Methylation-specific PCR allows for fast diagnosis of X chromosome disomy and reveals skewed inactivation of the X chromosome in men with Klinefelter syndrome.
Klinefelter syndrome (KS) remains the most common, yet often undiagnosed, chromosomal aberration in men. Early diagnosis and treatment can improve the health of patients with KS. The aim of this study was to evaluate the inactivation pattern of supernumerary X chromosomes. The secondary aim was to design a reliable and cost-effective molecular test for detection of X chromosome disomy. Methylation-specific polymerase chain reaction (M-PCR), with primers for familial mental retardation (FMR1) and X chromosome inactive-specific transcript (XIST) genes, was used to detect the presence of X chromosome disomy in men. Seventeen fertile males, 12 females, and 35 males with KS (28 with 47,XXY karyotype, and 7 with 47,XXY/46,XY mosaics) were included in the study. Results of the karyotype were compared with the results of semiquantitative M-PCR. Inactivation of X chromosomes was measured by XIST/FMR-1 methylation ratio. Differences in the methylation patterns of FMR1 and XIST genes between 46,XY men and men with X chromosome disomy allowed for rapid detection of the presence of an additional X chromosome, achieving 100% sensitivity and specificity using M-PCR. The methylated:unmethylated FMR1 amplicon ratio allowed the detection of 1 additional X chromosome per 100 normal XY cells (1% of XX/XY mosaicism). In our series, 50% of 47,XXY men showed skewed inactivation of the X chromosome. Men with KS can have incomplete inactivation of supernumerary X chromosomes. M-PCR is a sensitive, specific, fast, and relatively inexpensive test for the diagnosis of X chromosome disomy.


Computer-assisted correlation of structure and biological activity in a set of retinoids.
A computer-assisted pattern-recognition system (ADAPT) designed to elucidate structure-activity relationships was applied to a set of retinoids, potentially useful inhibitors of carcinogenesis. A data set of 67 retinoids was used as input to the ADAPT system; their structures were entered, and their 3-dimensional configurations were optimized by a molecular modelling algorithm. Forty of these retinoids were defined as the "more active" class based upon their ability to reverse keratinization in vitamin A-deficient hamster tracheal organ cultures at 10(-10) M or less. The remaining 27 retinoids were defined as the "less active" class due to their lack of ability to elicit this effect at 10(-8) M or more. Thirteen descriptors were generated by ADAPT for each of these retinoids based upon their structures, including: number of ring atoms; double bonds; del Ré sigma charges; and principal moments. Pattern recognition analysis techniques were applied to this data set to determine if information contained in these descriptors could generate a discriminant function equation which could separate more active from less active retinoids, successfully. Computer recognition of more active from less active retinoids was demonstrated by a number of pattern recognition techniques, and the discriminant function could predict correctly the relative activity of retinoids of "unknown" activity in 87% of trials. These results indicate the existence of distinct structure-activity relationships in this set of biologically important molecules.


Acupuncture in poststroke rehabilitation: a systematic review and meta-analysis of randomized trials.
Acupuncture is a low-risk treatment with purported claims of effectiveness for poststroke rehabilitation. To comprehensively assess the efficacy of acupuncture in poststroke rehabilitation, we conducted a systematic review and meta-analysis of all randomized clinical trials of acupuncture for poststroke rehabilitation. We searched 7 English and 2 Chinese databases from inception to September 2009. Eligible studies included randomized clinical trials that evaluated the clinical efficacy of acupuncture in adult patients with disability after stroke. We extracted data on trial quality, protocol, and outcomes assessed. A summary OR was calculated based on pooled dichotomous results. I(2) was used to infer heterogeneity and we conducted metaregression to determine if specific covariates explained heterogeneity. Thirty-five articles written in Chinese and 21 articles written in English were included. The overall quality of the studies was "fair" and most studies were small (median n=86; range, 16 to 241). The majority (80%) of the studies reported a significant benefit from acupuncture; however, there was some evidence of publication bias. In 38 trials, data were available for meta-analysis and metaregression, yielding an OR in favor of acupuncture compared with controls (OR=4.33, 95% CI: 3.09 to 6.08; I2=72.4%). Randomization, modes of delivery, method of control, study source country, and reporting of randomization may explain some of the heterogeneity observed between the studies. Randomized clinical trials demonstrate that acupuncture may be effective in the treatment of poststroke rehabilitation. Poor study quality and the possibility of publication bias hinder the strength of this recommendation and argue for a large, transparent, well-conducted randomized clinical trial to support this claim and implement changes to clinical practice.


Dynamin forms a Src kinase-sensitive complex with Cbl and regulates podosomes and osteoclast activity.
Podosomes are highly dynamic actin-containing adhesion structures found in osteoclasts, macrophages, and Rous sarcoma virus (RSV)-transformed fibroblasts. After integrin engagement, Pyk2 recruits Src and the adaptor protein Cbl, forming a molecular signaling complex that is critical for cell migration, and deletion of any molecule in this complex disrupts podosome ring formation and/or decreases osteoclast migration. Dynamin, a GTPase essential for endocytosis, is also involved in actin cytoskeleton remodeling and is localized to podosomes where it has a role in actin turnover. We found that dynamin colocalizes with Cbl in the actin-rich podosome belt of osteoclasts and that dynamin forms a complex with Cbl in osteoclasts and when overexpressed in 293VnR or SYF cells. The association of dynamin with Cbl in osteoclasts was decreased by Src tyrosine kinase activity and we found that destabilization of the dynamin-Cbl complex involves the recruitment of Src through the proline-rich domain of Cbl. Overexpression of dynamin increased osteoclast bone resorbing activity and migration, whereas overexpression of dynK44A decreased osteoclast resorption and migration. These studies suggest that dynamin, Cbl, and Src coordinately participate in signaling complexes that are important in the assembly and remodeling of the actin cytoskeleton, leading to changes in osteoclast adhesion, migration, and resorption.


Structural and Spectroscopic Properties of Assemblies of Self-Replicating Peptide Macrocycles.
Self-replication at the molecular level is often seen as essential to the early origins of life. Recently a mechanism of self-replication has been discovered in which replicator self-assembly drives the process. We have studied one of the examples of such self-assembling self-replicating molecules to a high level of structural detail using a combination of computational and spectroscopic techniques. Molecular Dynamics simulations of self-assembled stacks of peptide-derived replicators provide insights into the structural characteristics of the system and serve as the basis for semiempirical calculations of the UV-vis, circular dichroism (CD) and infrared (IR) absorption spectra that reflect the chiral organization and peptide secondary structure of the stacks. Two proposed structural models are tested by comparing calculated spectra to experimental data from electron microscopy, CD and IR spectroscopy, resulting in a better insight into the specific supramolecular interactions that lead to self-replication. Specifically, we find a cooperative self-assembly process in which β-sheet formation leads to well-organized structures, while also the aromatic core of the macrocycles plays an important role in the stability of the resulting fibers.


High efficiency of a new immunological magnetic cell sorting method for T cell depletion of human bone marrow.
Fresh human bone marrow (BM) mononuclear cells containing a mean of 11% T cells underwent T cell depletion utilizing a newly developed magnetic cell sorter. In order to remove T cells, 10(8) cells were labeled with either a specific CD3 monoclonal antibody or a cocktail of monoclonal CD2 + CD5 + CD7 antibodies and biotin-conjugated magnetic microparticles (size 100-150 nm) employing a streptavidin-FITC complex. Labeled cells were removed by using columns filled with a ferromagnetic matrix and placed within a recess in a strong permanent magnet. Recovery of non-T cells was 79% after the first passage and 61% after the second. The absolute recovery of BFU-E and CFU-GM was 70% and 51% respectively (n = 11). Limiting dilution analysis revealed less than 0.1% residual clonable BM T cells (cloning efficiency greater than 50%) which corresponds to a 2.1 (1st passage) and to a 2.3 (2nd passage) log depletion. This new separating system is a highly efficient, reproducible, and quick method of depleting T cells from human BM. It could be easily adapted to process large scale marrow specimens or for the elimination of residual tumor cells from BM in autologous transplantation.


[The role of cytokines in restenosing coronary stents and the efficiency of its secondary prophylaxis with statins].
This study was designed to assess the diagnostic value of dynamic patterns of anti-inflammatory cytokines (IL-1b, IL-6, TNF-alpha) in patients with ischemic heart disease (IHD) and restenosis of coronary stents 14 months after their implantation for long-term prophylaxis of dyslipoproteinemia. A total of 40 patients with IHD of advanced functional classes (FC) were examined. Blood cytokine levels were measured before, 1 day, and 12-18 months after coronary stenting. Two groups of 23 and 17 patients included cases with recurrent angina and without it respectively. The main parameters measured in the study were in-stent restenosis rate, incidence of' acute myocardial infarction (AMI), mortality rate, frequency of hospitalization for unstable angina, and the levels of proinflammatory cytokines. Considerable activation of cytokines in patients with post-infarction cardiac dysfunction who rarely resorted to therapy with statins (16.7%) was associated with the high rate of recurrent coronary insufficiency related to in-stent occlusion (8.7%), progressive atherosclerosis (65.2%), impaired myocardial perfusion, and restenosis of coronary stents (26.1%). Patients lacking apparent expression of serum cytokines after revascularization while receiving efficacious secondary prophylaxis of dyslipidemia (13.8 and 17% decrease of triglycerides (TG) and low density lipoproteins (LDL) cholesterol respectively, p = 0.04) had left ventricular ejection fraction (LVEF) improved by 12.5% (p = 0.03%), left ventricular end diastolic pressure (LVEDP) decreased by 15.8% (p = 0.03), and frequency of ischemic perfusion defect (PD) reduced by 45.3% (p = 0.01). Moreover, they showed low incidence of progressive coronary atherosclerosis (17.6%) in the absence of in-stent restenosis. It is concluded that the frequency of restenosis of coronary stents after endovascular myocardial revascularization depends on the preprocedural rise in IL-1b content (R = 0.62, p = 0.0023). It is concluded that long-term secondary prophylaxis of dyslipoproteinemia in patients with ischemic dysfunction at risk of coronary restenosis effectively (more than thrice) decreases the occurrence of coronary stent restenosis after endovascular revasularization.


