Ustekinumab as Induction and Maintenance Therapy for Crohn's Disease.
Ustekinumab, a monoclonal antibody to the p40 subunit of interleukin-12 and interleukin-23, was evaluated as an intravenous induction therapy in two populations with moderately to severely active Crohn's disease. Ustekinumab was also evaluated as subcutaneous maintenance therapy. We randomly assigned patients to receive a single intravenous dose of ustekinumab (either 130 mg or approximately 6 mg per kilogram of body weight) or placebo in two induction trials. The UNITI-1 trial included 741 patients who met the criteria for primary or secondary nonresponse to tumor necrosis factor (TNF) antagonists or had unacceptable side effects. The UNITI-2 trial included 628 patients in whom conventional therapy failed or unacceptable side effects occurred. Patients who completed these induction trials then participated in IM-UNITI, in which the 397 patients who had a response to ustekinumab were randomly assigned to receive subcutaneous maintenance injections of 90 mg of ustekinumab (either every 8 weeks or every 12 weeks) or placebo. The primary end point for the induction trials was a clinical response at week 6 (defined as a decrease from baseline in the Crohn's Disease Activity Index [CDAI] score of ≥100 points or a CDAI score <150). The primary end point for the maintenance trial was remission at week 44 (CDAI score <150). The rates of response at week 6 among patients receiving intravenous ustekinumab at a dose of either 130 mg or approximately 6 mg per kilogram were significantly higher than the rates among patients receiving placebo (in UNITI-1, 34.3%, 33.7%, and 21.5%, respectively, with P≤0.003 for both comparisons with placebo; in UNITI-2, 51.7%, 55.5%, and 28.7%, respectively, with P<0.001 for both doses). In the groups receiving maintenance doses of ustekinumab every 8 weeks or every 12 weeks, 53.1% and 48.8%, respectively, were in remission at week 44, as compared with 35.9% of those receiving placebo (P=0.005 and P=0.04, respectively). Within each trial, adverse-event rates were similar among treatment groups. Among patients with moderately to severely active Crohn's disease, those receiving intravenous ustekinumab had a significantly higher rate of response than did those receiving placebo. Subcutaneous ustekinumab maintained remission in patients who had a clinical response to induction therapy. (Funded by Janssen Research and Development; ClinicalTrials.gov numbers, NCT01369329 , NCT01369342 , and NCT01369355 .).


Magellan: a web based system for the integrated analysis of heterogeneous biological data and annotations; application to DNA copy number and expression data in ovarian cancer.
Recent advances in high throughput biological methods allow researchers to generate enormous amounts of data from a single experiment. In order to extract meaningful conclusions from this tidal wave of data, it will be necessary to develop analytical methods of sufficient power and utility. It is particularly important that biologists themselves be able to perform many of these analyses, such that their background knowledge of the experimental system under study can be used to interpret results and direct further inquiries. We have developed a web-based system, Magellan, which allows the upload, storage, and analysis of multivariate data and textual or numerical annotations. Data and annotations are treated as abstract entities, to maximize the different types of information the system can store and analyze. Annotations can be used in analyses/visualizations, as a means of subsetting data to reduce dimensionality, or as a means of projecting variables from one data type or data set to another. Analytical methods are deployed within Magellan such that new functionalities can be added in a straightforward fashion. Using Magellan, we performed an integrated analysis of genome-wide comparative genomic hybridization (CGH), mRNA expression, and clinical data from ovarian tumors. Analyses included the use of permutation-based methods to identify genes whose mRNA expression levels correlated with patient survival, a nearest neighbor classifier to predict patient survival from CGH data, and curated annotations such as genomic position and derived annotations such as statistical computations to explore the quantitative relationship between CGH and mRNA expression data.


Increasing proportion of carbapenemase-producing Enterobacteriaceae and emergence of a MCR-1 producer through a multicentric study among hospital-based and private laboratories in Belgium from September to November 2015.
Carbapenemase-producing Enterobacteriaceae (CPE) strains have been increasingly reported in Belgium. We aimed to determine the proportion of CPE among Enterobacteriaceae isolated from hospitalised patients and community outpatients in Belgium in 2015. For the hospitalised patients, the results were compared to a previous similar survey performed in the same hospitals in 2012. Twenty-four hospital-based and 10 private laboratories collected prospectively 200 non-duplicated Enterobacteriaceae isolates from clinical specimens. All isolates were screened locally by carbapenem disk diffusion using European Committee on Antimicrobial Susceptibility Testing methodology. Putative CPE strains with inhibition zone diameters below the screening breakpoints were referred centrally for confirmation of carbapenemase production. From September to November 2015, we found a proportion of clinical CPE of 0.55% (26/4,705) and of 0.60% (12/1,991) among hospitalised patients and among ambulatory outpatients respectively. Klebsiella pneumoniae (26/38) and OXA-48-like carbapenemase (28/38) were the predominant species and enzyme among CPE. One OXA-48-producing Escherichia coli isolated from a hospital was found carrying plasmid-mediated MCR-1 colistin resistance. Compared with the 2012 survey, we found a significant increased proportion of clinical CPE (0.55% in 2015 vs 0.25% in 2012; p = 0.02) and an increased proportion of hospitals (13/24 in 2015 vs 8/24 in 2012) with at least one CPE detected. The study results confirmed the concerning spread of CPE including a colistin-resistant MCR-1 producer in hospitals and the establishment of CPE in the community in Belgium.


Reversible Oligonucleotide Chain Blocking Enables Bead Capture and Amplification of T-Cell Receptor α and β Chain mRNAs.
Next-generation sequencing (NGS) has proven to be an exceptionally powerful tool for studying genetic variation and differences in gene expression profiles between cell populations. However, these population-wide studies are limited by their inability to detect variation between individual cells within a population, inspiring the development of single-cell techniques such as Drop-seq, which add a unique barcode to the mRNA from each cell prior to sequencing. Current Drop-seq technology enables capture, amplification, and barcoding of the entire mRNA transcriptome of individual cells. NGS can then be used to sequence the 3'-end of each message to build a cell-specific transcriptional landscape. However, current technology does not allow high-throughput capture of information distant from the mRNA poly-A tail. Thus, gene profiling would have much greater utility if beads could be generated having multiple transcript-specific capture sequences. Here we report the use of a reversible chain blocking group to enable synthesis of DNA barcoded beads having capture sequences for the constant domains of the T-cell receptor α and β chain mRNAs. We demonstrate that these beads can be used to capture and pair TCRα and TCRβ sequences from total T-cell RNA, enabling reverse transcription and PCR amplification of these sequences. This is the first example of capture beads having more than one capture sequence, and we envision that this technology will be of high utility for applications such as pairing the antigen receptor chains that give rise to autoimmune diseases or measuring the ratios of mRNA splice variants in cancer stem cells.


Slope distribution of a rough surface measured by transmission scattering and polarization.
Transmission scattering from medium to air was used to measure the slope distribution of the rough plane surface of a transparent glass hemisphere. A facet model successfully explained the measured results of refraction, scattering, and polarization: Transmission scattering existed for incident angles greater than the critical angle, all measured curves for the normalized scattered intensity versus the facet slope angle for different detection directions overlapped, and the measured polarization of scattering was approximately constant for >99% of the facets. The slope distribution obtained by transmission scattering agrees with those of the surface profiles in the valid range of the profiler and can represent the slope distribution of the rough surface.


C-reactive protein upregulates the whole blood expression of CD59 - an integrative analysis.
Elevated C-reactive protein (CRP) concentrations in the blood are associated with acute and chronic infections and inflammation. Nevertheless, the functional role of increased CRP in multiple bacterial and viral infections as well as in chronic inflammatory diseases remains unclear. Here, we studied the relationship between CRP and gene expression levels in the blood in 491 individuals from the Estonian Biobank cohort, to elucidate the role of CRP in these inflammatory mechanisms. As a result, we identified a set of 1,614 genes associated with changes in CRP levels with a high proportion of interferon-stimulated genes. Further, we performed likelihood-based causality model selection and Mendelian randomization analysis to discover causal links between CRP and the expression of CRP-associated genes. Strikingly, our computational analysis and cell culture stimulation assays revealed increased CRP levels to drive the expression of complement regulatory protein CD59, suggesting CRP to have a critical role in protecting blood cells from the adverse effects of the immune defence system. Our results show the benefit of integrative analysis approaches in hypothesis-free uncovering of causal relationships between traits.


Performance of a membrane bioreactor in extreme concentrations of bisphenol A.
In this study, a submerged membrane bioreactor was used to study the effect of low and high bisphenol A (BPA) concentration on the sludge biological activity. The pilot was operated over 540 days with hydraulic retention time and solid retention time of 5.5 hours and 140 days, respectively. As a hydrophobic compound, BPA was highly adsorbed by activated sludge. In lower concentrations, the biodegradation rate remained low, since the BPA concentration in the sludge was lower than 0.5 mg/g TS; yet, at an influent concentration up to 15 mg/L, the biodegradation rate was increasing, resulting in 99% BPA removal efficiency. The result for chemical oxygen demand removal showed that BPA concentration has no effect on the heterotrophic bacteria that were responsible for the organic carbon degradation. In higher concentrations, up to 16 mg of BPA was used for each gram of sludge as a source of carbon. However, the activity of autotrophic bacteria, including nitrifiers, was completely halted in the presence of 20 mg/L of BPA or more. Although nitrification was stopped after day 400, ammonia removal remained higher than 70% due to air stripping. Assimilation by bacteria was the only removal pathway for phosphorus, which resulted in an average 35% of P-PO4 removal efficiency.


Breastfeeding, the immune response, and long-term health.
Breastfeeding provides unsurpassed natural nutrition to the newborn and infant. Human breast milk also contains numerous protective factors against infectious disease and may influence immune system development, as noted in previous studies of infant response to vaccination and thymus gland development. If immune system development is significantly improved with the introduction of components of breast milk, then prematurely discontinued breastfeeding may facilitate pathogenesis of many chronic diseases later in life (eg, autoimmune disorders). The authors summarize the reported effects of breastfeeding on the development of the suckling infant's immune system and discuss possible consequences to immunologic health when breastfeeding is discontinued prematurely.


