Fluoride Modulates Parathyroid Hormone Secretion in vivo and in vitro.
The study objective was to investigate the effects of fluoride on intact parathyroid hormone (iPTH) secretion. Thyro-parathyroid complexes (TPC) from C3H (n = 18) and B6 (n = 18) mice were cultured in Ca²⁺-optimized medium. TPC were treated with 0, 250, or 500 µM NaF for 24 h and secreted iPTH assayed by ELISA. C3H (n = 78) and B6 (n = 78) mice were gavaged once with distilled or fluoride (0.001 mg [F⁻]/g of body weight) water. At serial time points (0.5-96 h) serum iPTH, fluoride, total calcium, phosphorus, and magnesium levels were determined. Expression of genes involved in mineral regulation via the bone-parathyroid-kidney (BPK) axis, such as parathyroid hormone (Pth), calcium-sensing receptor (Casr), vitamin D receptor (Vdr), parathyroid hormone-like hormone (Pthlh), fibroblast growth factor 23 (Fgf23), α-Klotho (αKlotho), fibroblast growth factor receptor 1c (Fgf1rc), tumor necrosis factor 11 (Tnfs11), parathyroid hormone receptor 1 (Pth1r), solute carrier family 34 member 1 (Slc34a1), solute carrier 9 member 3 regulator 1 (Slc9a3r1), chloride channel 5 (Clcn5), and PDZ domain-containing 1 (Pdzk1), was determined in TPC, humeri, and kidneys at 24 h. An in vitro decrease in iPTH was seen in C3H and B6 TPC at 500 µM (p < 0.001). In vivo levels of serum fluoride peaked at 0.5 h in both C3H (p = 0.002) and B6 (p = 0.01). In C3H, iPTH decreased at 24 h (p < 0.0001), returning to baseline at 48 h. In B6, iPTH increased at 12 h (p < 0.001), returning to baseline at 24 h. Serum total calcium, phosphorus, and magnesium levels did not change significantly. Pth, Casr,αKlotho,Fgf1rc,Vdr, and Pthlh were significantly upregulated in C3H TPC compared to B6. In conclusion, the effects of fluoride on TPC in vitro were equivalent between the 2 mouse strains. However, fluoride demonstrated an early strain-dependent effect on iPTH secretion in vivo. Both strains demonstrated differences in the expression of genes involved in the BPK axis, suggesting a possible role in the physiologic handling of fluoride.


Assessing the immediate and maintained effects of hypnosis on self-efficacy and soccer wall-volley performance.
This study evaluated the effects of hypnosis on self-efficacy and soccer performance. Fifty-nine collegiate soccer players were randomly allocated to either a hypnosis (n = 30) or video attention-control group (n = 29). A pretest-posttest design with an additional 4-week follow-up was used. Self-efficacy was measured via a task-specific questionnaire comprising 10 items relating to good performance on a soccer wall-volley task. The hypnotic intervention comprised three sessions using ego-strengthening suggestions. The control group watched edited videos of professional soccer games. Results indicated that, following the intervention, the hypnosis group were more efficacious and performed better than the control group. These differences were also seen at the 4-week follow-up stage. Although changes in self-efficacy were associated with changes in performance, the effect of hypnosis on performance was not mediated by changes in self-efficacy. The study demonstrates that hypnosis can be used to enhance and maintain self-efficacy and soccer wall-volley performance.