Multi-stage decomposition of 5-aminotetrazole derivatives: kinetics and reaction channels for the rate-limiting steps.
The thermal behavior, decomposition kinetics and mechanisms of 1-amino-1-(tetrazol-5-yldiazenyl) guanidine (tetrazene) and 2-(tetrazol-5-yldiazenyl) guanidine (MTX-1) have been investigated using DSC, TG techniques, and quantum chemical calculations. It has been found that MTX-1 is much more stable than tetrazene and MTX-1, and both of them decompose in three steps with different kinetic parameters. Tetrazene is melted-dehydrated at 128.4 °C with a heat absorption of 50 J g(-1) and then it starts to decompose at around 118.6 °C with a peak temperature of 126.3 °C covered by a heat release of 1037 J g(-1) at a heating rate of 1.0 °C min(-1), while MTX-1 starts at 167.7 °C with a main peak of 191.1 °C covered by a heat change of 1829 J g(-1) under the same conditions. The activation energy is almost the same for their first decomposition steps (225 kJ mol(-1)), which are controlled by a three dimensional nucleation and growth model (A3). The mechanisms of the rate-limiting steps are supported by quantum chemical calculations. They could undergo a similar rate-limiting chemical process producing 1H-tetrazole and N2 for both cases, while the former also produces aminocyanamide and the latter produces cyanamide.


Relationships between immune gene expression and circulating cytokine levels in wild house mice.
Quantitative PCR (qPCR) has been commonly used to measure gene expression in a number of research contexts, but the measured RNA concentrations do not always represent the concentrations of active proteins which they encode. This can be due to transcriptional regulation or post-translational modifications, or localization of immune environments, as can occur during infection. However, in studies using free-living non-model species, such as in ecoimmunological research, qPCR may be the only available option to measure a parameter of interest, and so understanding the quantitative link between gene expression and associated effector protein levels is vital.Here, we use qPCR to measure concentrations of RNA from mesenteric lymph node (MLN) and spleen tissue, and multiplex ELISA of blood serum to measure circulating cytokine concentrations in a wild population of a model species, Mus musculus domesticus.Few significant correlations were found between gene expression levels and circulating cytokines of the same immune genes or proteins, or related functional groups. Where significant correlations were observed, these were most frequently within the measured tissue (i.e., the expression levels of genes measured from spleen tissue were more likely to correlate with each other rather than with genes measured from MLN tissue, or with cytokine concentrations measured from blood).Potential reasons for discrepancies between measures including differences in decay rates and transcriptional regulation networks are discussed. We highlight the relative usefulness of different measures under different research questions and consider what might be inferred from immune assays.


Evaluation of protein supplementation for growing cattle fed grass silage-based diets: a meta-analysis.
The objective of this meta-analysis was to develop empirical equations predicting growth responses of growing cattle to protein intake. Overall, the data set comprised 199 diets in 80 studies. The diets were mainly based on grass silage or grass silage partly or completely replaced by whole-crop silages or straw. The concentrate feeds consisted of cereal grains, fibrous by-products and protein supplements. The analyses were conducted both comprehensively for all studies and also separately for studies in which soybean meal (SBM; n=71 diets/28 studies), fish meal (FM; 27/12) and rapeseed meal (RSM; 74/35) were used as a protein supplement. Increasing dietary CP concentration increased (P<0.01) BW gain (BWG), but the responses were quantitatively small (1.4 g per 1 g/kg dry matter (DM) increase in dietary CP concentration). The BWG responses were not different for bulls v. steers and heifers (1.4 v. 1.3 g per 1 g/kg DM increase in dietary CP concentration) and for dairy v. beef breeds (1.2 v. 1.7 g per 1 g/kg, respectively). The effect of increased CP concentration declined (P<0.01) with increasing mean BW of the animals and with improved BWG of the control animals (the lowest CP diet in each study). The BWG responses to protein supplementation were not related to the CP concentration in the control diet. The BWG responses increased (P<0.05) with increased ammonia N concentration in silage N and declined marginally (P>0.10) with increasing proportion of concentrate in the diet. All protein supplements had a significant effect on BWG, but the effects were greater for RSM (P<0.01) and FM (P<0.05) than for SBM. Increasing dietary CP concentration improved (P<0.01) feed efficiency when expressed as BWG/kg DM intake, but decreased markedly when expressed as BWG/kg CP intake. Assuming CP concentration of 170 g/kg BW marginal efficiency of the utilisation of incremental CP intake was only 0.05. Increasing dietary CP concentration had no effects on carcass weight, dressing proportion or conformation score, but it increased (P<0.01) fat score. Owing to limited production responses, higher prices of protein supplements compared with cereal grains and possible increases the N and P emissions, there is generally no benefit from using protein supplementation for growing cattle fed grass silage-based diets, provided that the supply of rumen-degradable protein is not limiting digestion in the rumen.


The Structure-Specific Endonucleases MUS81 and SEND1 Are Essential for Telomere Stability in Arabidopsis.
Structure-specific endonucleases act to repair potentially toxic structures produced by recombination and DNA replication, ensuring proper segregation of the genetic material to daughter cells during mitosis and meiosis. Arabidopsis thaliana has two putative homologs of the resolvase (structure-specific endonuclease): GEN1/Yen1. Knockout of resolvase genes GEN1 and SEND1, individually or together, has no detectable effect on growth, fertility, or sensitivity to DNA damage. However, combined absence of the endonucleases MUS81 and SEND1 results in severe developmental defects, spontaneous cell death, and genome instability. A similar effect is not seen in mus81 gen1 plants, which develop normally and are fertile. Absence of RAD51 does not rescue mus81 send1, pointing to roles of these proteins in DNA replication rather than DNA break repair. The enrichment of S-phase histone γ-H2AX foci and a striking loss of telomeric DNA in mus81 send1 further support this interpretation. SEND1 has at most a minor role in resolution of the Holliday junction but acts as an essential backup to MUS81 for resolution of toxic replication structures to ensure genome stability and to maintain telomere integrity.


Climate readiness of recovery plans for threatened Australian species.
The rapidly changing climate is posing growing threats for all species, but particularly for those already considered threatened. We reviewed 100 recovery plans for Australian terrestrial threatened species (50 fauna and 50 flora plans) written from 1997 to 2017. We recorded the number of plans that acknowledged climate change as a threat and of these how many proposed specific actions to ameliorate the threat. We classified these actions along a continuum from passive or incremental to active or interventionist. Overall, just under 60% of the sampled recovery plans listed climate change as a current or potential threat to the threatened taxa, and the likelihood of this acknowledgment increased over time. A far smaller proportion of the plans, however, identified specific actions associated with ameliorating climate risk (22%) and even fewer (9%) recommended any interventionist action in response to a climate-change-associated threat. Our results point to a disconnect between the knowledge generated on climate-change-related risk and potential adaptation strategies and the extent to which this knowledge has been incorporated into an important instrument of conservation action.


The genetic and environmental contributions to variation in the permanent dental arch form: a twin study.
The objective of this study was to examine the relative contributions of genetic and environmental influences on variation in dental arch form in individuals who have largely completed their craniofacial growth. The subjects of this study comprised dental casts of 50 monozygotic twins and 24 dizygotic twins from the collection of records of twins housed at the Adelaide Dental School, Australia. The subjects were of Western European descent, with an average age of 20.93 ± 5.58 years. Dental casts were scanned using a 3D scanner to analyse the dental arch form. Landmark-based inter-arch and intra-arch measurements were performed. Structural equation modelling was employed to analyse the quantitative data using the normal assumptions of the twin model. Genetic modelling revealed that additive genetic and unique environmental factors best explained the observed variation for all occlusal traits measured, except for mandibular intercanine width. High heritability was observed for most intra-arch occlusal variables (0.61-0.85) including the maxillary and mandibular intercanine and intermolar widths, arch depth and perimeter. In contrast, moderate heritability was found for inter-arch occlusal variables (0.52-0.59) such as overjet and overbite. Sexual dimorphism was evident, with males displaying larger posterior arch width than females (P < 0.05). Our sample was limited to individuals of Western European ancestry. The predominant source of occlusal variation within this group of Australian twins of Western European descent was controlled by genetic effects, and most were highly heritable. Generally, intra-arch occlusal variables showed greater heritability compared with inter-arch occlusal variables.


[Significance of lung function study in clinical monitoring of patients with mucoviscidosis].
Lung function tests as tools in the lifelong care of patients with cystic fibrosis can help to assess results of different therapeutic regimes and the prognosis, as there is a typical sequence of alterations of lung function parameters. They allow to assess the degree of disablement more precisely and more adequately than do clinical data; this is of special concern in questions related to social rehabilitation and the finding of an adequate job. Appropriate parameters are forced vital capacity, maximal mid-exspiratory flow, residual volume and partial pressure of oxygen and carbon dioxide in arterial blood.


A comparison of Espocan and Tuohy needles for the combined spinal-epidural technique for labor analgesia.
When using the needle-through-needle combined spinal-epidural (CSE) technique for labor analgesia, failure to obtain cerebrospinal fluid (CSF), paresthesias, and intrathecal or intravascular migration of the catheter are of concern. Epidural needles with spinal needle apertures, such as the back-hole Espocan (ES) needles, are available and may reduce these risks. We describe the efficacy and adverse events associated with a modified epidural needle (ES) versus a conventional Tuohy needle for CSE. One-hundred parturients requesting labor analgesia (CSE) were randomized into 2 groups: 50-ES 18-gauge modified epidural needle with 27-gauge Pencan atraumatic spinal needle, 50-conventional 18-gauge Tuohy needle with 27-gauge Gertie Marx atraumatic spinal needle. Information on intrathecal or intravascular catheter placement, paresthesia on introduction of spinal needle, failure to obtain CSF through the spinal needle after placement of epidural needle, unintentional dural puncture, and epidural catheter function was obtained. No intrathecal catheter placement occurred in either group. Rates of intravascular catheter placement and unintentional dural puncture were similar between the groups. Significant differences were noted regarding spinal needle-induced paresthesia (14% ES versus 42% Tuohy needles, P = 0.009) and failure to obtain CSF on first attempt (8% ES versus 28% Tuohy needles, P < 0.02). Use of ES needles for CSE significantly reduces paresthesia associated with the insertion of the spinal needle and is associated with more frequent successful spinal needle placement on the first attempt. The use of modified epidural needles with a back hole for combined spinal-epidural technique significantly reduces paresthesia associated with the insertion of the spinal needle and is associated with more frequent successful spinal needle placement on the first attempt.