Attitude of Law and Medical Students to Oocyte Donation.
Among the young generation, medical and law students' attitude towards third party reproduction is very important because they will be directly involved in restricting or developing the programs that will support it in the future. The aim of this survey was to investigate attitude of law and medical students to oocyte donation and key aspects of this kind of third party. In analytical cross-sectional study, 345 medical and law students were randomly selected using stratified sampling. Data was collected using attitude toward donation- oocyte (ATOD-O) questionnaire. Responses were on a 5-point Likert scale. Data were analyzed according to established statistical approach by Heeren and D'Agostino. The majority of the participants agreed with oocyte donation being the last choice for infertility treatment. There was a significant difference between medical students and law students regarding the acceptance of oocyte donation (3.23 vs. 3.53, P=0.025). In addition, female participants were more tolerant on receiving donated oocytes from their sisters than male participants (3.01 vs. 2.58, P=0.002) and finally, a higher number of the participants had a positive attitude towards anonymity of the donor and the recipient to one another (3.93 vs. 3.86, P=0.580). The vast majority of female students believed that the oocyte recipient naturally likes that child (P<0.0001). In the current study, a great majority of law and medical students support oocyte donation as an alternative way of starting a family. There is an interest among female students in donating oocytes anonymously. The majority believed that the oocyte recipient family will like the donor oocyte child naturally.


Home FES: An Exploratory Review.
This review of literature focuses on the multiple uses of Functional Electrical Stimulation (FES) and how this modality may be a valuable home-based therapy. Papers pertaining to home FES exercise were collected using the Web of Science, Google Scholar databases and collegial hints. In our opinion, the following statements summarize the results. FES may be used to induce health benefits in populations with paralysis, and in persons with musculoskeletal, cardiorespiratory and renal pathology. The EU Project Rise showed how FES could have a variety of encouraging outcomes for patients with denervated muscles following traumatic injuries. As suggested by recent literature, FES has proven to be a viable form of exercise for elderly individuals. Thus, Home FES may be an option for patients looking for an additional form of muscle and cardiopulmonary physical therapy.


Antibiotic prescription strategies for acute sore throat: a prospective observational cohort study.
Data from trials suggest that antibiotics reduce the risk of complications of sore throat by at least 50%, but few trials for complications have been done in modern settings, and datasets of delayed antibiotic prescription are underpowered. Observational evidence is important in view of poor compliance with antibiotic treatment outside trials, but no prospective observational cohort studies have been done to date. We generated a large prospective cohort from the DESCARTE study, and the PRISM component of DESCARTE, of 12,829 adults presenting with sore throat (≤ 2 weeks duration) in primary care. Our follow-up of the cohort was based on a detailed and structured review of routine medical records, and analysis of the comparison of three antibiotic prescription strategies (no antibiotic prescription, immediate antibiotic prescription, and delayed antibiotic prescription) to control for the propensity to prescribe antibiotics. Information about antibiotic prescription was recorded in 12,677 individuals (4805 prescribed no antibiotics, 6088 prescribed antibiotics immediately, and 1784 prescribed delayed antibiotics). We documented by review of patients' notes (n=11,950) the development of suppurative complications (eg, quinsy, impetigo and cellulitis, otitis media, and sinusitis) or reconsultation with new or non-resolving symptoms). We used multivariate analysis to control for variables significantly related to the propensity to prescribe antibiotics and for clustering by general practitioner. 164 (1.4%) of the 11,950 patients with information available developed complications; otitis media and sinusitis were the most common complications (101 patients [62%]). Compared with no antibiotic prescription, immediate antibiotic prescription was associated with fewer complications (adjusted risk ratio [RR] 0.62, 95% CI 0.43-0.91, estimated number needed to treat [NNT 193) as was delayed prescription of antibiotics (0.58, 0.34-0.98; NNT 174). 1787 of the 11,950 patients (15%) reconsulted with new or non-resolving symptoms; the risk of reconsultation was also reduced by immediate (0.83, 0.73-0.94; NNT 40) or delayed antibiotics (0.61, 0.50-0.74; NNT 18). Suppurative complications are not common in primary care and most are not serious. The risks of suppurative complications or reconsultation in adults are reduced by antibiotics, but not as much as the trial evidence suggests. In most cases, no antibiotic is needed, but a delayed prescription strategy is likely to provide similar benefits to an immediate antibiotic prescription.


Perceptual organization of speech signals by children with and without dyslexia.
Developmental dyslexia is a condition in which children encounter difficulty learning to read in spite of adequate instruction. Although considerable effort has been expended trying to identify the source of the problem, no single solution has been agreed upon. The current study explored a new hypothesis, that developmental dyslexia may be due to faulty perceptual organization of linguistically relevant sensory input. To test that idea, sentence-length speech signals were processed to create either sine-wave or noise-vocoded analogs. Seventy children between 8 and 11 years of age, with and without dyslexia participated. Children with dyslexia were selected to have phonological awareness deficits, although those without such deficits were retained in the study. The processed sentences were presented for recognition, and measures of reading, phonological awareness, and expressive vocabulary were collected. Results showed that children with dyslexia, regardless of phonological subtype, had poorer recognition scores than children without dyslexia for both kinds of degraded sentences. Older children with dyslexia recognized the sine-wave sentences better than younger children with dyslexia, but no such effect of age was found for the vocoded materials. Recognition scores were used as predictor variables in regression analyses with reading, phonological awareness, and vocabulary measures used as dependent variables. Scores for both sorts of sentence materials were strong predictors of performance on all three dependent measures when all children were included, but only performance for the sine-wave materials explained significant proportions of variance when only children with dyslexia were included. Finally, matching young, typical readers with older children with dyslexia on reading abilities did not mitigate the group difference in recognition of vocoded sentences. Conclusions were that children with dyslexia have difficulty organizing linguistically relevant sensory input, but learn to do so for the structure preserved by sine-wave signals before they do so for other sorts of signal structure. These perceptual organization deficits could account for difficulties acquiring refined linguistic representations, including those of a phonological nature, although ramifications are different across affected children.


An innovative peer assessment approach to enhance guideline adherence in physical therapy: single-masked, cluster-randomized controlled trial.
Clinical practice guidelines (CPGs) are not readily implemented in clinical practice. One of the impeding factors is that physical therapists do not hold realistic perceptions of their adherence to CPGs. Peer assessment (PA) is an implementation strategy that aims at improving guideline adherence by enhancing reflective practice, awareness of professional performance, and attainment of personal goals. The purpose of this study was to compare the effectiveness of PA with the usual case discussion (CD) strategy on adherence to CPGs for physical therapist management of upper extremity complaints. A single-masked, cluster-randomized controlled trial with pretest-posttest design was conducted. Twenty communities of practice (n=149 physical therapists) were randomly assigned to groups receiving PA or CD, with both interventions consisting of 4 sessions over 6 months. Both PA and CD groups worked on identical clinical cases relevant to the guidelines. Peer assessment focused on individual performance observed and evaluated by peers; CD focused on discussion. Guideline adherence was measured with clinical vignettes, reflective practice was measured with the Self-Reflection and Insight Scale (SRIS), awareness of performance was measured via the correlation between perceived and assessed improvement, and attainment of personal goals was measured with written commitments to change. The PA groups improved more on guideline adherence compared with the CD groups (effect=22.52; 95% confidence interval [95% CI]=2.38, 42.66; P=.03). The SRIS scores did not differ between PA and CD groups. Awareness of performance was greater for the PA groups (r=.36) than for the CD groups (r=.08) (effect=14.73; 95% CI=2.78, 26.68; P=.01). The PA strategy was more effective than the CD strategy in attaining personal goals (effect=0.50; 95% CI=0.04, 0.96; P=.03). Limited validity of clinical vignettes as a proxy measure of clinical practice was a limitation of the study. Peer assessment was more effective than CD in improving adherence to CPGs. Personal feedback may have contributed to its effectiveness. Future research should address the role of the group coach.


Development and Validation of a Simple Ultrasound Activity Score for Crohn's Disease.
To improve management of patients with Crohn's disease, objective measurements of disease activity are needed. Ileocolonoscopy is the current reference standard but has limitations that restrict repeated use. Ultrasonography is potentially useful for activity monitoring, but no validated sonographic activity index is currently in widespread use. Thus, we aimed to construct and validate a simple ultrasound score for Crohn's disease. Forty patients were prospectively examined with ultrasound and endoscopy in the development phase. The Simple Endoscopic Score for Crohn's Disease [SES-CD] was used as a reference standard. Seven ultrasound variables [bowel wall thickness, length, colour Doppler, stenosis, fistula, stratification and fatty wrapping] were initially included, and multiple linear regression was used to select the variables that should be included in the final score. Second, the ultrasound data from each patient were re-examined for interobserver assessment using weighted kappa and intraclass correlation. Finally, the activity index was validated in a new cohort of 124 patients. Length, fistula and stenosis were excluded. The combination of the remaining variables provided a multiple correlation coefficient of r = 0.78. Interobserver analysis revealed poor agreement for stratification and fatty wrapping and these were thus excluded. There was excellent interobserver agreement for the remaining score consisting of wall thickness and colour Doppler. In both patient cohorts, the ultrasound score correlated well with SES-CD [Development cohort: rho = 0.83, p < 0.001, Validation cohort: rho = 0.78, p < 0.001]. A receiver operating characteristic curve analysis revealed an area under the curve of 0.92 and 0.88 for detecting endoscopic activity and moderate endoscopic activity, respectively. A simple ultrasound activity index for Crohn's disease consisting of bowel wall thickness and colour Doppler was constructed and validated and correlated well with endoscopic disease activity.ClinicalTrials. gov ID: NCT03481751.


