simulated clinical trial-eligible population (age <75 years, no comorbidity, treated with chemotherapy), similar trends were noted. In subset analyses according to stage, type, and timing of prior cancer, no group of patients with prior cancer had inferior survival compared with patients without prior cancer. Among patients with stage IV lung cancer, prior cancer does not convey an adverse effect on clinical outcomes, regardless of prior cancer stage, type, or timing. Broader inclusion in clinical trials of advanced lung cancer patients with a history of prior cancer should be considered.


Chirped-quasi-periodic structure for quasi-phase-matching.
We propose in this paper a chirped-quasi-periodic structure using the projection method. This type of new structure combines the advantages of chirped and quasi-periodic structures, and can be used for both multiple quasi-phase-matching and multiple bandwidths control. Numerical simulation of second-harmonic generation performance is in good agreement with the Fourier spectrum of the structure.


Comparative assessment of treatment efficacy and adverse effects during nonextraction orthodontic treatment of Class I malocclusion patients with direct and indirect bonding: A parallel randomized clinical trial.
The objective of this 2-arm parallel trial was to compare the effects of direct and indirect bonding techniques on the orthodontic treatment process and outcomes. Thirty patients were randomly assigned to undergo bonding of brackets indirectly (group A, n = 15) or directly (group B, n = 15). Eligibility criteria included permanent dentition with bilateral Angle Class I molar and canine relationships, no previous orthodontic treatment, no skeletal discrepancy, and mild or moderate crowding. The main outcome was the orthodontic treatment results assessed using the American Board of Orthodontics Objective Grading System; the secondary outcomes were times taken to perform the laboratory and clinical steps, total treatment duration, plaque accumulation, formation of white spot lesions, bond failures, and need for additional archwire bending and bracket repositioning. The randomization sequence was created using an online randomization software. The patients were allocated with a 1:1 ratio using a block size of 4. The sequence generator was contacted by phone for group assignment after a patient was enrolled for allocation concealment. Blinding was implemented during the dental cast and radiographic evaluations, data entry, and data analysis. Patients were evaluated before treatment, and 1, 2, and 6 months after the start of treatment, and at the end of treatment. All patients completed the study and were analyzed. There were no dropouts. Marginal ridge (median difference, -1.000; 95% confidence interval [CI], -2.99 to -0.001; P = 0.03) and total Objective Grading System scores (median difference, -3.999; 95% CI, -6.000 to -0.005; P = 0.03) were significantly higher in group B than in group A; other Objective Grading System categories did not differ significantly between the groups. The clinical time was significantly longer in group B than in group A (mean difference, -26.51; 95% CI, -29.57 to -23.46; P <0.001), and the total time was significantly longer in group A than in group B (mean difference, 19.03; 95% CI, 15.32 to 22.74; P <0.001). There were no significant between-group differences in treatment duration, plaque accumulation, formation of white spot lesions, bond failure, or need for additional archwire bending or bracket repositioning. No harms were encountered. Indirect bonding was significantly faster than direct bonding in the clinical stage and yielded better marginal ridge and total scores. Both techniques showed similar rates of plaque accumulation, formation of white spot lesions, bond failure, and additional archwire bending and bracket repositioning. The trial was not registered. The protocol was not published before trial commencement.


Activation of peripheral nerve fibers by electrical stimulation in the sole of the foot.
Human nociceptive withdrawal reflexes (NWR) can be evoked by electrical stimulation applied to the sole of the foot. However, elicitation of NWRs is highly site dependent, and NWRs are especially difficult to elicit at the heel. The aim of the present study was to investigate potential peripheral mechanisms for any site dependent differences in reflex thresholds. The first part of the study investigated the neural innervation in different sites of the sole of the foot using two different staining techniques. 1) Staining for the Nav1.7 antigen (small nociceptive fibers) and 2) the Sihler whole nerve technique (myelinated part of the nerve). No differences in innervation densities were found across the sole of the foot using the two staining techniques: Nav1.7 immunochemistry (small nociceptive fibers (1-way ANOVA, NS)) and the Sihler's method (myelinated nerve fibers (1-way ANOVA, NS)). However, the results indicate that there are no nociceptive intraepidermal nerve fibers (IENFs) innervating the heel.Secondly, mathematical modeling was used to investigate to what degree differences in skin thicknesses affect the activation thresholds of Aδ and Aβ fibers in the sole of the foot. The modeling comprised finite element analysis of the volume conduction combined with a passive model of the activation of branching cutaneous nerve fibers. The model included three different sites in the sole of the foot (forefoot, arch and heel) and three different electrode sizes (diameters: 9.1, 12.9, and 18.3 mm). For each of the 9 combinations of site and electrode size, a total of 3000 Aβ fibers and 300 Aδ fibers was modeled. The computer simulation of the effects of skin thicknesses and innervation densities on thresholds of modeled Aδ and Aβ fibers did not reveal differences in pain and perception thresholds across the foot sole as have been observed experimentally. Instead a lack of IENFs at the heel decreased the electrical activation thresholds compared to models including IENFs. The nerve staining and modeling results do not explain differences in NWR thresholds across the sole of the foot which may suggest that central mechanisms contribute to variation in NWR excitability across the sole of the foot.