Osteoid osteoma of the calcaneus misdiagnosed as subtalar sprain.
Osteoid osteoma of foot and ankle account for ten percent of benign bone tumors and commonly involve the talus and metatarsals. Its occurrence in calcaneus is extremely rare and can mimic ankle instability, subtalar arthritis, osteochondritis or plantar fasciitis leading to delay in diagnosis. We present the case of a 17 year old boy with periarticular osteoid osteoma in the calcaneum, who presented following an ankle sprain. He was successfully treated with CT guided percutaneous radiofrequency ablation and we feel that it is a safe, precise and effective treatment option for even periarticular osteoid osteoma in the foot and ankle region.


[Preoperative revascularization in high-risk patients undergoing vascular surgery].
Patients undergoing vascular surgery are at increased risk for cardiac complications related to the presence of underlying coronary artery disease. Preoperative cardiac evaluation may help to identify high-risk patients in whom coronary angiography may be planned with subsequent coronary revascularization for the purpose of improving perioperative and long-term cardiac outcomes. However, the indications and efficacy for type of revascularization for the reduction of cardiac complications compared to medical therapy have been controversial. The aim of the review was to summarize the role of preoperative revascularization compared to conservative medical therapy before elective vascular surgery using current evidence from published studies.


Tracking acquired antibiotic resistance in commensal bacteria of Galápagos land iguanas: no man, no resistance.
Antibiotic resistance, evolving and spreading among bacterial pathogens, poses a serious threat to human health. Antibiotic use for clinical, veterinary and agricultural practices provides the major selective pressure for emergence and persistence of acquired resistance determinants. However, resistance has also been found in the absence of antibiotic exposure, such as in bacteria from wildlife, raising a question about the mechanisms of emergence and persistence of resistant strains under similar conditions, and the implications for resistance control strategies. Since previous studies yielded some contrasting results, possibly due to differences in the ecological landscapes of the studied wildlife, we further investigated this issue in wildlife from a remote setting of the Galapagos archipelago. Screening for acquired antibiotic resistance was carried out in commensal enterobacteria from Conolophus pallidus, the terrestrial iguana of Isla Santa Fe, where: i) the abiotic conditions ensure to microbes good survival possibilities in the environment; ii) the animal density and their habits favour microbial circulation between individuals; and iii) there is no history of antibiotic exposure and the impact of humans and introduced animal species is minimal except for restricted areas. Results revealed that acquired antibiotic resistance traits were exceedingly rare among bacteria, occurring only as non-dominant strains from an area of minor human impact. Where both the exposure to antibiotics and the anthropic pressure are minimal, acquired antibiotic resistance traits are not normally found in bacteria from wildlife, even if the ecological landscape is highly favourable to bacterial circulation among animals. Monitoring antibiotic resistance in wildlife from remote areas could also be a useful tool to evaluate the impact of anthropic pressure.


Visualizing of skin chromophore concentrations by use of RGB images.
A method is proposed for visualizing simply the concentrations of melanin, oxygenated blood, and deoxygenated blood in skin tissue using digital RGB images. The total blood concentration and oxygen saturation can also be reconstructed. Monte Carlo simulation of light transport specifies a relation between the chromophore concentrations and Commission Internationale de l'Eclairage XYZ, which are compatible with the common RGB working space. Experiments with a tissuelike agar gel phantom demonstrated the possibility of the method. In vivo imaging of a human hand during forearm occlusion demonstrated the ability of the method to evaluate hemodynamics of skin tissue.


Interaction between the promoter MUC5B polymorphism and mucin expression: is there a difference according to ILD subtype?
The MUC5B promoter variant rs35705950 is associated with idiopathic pulmonary fibrosis (IPF). MUC5B glycoprotein is overexpressed in IPF lungs. We examined immunohistochemical expression of MUC5B in different interstitial lung disease patterns according to rs35705950 T-allele carriage. We observed increased expression of MUC5B in T-allele carriers in both distal airways and honeycomb cysts in patients with IPF (n=23), but no difference in MUC5B expression according to T-carrier status in the distal airways of patients with idiopathic non-specific interstitial pneumonitis (n=17), in scleroderma-associated non-specific interstitial pneumonitis (n=15) or in control lungs (n=20), suggesting that tissue overexpression in MUC5B rs35705950 T-carriers is specific to IPF.


Sexual victimization, health status, and VA healthcare utilization among lesbian and bisexual OEF/OIF veterans.
Many lesbian and bisexual (LB) women veterans may have been targets of victimization in the military based on their gender and presumed sexual orientation, and yet little is known regarding the health or mental health of LB veterans, nor the degree to which they feel comfortable receiving care in the VA. The purpose of this study was to examine the prevalence of mental health and gender-specific conditions, VA healthcare satisfaction and trauma exposure among LB veterans receiving VA care compared with heterosexually-identified women veterans receiving. Prospective cohort study of Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) women veterans at two large VA facilities. Three hundred and sixty five women veterans that completed a baseline survey. Thirty-five veterans (9.6 %) identified as gay or lesbian (4.7 %), or bisexual (4.9 %). Measures included sexual orientation, military sexual trauma, mental and gender-specific health diagnoses, and VA healthcare utilization and satisfaction. LB OEF/OIF veterans were significantly more likely to have experienced both military and childhood sexual trauma than heterosexual women (MST: 31 % vs. 13 %, p < .001; childhood sexual trauma: 60 % vs. 36 %, p = .01), to be hazardous drinkers (32 % vs. 16 %, p = .03) and rate their current mental health as worse than before deployment (35 % vs. 16 %, p < .001). Many LB veterans have experienced sexual victimization, both within the military and as children, and struggle with substance abuse and poor mental health. Health care providers working with female Veterans should be aware of high rates of military sexual trauma and childhood abuse and refer women to appropriate VA treatment and support groups for sequelae of these experiences. Future research should focus on expanding this study to include a larger and more diverse sample of lesbian, gay, bisexual, and transgender veterans receiving care at VA facilities across the country.


Optimizing fluorophore density for single virus counting: a photophysical approach.
In health and environmental research, it is often necessary to quantify the concentrations of single (bio) nanoparticles present at very low concentrations. Suitable quantification approaches that rely on counting and tracking of single fluorescently labelled (bio) nanoparticles are often challenging since fluorophore self-quenching limits the maximum particle brightness. Here we study how the number of labels per nanoparticle influences the total brightness of fluorescently labelled cowpea chlorotic mottle virus (CCMV). We analyze in detail the photophysical interplay between the fluorophores on the virus particles. We deduce that the formation of dark aggregates and energy transfer towards these aggregates limits the total particle brightness that can be achieved. We show that by carefully selecting the number of fluorescent labels per CCMV, and thus minimizing the negative effects on particle brightness, it is possible to quantify fluorescently labelled CCMV concentrations down to fM concentrations in single particle counting experiments.


Cue interaction between buildings and street configurations during reorientation in familiar and unfamiliar outdoor environments.
Two experiments investigated how people use buildings and street configurations to reorient in large-scale environments. In immersive virtual environments, participants learned objects' locations in an intersection consisting of 4 streets. The objects' locations were specified by 2 cues: a building and/or the street configuration. During the test, participants localized objects with either or both cues. Participants were divided into a competition group and a no-competition group. The competition group learned both cues whereas the no-competition group learned the single cue for trials with single testing cue. For the trials with both testing cues, both groups learned both cues and these 2 cues were placed at the original locations or displaced relative to each other during testing. Critically, the familiarity with the environment was also manipulated: in Experiment 1, participants learned the same building at the same corner of the same intersection for all trials (familiar); in Experiment 2, participants learned different buildings at different corners of different intersections across trials (unfamiliar). The results showed that the performance in the competition group was impaired in unfamiliar environments but not in familiar environments. When displacement occurred, the participants' preference in unfamiliar environments was determined by the response accuracy of using the 2 cues respectively, whereas participants in the familiar environment preferred the street configuration with a probability higher than what was solely determined by response accuracy based on individual cues. When the 2 cues were consistent with each other, they were combined additively in both familiar and unfamiliar environments. (PsycINFO Database Record


A TOP-DOWN AUDITORY ATTENTION MODEL FOR LEARNING TASK DEPENDENT INFLUENCES ON PROMINENCE DETECTION IN SPEECH.
A top-down task-dependent model guides attention to likely target locations in cluttered scenes. Here, a novel biologically plausible top-down auditory attention model is presented to model such task-dependent influences on a given task. First, multi-scale features are extracted based on the processing stages in the central auditory system, and converted to low-level auditory "gist" features. These features capture rough information about the overall scene. Then, the top-down model learns the mapping between auditory gist features and the scene categories. The proposed top-down attention model is tested with prominent syllable detection task in speech. When tested on broadcast news-style read speech using the BU Radio News Corpus, the model achieves 85.8% prominence detection accuracy at syllable level. The results compare well to the reported human performance on this task.


Reimagining the NICU: a human-centered design approach to healthcare innovation.
Design charettes have been utilized in architectural and design practice to generate innovative ideas. The Reimagining Workshop is a version that combines practical and blue-sky thinking to improve healthcare facility design. The workshop engages diverse stakeholders who follow a human-centered design framework. The Reimagining the Neonatal Intensive Care Unit workshop sought to generate ideas for the future, optimal NICU without specific site or client constraints. Key themes include family-centered care, technology-enabled care, neighborhood and village design and investing in the care team. Recommendations include a supportive physical environment, celebrating milestones, complementary and alternative medicine, enhancing the transition of care, aiding the transition period, and leveraging technology. The workshop showcased the potential for transformative change in NICU design and provided a roadmap for future advancements. These findings can inform regulatory standards for NICU design and drive improvements in family-centered care, patient experiences, and outcomes within the NICU environment.


Top-down network analysis characterizes hidden termite-termite interactions.
The analysis of ecological networks is generally bottom-up, where networks are established by observing interactions between individuals. Emergent network properties have been indicated to reflect the dominant mode of interactions in communities that might be mutualistic (e.g., pollination) or antagonistic (e.g., host-parasitoid communities). Many ecological communities, however, comprise species interactions that are difficult to observe directly. Here, we propose that a comparison of the emergent properties from detail-rich reference communities with known modes of interaction can inform our understanding of detail-sparse focal communities. With this top-down approach, we consider patterns of coexistence between termite species that live as guests in mounds built by other host termite species as a case in point. Termite societies are extremely sensitive to perturbations, which precludes determining the nature of their interactions through direct observations. We perform a literature review to construct two networks representing termite mound cohabitation in a Brazilian savanna and in the tropical forest of Cameroon. We contrast the properties of these cohabitation networks with a total of 197 geographically diverse mutualistic plant-pollinator and antagonistic host-parasitoid networks. We analyze network properties for the networks, perform a principal components analysis (PCA), and compute the Mahalanobis distance of the termite networks to the cloud of mutualistic and antagonistic networks to assess the extent to which the termite networks overlap with the properties of the reference networks. Both termite networks overlap more closely with the mutualistic plant-pollinator communities than the antagonistic host-parasitoid communities, although the Brazilian community overlap with mutualistic communities is stronger. The analysis raises the hypothesis that termite-termite cohabitation networks may be overall mutualistic. More broadly, this work provides support for the argument that cryptic communities may be analyzed via comparison to well-characterized communities.