Safety limit warning levels for the avoidance of excessive sound amplification to protect against further hearing loss.
To determine safe output sound pressure levels (SPL) for sound amplification devices to preserve hearing sensitivity after usage. A mathematical model consisting of the Modified Power Law (MPL) (Humes & Jesteadt, 1991 ) combined with equations for predicting temporary threshold shift (TTS) and subsequent permanent threshold shift (PTS) (Macrae, 1994b ) was used to determine safe output SPL. The study involves no new human subject measurements of loudness tolerance or threshold shifts. PTS was determined by the MPL model for 234 audiograms and the SPL output recommended by four different validated prescription recommendations for hearing aids. PTS can, on rare occasion, occur as a result of SPL delivered by hearing aids at modern day prescription recommendations. The trading relationship of safe output SPL, decibel hearing level (dB HL) threshold, and PTS was captured with algebraic expressions. Better hearing thresholds lowered the safe output SPL and higher thresholds raised the safe output SPL. Safe output SPL can consider the magnitude of unaided hearing loss. For devices not set to prescriptive levels, limiting the output SPL below the safe levels identified should protect against threshold worsening as a result of long-term usage.


Feasibility of percutaneous implantation of transapical endocardial left ventricular pacing electrode for cardiac resynchronization therapy.
Failure of coronary sinus lead implantation for resynchronization therapy requires alternative approaches. For such events we have developed a transapical implantation technique as a feasible alternative. We report the outcome of this technique and its evolution from a minithoracotomy to a percutaneous approach. Twenty patients underwent alternative resynchronization therapy with transapical endocardial left ventricular (LV) pacing lead implantation in a multicentre, international study between October 2007 and March 2010. Eighteen patients underwent minithoracotomy and transapical puncture under direct observation. Two recent patients had transthoracic echocardiography-guided percutaneous apical puncture to enter the LV cavity. A 19 or 21 ga needle and two-stage Seldinger dilatation with 4 and 7 Fr sheaths were then used to introduce the lead. In the two patients with closed-chest insertion of the electrode there was no puncture related bleeding or lung damage. Lead dislocation occurred in two minithoracotomy patients. Repositioning was performed without re-opening the pleural cavity. One patient developed right-sided implanted cardiac defibrillator lead endocarditis requiring complete system removal. Twelve patients have >1 year follow-up; all have sustained and significant improvement in LV dimensions (diastolic Δ4.2 ± 2.9, systolic Δ7.2 ± 5.8 mm), ejection fraction (Δ9.5 ± 9.6%), and functional status (Δ1.1 ± 0.3). Transapical placement of LV endocardial pacing lead is an effective alternative strategy for cardiac resynchronization. A closed-chest, percutaneous approach is feasible and should offer even less invasive intervention.


Histone deacetylation critically determines T cell subset radiosensitivity.
Lymphocytes are sensitive to ionizing radiation and naive lymphocytes are more radiosensitive than their memory counterparts. Less is known about radiosensitivity of memory cell subsets. We examined the radiosensitivity of naive (TN), effector memory (TEM), and central memory (TCM) T cell subsets in C57BL/6 mice and found TEM to be more resistant to radiation-induced apoptosis than either TN or TCM. Surprisingly, we found no correlation between the extent of radiation-induced apoptosis in T cell subsets and 1) levels of pro- and antiapoptotic Bcl-2 family members or 2) the H2AX content and maximal γH2AX fold change. Rather, TEM cell survival correlated with higher levels of immediate γH2AX marking, immediate break binding and genome-wide open chromatin structure. T cells were able to mark DNA damage seemingly instantly (30 s), even if kept on ice. Relaxing chromatin with the histone deacetylase inhibitor valproic acid following radiation or etoposide treatment improved the survival of TCM and TN cells up to levels seen in the resistant TEM cells but did not improve survival from caspase-mediated apoptosis. We conclude that an open genome-wide chromatin state is the key determinant of efficient immediate repair of DNA damage in T cells, explaining the observed T cell subset radiosensitivity differences.


Growth response of Lebanon cedar (Cedrus libani) plantations to thinning intensity in Western Turkey.
This paper presents the growth response of 25 yr old Lebanon cedar (Cedrus libani A. Rich.) plantation to thinnings of different intensities in Isparta in western Turkey. The thinning intensity was measured by using the residual basal area (%) as parameter. In spring of 2005, three treatments were tested; light, moderate and heavy thinning with respectively 10, 25 and 35% of basal area removed. The statistical design of the experiment was a randomized incomplete block with two blocks and three treatments. Variables such as diameter at breast height (diameter) and height were measured. Growth rate ratios of diameter in moderately thinned and heavily thinned stands were 1.02 and 1.03, respectively. Basal area growth rates in moderately thinned and heavily thinned plots were 0.93 and 1.05, respectively. The largest values for the mean tree were observed with the heaviest thinning treatment. Absolute diameter increment was positively correlated with initial diameter in all plots. Relative diameter growth was negatively correlated with initial diameter. Growth rate interpretations were supported by analysis of variance using Duncan's test of range multiple. The results obtained show significant differences between treatments for tree height growth, for the two inventories carried out (2005, 2008). However diameter basal area and volume were no found between treatments for tree.


Sleep deprivation and activation of morning levels of cellular and genomic markers of inflammation.
Inflammation is associated with increased risk of cardiovascular disorders, arthritis, diabetes mellitus, and mortality. The effects of sleep loss on the cellular and genomic mechanisms that contribute to inflammatory cytokine activity are not known. In 30 healthy adults, monocyte intracellular proinflammatory cytokine production was repeatedly assessed during the day across 3 baseline periods and after partial sleep deprivation (awake from 11 pm to 3 am). We analyzed the impact of sleep loss on transcription of proinflammatory cytokine genes and used DNA microarray analyses to characterize candidate transcription-control pathways that might mediate the effects of sleep loss on leukocyte gene expression. In the morning after a night of sleep loss, monocyte production of interleukin 6 and tumor necrosis factor alpha was significantly greater compared with morning levels following uninterrupted sleep. In addition, sleep loss induced a more than 3-fold increase in transcription of interleukin 6 messenger RNA and a 2-fold increase in tumor necrosis factor alpha messenger RNA. Bioinformatics analyses suggested that the inflammatory response was mediated by the nuclear factor kappaB inflammatory signaling system as well as through classic hormone and growth factor response pathways. Sleep loss induces a functional alteration of the monocyte proinflammatory cytokine response. A modest amount of sleep loss also alters molecular processes that drive cellular immune activation and induce inflammatory cytokines; mapping the dynamics of sleep loss on molecular signaling pathways has implications for understanding the role of sleep in altering immune cell physiologic characteristics. Interventions that target sleep might constitute new strategies to constrain inflammation with effects on inflammatory disease risk.


Chronic common carotid occlusion.
Twelve patients with chronic common carotid artery (CCA) occlusion were studied. There were 8 patients with TIAs (3 hemispheric and 5 vertebral-basilar), one with a completed stroke, and 3 were asymptomatic. The ipsilateral internal carotid artery (ICA) was confirmed patent in 6 patients at the time of operation, although angiograms had demonstrated patency in only two. The ipsilateral external carotid artery (ECA) was patent in all but one patient. Arterial reconstructions were done on 7 patients. The carotid bifurcation was revascularized by subclavian-to-carotid bypass grafts in 5 patients, 3 with vertebral-basilar (V-B) TIAs, one with hemispheric TIAs, and one with a completed stroke. Vertebral revascularization was done on 2 patients, one with V-B TIAs and one who was asymptomatic. All revascularized patients had satisfactory results. Symptomatic patients can be treated by cerebral revascularization through either the ICA, if patent, the ECA via the ophthalmic collaterals, or through the vertebrals when hypoperfused. The ICA is preferentially revascularized and exploration often reveals a patent ICA that was not visualized angiographically. Recently, directional Doppler studies have proved useful in determining ICA patency.


Sex differences in smoking constructs and abstinence: The explanatory role of smoking outcome expectancies.
Scientific evidence suggests women experience more severe problems when attempting to quit smoking relative to men. Yet, little work has examined potential explanatory variables that maintain sex differences in clinically relevant smoking processes. Smoking outcome expectancies have demonstrated sex differences and associative relations with the smoking processes and behavior, including problems when attempting to quit, smoking-specific experiential avoidance, perceived barriers to quitting, and smoking abstinence. Thus, expectancies about the consequences of smoking may explain sex differences across these variables. Accordingly, the current study examined the explanatory role of smoking-outcome expectancies (e.g., long-term negative consequences, immediate negative consequences, sensory satisfaction, negative affect reduction, and appetite weight control) in models of sex differences across cessation-related problems, smoking-specific experiential avoidance, perceived barriers to quitting, and smoking abstinence. Participants included 450 (48.4% female; Mage = 37.45, SD = 13.50) treatment-seeking adult smokers. Results indicated that sex had an indirect effect on problems when attempting to quit smoking through immediate negative consequences and negative affect reduction expectancies; on smoking-specific experiential avoidance through long-term negative consequences, immediate negative consequences, and negative affect reduction expectancies; on barriers to quitting through negative affect reduction expectancies; and on abstinence through appetite weight control expectancies. The current findings suggest that sex differences in negative affect reduction expectancies and negative consequences expectancies may serve to maintain maladaptive smoking processes, whereas appetite weight control expectancies may promote short-term abstinence. These findings provide initial evidence for the conceptual role of smoking expectancies as potential "linking variables" for sex differences in smoking variables. (PsycINFO Database Record


Early adoption of non-pharmaceutical interventions and COVID-19 mortality.
To contain the spread of the COVID-19 pandemic, many countries around the globe have adopted social distancing measures. Yet, establishing the causal effect of non-pharmaceutical interventions (NPIs) is difficult because they do not occur arbitrarily. We exploit a quasi-random source of variation for identification purposes -namely, regional differences in the placement on the pandemic curve following an unexpected and nationwide lockdown. Our results reveal that regions where the outbreak had just started when the lockdown was implemented had 1.62 fewer daily deaths per 100,000 inhabitants when compared to regions for which the lockdown arrived 10+ days after the pandemic's outbreak. As a result, a total of 4,642 total deaths (232 deaths/daily) could have been avoided by the end of our period of study -a figure representing 23% of registered deaths in Spain at the time. We rule out differential pre-COVID mortality trends and self-distancing behaviors across the compared regions prior to the swift lockdown, which was also uniformly observed nationwide. In addition, we provide supporting evidence for contagion deceleration as the main mechanism behind the effectiveness of the early adoption of NPIs in lowering the death rate, rather than an increased healthcare capacity.