Hemodynamic effects of HPMA copolymer based doxorubicin conjugate: A randomized controlled and comparative spectral study in conscious rats.
Conjugation of Doxorubicin (DOX) to N-(2-hydroxypropyl) methylacrylamide copolymer (HPMA) has significantly reduced the DOX-associated cardiotoxicity. However, the reports on the impact of HPMA-DOX conjugates on the cardiovascular system such as blood pressure (BP) and heart rate (HR) were in restrained animals using tail cuff and/or other methods that lacked the resolution and sensitivity. Herein, we employed radiotelemetric-spectral-echocardiography approach to further understand the in vivo cardiovascular hemodynamics and variability post administration of free DOX and HPMA-DOX. Rats implanted with radio-telemetry device were administered intravenously with DOX (5 mg/kg), HPMA-DOX (5 mg DOX equivalent/kg) and HPMA copolymer and subjected to continuous cardiovascular monitoring and echocardiography for 140 days. We found that DOX-treated rats had ruffled fur, reduced body weight (BW) and a low survival rate. Although BP and HR were normal, spectral analysis indicated that their BP and HR variabilities were reduced. All rats exhibited typical signs of cardiotoxicity at histopathology. In contrast, HPMA-DOX rats gained weight over time and survived. Although BP, HR and related variabilities were unaffected, the left ventricular end diastolic volume (EDV) of these rats, as well as of the HPMA copolymer-treated rats, was found increased at the end of observation period. Additionally, HPMA copolymer caused microscopic injury of the heart tissue. All of these suggest the necessity of caution when employing HPMA as carrier for prolonged drug delivery. The current study also indicates the potential of radiotelemetric-spectral-echocardiography approach for improved preclinical cardiovascular risk assessment of polymer-drug conjugate and other nano-sized-drug constructs.


Microvascular and Cardiovascular Outcomes According to Renal Function in Patients Treated With Once-Weekly Exenatide: Insights From the EXSCEL Trial.
To evaluate the impact of once-weekly exenatide (EQW) on microvascular and cardiovascular (CV) outcomes by baseline renal function in the Exenatide Study of Cardiovascular Event Lowering (EXSCEL). Least squares mean difference (LSMD) in estimated glomerular filtration rate (eGFR) from baseline between the EQW and placebo groups was calculated for 13,844 participants. Cox regression models were used to estimate effects by group on incident macroalbuminuria, retinopathy, and major adverse CV events (MACE). Interval-censored time-to-event models estimated effects on renal composite 1 (40% eGFR decline, renal replacement, or renal death) and renal composite 2 (composite 1 variables plus macroalbuminuria). EQW did not change eGFR significantly (LSMD 0.21 mL/min/1.73 m2 [95% CI -0.27 to 0.70]). Macroalbuminuria occurred in 2.2% of patients in the EQW group and in 2.5% of those in the placebo group (hazard ratio [HR] 0.87 [95% CI 0.70-1.07]). Neither renal composite was reduced with EQW in unadjusted analyses, but renal composite 2 was reduced after adjustment (HR 0.85 [95% CI 0.74-0.98]). Retinopathy rates did not differ by treatment group or in the HbA1c-lowering or prior retinopathy subgroups. CV outcomes in those with eGFR <60 mL/min/1.73 m2 did not differ by group. Those with eGFR ≥60 mL/min/1.73 m2 had nominal risk reductions for MACE, all-cause mortality, and CV death, but interactions by renal function group were significant for only stroke (HR 0.74 [95% CI 0.58-0.93]; P for interaction = 0.035) and CV death (HR 1.08 [95% CI 0.85-1.38]; P for interaction = 0.031). EQW had no impact on unadjusted retinopathy or renal outcomes. CV risk was modestly reduced only in those with eGFR ≥60 mL/min/1.73 m2 in analyses unadjusted for multiplicity.


Generation of a transgenic mouse model with chondrocyte-specific and tamoxifen-inducible expression of Cre recombinase.
Postnatal cartilage development and growth are regulated by key growth factors and signaling molecules. To fully understand the function of these regulators, an inducible and chondrocyte-specific gene deletion system needs to be established to circumvent the perinatal lethality. In this report, we have generated a transgenic mouse model (Col2a1-CreER(T2)) in which expression of the Cre recombinase is driven by the chondrocyte-specific col2a1 promoter in a tamoxifen-inducible manner. To determine the specificity and efficiency of the Cre recombination, we have bred Col2a1-CreER(T2) mice with Rosa26R reporter mice. The X-Gal staining showed that the Cre recombination is specifically achieved in cartilage tissues with tamoxifen-induction. In vitro experiments of chondrocyte cell culture also demonstrate the 4-hydroxy tamoxifen-induced Cre recombination. These results demonstrate that Col2a1-CreER(T2) transgenic mice can be used as a valuable tool for an inducible and chondrocyte-specific gene deletion approach.