[Leiomyosarcoma associated hypoglycemia--report of two cases].
We report 2 cases of leiomyosarcoma associated hypoglycemia. Case 1 had had a tumor over his left thigh area for 13 years and a few episodes of hypoglycemia occurred when the tumor grew rather large (10 cm x 10 cm x 6 cm). Abdominal sonogram showed metastatic masses in the left lobe of liver. Hypoglycemia syndrome improved after chemotherapy, but relapse was noted later. Another case suffered from progressive abdominal distension for about one year and a huge mass (19 cm x 15 cm x 12 cm) over small intestine was found. Although surgical resection of the tumor and adjuvant chemotherapy was performed, recurrence of the tumor with hypoglycemia was noted. Both of the cases produced hypoglycemia in a fasting state rather than postprandial hypoglycemia. Hypoglycemia associated with non-islet cell tumor is one of the endocrinologic paraneoplastic Syndromes. The most common tumor found in this syndrome is sarcoma and such tumors are usually large when hypoglycemia is noted. Treatment of paraneoplastic hypoglycemia initially requires glucose infusion for acute symptomatic relief, then treatment of the underlying tumor. Reduction of tumor, radiotherapy or chemotherapy can improve the hypoglycemia syndrome, but it readily relapses.


Gut microbiota in patients with newly diagnosed acromegaly: a pilot cross-sectional study.
Microbiota has crucial biological importance for human well-being. Bidirectional interaction exists between microbiota and the host, and there have been no studies investigating this interaction in patients with acromegaly. We aimed to analyze the composition of microbiota in patients with newly diagnosed acromegaly. Stool samples were obtained from the patients with newly diagnosed acromegaly in the Endocrinology Clinic of Erciyes University Medical School. The composition of microbiota was analyzed, and the results were compared to healthy volunteers matched to the patients in terms of age, gender and body mass index. Seven patients (three male, four female) with a mean age of 48 ± 17.6 years were included in the study. The stool analysis revealed a significantly lower bacterial diversity in the patients with acromegaly. Bacteroidetes phylum was predominating in the patient group, and Firmicutes/Bacteroidetes ratio was altered significantly. Bifidobacterium, Collinsella, Bacteroides, Butyricimonas, Clostridium, Oscillospira, and Dialister were predominating in the control group. The gut microbiota is significantly altered in patients with newly diagnosed acromegaly. Further prospective studies are needed to elucidate the causative relationship between acromegaly, colorectal pathologies, and microbial alterations.


Adjuvant nivolumab for stage III/IV melanoma: evaluation of safety outcomes and association with recurrence-free survival.
Several therapeutic options are now available in the adjuvant melanoma setting, mandating an understanding of their benefit‒risk profiles in order to make informed treatment decisions. Herein we characterize adjuvant nivolumab select (immune-related) treatment-related adverse events (TRAEs) and evaluate possible associations between safety and recurrence-free survival (RFS) in the phase III CheckMate 238 trial. Patients with resected stage IIIB-C or IV melanoma received nivolumab 3 mg/kg every 2 weeks (n=452) or ipilimumab 10 mg/kg every 3 weeks for four doses and then every 12 weeks (n=453) for up to 1 year or until disease recurrence, unacceptable toxicity, or consent withdrawal. First-occurrence and all-occurrence select TRAEs were analyzed within discrete time intervals: from 0 to 3 months of treatment, from >3-12 months of treatment, and from the last dose (regardless of early or per-protocol treatment discontinuation) to 100 days after the last dose. Possible associations between select TRAEs and RFS were investigated post randomization in 3-month landmark analyses and in Cox model analyses (including a time-varying covariate of select TRAE), within and between treatment groups. From the first nivolumab dose to 100 days after the last dose, first-occurrence select TRAEs were reported in 67.7% (306/452) of patients. First-occurrence select TRAEs were reported most frequently from 0 to 3 months (48.0%), during which the most common were pruritus (15.5%) and diarrhea (15.3%). Most select TRAEs resolved within 6 months. There was no clear association between the occurrence (or not) of select TRAEs and RFS by landmark analysis or by Cox model analysis within treatment arms or comparing nivolumab to the ipilimumab comparator arm. Results of this safety analysis of nivolumab in adjuvant melanoma were consistent with its established safety profile. In the discrete time intervals evaluated, most first-occurrence TRAEs occurred early during treatment and resolved. No association between RFS and select TRAEs was evident. NCT02388906.


Benefits of chronic blood transfusion in hemoglobin E/β thalassemia with pulmonary arterial hypertension.
The aim of the research reported here was to compare pulmonary artery systolic pressure (PASP) and 6-minute walk distance after 1 year of follow-up in hemoglobin E/β thalassemia (E/β-Thal) with pulmonary arterial hypertension (PAH) patients who received chronic blood transfusions versus those who received occasional transfusions. A nonrandomized clinical trial was conducted at the Hematological Outpatient Clinic of Chiang Rai Hospital, Thailand. All adult cases of E/β-Thal with PAH (defined as PASP >35 mmHg by Doppler echocardiography) were evaluated and followed for the next 12 months. The patients were classified into two groups by patient preference. Group 1 patients received chronic blood transfusions - one to two units of leukocyte-poor packed red cells every 2-4 weeks - over 1 year to maintain pre-transfusion hemoglobin levels of ≥7.0 g/dL. Group 2 patients received occasional transfusions over the course of 1 year, with more than 4 weeks between transfusions. All patients were treated with iron chelation when serum ferritin levels were ≥1,000 μg/dL. PASP and the 6-minute walk distance were evaluated at baseline and at 6 and 12 months. Propensity score adjustment was used to control for confounding by indication and contraindication. Multivariable regression analysis was used to evaluate the effects of chronic blood transfusion. There were 16 (53.3%) patients in Group 1 and 14 (46.7%) in Group 2. At 12 months, patients in Group 1 had a greater reduction in PASP than those in Group 1 (adjusted mean difference, -16.83; 95% confidence interval, -26.35 to -7.32; P=0.001). The 6-minute walk distance at 12 months in Group 1 patients was greater than that in Group 2 patients (adjusted mean difference, 46.55; 95% confidence interval, 18.08 to 75.02; P=0.001). This study found evidence that chronic blood transfusions may have beneficial effects in PAH in thalassemia patients over 1 year.


Backprojection Wiener deconvolution for computed tomographic reconstruction.
Analytical CT reconstruction is popular in practice because of its computational efficiency, but it suffers from low reconstruction quality when an insufficient number of projections are used. To address this issue, this paper presents a new analytical method of backprojection Wiener deconvolution (BPWD). BPWD executes backprojection first, and then applies a Wiener deconvolution to the whole backprojected image. The Wiener filter is derived from a ramp filter, enabling the proposed approach to perform reconstruction and denoising simultaneously. The use of a filter after backprojection does not differentiate between real sampled projections and interpolated ones, introducing reconstruction errors. Therefore a weighted ramp filter was applied to increase the contribution of real sampled projections in the reconstruction, thus improving reconstruction quality. Experiments on synthetic data and real phase-contrast x-ray images showed that the proposed approach yields better reconstruction quality compared to the classical filtered backprojection (FBP) method, with comparable reconstruction speed.


[The effect of nitrosoguanidine on carotene-synthesizing and pigment-free yeasts].
A number of mutants with a demand for amino acids, vitamins and nitrous bases has been obtained under effect of nitrosoguanidine (0.05%) on the yeast Candida utilis and carotene-synthesizing yeast Rhodosporidium diobovatum, Rhodotorula glutinis var. glutinis and Rh. rubra. Concentration of auxotrophs due to the death of prototrophs has been achieved in the studied yeast, with the exception of Rh. rubra using additional treatment by levorin (200 units/ml). When selecting quickly growing mutants of carotene-synthesizing yeast obtained after treatment by nitrosoguanidine, the primary selection by the intensity of red-orange colour of the colonies proved to be more efficient than that by resistance to monoiodoacetic acid. The selected mutants of the pigmented yeast surpassed by primary culture as to the harvest of carotenoids (including beta-carotene) and biomass in the periodic and continuous processes.


The Structure of Density-Potential Mapping. Part I: Standard Density-Functional Theory.
The Hohenberg-Kohn theorem of density-functional theory (DFT) is broadly considered the conceptual basis for a full characterization of an electronic system in its ground state by just the one-body particle density. Part I of this review aims at clarifying the status of the Hohenberg-Kohn theorem within DFT and Part II at different extensions of the theory that include magnetic fields. We collect evidence that the Hohenberg-Kohn theorem does not so much form the basis of DFT, but is rather the consequence of a more comprehensive mathematical framework. Such results are especially useful when it comes to the construction of generalized DFTs.


Interference patterns generated by a plane-parallel plate.
A simple geometrical theory is developed to evaluate the interference pattern that is generated by a plane-parallel plate illuminated with a monochromatic point source. It is shown that a specific tilt of the plate exists with respect to incident illumination, at which the spatial distribution of the interference fringes becomes uniform. Experimental evaluation of the fringe patterns by superposition moiré techniques supports the theoretical results.