Ageing of atrazine in manure amended soils assessed by bioavailability to Pseudomonas sp. strain ADP.
Animal manure is applied to agricultural land in areas of high livestock production. In the present study, we evaluated ageing of atrazine in two topsoils with and without addition of manure and in one subsoil. Ageing was assessed as the bioavailability of atrazine to the atrazine mineralizing bacteria Pseudomonas sp. strain ADP. Throughout an ageing period of 90 days bioavailability was investigated at days 1, 10, 32, 60 and 90, where ~10(8) cells g(-1) of the ADP strain was inoculated to the (14)C-atrazine exposed soil and (14)CO2 was collected over 7 days as a measure of mineralized atrazine. Even though the bioavailable residue decreased in all of the three soils as time proceeded, we found that ageing occurred faster in the topsoils rich in organic carbon than in subsoil. For one topsoil rich in organic carbon content, Simmelkær, we observed a higher degree of ageing when treated with manure. Contrarily, sorption experiments showed less sorption to Simmelkær treated with manure than the untreated soil indicating that sorption processes are not the only mechanisms of ageing. The other topsoil low in organic carbon content, Ringe, showed no significant difference in ageing between the manure-treated and untreated soil. The present study illustrates that not simply the organic carbon content influences adsorption and ageing of atrazine in soil but the origin and composition of organic matter plays an important role.


Clinical and public health implications of acute and early HIV detection and treatment: a scoping review.
The unchanged global HIV incidence may be related to ignoring acute HIV infection (AHI). This scoping review examines diagnostic, clinical, and public health implications of identifying and treating persons with AHI. We searched PubMed, in addition to hand-review of key journals identifying research pertaining to AHI detection and treatment. We focused on the relative contribution of AHI to transmission and the diagnostic, clinical, and public health implications. We prioritized research from low- and middle-income countries (LMICs) published in the last fifteen years. Extensive AHI research and limited routine AHI detection and treatment have begun in LMIC. Diagnostic challenges include ease-of-use, suitability for application and distribution in LMIC, and throughput for high-volume testing. Risk score algorithms have been used in LMIC to screen for AHI among individuals with behavioural and clinical characteristics more often associated with AHI. However, algorithms have not been implemented outside research settings. From a clinical perspective, there are substantial immunological and virological benefits to identifying and treating persons with AHI - evading the irreversible damage to host immune systems and seeding of viral reservoirs that occurs during untreated acute infection. The therapeutic benefits require rapid initiation of antiretrovirals, a logistical challenge in the absence of point-of-care testing. From a public health perspective, AHI diagnosis and treatment is critical to: decrease transmission via viral load reduction and behavioural interventions; improve pre-exposure prophylaxis outcomes by avoiding treatment initiation for HIV-seronegative persons with AHI; and, enhance partner services via notification for persons recently exposed or likely transmitting. There are undeniable clinical and public health benefits to AHI detection and treatment, but also substantial diagnostic and logistical barriers to implementation and scale-up. Effective early ART initiation may be critical for HIV eradication efforts, but widespread use in LMIC requires simple and accurate diagnostic tools. Implementation research is critical to facilitate sustainable integration of AHI detection and treatment into existing health systems and will be essential for prospective evaluation of testing algorithms, point-of-care diagnostics, and efficacious and effective first-line regimens.


LED-controlled tuning of ZnO nanowires' wettability for biosensing applications.
Wettability is an important property of solid materials which can be controlled by surface energy. Dynamic control over the surface wettability is of great importance for biosensing applications. Zinc oxide (ZnO) is a biocompatible material suitable for biosensors and microfluidic devices. Nanowires of ZnO tend to show a hydrophobic nature which decelerates the adhesion or adsorption of biomolecules on the surface and, therefore, limits their application. Surface wettability of the ZnO nanowires can be tuned using light irradiation. However, the control over wettability using light-emitting diodes (LEDs) and the role of wavelength in controlling the wettability of ZnO nanowires are unclear. This is the first report on LED-based wettability control of nanowires, and it includes investigations on tuning the desired wettability of ZnO nanowires using LEDs as a controlling tool. The investigations on spectral properties of the LED emission on ZnO nanowires' wettability have shown strong dependency on the spectral overlap of LED emission on ZnO absorption spectra. Results indicate that LEDs offer an advanced control on dynamically tuning the wettability of ZnO nanowires. The spectral investigations have provided significant insight into the role of irradiating wavelength of light and irradiation time on the surface wettability of ZnO nanowires. This process is suitable to realize on chip based integrated sensors and has huge potential for eco-friendly biosensing and environmental sensing applications.


Atypical Presentation of Primary Cutaneous CD8 Positive Aggressive Epidermotropic Cytotoxic T-Cell Lymphoma.
Primary cutaneous CD8 positive aggressive epidermotropic cytotoxic T-cell lymphoma (PCAT) is a rare and heterogeneous entity with less than 100 published cases to date. A 68-year-old man was following up for an inflammatory lichen-lupus overlap dermatosis of 3 years duration. Treatment with methotrexate was started, observing a dramatic change in the skin lesions that became infiltrated plaques and generalized ulcerated tumours distributed over trunk and extremities. Histological study showed marked epidermotropism of CD8 positive cells and monoclonality was demonstrated by the polymerase chain reaction. Diagnosis of PCAT was concluded. Treatment with polychemotherapy was indicated. The PCAT is characterized by a rapid clinical history of generalized papules, plaques, nodules and tumours with frequent ulceration and necrosis. Although it has no pathognomonic clinical features, there are clinical, histological and prognostic data that define them as a group and differentiate them from other lymphomas. Exceptionally, there are cases reported which have been triggered following treatment with immunosuppressive drugs. In our patient we think that PCAT was triggered by the transformation of a pre-existing dermatosis, which had never showed a lymphoproliferative profile in biopsies before. A possible pathogenic mechanism is that in some inflammatory dermatoses, chronic antigenic stimulation in a situation of iatrogenic immunosuppression may favour the development of a malignant clonal T cell.


Syncope.
Syncope is a prevalent syndrome with diverse causes, which have in common a sudden transient failure of the autonomic nervous system to maintain blood pressure against the force of gravity at a level sufficient for cerebral perfusion. Neurally mediated syncope is an episodic phenomenon in which autonomic nervous system function is normal the rest of the time. Although relatively benign, syncope increases the risk for injury from falling and can substantially impair patients' quality of life. Recognition of its various clinical presentations and knowledge of the underlying pathophysiology are essential for accurate diagnosis and successful management. The most effective forms of treatment remain education of patients, avoidance of triggers, physical counterpressure maneuvers, and hydration or intravascular volume expansion. Pharmacologic interventions may be appropriate for some patients but, in general, have limited evidence of efficacy in preventing syncope. Based on the findings of a recent study, the possibility of pulmonary embolism should be considered in patients hospitalized for syncope, whether or not an alternative etiology for syncope is identified. This article focuses on the neurologic diagnosis, differential diagnosis, physiology, and management strategies for syncope, with an emphasis on neurally mediated syncope.


Masturbation frequency and sexual function domains are associated with serum reproductive hormone levels across the menopausal transition.
To determine whether reproductive hormones are related to sexual function during the menopausal transition. The Study of Women's Health Across the Nation (SWAN) is a multiethnic cohort study of the menopausal transition located at seven US sites. At baseline, the 3302 community-based participants, aged 42-52, had an intact uterus and at least one ovary and were not using exogenous hormones. Participants self-identified as White, Black, Hispanic, Chinese, or Japanese. At baseline and at each of the 10 follow-up visits, sexual function was assessed by self-administered questionnaires, and blood was drawn to assay serum levels of T, estradiol, FSH, SHBG, and dehydroepiandrosterone sulfate. Self-reported frequency of masturbation, sexual desire, sexual arousal, orgasm, and pain during intercourse. Masturbation, sexual desire, and arousal were positively associated with T. Masturbation, arousal, and orgasm were negatively associated with FSH. Associations were modest. Estradiol was not related to any measured sexual function domain. Pain with intercourse was not associated with any hormone. Reproductive hormones were associated with sexual function in midlife women. T was positively associated, supporting the role of androgens in female sexual function. FSH was negatively associated, supporting the role of menopausal status in female sexual function. The modest associations in this large study suggest that the relationships are subtle and may be of limited clinical significance.


Tidal pressure/volume and flow/volume respiratory loop patterns in human neonates.
1. Tidal pressure/volume and flow/volume respiratory loops were constructed from records obtained during 98 studies on 48 neonates of various ages and gestations. Records were obtained with a total body plethysmograph and an oesophageal balloon. Total pulmonary resistance was computed at five separate levels in the breathing cycle and results were expressed graphically as tidal resistance profiles by plotting total pulmonary resistance against percentage tidal volume above functional residual capacity. 2. Values obtained for standard pulmonary mechanical measurements and thoracic gas volume were similar to those of other workers. In addition six distinctive resistance profile patterns were found and related to different breathing patterns. 3. The technique appeared to be particularly useful in identifying air trapping and also demonstrated that total pulmonary resistance is open to misinterpretation when measured only at the mid-tidal-volume level, as is the present convention.


Interleukin-10 suppresses tissue factor expression in lipopolysaccharide-stimulated macrophages via inhibition of Egr-1 and a serum response element/MEK-ERK1/2 pathway.
Atherosclerosis is considered to be an inflammatory disease. Tissue factor (TF), a prothrombotic molecule expressed by various cell types within atherosclerotic plaques, is thought to play an essential role in thrombus formation after atherosclerotic plaque rupture. Recent studies suggest that the antiinflammatory cytokine interleukin-10 (IL-10) has many antiatherosclerotic properties. Therefore, the effects of IL-10 on TF expression in response to inflammation were investigated. Mouse macrophages were stimulated with lipopolysaccharide (LPS) in the presence or absence of IL-10. Pretreatment with IL-10 resulted in a 50% decrease in TF mRNA expression and TF promoter activity. Binding of early growth response gene-1 (Egr-1) to the consensus DNA sequence, a key transcriptional activator of TF expression in response to inflammation, and the expression of Egr-1 mRNA were also inhibited by IL-10. This inhibition was independent of the induction of suppressor of cytokine signaling protein-3 by IL-10. Macrophages that had been transfected with luciferase reporter constructs containing the murine Egr-1 5'-flanking sequence exhibited reduced reporter gene activity in response to LPS stimulation with IL-10 pretreatment. Studies with deletion constructs of the Egr-1 promoter identified the proximal serum response element SRE3 as a potential regulatory site for the IL-10 mediated suppression of Egr-1 expression. Furthermore, activation of the upstream signal-transduction elements, such as mitogen-activated protein kinase kinase (MEK) 1/2, extracellular signal-regulated kinase 1/2, and Elk-1 were also inhibited by IL-10 pretreatment. Taken together, these results demonstrate a pathway for the IL-10 mediated inhibition of TF expression during inflammation and may explain the antiatherosclerotic effects of IL-10.