Surgical versus nonsurgical interventions to relieve upper airway obstruction in children with Pierre Robin sequence.
Newborns with Pierre Robin sequence (PRS) often experience chronic intermittent hypoxemia/hypoventilation associated with airway obstruction. The heterogeneity of the severity of upper airway obstruction makes management a challenge; the optimal intervention in individual cases is not clear. To investigate the prevalence of surgical/nonsurgical interventions for PRS at two children's hospitals. Patient characteristics and outcomes were examined. The present retrospective chart review identified 139 patients with PRS born between 2000 and 2010. Demographic information, mode of airway management, associated anomalies and syndromes, polysomnography results, length of intensive care unit and hospital stay, complications and deaths were extracted. Interventions included prone positioning (alone [61%]), tongue-lip adhesion (45%), nasopharyngeal intubation (28%), continuous positive airway pressure (20%), tracheostomy (19%) and mandibular distraction osteogenesis (5%). Tracheostomies were more prevalent in syndromic patients (P=0.03). Patients who underwent tracheostomy had a lower birth weight (P=0.03) compared with newborns with other interventions. Patients who underwent surgical interventions had longer intensive care unit stays (P<0.001). No intervention was associated with a statistically significant likelihood of requiring a subsequent intervention. Thirty percent of patients underwent polysomnography, with a higher proportion of these using continuous positive airway pressure (n=15) (P<0.01). In the present descriptive study, patients with syndromic PRS or low birth weight underwent early intervention, which included a tracheostomy. Objective measures of airway obstruction were underutilized. Decision making regarding evaluation and management of upper airway obstruction in this population remains clinician and resource dependent. Reporting data obtained from a large cohort of PRS patients is important to compare experiences and motivate future studies investigating this complex condition.


Salivary gland extracts of partially fed Dermacentor reticulatus ticks decrease natural killer cell activity in vitro.
The salivary glands and saliva of ticks (Arachnida, Acari, Ixodida) play a vital role in blood feeding, including manipulation of the host's immune response to tick infestation. Furthermore, a diverse number of tick-borne pathogens are transmitted to vertebrate hosts via tick saliva. A factor synthesized in the salivary glands of feeding ticks potentiates the transmission of certain tick-borne viruses. We show that salivary gland extracts (SGE) derived from Dermacentor reticulatus female ticks fed for 6 days on laboratory mice (SGED6) induced a decrease in the natural killer (NK) activity of effector cells obtained from 16 healthy blood donors. The decreased activity ranged from 14 to 69% of NK activity observed with the respective untreated effector cells. Such a decrease was not observed after treatment of effector cells with SGE from unfed ticks. Ten-fold dilution of SGED6 significantly reduced the capacity to decrease NK activity and a further 10-fold dilution almost eliminated the effect. After addition of IFN-alpha 2, the SGED6-induced decrease in NK activity was restored to activity levels approaching those of untreated cells. The apparent reversibility of the inhibition indicates that the effect of SGED6 on NK activity was not due to cytotoxicity. The results demonstrate the presence of a factor(s) in the salivary gland products of feeding D. reticulatus female ticks that influences human NK activity in vitro. These data suggest a possible mechanism by which tick SGE potentiates the transmission of some tick-borne viruses through suppression of NK activity.