Cytokine levels at a single time point following a reminder stimulus among women in abusive dating relationships: Relationship to emotional states.
Stressful events and reminders of such events may influence circulating cytokine levels, just as they influence several neuroendocrine processes. However, these cytokine changes may vary with the severity and chronicity of the stressor experienced, as well as the specific mood responses that participants express. In the present investigation, women in abusive or non-abusive dating relationship (N=75) read a script about an abusive or non-abusive relationship and then reported their mood states, followed by the collection of a single blood sample 30 min later. The abused women who read the abuse-related script reported greater anger, sadness, shame, and anxiety than did the non-abused women. In non-abused women greater levels of anger and sadness, but not shame or anxiety, were associated with higher levels of the proinflammatory cytokine, interleukin-6 (IL-6), as well as the anti-inflammatory cytokine, IL-10, irrespective of whether they had read a script regarding an abusive relationship or a neutral script. In contrast, among abused women shown a neutral script, neither IL-6 nor IL-10 levels were related to their anger and sadness, whereas mood levels following the reading of a script regarding abuse were directly related to IL-6, although the extent of the association was lower than that evident in non-abused women. Levels of IL-10 in the abused women, unlike their non-abused counterparts, did not vary with mood state. These data suggest that cytokine levels and the relative balance of IL-6 and IL-10 ordinarily are associated with specific moods, but this relationship is not apparent among women in a chronic stress state.


Re-evaluation of characters in Apolemiidae (Siphonophora), with description of two new species from Monterey Bay, California.
Siphonophores are polymorphic planktonic marine Cnidarians. The family Apolemiidae is sister to all other species of physonect and calycophoran siphonophores. Although this enigmatic group arguably includes the longest animal species on the planet, their colony-level organization and growth patterns are not well understood. Here we describe two new apolemiid species: Apolemia lanosa sp. nov. and A. rubriversa sp. nov. We provide detailed descriptions of zooid budding and the organization of mature zooids within the siphosome. Our findings reveal that at least two distinct general patterns of siphosomal organization are found in different Apolemia species. In the first pattern, dispersed organization, zooids independently attach directly to the siphosomal stem. In the second pattern, pedunculate organization, only the gastrozooid is attached directly to the stem, and the other zooids of the cormidium branch from its peduncle. This diversity within Apolemia indicates that fundamental aspects of zooid budding and organization are homoplastic within Siphonophora, as both patterns are also found in other siphonophores. The observations presented here greatly clarify the interpretation of diagnostic characters within Apolemiidae, bear on the status of the three previously described species, provide critical detail for understanding the diversity of colony-level organization in siphonophores, and establish a foundation for the description of additional apolemiid species.


Percutaneous treatment of herniated lumbar disc by intradiscal oxygen-ozone injection.
We report our experience of treating lumbar herniated disc by intradiscal injection of an oxygen-ozone mixture. Ozone (03, MW = 48) is a triatomic molecule, having antiviral, disinfectant and antiseptic properties. Several mechanisms of action have been proposed to explain the efficacy of the treatment: 1) analgesic action; 2) anti-inflammatory action; 3) oxidant action on the proteoglycan in the nucleus pulposus. We treated 93 patients (50 women, 43 men) aged from 24 to 45 yrs (average age 38 yrs) from June 1996 to April 1998. All patients presented sciatica and/or low back pain, lasting two or more months; patients had in the mean time received both medical and physical therapy with mild or no benefit. Diagnostic tests in all patients included plain film x-ray, CT and/or MR at the level of the lumbar spine disclasing a herniated or protruded disc with nerve root or thecal sac compression. We divided patients to be treated in to two groups: the first one group included 35 patients already selected for surgery who presented herniated or protruded disc with radicular pain with associated neurological deficit (hypoesthesia and partial loss of reflex). Those patients had already had medical and physical therapy for two or more months and agreed to try the percutaneous treatment before surgery. CT or MR in this group demonstrated the presence of intraforaminal, extra or sub-ligamentary and sequestrated herniated disc. The second group included 58 patients with radicular pain but without neurological deficit; patients in this group had received medical and/or physical therapy for two or more months and CT showed the presence of a small subligamentary herniated or protruded disc. We considered the results according to the modified MacNab method. In the first group we had "failure" in all patients; in seven cases the symptoms improved for one month, but recurred later on. In the second group 45 patients had "success" showing complete clinical recovery within five to six days after treatment, all remained without symptoms up to six months or more of follow-up. The remaining 13 patients presented the same symptoms again within three months after a temporary clinical recovery. The goal of this study was to present this new technique that can also be compared with a previous study of different percutaneous treatment. Clinical and neuroradiological indications and the contraindications are well known, and must be followed to achieve good results and avoid complications.