SHP2 inhibitor protects AChRs from effects of myasthenia gravis MuSK antibody.
To determine whether an SRC homology 2 domain-containing phosphotyrosine phosphatase 2 (SHP2) inhibitor would increase muscle-specific kinase (MuSK) phosphorylation and override the inhibitory effect of MuSK-antibodies (Abs). The effect of the SHP2 inhibitor NSC-87877 on MuSK phosphorylation and AChR clustering was tested in C2C12 myotubes with 31 MuSK-myasthenia gravis (MG) sera and purified MuSK-MG IgG4 preparations. In the absence of MuSK-MG Abs, NSC-87877 increased MuSK phosphorylation and the number of AChR clusters in C2C12 myotubes in vitro and in DOK7-overexpressing C2C12 myotubes that form spontaneous AChR clusters. In the presence of MuSK-MG sera, the AChR clusters were reduced, as expected, but NSC-87877 was able to protect or restore the clusters. Two purified MuSK-MG IgG4 preparations inhibited both MuSK phosphorylation and AChR cluster formation, and in both, clusters were restored with NSC-87877. Stimulating the agrin-LRP4-MuSK-DOK7 AChR clustering pathway with NSC-87877, or other drugs, could represent a novel therapeutic approach for MuSK-MG and could potentially improve other NMJ disorders with reduced AChR numbers or disrupted NMJs.


Effects of music therapy for children and adolescents with psychopathology: a meta-analysis.
The objectives of this review were to examine the overall efficacy of music therapy for children and adolescents with psychopathology, and to examine how the size of the effect of music therapy is influenced by the type of pathology, client's age, music therapy approach, and type of outcome. Eleven studies were included for analysis, which resulted in a total of 188 subjects for the meta-analysis. Effect sizes from these studies were combined, with weighting for sample size, and their distribution was examined. After exclusion of an extreme positive outlying value, the analysis revealed that music therapy has a medium to large positive effect (ES =.61) on clinically relevant outcomes that was statistically highly significant (p <.001) and statistically homogeneous. No evidence of a publication bias was identified. Effects tended to be greater for behavioural and developmental disorders than for emotional disorders; greater for eclectic, psychodynamic, and humanistic approaches than for behavioural models; and greater for behavioural and developmental outcomes than for social skills and self-concept. Implications for clinical practice and research are discussed.


Inhibition of orthotopic human bladder tumor growth by lentiviral gene transfer of endostatin.
Inhibitors of endothelial cell proliferation, such as endostatin, result in suppression of tumor-associated angiogenesis and can achieve growth-inhibitory effects depending on the type of tumor treated. The purpose of this study was to investigate whether local overexpression of endostatin could serve to diminish tumor growth of bladder cancer in vivo. We examined the capability of lentiviral-mediated gene transfer in vitro and therapeutic effects of lentivirus-based vectors expressing endostatin on tumor growth using an orthotopic human bladder tumor model. We found that self-inactivating lentivirus vectors containing green fluorescent protein, alone or in combination with endostatin, were capable of efficient and stable gene transfer to a variety of human bladder tumor cell lines. The production and secretion of endostatin from lentivirus-transduced KU-7 human bladder cancer cells was confirmed by Western blot and competitive enzyme immunoassay. Intravesical instillation of untransduced, green fluorescent protein control lentivirus-transduced, and endostatin-transduced KU-7 cells was performed in murine models to establish orthotopic tumors. Sustained long-term expression of endostatin was achieved in lentivirus-transduced orthotopic bladder tumors, and it was associated with decreased vascularization and inhibition of tumor growth. Lentivirus vector-mediated overexpression of endostatin did not affect the intrinsic production of basic fibroblast growth factor and vascular endothelial growth factor. These findings suggest that lentivirus-mediated gene transfer might represent an effective strategy for expression of angioinhibitory peptides to achieve inhibition of human bladder cancer proliferation and tumor progression.


Development of a monitoring system for heroin-assisted substitution treatment in Switzerland.
Switzerland introduced heroin-assisted treatment as a routine treatment for drug addicts. As a result the evaluation instruments were changed from a detailed scientific project to a routine monitoring system. The process for developing this monitoring system is described. The questionnaires and assessment instruments were restyled with staff of the treatment agencies. Indicators measuring quality of treatment and measures from the future national statistic on the addiction support system were integrated into admission, course and discharge questionnaires. Currently a system for feedback to treatment agencies is being developed. All 21 treatment agencies are participating in the monitoring. Assessment quality is high. The described monitoring should provide continuous delivery of basic relevant data on patients.


Activation of the gab operon in an RpoS-dependent manner by mutations that truncate the inner core of lipopolysaccharide in Escherichia coli.
The gab operon (gabDTPC) in Escherichia coli functions in the conversion of gamma-aminobutyrate to succinate. One component of gab operon regulation involves the RpoS sigma factor, which mediates activation at high cell density. Transposon mutagenesis was used to identify new genes that regulate gab operon expression in rich media. A Tn5tmp insertion in the hldD (formerly rfaD) gene increased gabT::lacZ expression 12-fold. The hldD gene product, an ADP-L-glycerol-D-mannoheptose-6-epimerase, catalyzes the conversion of ADP-D-glycerol-D-mannoheptose to ADP-L-glycerol-D-mannoheptose, a precursor for the synthesis of inner-core lipopolysaccharide (LPS). Defined mutations in hldE, required for heptose synthesis, and waaF, required for the addition of the second heptose to the inner core, also resulted in high-level gabT::lacZ expression. The hldD, hldE, and waaF mutants exhibited a mucoid colony phenotype due to production of a colanic acid capsule. However, in the hldD::cat background, the high-level expression of gabT::lacZ was independent of the regulatory components for colanic acid synthesis (rcsA, rcsB, and rcsC) and also independent of manC (cpsB), a structural gene for colanic acid synthesis. Activation of gabT::lacZ in the hldD::cat background was dependent on the RpoS sigma factor. The hldD::cat mutation resulted in a sixfold increase in the levels of a translational RpoS-LacZ fusion and had a marginal effect on a transcriptional fusion. This study reveals a stress-induced pathway, mediated by loss of the LPS inner core, that increases RpoS translation and gab operon expression in E. coli.


Multisensory integration in dynamical behaviors: maximum likelihood estimation across bimanual skill learning.
Optimal integration of different sensory modalities weights each modality as a function of its degree of certainty (maximum likelihood). Humans rely on near-optimal integration in decision-making tasks (involving e.g., auditory, visual, and/or tactile afferents), and some support for these processes has also been provided for discrete sensorimotor tasks. Here, we tested optimal integration during the continuous execution of a motor task, using a cyclical bimanual coordination pattern in which feedback was provided by means of proprioception and augmented visual feedback (AVF, the position of both wrists being displayed as the orthogonal coordinates of a single cursor). Assuming maximum likelihood integration, the following predictions were addressed: (1) the coordination variability with both AVF and proprioception available is smaller than with only one of the two modalities, and should reach an optimal level; (2) if the AVF is artificially corrupted by noise, variability should increase but saturate toward the level without AVF; (3) if the AVF is imperceptibly phase shifted, the stabilized pattern should be partly adapted to compensate for this phase shift, whereby the amount of compensation reflects the weight assigned to AVF in the computation of the integrated signal. Whereas performance variability gradually decreased over 5 d of practice, we showed that these model-based predictions were already observed on the first day. This suggests not only that the performer integrated proprioceptive feedback and AVF online during task execution by tending to optimize the signal statistics, but also that this occurred before reaching an asymptotic performance level.


The polyphenol oxidase gene family in land plants: Lineage-specific duplication and expansion.
Plant polyphenol oxidases (PPOs) are enzymes that typically use molecular oxygen to oxidize ortho-diphenols to ortho-quinones. These commonly cause browning reactions following tissue damage, and may be important in plant defense. Some PPOs function as hydroxylases or in cross-linking reactions, but in most plants their physiological roles are not known. To better understand the importance of PPOs in the plant kingdom, we surveyed PPO gene families in 25 sequenced genomes from chlorophytes, bryophytes, lycophytes, and flowering plants. The PPO genes were then analyzed in silico for gene structure, phylogenetic relationships, and targeting signals. Many previously uncharacterized PPO genes were uncovered. The moss, Physcomitrella patens, contained 13 PPO genes and Selaginella moellendorffii (spike moss) and Glycine max (soybean) each had 11 genes. Populus trichocarpa (poplar) contained a highly diversified gene family with 11 PPO genes, but several flowering plants had only a single PPO gene. By contrast, no PPO-like sequences were identified in several chlorophyte (green algae) genomes or Arabidopsis (A. lyrata and A. thaliana). We found that many PPOs contained one or two introns often near the 3' terminus. Furthermore, N-terminal amino acid sequence analysis using ChloroP and TargetP 1.1 predicted that several putative PPOs are synthesized via the secretory pathway, a unique finding as most PPOs are predicted to be chloroplast proteins. Phylogenetic reconstruction of these sequences revealed that large PPO gene repertoires in some species are mostly a consequence of independent bursts of gene duplication, while the lineage leading to Arabidopsis must have lost all PPO genes. Our survey identified PPOs in gene families of varying sizes in all land plants except in the genus Arabidopsis. While we found variation in intron numbers and positions, overall PPO gene structure is congruent with the phylogenetic relationships based on primary sequence data. The dynamic nature of this gene family differentiates PPO from other oxidative enzymes, and is consistent with a protein important for a diversity of functions relating to environmental adaptation.