Changes in primary care physician's management of low back pain in a model of interprofessional collaborative care: an uncontrolled before-after study.
Tracking how clinicians treat patients provides an opportunity to explore how the clinical management of common musculoskeletal disorders evolves over time. We present an uncontrolled before-after study of a primary care physician's management of low back pain and describe how his involvement in an interprofessional collaborative practice was associated with a change in the management of patients with low back pain. Data from the electronic medical record of one primary care physician who participated in a study of a model of chiropractic-medical collaboration were retrospectively collected. Records of a sample of consecutive patients prior to the start (i.e. pre-study, n = 51) and at the end of the collaborative study (i.e. study, n = 49) were collected. Demographics were similar in both groups but median number of physician visits (2.5 and 1.0), average prescriptions per patients (1.24 and 0.47), and total number of narcotic prescriptions (14 and 6) differed between pre-study and study groups, respectively. Separate analysis of only the records of low back pain study patients revealed that 61% were referred for chiropractic care during the study period. Patients who were not referred had more neurological deficits and leg pain but back pain severity and average number of prescriptions was about the same. Referred patients in the study group had about 25% fewer physician visits and imaging requests. Based on this study of a single primary care physician, we hypothesize that doctors may change their prescribing behaviours and consultation rate for patients with low back pain when engaged in interprofessional collaborative care. Further research is required to test this observation in the population.


[Introduction of proteomic approach to environmental medicine].
Recent progress in life science technology and the availability of much information on genes obtained by genome analysis has enabled us to analyze the changes of proteins on a large scale. Sets of proteins are called proteomes, and proteomics is the scientific field of proteome analysis including differential, post translational modification and interaction analyses. Various proteomic techniques, particularly two-dimensional gel electrophoresis (2-DE), mass spectrometry, protein chip methods, and surface plasmon resonance (SPR), are very useful for acquiring proteomes in cells, tissues and body fluid, and for analyzing interactions between a protein and other biofactors including proteins. A proteomic approach is also useful for determining biomarkers of diseases and key proteins involved in various stages of metabolism such as differentiation, cell cycle and apoptosis. Environmental pollutants including endocrine disruptors inhibit activities of various organs in wild animals and humans. Proteomic approaches could be very useful tools for elucidating the mechanisms of damage caused by environmental pollutants. In this review, we describe the application of a proteomic approach to the field of environmental medicine.


Therapeutic efficacy of GAR-936, a novel glycylcycline, in a rat model of experimental endocarditis.
GAR-936, a novel glycylcycline, was investigated with a rat model of experimental endocarditis. It was compared with vancomycin against both vancomycin-susceptible and -resistant Enterococcus faecalis and methicillin-resistant Staphylococcus aureus. GAR-936 exhibited the lowest MICs (</=0.12 microgram/ml) in vitro against each of the isolates tested. Endocarditis was established by placement of a catheter across the aortic valve, followed by intravenous injection of 10(6) CFU of bacteria 48 h later. Treatment with GAR-936 or vancomycin was initiated 24 to 36 h after bacterial infection and administered subcutaneously twice a day for 3 days at ascending doses. GAR-936 reduced bacterial vegetation titers by >2 log(10) CFU, compared to those in untreated controls, for both vancomycin-susceptible and -resistant (VanA and VanB) E. faecalis strains and >4 log(10) CFU for a methicillin-resistant S. aureus isolate. The glycylcycline was more efficacious at a lower administered dose in the rat model of endocarditis than was vancomycin. The efficacy of GAR-936 in this model was apparently not enhanced by a factor in rat serum, as was observed for vancomycin with a time-kill curve. The results of this study demonstrate the therapeutic potential of GAR-936 for the treatment of enterococcal and staphylococcal infections and warrant further investigation.