[Development of information, counseling and treatment status for patients with hypertension from 1984-91 in West Germany].
Data from three nationally representative cross-sectional health surveys from 1984-86 (T0, n = 4790), 1987-88 (T1, n = 5335), and 1990-91 (T2, n = 5311) were analysed to determine changes in the utilisation of ambulatory services, degree of monitoring, risk factor awareness, drug treatment, and control, and medical counselling of hypertensive patients (actual hypertension prevalence) in West Germany. The percentage of hypertensives who had consulted a physician within the last year increased from 87% (T0) to 92% (T2) in men (p < 0.01), and from 94% to 96% in women (p > 0.05). The proportion of male (female) hypertensive patients who had their blood pressure measured by a physician within the last year was 87% (92%) in T2 (p-value for seven-year changes > 0.05). At T2, 50% (58%) of all male (female) hypertensives, whose blood pressure had been measured, were aware of their hypertension, with no significant changes during the study period. At T2, male (female) hypertensives in contact with a physician reported on medical recommendation of more physical activity in 16% (14%), reduced salt intake in 21% (25%), and reduced smoking/smoking cessation (only actual smokers) in 35% (31%) of cases. Counselling improved significantly only in hypertensive women. Although females had their hypertension more frequently treated with antihypertensive drugs (T0: 53%, T1: 53%, T2: 55%, p > 0.05), the increase of pharmaceutical treatment was stronger in men (T0: 34%, T1: 42%, T2: 45%, p < 0.01). Of those hypertensives treated with antihypertensive drugs, 55% (men) and 50% (women) had their blood pressure controlled below the 160/95 mmHg threshold in T2 with no significant changes during the study period. Suggestions are made for improving risk-factor awareness, and a higher quality and better integration of pharmaceutical treatment and non-pharmaceutical counselling of hypertensive patients.


Blood type gene locus has no influence on ACE association with Alzheimer's disease.
The ABO blood group locus was recently found to contribute independently and via interactions with angiotensin-converting enzyme (ACE) gene variation to plasma levels of ACE. Variation in ACE has previously been not only implicated as individually conferring susceptibility for Alzheimer's disease (AD) but also proposed to confer risk via interactions with other as yet unknown genes. More recently, larger studies have not supported ACE as a risk factor for AD, whereas the role of ACE pathway in AD has come under increased levels of scrutiny with respect to various aspects of AD pathology and possible therapies. We explored the potential combined involvement of ABO and ACE variations in the genetic susceptibility of 2067 AD cases compared with 1376 nondemented elderly. Including the effects of ABO haplotype did not provide any evidence for the genetic association of ACE with AD.


The perception of frequency peaks and troughs in wide frequency modulations. IV. Effects of modulation waveform.
This work extends previous studies on the perceptual asymmetry between the local maxima and minima of wide frequency modulations (FMs) [L. Demany and K. I. McAnally, J. Acoust. Soc. Am. 96, 706-715 (1994); L. Demany and S. Clément, J. Acoust. Soc. Am. 97, 2454-2459 (1995); L. Demany and S. Clément, J. Acoust. Soc. Am. 98, 2515-2523 (1995)]. In experiment 1, subjects had to discriminate frequency shifts in the temporally central vertex of V- and A-shaped FMs imposed on 200-ms sinusoidal tone bursts. The precise shapes of these FMs varied in eight steps from quasi-triangles (with a durationless central vertex) to quasi-squares (with a long-duration central vertex). The central vertex was either a minimum or a maximum, but in each case the corresponding frequency was near 1000 Hz and the FM span was about 0.5 oct. For each FM shape, the discrimination threshold was lower when the vertex was a maximum than when it was a minimum, but (in four subjects out of five) this difference decreased monotonically as the FM became less and less triangular. FM shape had a remarkably small effect on the discrimination of the maxima, and the thresholds measured for the sharpest maxima were unexpectedly low. In subsequent experiments, subjects had to discriminate frequency shifts in the starting point or the final point of unidirectional FMs (tone glides) that spanned about 0.5 oct in 100 ms. The relevant frequency extremum was near 1000 Hz in each condition. At the final point of the glides, discrimination was better for rising glides than for falling glides. At the starting point of the glides, discrimination was better for falling glides than for rising glides. Thus discrimination was always better when the relevant frequency extremum was a maximum than when it was a minimum, and this effect was produced both "forward" and "backward." The latter fact suggests that the perceptual asymmetry of FM originates at least partly from central factors.


Peroxynitrite modulates release of inflammatory mediators from guinea pig lung mast cells activated by antigen-antibody reaction.
Peroxynitrite (ONOO-), the product of the reaction between the superoxide anion (*O2-) and nitric oxide (NO), is produced during inflammatory disease and may be a major cytotoxic agent. No reports are available as to whether ONOO- generates or modulates inflammatory mediator release from activated guinea pig lung mast cells. In this study, we explored the modulatory role of intracellular ONOO- on inflammatory mediator release (histamine and leukotrienes) from activated mast cells. Guinea pig lung mast cells were purified by the enzyme digestion, and by using the rough and discontinuous Percoll density gradients. Mast cells were sensitized with IgG1 (anti-ovalbumin) antibody and challenged with ovalbumin (OVA). The intracellular ROS formation was determined by following the oxidative production of 2', 7'-dichlorofluorescein diacetate (DCFH-DA), dihydrorhodamine 123 (DHR), and anti-nitrotyrosine antibody immunofluorescence. Histamine was assayed using a fluorometric analyzer, leukotrienes by radioimmunoassay, intracellular Ca2+ levels by confocal scanning microscopy, and PLA(2) activity using prelabeling of [3H]arachidonic acid. ROS detected by DCFH-DA weakly increased in mast cells activated with OVA (1.0 g/ml), and the ROS so generated was inhibited by ebselen (50 microM). However, the ROS detected by DHR increased 3-fold under the same conditions. Peroxynitrite scavengers sL-MT, DMTU, and inhibitor FeTPPS inhibited ROS formation but the NADPH oxidase inhibitor diphenyleneiodonium (DPI) only partially inhibited this formation. Dimethyl thiourea (DMTU) and seleno-L-methionine (sL-MT) inhibited the tyrosine nitration of cytosolic proteins, the release of histamine and leukotrienes, Ca2+ influx, and the PLA(2) activity evoked by mast cell activation. The data obtained suggests that the ROS generated by the antigen/antibody reaction activated mast cells is ONOO-, and that this modulates the release of inflammatory mediators via Ca2+ -dependent PLA(2) activity.


Epidermal growth factor receptor tyrosine kinase mediates Ras activation by gonadotropin-releasing hormone.
Gonadotropin releasing hormone (GnRH) contributes to the maintenance of gonadotrope function by increasing extracellular signal-regulated kinase (ERK) activity subsequent to binding to its cognate G-protein-coupled receptor. As the GnRH receptor exclusively interacts with G(q/11) proteins and as receptor expression is regulated in a beta-arrestin-independent fashion, it represents a good model to systematically dissect underlying signaling pathways. In alphaT3-1 gonadotropes endogenously expressing the GnRH receptor, GnRH challenge resulted in a rapid increase in ERK activity which was attenuated by the epidermal growth factor receptor (EGFR)-specific tyrosine kinase inhibitor AG1478. In COS-7 cells transiently expressing the human GnRH receptor, agonist-induced ERK activation was independent of free Gbetagamma subunits but could be mimicked by short-term phorbol ester treatment. Most notably, G(q/11)-induced ERK activation was sensitive to N17-Ras and to expression of the C-terminal Src kinase but also to other dominant negative mutants of signaling components localized upstream of Ras, like Shc and the EGFR. GnRH as well as phorbol esters led to Ras activation in COS-7 and alphaT3-1 cells, which was dependent on Src and EGFR tyrosine kinases, indicating that both tyrosine kinases act downstream of protein kinase C (PKC) and upstream of Ras. However, Src did not contribute to Shc tyrosine phosphorylation. GnRH or phorbol ester challenge resulted in PKC-dependent EGFR autophosphorylation. Furthermore, a 5-min phorbol ester treatment was sufficient to trigger tyrosine phosphorylation of the platelet-derived growth factor-beta receptor in L cells. Thus, in several cell systems PKC is able to stimulate Ras via activation of receptor tyrosine kinases.


Programmable mismatch-fueled high-efficiency DNA signal converter.
Herein, by directly introducing mismatched reactant DNA, high-reactivity and high-threshold enzyme-free target recycling amplification (EFTRA) is explored. The developed high-efficiency EFTRA (HEEFTRA) was applied as a programmable DNA signal converter, possessing higher conversion efficiency than the traditional one with perfect complement owing to the more negative reaction standard free energy (ΔG). Once traces of input target miRNA interact with the mismatched reactant DNA, amounts of ferrocene (Fc)-labeled output DNA could be converted via the EFTRA. Impressively, the Fc-labeled output DNA could be easily captured by the DNA tetrahedron nanoprobes (DTNPs) on the electrode surface to form triplex-forming oligonucleotide (TFO) at pH = 7.0 for sensitive electrochemical signal generation and the DTNPs could be regenerated at pH = 10.0, from which the conversion efficiency (N) will be accurately obtained, benefiting the selection of suitable mismatched bases to obtain high-efficiency EFTRA (HEEFTRA). As a proof of concept, the HEEFTRA as an evolved DNA signal converter is successfully applied for the ultrasensitive detection of miRNA-21, which gives impetus to the design of other signal converters with excellent efficiency for ultimate applications in sensing analysis, clinical diagnosis, and other areas.


Simple fixed functional space maintainer.
Premature loss of a primary tooth is one of the most common etiology for malocclusion. Space maintainers are employed to prevent this complication. In anterior region, esthetics is an important concern along with function and space management. Fiber-reinforced composite (FRC) retained space maintainer solves all these purposes ef ficiently and ef fectively. In addition, the technique is simple and the appliance is very comfortable inside the oral cavity. Here is a case of premature loss of anterior primary tooth which was replaced by FRC retained esthetic functional space maintainer. The appliance was found to be functioning satisfactorily inside the oral cavity till the last visit (1 Year). How to cite this article: Goenka P, Sarawgi A, Marwah N, Gumber P, Dutta S. Simple Fixed Functional Space Maintainer. Int J Clin Pediatr Dent 2014;7(3):225-228.


Improving child and parent mental health in primary care: a cluster-randomized trial of communication skills training.
We examined child and parent outcomes of training providers to engage families efficiently and to reduce common symptoms of a range of mental health problems and disorders. Training involved three 1-hour discussions structured around video examples of family/provider communication skills, each followed by practice with standardized patients and self-evaluation. Skills targeted eliciting parent and child concerns, partnering with families, and increasing expectations that treatment would be helpful. We tested the training with providers at 13 sites in rural New York, urban Maryland, and Washington, DC. Children (5-16 years of age) making routine visits were enrolled if they screened "possible" or "probable" for mental disorders with the Strengths and Difficulties Questionnaire or if their provider said they were likely to have an emotional or behavioral problem. Children and their parents were then monitored for 6 months, to assess changes in parent-rated symptoms and impairment and parent symptoms. Fifty-eight providers (31 trained and 27 control) and 418 children (248 patients of trained providers and 170 patients of control providers) participated. Among the children, 72% were in the possible or probable categories. Approximately one half (54%) were white, 30% black, 12% Latino, and 4% other ethnicities. Eighty-eight percent (367 children) completed follow-up monitoring. At 6 months, minority children cared for by trained providers had greater reduction in impairment (-0.91 points) than did those cared for by control providers but no greater reduction in symptoms. Seeing a trained provider did not have an impact on symptoms or impairment among white children. Parents of children cared for by trained providers experienced greater reduction in symptoms (-1.7 points) than did those cared for by control providers. Brief provider communication training had a positive impact on parent mental health symptoms and reduced minority children's impairment across a range of problems.