Childhood maltreatment and attention deficit hyperactivity disorder symptoms in adults: a large twin study.
Childhood maltreatment (CM) has been associated with increased risk of attention deficit hyperactivity disorder (ADHD) in children and adults. It is, however, unclear whether this association is causal or due to familial confounding. Data from 18 168 adult twins, aged 20-46 years, were drawn from the population-based Swedish twin registry. Retrospective self-ratings of CM (emotional and physical neglect, physical and sexual abuse and witnessing family violence), and self-ratings for DSM-IV ADHD symptoms in adulthood were analysed. Possible familial confounding was investigated using a within twin-pair design based on monozygotic (MZ) and dizygotic (DZ) twins. CM was significantly associated with increased levels of ADHD symptom scores in adults [regression coefficient: 0.40 standard deviations, 95% confidence interval (CI) 0.37-0.43]. Within twin-pair analyses showed attenuated but significant estimates within DZ (0.29, 95% CI 0.21-0.36) and MZ (0.18, 95% CI 0.10-0.25) twin pairs. Similar results emerged for hyperactive/impulsive and inattentive ADHD symptom scores separately in association with CM. We conducted sensitivity analyses for early maltreatment, before age 7, and for abuse and neglect separately, and found similarly reduced estimates in DZ and MZ pairs. Re-traumatization after age 7 did not significantly influence results. CM was significantly associated with increased ADHD symptoms in adults. Associations were partly due to familial confounding, but also consistent with a causal interpretation. Our findings support cognitive neuroscience studies investigating neural pathways through which exposure to CM may influence ADHD. Clinicians treating adults with ADHD should be aware of the association with maltreatment.


A concise method for reducing photographic spectrograph calibrations.
An accurate and concise method of fitting and presenting photographic spectrographic calibration data has been developed that overcomes the shortcomings imposed by polynomial fitting techniques. This approach utilizes hitherto ignored correlatible data from neighboring wavelengths to increase the accuracy and smoothness of data at each particular wavelength. The results empirically confirm the assumption that an over-all system H-D curve at one wavelength can be accurately mapped into the H-D curve at a near wavelength using only a scaling constant Agamma and a translation constant Bgamma. This method also allows extrapolation beyond some of the raw data calibration ranges.


Double-blind comparison of first- and second-generation antipsychotics in early-onset schizophrenia and schizo-affective disorder: findings from the treatment of early-onset schizophrenia spectrum disorders (TEOSS) study.
Atypical (second-generation) antipsychotics are considered standard treatment for children and adolescents with early-onset schizophrenia and schizoaffective disorder. However, the superiority of second-generation antipsychotics over first-generation antipsychotics has not been demonstrated. This study compared the efficacy and safety of two second-generation antipsychotics (olanzapine and risperidone) with a first-generation antipsychotic (molindone) in the treatment of early-onset schizophrenia and schizoaffective disorder. This double-blind multisite trial randomly assigned pediatric patients with early-onset schizophrenia and schizoaffective disorder to treatment with either olanzapine (2.5-20 mg/day), risperidone (0.5-6 mg/day), or molindone (10-140 mg/day, plus 1 mg/day of benztropine) for 8 weeks. The primary outcome was response to treatment, defined as a Clinical Global Impression (CGI) improvement score of 1 or 2 and >or=20% reduction in Positive and Negative Syndrome Scale (PANSS) total score after 8 weeks of treatment. In total, 119 youth were randomly assigned to treatment. Of these subjects, 116 received at least one dose of treatment and thus were available for analysis. No significant differences were found among treatment groups in response rates (molindone: 50%; olanzapine: 34%; risperidone: 46%) or magnitude of symptom reduction. Olanzapine and risperidone were associated with significantly greater weight gain. Olanzapine showed the greatest risk of weight gain and significant increases in fasting cholesterol, low density lipoprotein, insulin, and liver transaminase levels. Molindone led to more self-reports of akathisia. Risperidone and olanzapine did not demonstrate superior efficacy over molindone for treating early-onset schizophrenia and schizoaffective disorder. Adverse effects were frequent but differed among medications. The results question the nearly exclusive use of second-generation antipsychotics to treat early-onset schizophrenia and schizoaffective disorder. The safety findings related to weight gain and metabolic problems raise important public health concerns, given the widespread use of second-generation antipsychotics in youth for nonpsychotic disorders.


Immunohistochemical expression of aromatase cyp19a1a and cyp19a1b in the ovary and brain of zebrafish (Danio rerio) exposed to different concentrations of bisphenol A.
Bisphenol A (BPA) is used to produce plastic and plastic derived products in multitude of daily utensils, being one of the industrial compounds most widely used. This endocrine disrupting chemical (EDCs) is a well-known environmental pollutant released into the aquatic environment from industrial wastewater, sewage sludge or landfill leachate. Aromatases are considered potential targets of EDCs with characteristics that make them suitable biomarkers of exposure to their effects. The main objective of our study was to evaluate the expression of cyp19a aromatase as a toxicological endpoint after BPA exposure through the identification and assessment of alterations of the main cells responsible for cyp19a1a and cyp19a1b expression in the zebrafish ovary and brain using different concentrations of BPA in water. Immunohistochemistry was used to analyze the expression of these enzymes in female zebrafish exposed and not exposed to different concentrations of BPA (1, 10, 100 and 1000 μg / L) in water (n = 6/group) for 14 days. The results obtained in this study showed that the cyp19a aromatase system, involved in the synthesis of steroid compounds, is specially located in distinct oocyte stages in the ovary (cyp19a1a) and in radial glial cells of the brain (cyp19a1b). An overexpression of these aromatases was observed after BPA exposure in zebrafish, peaking from a concentration of 10 µg/L and showing to be good biomarkers of exposure to identify the early effects of low BPA concentrations. To our knowledge, this study is the first to localize and quantify the expression of cyp19a1a and cyp19a1b in the cells of brain and ovary after fish exposure to different BPA concentrations in water.


Phylogenetic relationships within Chamaecrista sect. Xerocalyx (Leguminosae, Caesalpinioideae) inferred from the cpDNA trnE-trnT intergenic spacer and nrDNA ITS sequences.
Chamaecrista belongs to subtribe Cassiinae (Caesalpinioideae), and it comprises over 330 species, divided into six sections. The section Xerocalyx has been subjected to a profound taxonomic shuffling over the years. Therefore, we conducted a phylogenetic analysis using a cpDNA trnE-trnT intergenic spacer and nrDNA ITS/5.8S sequences from Cassiinae taxa, in an attempt to elucidate the relationships within this section from Chamaecrista. The tree topology was congruent between the two data sets studied in which the monophyly of the genus Chamaecrista was strongly supported. Our analyses reinforce that new sectional boundaries must be defined in the Chamaecrista genus, especially the inclusion of sections Caliciopsis and Xerocalyx in sect. Chamaecrista, considered here paraphyletic. The section Xerocalyx was strongly supported as monophyletic; however, the current data did not show C. ramosa (microphyllous) and C. desvauxii (macrophyllous) and their respective varieties in distinct clades, suggesting that speciation events are still ongoing in these specimens.


Development of a gene silencing DNA vector derived from a broad host range geminivirus.
Gene silencing is proving to be a powerful tool for genetic, developmental, and physiological analyses. The use of viral induced gene silencing (VIGS) offers advantages to transgenic approaches as it can be potentially applied to non-model systems for which transgenic techniques are not readily available. However, many VIGS vectors are derived from Gemini viruses that have limited host ranges. We present a new, unipartite vector that is derived from a curtovirus that has a broad host range and will be amenable to use in many non-model systems. The construction of a gene silencing vector derived from the geminivirus Beet curly top virus (BCTV), named pWSRi, is reported. Two versions of the vector have been developed to allow application by biolistic techniques or by agro-infiltration. We demonstrate its ability to silence nuclear genes including ribulose bisphosphate carboxylase small subunit (rbcS), transketolase, the sulfur allele of magnesium chelatase (ChlI), and two homeotic transcription factors in spinach or tomato by generating gene-specific knock-down phenotypes. Onset of phenotypes occurred 3 to 12 weeks post-inoculation, depending on the target gene, in organs that developed after the application. The vector lacks movement genes and we found no evidence for significant spread from the site of inoculation. However, viral amplification in inoculated tissue was detected and is necessary for systemic silencing, suggesting that signals generated from active viral replicons are efficiently transported within the plant. The unique properties of the pWSRi vector, the ability to silence genes in meristem tissue, the separation of virus and silencing phenotypes, and the broad natural host range of BCTV, suggest that it will have wide utility.


Context-based tourism information filtering with a semantic rule engine.
This paper presents the CONCERT framework, a push/filter information consumption paradigm, based on a rule-based semantic contextual information system for tourism. CONCERT suggests a specific insight of the notion of context from a human mobility perspective. It focuses on the particular characteristics and requirements of travellers and addresses the drawbacks found in other approaches. Additionally, CONCERT suggests the use of digital broadcasting as push communication technology, whereby tourism information is disseminated to mobile devices. This information is then automatically filtered by a network of ontologies and offered to tourists on the screen. The results obtained in the experiments carried out show evidence that the information disseminated through digital broadcasting can be manipulated by the network of ontologies, providing contextualized information that produces user satisfaction.


Comprehensive connectivity of the mouse main olfactory bulb: analysis and online digital atlas.
We introduce the first open resource for mouse olfactory connectivity data produced as part of the Mouse Connectome Project (MCP) at UCLA. The MCP aims to assemble a whole-brain connectivity atlas for the C57Bl/6J mouse using a double coinjection tracing method. Each coinjection consists of one anterograde and one retrograde tracer, which affords the advantage of simultaneously identifying efferent and afferent pathways and directly identifying reciprocal connectivity of injection sites. The systematic application of double coinjections potentially reveals interaction stations between injections and allows for the study of connectivity at the network level. To facilitate use of the data, raw images are made publicly accessible through our online interactive visualization tool, the iConnectome, where users can view and annotate the high-resolution, multi-fluorescent connectivity data (www.MouseConnectome.org). Systematic double coinjections were made into different regions of the main olfactory bulb (MOB) and data from 18 MOB cases (~72 pathways; 36 efferent/36 afferent) currently are available to view in iConnectome within their corresponding atlas level and their own bright-field cytoarchitectural background. Additional MOB injections and injections of the accessory olfactory bulb (AOB), anterior olfactory nucleus (AON), and other olfactory cortical areas gradually will be made available. Analysis of connections from different regions of the MOB revealed a novel, topographically arranged MOB projection roadmap, demonstrated disparate MOB connectivity with anterior versus posterior piriform cortical area (PIR), and exposed some novel aspects of well-established cortical olfactory projections.