Changing attitudes towards management of men with locally advanced prostate cancer following radical prostatectomy: A follow-up survey of Australia-based urologists.
This study examined whether there has been change among Australia-based urologists' knowledge, attitudes and beliefs relating to guideline-recommended adjuvant radiotherapy for men with adverse pathologic features following radical prostatectomy since a prior survey in 2012 and investigated associations between attitudes and treatment preferences. A nationwide survey of Australia-based urologist members of the Urological Society of Australia and New Zealand. Ninety-six respondents completed the 2015 survey (30% response rate) compared with 157 (45% response rate) in 2012. There was no significant change in awareness of national clinical practice guidelines for the management of prostate cancer. When considering adjuvant against salvage radiotherapy, urologists were significantly less favourable towards adjuvant radiotherapy in 2015 than in 2012 for two of three hypothetical clinical case scenarios with a high 10-year risk of biochemical relapse according to Memorial Sloan Kettering Cancer Center nomograms (P < 0.001 for both cases). In 2015, urologists were less positive overall towards the recommendation for post-operative adjuvant radiotherapy for men with locally advanced prostate cancer than in 2012 (P < 0.001), reflecting a significant change across a number of attitudes and beliefs. Of note, urologists felt other urologists would more likely be critical if they routinely referred the target patient group for radiotherapy in 2015 compared with 2012 (P = 0.007). In 2015 Australia-based urologists were less favourable towards adjuvant radiotherapy over watchful waiting for men with high-risk pathologic features post-prostatectomy than in 2012. We could find no new published research that precipitated this change in attitude.


Fracture toughness of experimental dental composites aged in ethanol.
Fracture toughness (KIc) is an intrinsic property which may be related to the ability of a restorative material to resist fracture and abrasion. This property may change for a dental composite restorative due to the effects of various oral solvents. The hypothesis to be tested was that aging in ethanol would cause a reduction in the fracture toughness of dental composites, and that the extent of this reduction might be dependent upon certain compositional variables. The fracture toughnesses of three series of experimental composites with various degrees of conversion, filler volume, and percent of silane-treated fillers were compared after the composites were aged for periods of one month and six months in 75% ethanol/water, a solvent which serves as a food-simulating liquid. An unfilled Bis-GMA/TEGDMA resin served as the control. All composites, with the exception of one subjected to a post-light-curing heat treatment, experienced a significant reduction (from 30 to 56%) in KIc after being aged in 75% ethanol for six months. A similar reduction in KIc of 58% for the unfilled resin suggested that the reduction for the composites was due to a weakening of the resin matrix, which facilitated crack propagation. A simultaneous reduction in microhardness was also demonstrated. One month of aging in ethanol also produced large reductions in KIc for specimens with insufficient cure and minimal filler volume, suggesting that the properties of the resin matrix predominated for these composites.(ABSTRACT TRUNCATED AT 250 WORDS)


Quantum-interference-controlled molecular electronics.
Quantum interference in coherent transport through single molecular rings may provide a mechanism to control the current in molecular electronics. We investigate its applicability, using a single-particle Green function method combined with ab initio electronic structure calculations. We find that the quantum interference effect (QIE) is strongly dependent on the interaction between molecular pi-states and contact sigma-states. It is masked by sigma tunneling in small molecular rings with Au leads, such as benzene, due to strong pi-sigma hybridization, while it is preserved in large rings, such as [18]annulene, which then could be used to realize quantum interference effect (QIE) transistors.


Vaginal blood flow after radical hysterectomy with and without nerve sparing. A preliminary report.
Radical hysterectomy with pelvic lymphadenectomy (RHL) for cervical cancer causes damage to the autonomic nerves, which are responsible for increased vaginal blood flow during sexual arousal. The aim of the study of which we now report preliminary data was to determine whether a nerve-sparing technique leads to an objectively less disturbed vaginal blood flow response during sexual stimulation. Photoplethysmographic assessment of vaginal pulse amplitude (VPA) during sexual stimulation by erotic films was performed. Subjective sexual arousal was assessed after each stimulus. Thirteen women after conventional RHL, 10 women after nerve-sparing RHL, and 14 healthy premenopausal women participated. Data were collected between January and August 2006. The main outcome measure was the logarithmically transformed mean VPA. To detect statistically significant differences in mean VPA levels between the three groups, a univariate analysis of variance was used. Mean VPA differed between the three groups (P= 0.014). The conventional group had a lower vaginal blood flow response than the control group (P= 0.016), which tended also to be lower than that of the nerve-sparing group (P= 0.097). These differences were critically dependent on baseline vaginal blood flow differences between the groups. The conventional group follows a vaginal blood flow pattern similar to postmenopausal women. Conventional RHL is associated with an overall disturbed vaginal blood flow response compared with healthy controls. Because it is not observed to the same extent after nerve-sparing RHL, it seems that the nerve-sparing technique leads to a better overall vaginal blood flow caused by less denervation of the vagina.