A quantitative analysis of apolipoprotein binding to SR-BI: multiple binding sites for lipid-free and lipid-associated apolipoproteins.
Competitive binding experiments were performed using Y1-BS1 adrenal cells to provide information about the interaction of HDL apolipoproteins with scavenger receptor class B, type I (SR-BI). Exchangeable apolipoproteins apolipoprotein A-I (apoA-I), apoA-II, apoE-2, apoE-3, and apoE-4 as phospholipid complexes bind like HDL3 to SR-BI via their multiple amphipathic alpha-helices; the concentrations required to reduce the binding of HDL3 to SR-BI by 50% (IC50) were similar and in the range of 35-50 microgram protein/ml. In the case of apoA-I, peptides corresponding to segments 1-85, 44-65, 44-87, 149-243, and 209-241 all had the same IC50 as each other (P = 0.86), showing that a specific amino acid sequence in apoA-I is not responsible for the interaction with SR-BI. The distribution of charged residues in the amphipathic alpha-helix affects the interaction, with class A and Y helices binding better than class G* helices. Synthetic alpha-helical peptides composed of either l or d amino acids can bind equally to the receptor. Association with phospholipid increases the amount of apolipoprotein binding to SR-BI without altering the affinity of binding. Lipid-free apolipoproteins compete only partially with the binding of HDL to SR-BI, whereas lipidated apolipoproteins compete fully. These results are consistent with the existence of more than one type of apolipoprotein binding site on SR-BI.


The effects of preparation conditions for a BaNbO2 N photocatalyst on its physical properties.
BaNbO2 N is a semiconductor photocatalyst active for water oxidation under visible-light irradiation up to λ=740 nm. It is important to understand the nitridation processes of precursor materials to form BaNbO2 N to tune the physical properties and improve the photocatalytic activity. Comprehensive experiments and analyses of temperatures, durations, ammonia flow rates, and barium/niobium ratios in the precursor during the nitridation process reveals that faster ammonia flow rates and higher barium/niobium ratios in the precursors help to suppress reduction of pentavalent niobium ions in the nitridation products and that the use of a precursor prepared by a soft-chemistry route allows the production of BaNbO2 N at lower temperatures in shorter times than the use of physical mixtures of BaCO3 and Nb2 O5 because the niobium species is dispersed among the barium species. BaNbO2 N prepared by the soft-chemistry route exhibits comparatively higher activity than that prepared from physical mixtures of BaCO3 and Nb2 O5 , probably because of lower nitridation temperatures, which suppress excessive dissociation of ammonia, and thereby reduce pentavalent niobium ions, and intimate interaction of niobium and barium sources, which lowers the densities of mid-gap states associated with defects.


Racial disparities in lipid control in patients with diabetes.
To describe lipid management over time in a cohort of insured patients with diabetes and evaluate differences between African American and white patients. Automated claims data were used to identify a cohort of 11,411 patients with diabetes in 1997 to 1998. Patients were followed through 2007. Rates of hypercholesterolemia testing, treatment, and goal attainment were measured annually. Treatment was determined by a claim for lipid-lowering agents, and goal attainment was defined as a low-density lipoprotein cholesterol (LDL-C) level <100 mg/dL. During the study period, LDL-C testing increased from 48% to 70% among African American patients and from 61% to 77% among white patients. Treatment with lipid-lowering drugs increased from 23% to 56% among African American patients and 33% to 61% among white patients. The proportion at goal increased from 35% to 76% and from 24% to 59% among white and African American patients, respectively. African American patients were less likely to be tested for LDL-C (odds ratio [OR] 0.79; 95% confidence interval [CI] 0.73-0.86), treated with lipidlowering agents (OR 0.72; 95% CI 0.65-0.80), have their medication dosage altered (OR 0.65; 95% CI 0.59-0.73), or attain LDL-C goal (OR 0.59; 95% CI 0.56-0.63) compared with white patients. Although rates of LDL-C testing, treatment, and goal attainment improved over time, racial disparities in dyslipidemia management continued to exist. Further studies to determine the causes of differences in management by race are warranted.


Increased Aperiodic Neural Activity During Sleep in Major Depressive Disorder.
In major depressive disorder (MDD), patients often express subjective sleep complaints, while polysomnographic studies report only subtle alterations of the electroencephalographic signal. We hypothesize that differentiating the signal into its oscillatory and aperiodic components may bring new insights into our understanding of sleep abnormalities in MDD. Specifically, we investigated aperiodic neural activity during sleep and its relationships with sleep architecture, depression severity, and responsivity to antidepressant treatment. Polysomnography was recorded in 38 patients with MDD (in unmedicated and 7-day-medicated states) and 38 age-matched healthy control subjects (N= 76). The aperiodic power component was calculated using irregularly resampled auto-spectral analysis. Depression severity was assessed with the Hamilton Depression Rating Scale. We replicated the analysis using 2 independently collected datasets of medicated patients and control subjects (N = 60 and N = 80, respectively). Unmedicated patients showed flatter aperiodic slopes compared with control subjects during non-rapid eye movement (non-REM) stage 2 sleep (p = .009). Medicated patients showed flatter aperiodic slopes compared with their earlier unmedicated state (p values < .001) and control subjects during all sleep stages (p values < .03). In medicated patients, flatter aperiodic slopes during non-REM sleep were linked to the higher proportion of N1, lower proportion of REM, delayed onset of N3 and REM, and shorter total sleep time. Flatter slopes of aperiodic electroencephalographic power may reflect noisier neural activity due to increased excitation-to-inhibition balance, representing a new disease-relevant feature of sleep in MDD.


Spontaneous pubertal development in Turner's syndrome. Italian Study Group for Turner's Syndrome.
The incidence of spontaneous puberty in Turner's syndrome is reported to be between 5-10% and, more recently in some series, as high as 20%. In an Italian retrospective multicenter study, of 522 patients older than 12 yr with Turner's syndrome, 84 patients (16, 1%) presented spontaneous pubertal development with menarche that occurred at a chronological age of 13.2 +/- 1.5 yr (mean +/- SD) and a bone age of 12.9 +/- 1.9 yr. Karyotype distribution in the whole group was as follows: 52.1% (272 patients) X-monosomy (45,X), 13.2% (69 patients) mosaicism characterized by X-monosomy and cellular line with no structural abnormalities of the second X, 19.9% (104 patients) mosaicism characterized by X-monosomy and cellular line with structural abnormalities of the second X, and 14.8% (77 patients) structural abnormalities of the second X. Menstrual cycles were still regular in 30 patients at 9.2 +/- 5.0 yr after menarche, 12 developed secondary amenorrhea 1.6 +/- 2.0 yr after menarche, and 19 had irregular menstrual cycles 0.9 +/- 1.8 yr after menarche. As signs of spontaneous puberty developed in 14.0% of X-monosomic patients and in 32.0% of patients with cell lines with more than one X, the presence of the second X seems to have a cardinal influence on the appearance of spontaneous puberty. Spontaneous pregnancy occurred in 3 patients (3.6%). The presence of chromosomal abnormalities and malformations in 2 of 3 pregnancies led us to agree with other investigators in discouraging unassisted pregnancies. Treatment with GH does not seem to exert any influence on either the age of onset or the prevalence of spontaneous pubertal development in Turner's syndrome. The increased percentage of spontaneous menarche is Turner's syndrome reported in the recent literature might be due to increased ascertainment by diligent screening for Turner's syndrome in girls with short stature and mild or no Turner's syndrome stigmata, even though they may be menstruating.


Bcl-xS enhances adenoviral vector-induced apoptosis in neuroblastoma cells.
bcl-x is a member of the bcl-2 family of genes and by alternative splicing gives rise to two distinct mRNAs: bcl-xL and bcl-xS. We have previously investigated the expression of Bcl-x in neuroblastoma (NB) cell lines and have shown that Bcl-xL is expressed and functions to inhibit chemotherapy-induced apoptosis. However, none of the NB cell lines expressed Bcl-xS. The aim of the present study was to determine the effects of Bcl-xS expression on the viability of NB cells. A panel of NB cell lines (CHP-382, GOTO, SHEP-1, SHSY-5Y, and GI-CA-N) were infected with either a bcl-xS adenovirus (pAdRSV-bcl-xS) or a control virus (pAdRSV-lac-z). NB cells showed loss of viability with both viruses, although the bcl-xS virus was most toxic. Importantly, infection with the bcl-xS adenovirus resulted in rapid loss of cell viability, DNA fragmentation, and morphological features of apoptosis even in NB cells transfected to overexpress Bcl-2 and Bcl-xL. These findings suggest that deregulated expression of Bcl-xS using an adenovirus may provide a novel mechanism for initiating cell death in tumors that express Bcl-2 or Bcl-xL.


Taxonomic challenges in freshwater fishes: a mismatch between morphology and DNA barcoding in fish of the north-eastern part of the Congo basin.
This study evaluates the utility of DNA barcoding to traditional morphology-based species identifications for the fish fauna of the north-eastern Congo basin. We compared DNA sequences (COI) of 821 samples from 206 morphologically identified species. Best match, best close match and all species barcoding analyses resulted in a rather low identification success of 87.5%, 84.5% and 64.1%, respectively. The ratio 'nearest-neighbour distance/maximum intraspecific divergence' was lower than 1 for 26.1% of the samples, indicating possible taxonomic problems. In ten genera, belonging to six families, the number of species inferred from mtDNA data exceeded the number of species identified using morphological features; and in four cases indications of possible synonymy were detected. Finally, the DNA barcodes confirmed previously known identification problems within certain genera of the Clariidae, Cyprinidae and Mormyridae. Our results underscore the large number of taxonomic problems lingering in the taxonomy of the fish fauna of the Congo basin and illustrate why DNA barcodes will contribute to future efforts to compile a reliable taxonomic inventory of the Congo basin fish fauna. Therefore, the obtained barcodes were deposited in the reference barcode library of the Barcode of Life Initiative.