Current use and future needs of biodosimetry in studies of long-term health risk following radiation exposure.
Biodosimetry measurements can potentially be an important and integral part of the dosimetric methods used in long-term studies of health risk following radiation exposure. Such studies rely on accurate estimation of doses to the whole body or to specific organs of individuals in order to derive reliable estimates of cancer risk. However, dose estimates based on analytical dose reconstruction (i.e., models) or personnel monitoring measurements (i.e., film badges) can have substantial uncertainty. Biodosimetry can potentially reduce uncertainty in health risk studies by corroboration of model-based dose estimates or by using them to assess bias in dose models. While biodosimetry has begun to play a more significant role in long-term health risk studies, its use is still generally limited in that context due to one or more factors including inadequate limits of detection, large inter-individual variability of the signal measured, high per-sample cost, and invasiveness. Presently, the most suitable biodosimetry methods for epidemiologic studies are chromosome aberration frequencies from fluorescence in situ hybridization (FISH) of peripheral blood lymphocytes and electron paramagnetic resonance (EPR) measurements made on tooth enamel. Both types of measurements, however, are usually invasive and require biological samples that can be difficult to obtain. Moreover, doses derived from these methods are not always directly relevant to the tissues of interest. To increase the value of biodosimetry to epidemiologic studies, a number of issues need to be considered, including limits of detection, effects of inhomogenous exposure of the body, how to extrapolate from the tissue sampled to the tissues of interest, and how to adjust dosimetry models applied to large populations based on sparse biodosimetry measurements. The requirements of health risk studies suggest a set of characteristics that, if satisfied by new biodosimetry methods, would increase the overall usefulness of biodosimetry in determining radiation health risks.


Dynamics of the ventilatory response to hypoxia in humans.
Dynamic responses of the ventilatory system to rapid variations in isocapnic hypoxia were studied in five subjects. Sawtooth-shaped inputs were presented at constant amplitude with periods of 120, 90, 60, 45 and 30 sec, and square-wave inputs at different amplitudes with periods of 120, 60 and 30 sec. A breath-by-breath model fitting technique was used to assess whether any of a number of first order models of hypoxic ventilatory dynamics could fit the data adequately. The following was found: 1) An equation for the desaturation of haemoglobin provided a better expression for hypoxia in the model than did a hyperbolic function of PO2. 2) The gain and/or offset model parameters varied significantly between experiments, but the time constant and pure delay terms did not. 3) The time constants, and to a lesser extent the pure delays, were found to vary significantly between sawtooth experiments of different frequencies. The failure of a single set of dynamic parameters to describe all the responses suggests that the model is incomplete. 4) There was significant asymmetry in the hypoxic response with the on-transient dynamics faster than the off-transient dynamics. The results of the model fitting study suggest that a first order model cannot fully describe the hypoxic ventilatory dynamics.


What are the experiences of therapists using the online Back Skills Training and implementing it within clinical practice?
The purpose of the present study was to explore the experiences of physiotherapists using the online Back Skills Training (i-BeST). The aim of the this programme was to enable clinicians to facilitate group-based treatment based on a cognitive behavioural (CB) approach to the treatment of lower back pain (LBP). A qualitative, exploratory approach was chosen. Seven physiotherapists were interviewed. Participants were asked broad, open-ended questions in order to explore: (a) their experiences with the training; (b) the online method; and (c) the implementation of BeST into clinical practice. The interviews were transcribed and analysed manually using interpretive phenomenological analysis. Four main themes were identified following the analysis: (a) Flexibility but lack of interactivity; (b) CB approach is a new way of working; (c) Facilitating group work after i-BeST training; and (d) The need for managerial support. The flexibility of the online tool was perceived as a major advantage. However, lack of interactivity was identified by most participants as the biggest challenge. Participants found the online tool to be acceptable for attaining knowledge but not adequate for developing skills. After completing BeST, participants reported the application of key principles of the CB approach within routine physiotherapeutic practice, but were reluctant to refer into the group-based treatment programme. Coordination of implementation of the group-based treatment programme throughout a large trust was perceived as necessary, including sufficient staff training for all clinicians. I-Best can be implemented within everyday clinical settings but should be enhanced with additional face-to-face support mechanisms to improve effectiveness.


Sensitivity of computed tomography performed within six hours of onset of headache for diagnosis of subarachnoid haemorrhage: prospective cohort study.
To measure the sensitivity of modern third generation computed tomography in emergency patients being evaluated for possible subarachnoid haemorrhage, especially when carried out within six hours of headache onset. Prospective cohort study. 11 tertiary care emergency departments across Canada, 2000-9. Neurologically intact adults with a new acute headache peaking in intensity within one hour of onset in whom a computed tomography was ordered by the treating physician to rule out subarachnoid haemorrhage. Subarachnoid haemorrhage was defined by any of subarachnoid blood on computed tomography, xanthochromia in cerebrospinal fluid, or any red blood cells in final tube of cerebrospinal fluid collected with positive results on cerebral angiography. Of the 3132 patients enrolled (mean age 45.1, 2571 (82.1%) with worst headache ever), 240 had subarachnoid haemorrhage (7.7%). The sensitivity of computed tomography overall for subarachnoid haemorrhage was 92.9% (95% confidence interval 89.0% to 95.5%), the specificity was 100% (99.9% to 100%), the negative predictive value was 99.4% (99.1% to 99.6%), and the positive predictive value was 100% (98.3% to 100%). For the 953 patients scanned within six hours of headache onset, all 121 patients with subarachnoid haemorrhage were identified by computed tomography, yielding a sensitivity of 100% (97.0% to 100.0%), specificity of 100% (99.5% to 100%), negative predictive value of 100% (99.5% to 100%), and positive predictive value of 100% (96.9% to 100%). Modern third generation computed tomography is extremely sensitive in identifying subarachnoid haemorrhage when it is carried out within six hours of headache onset and interpreted by a qualified radiologist.


Predictors of persistent villous atrophy in coeliac disease: a population-based study.
Villous atrophy (VA) with intraepithelial lymphocytosis is the histological hallmark of coeliac disease (CD), but reported rates of mucosal recovery are variable. To determine the impact of age and other demographic variables on the probability of persistent VA on follow-up biopsy. We identified patients with VA on duodenal histology at all 28 Swedish pathology departments during the years spanning 1969-2008. We examined age, gender, calendar period, duration of disease and educational attainment to determine predictors of persistent VA. Of 7648 patients with CD who underwent follow-up biopsy, persistent VA was present in 3317 (43%; 95% CI 42-44%). The effect of age on persistent VA varied according to time period; among those biopsied in the years spanning 2000-2008, the prevalence of persistent VA was 31%, and increasing age was associated with increasing rates of persistent VA (17% among those younger than 2 years compared to 56% among those ≥70 years). In contrast, persistent VA did not vary widely by age in earlier years. On multivariate analysis (restricted to the calendar period 2000-2008, 2-5 years after CD diagnosis), persistent VA was more common among males (OR 1.43; 95% CI 1.07-1.90) and less common among patients with higher educational attainment (OR for college degree vs. <2 years of high school 0.52, 95% CI 0.35-0.78). The prevalence of persistent villous atrophy has changed over time, with greater rates of healing in recent years. Social differences in persistent villous atrophy suggest that access and/or education regarding the gluten-free diet impact mucosal healing.


Estimating Sensorimotor Mapping From Stimuli to Behaviors to Infer C. elegans Movements by Neural Transmission Ability Through Connectome Databases.
One of the ultimate goals of computational neuroscience is to quantitatively connect between complex neural circuits and behaviors. In the past decades, the touch response circuit in Caenorhabditis elegans (C. elegans) has extensively been investigated in studies using genetically modified or laser-ablated worms. Synaptic connections, including chemical and electrical synapses, have been identified for most neurons in the C. elegans. However, we still do not know whether the empirically observed touch responses can be derived from connectome reconstructed from databases. To address this issue, we defined the transmission abilities (or levels) of neurons in a rate model in order to infer the behaviors of wild-type and ablated worms in response to posterior/nose/anterior touch stimuli. Our analysis showed that transmission abilities can be used to identify sensorimotor mapping from stimuli to movements and then to infer the C. elegans behaviors under simulations based on the perspective of decision-making, and provide useful information about how chemical and electronic synapses should be combined in the neural network movement analysis. This paper reveals an efficient tool that provided insights into the functions of complex neural circuits.


Timing of fat and liquid sugar intake alters substrate oxidation and food efficiency in male Wistar rats.
In addition to the amount of ingested calories, both timing of food intake and meal composition are determinants of body weight gain. However, at present, it is unknown if the inappropriate timing of diet components is responsible for body weight gain. In the present study, we therefore studied a time-dependent effect of the diet composition on energy homeostasis. Male Wistar rats were subjected to chow ad libitum (chow group) or a choice diet with saturated fat, a 30% sugar solution, chow and tap water. The choice diet was provided either with all components ad libitum (AL), with ad libitum access to chow, tap water and a 30% sugar solution, but with access to saturated fat only during the light period (LF), or with ad libitum access to chow, tap water and saturated fat, but access to a 30% sugar solution only during the light period (LS). Caloric intake and body weight gain were monitored during 31 days. Energy expenditure was measured in the third week in calorimetric cages. All rats on a choice diet showed hyperphagia and gained more body weight compared to the chow group. Within the choice diet groups, rats on the LS diet were most food efficient (i.e. gained most body weight per ingested calorie) and showed a lower respiratory exchange ratio (RER) with an anti-phasic pattern, whereas no differences in locomotor activity or heat production were found. Collectively these data indicate that the timing of the diet composition affects food efficiency, most likely due to a shifted oxidation pattern, which can predispose for obesity. Further studies are underway to assess putative mechanisms involved in this dysregulation.