Corn processing method in finishing diets containing wet corn gluten feed.
Two trials were conducted to determine the effect of corn processing method on performance and carcass traits in steers fed finishing diets containing wet corn gluten feed (WCGF). In Trial 1, 480 steer calves (303 kg initial BW) were fed eight finishing diets: 1) dry-rolled corn (DRC) without; and 2) with 32% (DM basis) WCGF; 3) steam-flaked corn (SFC) without; and 4) with WCGF; 5) a combination of DRC and SFC without WCGF; 6) finely-ground corn (FGC) with WCGF; 7) high-moisture corn (HMC) with WCGF; and 8) whole corn (WC) with WCGF. Feeding WC + WCGF increased (P < 0.10) DMI and decreased gain:feed compared with all other treatments. Feeding DRC + WCGF increased (P < 0.10) DMI and decreased (P < 0.10) gain:feed compared with treatments other than WC + WCGF. Steers on treatments that included WCGF gained similarly, regardless of corn processing method, and at a rate 6% faster (P < 0.10) than steers fed diets that did not include WCGF. Gain:feed did not differ among steers fed SFC, SFC + WCGF, SFC + DRC, and HMC + WCGF. Steers fed SFC or SFC + WCGF were more efficient (P < 0.10) than steers fed DRC or FGC + WCGF. In Trial 2, 288 steer calves (382 kg initial BW) were fed six finishing diets: 1) DRC without; and 2) with 22% (DM basis) WCGF; 3) SFC without; and 4) with WCGF; 5) finely rolled corn (FRC) with WCGF; and 6) HMC corn with WCGF. Steers fed DRC + WCGF or FRC + WCGF consumed more DM (P < 0.10) than steers fed DRC, SFC, or SFC + WCGF. Feed intake did not differ between steers fed SFC + WCGF and HMC + WCGF. All treatment groups receiving WCGF consumed more DM (P < 0.10) feed than steers fed DRC or SFC without WCGF. Steers fed SFC + WCGF gained 8% faster (P < 0.10), and steers fed DRC 9.5% slower (P < 0.10) than steers receiving all other treatments. Daily gains did not differ among other treatment groups. Steers fed SFC or SFC + WCGF gained 10% more (P < 0.10) efficiently than all other treatment groups. Feed efficiency did not differ among steers fed DRC, DRC + WCGF, FRC + WCGF, and HMC + WCGF. Estimates for the NEg of WCGF calculated from animal performance indicated that WCGF contained approximately 25.3% more energy when fed with SFC than when fed with DRC. In general, more intensively processing corn improved gain:feed in finishing diets containing WCGF.


A survey of localized sequence rearrangements in human DNA.
Genomes mutate and evolve in ways simple (substitution or deletion of bases) and complex (e.g. chromosome shattering). We do not fully understand what types of complex mutation occur, and we cannot routinely characterize arbitrarily-complex mutations in a high-throughput, genome-wide manner. Long-read DNA sequencing methods (e.g. PacBio, nanopore) are promising for this task, because one read may encompass a whole complex mutation. We describe an analysis pipeline to characterize arbitrarily-complex 'local' mutations, i.e. intrachromosomal mutations encompassed by one DNA read. We apply it to nanopore and PacBio reads from one human cell line (NA12878), and survey sequence rearrangements, both real and artifactual. Almost all the real rearrangements belong to recurring patterns or motifs: the most common is tandem multiplication (e.g. heptuplication), but there are also complex patterns such as localized shattering, which resembles DNA damage by radiation. Gene conversions are identified, including one between hemoglobin gamma genes. This study demonstrates a way to find intricate rearrangements with any number of duplications, deletions, and repositionings. It demonstrates a probability-based method to resolve ambiguous rearrangements involving highly similar sequences, as occurs in gene conversion. We present a catalog of local rearrangements in one human cell line, and show which rearrangement patterns occur.