Clinical and magnetic resonance imaging findings in 92 cats with clinical signs of spinal cord disease.
Medical records of 92 cats presented with clinical signs of spinal cord disease, which had undergone magnetic resonance imaging (MRI), were reviewed. The cats were grouped into seven categories based upon the diagnosis suggested by results of MRI, cerebrospinal fluid analysis and other diagnostic procedures: neoplastic (n=25), inflammatory or infectious (n=13), traumatic (n=8), vascular (n=6), degenerative (n=5), anomalous (n=3) and those with an unremarkable MRI (n=32). There were two independent predictors of abnormal MRI findings: severity of clinical signs and presence of spinal pain. Abnormal MRI findings and speed of onset of disease were significantly associated with survival. For the 32 cats with unremarkable MRI findings, only nine died due to spinal disease and, therefore, the median survival time (MST) was not reached (lower 95% confidence interval (CI)=970 days). For the 60 cats with abnormal MRI findings, 37 died due to their disease and the MST was 138 days (95% CI: 7-807).


Tracer studies of the interconversion of R- and S-methylmalonic semialdehydes in man.
Two human subjects were given separate oral doses of sodium [2H6]isobutyrate and [methyl-2H3]thymine and the labelling patterns of urinary metabolites were determined. Ingestion of deuterated isobutyrate resulted in the excretion of 2H5-labelled S-3-hydroxyisobutyric acid, formed on the direct catabolic pathway, and of S- and R-[2H4]-3-hydroxyisobutyric acids, formed by the reduction of S- and R-methylmalonic semialdehydes respectively. Only the R-enantiomer of urinary 3-hydroxyisobutyric acid was labelled by thymine. This labelling pattern indicates a flow from S- to R-methylmalonic semialdehyde, suggesting that the R-enantiomer is the substrate of methylmalonic semialdehyde dehydrogenase.


Precision medicine advancements in glioblastoma: A systematic review.
Glioblastoma multiforme, commonly known as GBM or glioblastoma is a grade IV astrocytoma. Brain tumors are difficult to treat and lead to poor prognosis and survival in patients. Gliomas are categorized into four different grades among which GBM is the worst grade primary brain tumor with a survival of less than a year. The genomic heterogeneity of the brain tumor results in different profiles for patients diagnosed with glioblastoma. Precision medicine focuses on this specific tumor type and suggests specialized treatment for better prognosis and overall survival (OS). With the recent advancements in Genome-Wide Studies (GWS) and various characterizations of brain tumors based on genetic, transcriptomic, proteomic, epigenetic, and metabolomics, this review discusses the advancements and opportunities of precision medicine therapeutics, drugs, and diagnosis methods based on the different profiles of glioblastoma. This review has exhaustively surveyed several pieces of works from various literature databases. It is evident that most primary brain tumors including glioblastoma require specific and precision therapeutics for better prognosis and OS. In present and future, molecular understanding and discovering specific therapies are essential for treatment in the field of neurooncology.


Regulation of interleukin 2 synthesis by cAMP in human T cells.
T cell activation requires two initial signals that first lead to the expression of interleukin 2 (IL 2) receptors and the initiation of IL 2 synthesis and then to T cell proliferation. Jurkat T lymphoma cells have been shown to be a good model for studying IL 2 synthesis because these cells also require two signals for activation. The first signal can be provided by the lectin phytohaemagglutinin (PHA), and the second one by the phorbol ester, 12-o-tetradecanoylphorbol 13-acetate (TPA). The regulation of IL 2 synthesis in Jurkat cells, however, is unclear, and the present study deals with the role of cAMP on IL 2 synthesis. In Jurkat cells, IL 2 synthesis appears to be highly regulated by the activity of adenylate cyclase. This was demonstrated by using different means to increase intracellular cAMP level, namely by using permeant cAMP analogs, using the activator of adenylate cyclase, forskolin, using the activator of the alpha subunit of the stimulatory GTP binding protein cholera toxin, and using inhibitors of phosphodiesterase. In addition, prostaglandins E1 and E2 were shown to bind specifically to Jurkat cells, to induce a rise in intracellular cAMP level, and to markedly decrease IL 2 synthesis. All together, these results suggest that in T lymphocytes, the prostaglandin E2 receptor is linked to adenylate cyclase through a GTP binding protein and regulates the production of IL 2 by controlling the intracellular cAMP level.


Role of metalloproteinases at the onset of liver development.
At the onset of liver development, the hepatic precursor cells, namely, the hepatoblasts, derive from the ventral foregut endoderm and form a bud surrounded by a basement membrane (BM). To initiate liver growth, the hepatoblasts migrate across the BM and invade the neighboring septum transversum mesenchyme. In the present study, carried out in the mouse embryo, we searched for effectors involved in this process and we examined the role of matrix metalloproteinases (MMPs). We found expression of a broad range of MMPs, among which MMP-2 was predominantly expressed in the septum transversum and MMP-14 in the hepatoblasts. Using a new liver explant culture system we showed that inhibition of MMP activity represses migration of the hepatoblasts. We conclude that MMPs are required to initiate expansion of the liver during development and that our culture system provides a new model to study hepatoblast migration.


A Systematic Review on Cognitive Effects of Electroconvulsive Therapy in Asian Patients.
Electroconvulsive therapy (ECT) is the most efficacious treatment for many major mental illnesses but is limited by cognitive side effects. However, research on the pattern and severity of ECT-related cognitive side effects is inconsistent. Furthermore, little is known about the cognitive effects of ECT in Asian populations. A systematic review was conducted to examine objective cognitive performance following ECT in the Asian context. This review systematically identified studies assessing ECT-related cognitive effects in PubMED, PsychINFO, The Cochrane Library, Journal of ECT and major databases in Asian countries. The search included publications from peer-reviewed journals of languages other than English. A total of 6,322 studies were identified; 823 were assessed for eligibility, of which 16 studies met the search criteria and were included in this review. Majority used high dose Bitemporal ECT for Depression and/or Schizophrenia. Cognitive impairment, which could occur immediate to the first ECT session, was reported in only 9 out of the 16 studies. However, deficits were observed to resolve as early as 3 weeks after the initiation of ECT. The remaining studies reported no impairment or even improvement after ECT. There is no consistent evidence that suggests ECT causes cognitive deficits in patients, despite the widespread use of high dose Bitemporal ECT. This review suggests that Asian patients, presenting with a different psychiatric profile, may respond to high-dose Bitemporal ECT differently from Western samples.


The TUBEX test detects not only typhoid-specific antibodies but also soluble antigens and whole bacteria.
TUBEX (IDL Biotech) is a 5 min semiquantitative colorimetric test for typhoid fever, a widely endemic disease. TUBEX detects anti-Salmonella O9 antibodies from a patient's serum by the ability of these antibodies to inhibit the binding between an indicator antibody-bound particle and a magnetic antigen-bound particle. Herein, we report that TUBEX could also be used to specifically detect soluble O9 lipopolysaccharide in antigen-spiked buffer by the ability of the antigen to inhibit the same binding between the particles. Sensitivity of antigen detection was improved (8-31 mug ml(-1)) by using a modified protocol in which the test sample was mixed with the indicator particles first, rather than with the magnetic particles as for antibody detection. The antigen was also detectable in spiked serum and urine samples, albeit less well (2-4-fold) than in buffer generally. However, no antigen was detected from six typhoid sera examined, all of which had anti-O9 antibodies. In addition, whole organisms of Salmonella Typhi (15 strains) and Salmonella Enteritidis (6 strains) (both O9(+) Salmonella), grown in simulated blood broths or on MacConkey agar, were also detectable by TUBEX when suspended at >9 x 10(8) organisms ml(-1). Expectedly, Salmonella Paratyphi A (7 strains), Salmonella Typhimurium (1 strain) and Escherichia coli (2 strains) were negative in the test. Thus, the same TUBEX kit may be used in several ways both serologically and microbiologically for the rapid diagnosis of typhoid fever. However, validation of the newer applications will require the systematic examination of real patient and laboratory materials.


Potential roles of eosinophils in cancer therapy: epidemiological studies, experimental models, and clinical pathology.
Eosinophils play important roles in allergic diseases as well as during helminth infection. As multifunctional leukocytes, eosinophils have also been indicated in anti-cancer immunity. Published studies have suggested an association between allergic conditions and a trend of decreased risk in numerous malignances. Moreover, eosinophil infiltration in tumor tissue is considered an independent prognostic factor. Eosinophils are often recruited to tumor sites, where eosinophil granule proteins and cytokines are released upon activation, which in turn damage and kill tumor cells. In the last decade, a number of patents based on potential cancer therapy using eosinophilic cytokines have been awarded. In this article, we review the current findings on epidemiology, experimental models, clinical pathology, and molecular mechanisms involved in the response of eosinophils towards cancer. Moreover, we discuss promising targeted therapies with eosinophilic cytokines as a novel perspective to combat cancer.


Parental stress when caring for a child with cancer in Jordan: a cross-sectional survey.
Most studies report that being parents of a child with cancer is a stressful experience, but these have tended to focus on mothers and few have included both parents. Moreover, studies have focussed on families in Western countries and none have been published examining the psychological outcomes for parents living in an Arabic country.This research explores the stress levels of Jordanian parents caring for a child with cancer in order to identify the psychological needs of parents in this environment and to explore how mothers and fathers stress levels might differ. The study was carried out in Jordan using the Perceived Stress Scale 10-items (PSS10). The questionnaire was completed by 300 couples with a child who has cancer and a comparison group of 528 couples where the children do not have any serious illness. Multivariate backward regression analysis was carried out. Analysis adjusting for spousal stress and sociodemographic predictors revealed that stress levels of mothers with a child who had cancer remained significantly higher than mothers whose children did not have any serious illness (p < 0.001). However, having a child with cancer did not show a significant association with the fathers' reported stress scores (p = 0.476) when spousal stress was in the model, but was highly significant once that was removed (p < 0.001).Parental stress was analysed for those with a child who has cancer and in models which included spouse's stress scores, sociodemographic and cancer-related predictors 64 % of the variance was explained for mothers (adjusted R2 = 0.64, p < 0.001) and fathers (adjusted R2 = 0.64, p < 0.001). Models excluding spousal stress scores explained just 26 % of the variance for fathers and 22 % for mothers. This is the first study into the psychological outcomes for parents living in an Arabic country who care for a child with cancer. Both mothers and fathers with a child diagnosed with cancer reported higher stress levels than those from the normal Jordanian parent population. Mothers and fathers of children with cancer reported significantly different levels of stress to each other but models reveal significant contributions of the stress score of fathers upon mothers, and vice versa. The findings provide evidence of the need for psychological support to be developed for families caring for a child with cancer in Jordan.