Use of thiazolidinediones and risk of osteoporotic fracture: disease or drugs?
Clinical and observational studies suggest that use of thiazolidinediones (TZDs) is associated with an increased fracture risk. In addition, type 2 diabetes mellitus (T2DM) is a risk factor for osteoporotic fracture. Our aim was to estimate fracture risks in TZD users and users of other antidiabetic drugs, classified according to proxies of disease severity. We conducted a population-based cohort study utilizing the Dutch PHARMO database (1998-2008). PHARMO links pharmacy-dispensing data to the National Hospital Registry. Oral antidiabetic users (n = 123,452) were matched 1:4 by year of birth and sex to non-users. Cox proportional hazards models were used to estimate hazard ratios (HRs) of fracture in TZD users. We created a proxy indicator for disease severity. The first stage was defined as current use of either a biguanide or a sulfonylureum, the second stage as current use of a biguanide and a sulfonylureum at the same time, the third stage was assigned to patients using TZDs and the fourth stage to patients using insulin. The risk of osteoporotic fracture was increased 1.5-fold (HR 1.49, 95%CI 1.28-1.73) in patients who currently used TZDs (stage 3), and for patients using insulin (stage 4), the risk was increased 1.2-fold (HR 1.24, 1.14-1.36), as compared with controls. In the first and second stages, risks were lower: HR 1.11 (1.06-1.17) for stage 1 and HR 1.03 (0.96-1.11) for stage 2. When observational studies assess risk of fracture in patients with TZDs, the severity of T2DM should be taken into account.


Environmental and climatic determinants of molecular diversity and genetic population structure in a coenagrionid damselfly.
Identifying environmental factors that structure intraspecific genetic diversity is of interest for both habitat preservation and biodiversity conservation. Recent advances in statistical and geographical genetics make it possible to investigate how environmental factors affect geographic organisation and population structure of molecular genetic diversity within species. Here we present a study on a common and wide ranging insect, the blue tailed damselfly Ischnuraelegans, which has been the target of many ecological and evolutionary studies. We addressed the following questions: (i) Is the population structure affected by longitudinal or latitudinal gradients?; (ii) Do geographic boundaries limit gene flow?; (iii) Does geographic distance affect connectivity and is there a signature of past bottlenecks?; (iv) Is there evidence of a recent range expansion and (vi) what is the effect of geography and climatic factors on population structure? We found low to moderate genetic sub-structuring between populations (mean F(ST) = 0.06, D(est) = 0.12), and an effect of longitude, but not latitude, on genetic diversity. No significant effects of geographic boundaries (e.g. water bodies) were found. F(ST)-and D(est)-values increased with geographic distance; however, there was no evidence for recent bottlenecks. Finally, we did not detect any molecular signatures of range expansions or an effect of geographic suitability, although local precipitation had a strong effect on genetic differentiation. The population structure of this small insect has probably been shaped by ecological factors that are correlated with longitudinal gradients, geographic distances, and local precipitation. The relatively weak global population structure and high degree of genetic variation within populations suggest that I. elegans has high dispersal ability, which is consistent with this species being an effective and early coloniser of new habitats.


Use of a hyaluronate membrane for jejunal anastomosis in horses.
To compare the outcomes of double-layer inverting anastomosis (DIA), single-layer anastomosis (SLA), and single-layer anastomosis combined with a hyaluronate membrane (SLA+HA-membrane) with respect to stomal diameter, adhesion formation, surgery time, and anastomotic healing in horses. 18 adult horses. Midline celiotomy and end-to-end anastomoses were performed. In control horses (n = 6), DIA was performed; in treated horses, SLA was performed (6) or SLA+HA-membrane was performed (6). Horses were euthanatized 21 days after surgery. Abdominal adhesions were evaluated grossly and histologically. Stomal diameters were measured ultrasonographically and compared with adjacent luminal diameters. Anastomotic healing was evaluated histologically for fibrosis and inflammation, tissue alignment, and inversion. Surgery times were recorded for the anastomotic procedure and compared among groups. There were significantly more adhesions in the SLA group, compared with the DIA and SLA+HA-membrane groups. Reduction in stomal diameters in the DIA group was significantly greater than the SLA and SLA+HA-membrane groups. Surgery times for the DIA group were significantly greater than the SLA and SLA+HA-membrane groups. Histologic findings of fibrosis, inflammation, and mucosal healing were similar among groups. There was significant tissue inversion in the DIA group, compared with the 2 treatment groups. Tissue alignment was not different among groups. Use of a SLA+HA-membrane was an effective small intestinal anastomotic technique. This technique was faster to perform and resulted in a larger stomal diameter, compared with the DIA technique and significantly fewer perianastomotic adhesions, compared with the SLA technique.


Pulpal response to Er:YAG laser drilling of dentine in healthy human third molars.
Maintenance of pulpal health is a critical prerequisite for successful application of light amplification by stimulated emission of radiations (lasers) in the hard tissue management of vital teeth. The purpose of this study was to investigate the short- and long-term pulpal effects to cavity-preparations in healthy human teeth using erbium-doped:yttrium, aluminum, and garnet (Er:YAG) laser. A total of seven healthy third molars that were to be removed due to space-problem were used. Following the laser excavation, the cavities in dentine were closed temporarily and the teeth were extracted after 7 days (n = 5) and 3 months (n = 2) post-operation. The specimens were fixed, decalcified, subdivided, and processed for light and transmission electron microscopy. In the short-term group, four of the five laser-drilled teeth did not reveal any pathological changes in the pulp-dentine complex. One tooth showed mild disruption of odontoblasts (OB) and vascular dilatation subjacent to the deepest point of the cavity-preparation with a remaining dentine thickness (RDT) of less than 80 microm. The two teeth under long-term observation revealed distinct apposition of tertiary dentine (TD), lined predominantly with cuboidal cells on its pulpal aspect. These results would allow a conclusion to be drawn that the Er:YAG laser under investigation is a pulp preserving hard-tissue drilling tool when used with the specific energy settings and emitting radiation at a wavelength of 2.94 microm.


Analytical approach to an integrate-and-fire model with spike-triggered adaptation.
The calculation of the steady-state probability density for multidimensional stochastic systems that do not obey detailed balance is a difficult problem. Here we present the analytical derivation of the stationary joint and various marginal probability densities for a stochastic neuron model with adaptation current. Our approach assumes weak noise but is valid for arbitrary adaptation strength and time scale. The theory predicts several effects of adaptation on the statistics of the membrane potential of a tonically firing neuron: (i) a membrane potential distribution with a convex shape, (ii) a strongly increased probability of hyperpolarized membrane potentials induced by strong and fast adaptation, and (iii) a maximized variability associated with the adaptation current at a finite adaptation time scale.


Scalable enhancement of graphene oxide properties by thermally driven phase transformation.
Chemical functionalization of graphene is promising for a variety of next-generation technologies. Although graphene oxide (GO) is a versatile material in this direction, its use is limited by the production of metastable, chemically inhomogeneous and spatially disordered GO structures under current synthetic protocols, which results in poor optoelectronic properties. Here, we present a mild thermal annealing procedure, with no chemical treatments involved, to manipulate as-synthesized GO on a large scale to enhance sheet properties with the oxygen content preserved. Using experiments supported by atomistic calculations, we demonstrate that GO structures undergo a phase transformation into prominent oxidized and graphitic domains by temperature-driven oxygen diffusion. Consequently, as-synthesized GO that absorbs mainly in the ultraviolet region becomes strongly absorbing in the visible region, photoluminescence is blue shifted and electronic conductivity increases by up to four orders of magnitude. Our thermal processing method offers a suitable way to tune and enhance the properties of GO, which creates opportunities for various applications.


Anodal transcranial direct current stimulation of the prefrontal cortex enhances complex verbal associative thought.
The remote associates test (RAT) is a complex verbal task with associations to both creative thought and general intelligence. RAT problems require not only lateral associations and the internal production of many words but a convergent focus on a single answer. Complex problem-solving of this sort may thus require both substantial verbal processing and strong executive function capacities. Previous studies have provided evidence that verbal task performance can be enhanced by noninvasive transcranial direct current stimulation (tDCS). tDCS modulates excitability of neural tissue depending on the polarity of the current. The after-effects of this modulation may have effects on task performance if the task examined draws on the modulated region. Studies of verbal cognition have focused largely on the left dorsolateral prefrontal cortex (F3 of the 10-20 EEG system) as a region of interest. We planned to assess whether modulating excitability at F3 could affect complex verbal abilities. In Experiment 1 (anodal, cathodal, or sham stimulation over F3 with the reference electrode over the contralateral supraorbital region), we found a significant overall effect of stimulation condition on RAT performance. Post hoc tests showed an increase in performance after anodal stimulation (1 mA) compared to sham (p = .025) and to cathodal stimulation (p = .038). In Experiment 2 (either anodal stimulation at F3 or separately at its homologue F4), we replicated the anodal effect of the first study, but also showed that anodal stimulation of F4 had no effect on RAT performance. These data provide evidence that anodal stimulation of the left dorsolateral prefrontal cortex can improve performance on a complex verbal problem-solving task believed to require significant executive function capacity.


Expression and amplification in transgenic mice of a polyoma virus mutant regulatory region.
Two hybrid gene constructs consisting of wild-type and mutant polyoma regulatory regions fused to a bacterial reporter gene were inserted in the mouse germline. Both transgenes were expressed in a large number of different organs. However, marker gene expression controlled by the polyoma wild-type regulatory region was not detectable in the early embryo and remained low throughout the life of the animal while expression controlled by the polyoma F9-1 mutation was detectable in blastocysts and was significantly higher at later stages of development. The F9-1 hybrid gene was also amplifiable when large T-antigen was supplied in trans to mice or to kidney cells derived from these transgenic mice. Amplification resulted in the appearance of several hundred copies of episomal transgenes and a marked increase of marker gene RNA and protein. Our results suggest that the F9-1 mutation does not alter the target spectrum of gene expression in vivo but does create a more efficient enhancer element in the polyoma early control region. Transgene amplification based upon use of the polyoma regulatory elements may be a means of increasing expression of genes in transgenic mice.