Post-resuscitation care following out-of-hospital and in-hospital cardiac arrest.
Cardiac arrest is a leading cause of death in developed countries. Although a majority of cardiac arrest patients die during the acute event, a substantial proportion of cardiac arrest deaths occur in patients following successful resuscitation and can be attributed to the development of post-cardiac arrest syndrome. There is growing recognition that integrated post-resuscitation care, which encompasses targeted temperature management (TTM), early coronary angiography and comprehensive critical care, can improve patient outcomes. TTM has been shown to improve survival and neurological outcome in patients who remain comatose especially following out-of-hospital cardiac arrest due to ventricular arrhythmias. Early coronary angiography and revascularisation if needed may also be beneficial during the post-resuscitation phase, based on data from observational studies. In addition, resuscitated patients usually require intensive care, which includes mechanical ventilator, haemodynamic support and close monitoring of blood gases, glucose, electrolytes, seizures and other disease-specific intervention. Efforts should be taken to avoid premature withdrawal of life-supporting treatment, especially in patients treated with TTM. Given that resources and personnel needed to provide high-quality post-resuscitation care may not exist at all hospitals, professional societies have recommended regionalisation of post-resuscitation care in specialised 'cardiac arrest centres' as a strategy to improve cardiac arrest outcomes. Finally, evidence for post-resuscitation care following in-hospital cardiac arrest is largely extrapolated from studies in patients with out-of-hospital cardiac arrest. Future studies need to examine the effectiveness of different post-resuscitation strategies, such as TTM, in patients with in-hospital cardiac arrest.


NMR structures reveal how oxidation inactivates thrombomodulin.
Oxidation of Met 388, one of the three linker residues connecting the fourth and fifth EGF-like domains of thrombomodulin (TM), is deleterious for TM activity. An NMR structure of the smallest active fragment of TM (TMEGF45) and a crystal structure of a larger fragment (TMEGF456) bound to thrombin both show that Met 388 is packed into the fifth domain. Using multidimensional NMR, we have solved the structure of TMEGF45 in which Met 388 is oxidized (TMEGF45ox) and the structure of TMEGF45 in which Met 388 is mutated to Leu (TMEGF45ML). Comparison of the structures shows that the fifth domain has a somewhat different structure depending on the residue at position 388, and several of the thrombin-binding residues are packed into the fifth domain in the oxidized protein while they are exposed and free to interact with thrombin in the native structure and the Met-Leu mutant. This observation is consistent with kinetic measurements showing that the K(m) for TMEGF45ox binding to thrombin is 3.3-fold higher than for the native protein. Most importantly, the connection between the two domains, as indicated by interdomain NOEs, appears to be essential for activity. In the TMEGF45ox structure which has a reduced k(cat) for protein C activation by the thrombin-TMEGF45ox complex, interaction between the two domains is lost. Conversely, a tighter connection is observed between the two domains in TMEGF45ML, which has a higher k(cat) for protein C activation by the thrombin-TMEGF45ML complex.