Long-enduring primary hepatocyte-based co-cultures improve prediction of hepatotoxicity.
The failure of drug candidates during clinical trials and post-marketing withdrawal due to Drug Induced Liver Injury (DILI), results in significant late-stage attrition in the pharmaceutical industry. Animal studies have proven insufficient to definitively predict DILI in the clinic, therefore a variety of in vitro models are being tested in an effort to improve prediction of human hepatotoxicity. The model system described here consists of cryopreserved primary rat, dog or human hepatocytes co-cultured together with a fibroblast cell line, which aids in the hepatocytes' maintenance of more in vivo-like characteristics compared to traditional hepatic mono-cultures, including long term viability and retention of activity of cytochrome P450 isozymes. Cell viability was assessed by measurement of ATP following treatment with 29 compounds having known hepatotoxic liabilities. Hμrelrat™, Hμreldog™, and Hμrelhuman™ hepatic co-cultures were treated for 24h, or under repeat-dosing for 7 or 13days, and compared to rat and human hepatic mono-cultures following single-dose exposure for 24h. The results allowed for a comparison of cytotoxicity, species-specific responses and the effect of repeat compound exposure on the prediction of hepatotoxic potential in each model. Results show that the co-culture model had greater sensitivity compared to that of the hepatic mono-cultures. In addition, "time-based ratios" were determined by dividing the compounds' 24-hour TC50/Cmax values by TC50/Cmax values measured after dosing for either 7 or 13days. The results suggest that this approach may serve as a useful adjunct to traditional measurements of hepatotoxicity, improving the predictive value of early screening studies.


Persistence of smoking-cessation decision support use in a dental practice.
A computer-assisted tobacco decision support tool increased dental practitioners' (dentists and dental hygienists) advice to quit smoking and referral to a quitline during a group randomized trial. The purpose of this study is to document the extent to which use persisted after the trial. Electronic dental record (EDR) data from 2010 to 2013 were analyzed in 2014 for use of computer-assisted tobacco intervention tool advice scripts and referral to a quitline during four periods: during the trial and post-trial when only intervention clinic dental practitioners had access to the tool, and during full deployment, both before and after an EDR modification. Intervention clinic dental practitioners (18.5 dentist full-time equivalents [FTEs] and 27.8 dental hygienist FTEs practicing in seven clinics) referred 19.0% of 1,368 smokers to a quitline during the trial and referred 15.4% of 4,011 smokers post-trial. After full tool deployment but pre-EDR change, these dental practitioners referred 15.6% of 2,214 intervention clinic smokers, whereas 18.3 dentist FTEs and 29.7 dental hygienist FTEs practicing in eight clinics referred 8.5% of 2,113 smokers. Post-EDR change, dental practitioners referred 12.2% of 2,214 intervention clinic smokers and 8.1% of 2,399 control clinic smokers to a quitline. In the last three quarters of observation, clinic script use ranged from 15.4% to 65.8% and referral to a quitline ranged from 2.0% to 18.7% of visits. Although EDR design affected rates of referral, dental practitioners persisted in using a computer-assisted tobacco intervention tool to refer smokers to a quitline.


New Method to Global Exponential Stability Analysis for Switched Genetic Regulatory Networks With Mixed Delays.
In this paper, the sufficient conditions for the global exponential stability of the switched genetic regulatory networks with mixed time delays are obtained. The proposed method does not need the construction of Lyapunov-Krasovskii functional, but is directly proceeded by the definition of global exponential stability. The derived sufficient conditions can easily be verified by checking the eigenvalues of a constant matrix or solving several simple linear matrix inequalities. Finally, two numerical examples are presented to illustrate that the obtained global exponential stability criteria are available.


Mutation analysis of NF-κB signal pathway-related genes in ocular MALT lymphoma.
Constitutive nuclear factor-kappa B (NF-κB) activation has been reported in ocular adnexal lymphoma (OAL). TNFAIP3/A20 is a "global" inhibitor of NF-κB pathway. We have shown that OAL has preferential loss of the 6q23.3 region where TNFAIP3/A20 exist, which is suggested to involve in lymphomagenesis of OAL. The mechanisms causing NF-κB activity in OAL remain elusive. Recently, NF-κB canonical pathway genes including CARD11, CD79B and MYD88 were shown to be frequently mutated in diffuse large B-cell lymphomas. In this study, we analyzed the mutation status of these genes by direct sequencing in 24 OAL cases including 9 cases with loss of 6q23.3 previously identified by array comparative genomic hybridization. We showed that genetic alterations of these genes were not found in OAL, a finding differing from that of most B-cell lymphomas. Genetic or epigenetic alterations in other genes are likely to be relevant in pathogenesis of OAL case without A20 loss.


IGFBP6 controls the expansion of chemoresistant glioblastoma through paracrine IGF2/IGF-1R signaling.
Glioblastomas (GBMs), the most common and most lethal of the primary brain tumors, are characterized by marked intra-tumor heterogeneity. Several studies have suggested that within these tumors a restricted population of chemoresistant glioma cells is responsible for recurrence. However, the gene expression patterns underlying chemoresistance are largely unknown. Numerous efforts have been made to block IGF-1R signaling pathway in GBM. However, those therapies have been repeatedly unsuccessful. This failure may not only be due to the complexity of IGF receptor signaling, but also due to complex cell-cell interactions in the tumor mass. We hypothesized that differential expression of proteins in the insulin-like growth factor (IGF) system underlie cell-specific differences in the resistance to temozolomide (TMZ) within GBM tumors. Expression of IGF-1R was analyzed in cell lines, patient-derived xenograft cell lines and human biopsies by cell surface proteomics, flow cytometry, immunofluorescence and quantitative real time polymerase chain reaction (qRT-PCR). Using gain-of-function and loss-of-function strategies, we dissected the molecular mechanism responsible for IGF-binding protein 6 (IGFBP6) tumor suppressor functions both in in vitro and in vivo. Site direct mutagenesis was used to study IGFBP6-IGF2 interactions. We determined that in human glioma tissue, glioma cell lines, and patient-derived xenograft cell lines, treatment with TMZ enhances the expression of IGF1 receptor (IGF-1R) and IGF2 and decreases the expression of IGFBP6, which sequesters IGF2. Using chemoresistant and chemosensitive wild-type and transgenic glioma cells, we further found that a paracrine mechanism driven by IGFBP6 secreted from TMZ-sensitive cells abrogates the proliferation of IGF-1R-expressing TMZ-resistant cells in vitro and in vivo. In mice bearing intracranial human glioma xenografts, overexpression of IGFBP6 in TMZ-resistant cells increased survival. Finally, elevated expression of IGF-1R and IGF2 in gliomas associated with poor patient survival and tumor expression levels of IGFBP6 directly correlated with overall survival time in patients with GBM. Our findings support the view that proliferation of chemoresistant tumor cells is controlled within the tumor mass by IGFBP6-producing tumor cells; however, TMZ treatment eliminates this population and enriches the TMZ-resistant cell populationleading to accelerated growth of the entire tumor mass.


Role of orbital cortex in regulation of thalamocortical electrical activity.
The orbital region of the cortex in the cat is essential to the occurrence of spontaneous spindle bursts and thalamically induced recruiting responses, observed in both cortex and thalamus. Ablations of the entire dorsal convexity, and of the mesial and cingulate regions of the cortex, failed to interfere with the spindle bursts and recruiting responses, whereas ablations confined to the orbital cortex alone abolished completely these potentials in the cortex and thalamus. Therefore, the orbital cortex appears to be the only region of the neocortex to play a crucial role in the regulation of thalamocortical synchronizing and integrating functions. These functions are believed to be associated with a nonspecific system governing internal inhibition which manifests itself in inattention, drowsiness, and sleep.


Advances in luminescence-based technologies for drug discovery.
Luminescence-based technologies, specifically bioluminescence and chemiluminescence, are powerful tools with extensive use in drug discovery. Production of light during chemiluminescence and bioluminescence, unlike fluorescence, doesn't require an excitation light source, resulting in high signal-to-noise ratio, less background interference, and no issues from phototoxicity and photobleaching. These characteristics of luminescence technologies offer unique advantages for experimental designs, allowing for greater flexibility to target a wide range of proteins and biological processes for drug discovery at different stages. This review provides a basic overview of luciferase-based technologies and details recent advances and use cases of luciferase and luciferin variations and their applicability in the drug discovery toolset. The authors expand upon specific applications of luciferase technologies, including chemiluminescent and bioluminescent-based microscopy. Finally, the authors lay out forward-looking statements on the field of luminescence and how it may shape the translational scientists' work moving forward. The demand for improved luciferase and luciferin pairs correlates strongly with efforts to improve the sensitivity and robustness of high-throughput assays. As luminescent reporter systems improve, so will the expansion of use cases for luminescence-based technologies in early-stage drug discovery. With the synthesis of novel, non-enzymatic chemiluminescence-based probes, which previously were restrained to only basic research applications, they may now be readily implemented in drug discovery campaigns.


Inactivation of vaccinia virus by natural sunlight and by artificial UVB radiation.
This study determined the sensitivity of vaccinia virus, an orthopox virus commonly used as a surrogate for variola virus (etiological agent of smallpox), exposed to UVB radiation emitted by a solar simulator, or to direct natural sunlight. The data obtained indicate that: (1) the virucidal effect of natural sunlight can be mimicked adequately by an artificial light source with similar spectral characteristics in the UVB, (2) viral sensitivity to UVB or to solar radiation can be correlated with experimental data previously obtained with UVC, (3) the correlation factor between virus inactivation by solar radiation (measured at 300 ± 5 nm) and by UVC (254 nm) is between 33 and 60, and (4) the sensitivity of viruses either dry on glass surfaces or in liquid suspension is similar when in the presence of similar amounts of cellular debris and growth media. The findings reported in this study should assist in estimating the threat posed by the persistence of virus during epidemics or after an accidental or intentional release.