Molasses as a possible cause of an "endocrine disruptive syndrome" in calves.
During the mid 1990s a potentially serious, chronic syndrome was reported in well-managed beef and dairy herds from unrelated parts of South Africa. Farmers reported that it manifested as various combinations of decreased production, decreased weaning masses, apparent immune breakdown in previously immunocompetent animals, increased reproductive disorders, various mineral imbalances in non-deficient areas and goitre, noticeable as enlarged thyroid glands. The farmers associated this syndrome with certain batches of sugar cane molasses and molasses-based products. The syndrome was reminiscent of an "endocrine disruptive syndrome". The objective of this study was to evaluate the suspected endocrine disruptive effect of molasses included in cattle feed. Using existing in vitro assays, four batches of molasses syrup were screened for possible inclusion in a calf feeding trial. Two batches were selected for the trial. Thirty-two, 4- to 6-week-old, weaned Holstein bull calves were included in the single phase, three treatment, parallel design experiment. In two of the groups of calves, two different batches of molasses were included in their rations respectively. The control group was fed a ration to which no molasses was added, but which was balanced for energy and mineral content. The mass gain of the calves was recorded over the 6-month study period. The calves were clinically examined every week and clinical pathology parameters, immune responses and endocrine effects were regularly evaluated. Even though endocrine disrupting effects were detected with the in vitro screening assays, these could not be reproduced in the calves in the experiment. The two batches of molasses utilized in the calf feeding trial did not induce major differences in any of the parameters measured, with the exception of a lower mass gain in one of the molasses-fed groups (Group 1), which tended towards significance. The results of the study indicate that the two batches of molasses had no endocrine disruptive or immunosuppressive effects in calves.


Germline Loss-of-Function Mutations in EPHB4 Cause a Second Form of Capillary Malformation-Arteriovenous Malformation (CM-AVM2) Deregulating RAS-MAPK Signaling.
Most arteriovenous malformations (AVMs) are localized and occur sporadically. However, they also can be multifocal in autosomal-dominant disorders, such as hereditary hemorrhagic telangiectasia and capillary malformation (CM)-AVM. Previously, we identified RASA1 mutations in 50% of patients with CM-AVM. Herein we studied non-RASA1 patients to further elucidate the pathogenicity of CMs and AVMs. We conducted a genome-wide linkage study on a CM-AVM family. Whole-exome sequencing was also performed on 9 unrelated CM-AVM families. We identified a candidate gene and screened it in a large series of patients. The influence of several missense variants on protein function was also studied in vitro. We found evidence for linkage in 2 loci. Whole-exome sequencing data unraveled 4 distinct damaging variants in EPHB4 in 5 families that cosegregated with CM-AVM. Overall, screening of EPHB4 detected 47 distinct mutations in 54 index patients: 27 led to a premature stop codon or splice-site alteration, suggesting loss of function. The other 20 are nonsynonymous variants that result in amino acid substitutions. In vitro expression of several mutations confirmed loss of function of EPHB4. The clinical features included multifocal CMs, telangiectasias, and AVMs. We found EPHB4 mutations in patients with multifocal CMs associated with AVMs. The phenotype, CM-AVM2, mimics RASA1-related CM-AVM1 and also hereditary hemorrhagic telangiectasia. RASA1-encoded p120RASGAP is a direct effector of EPHB4. Our data highlight the pathogenetic importance of this interaction and indicts EPHB4-RAS-ERK signaling pathway as a major cause for AVMs.


Modeling of dielectric properties of aqueous salt solutions with an equation of state.
The static permittivity is the most important physical property for thermodynamic models that account for the electrostatic interactions between ions. The measured static permittivity in mixtures containing electrolytes is reduced due to kinetic depolarization and reorientation of the dipoles in the electrical field surrounding ions. Kinetic depolarization may explain 25-75% of the observed decrease in the permittivity of solutions containing salts, but since this is a dynamic property, this effect should not be included in the thermodynamic modeling of electrolytes. Kinetic depolarization has, however, been ignored in relation to thermodynamic modeling, and authors have either neglected the effect of salts on permittivity or used empirical correlations fitted to the measured static permittivity, leading to an overestimation of the reduction in the thermodynamic static permittivity. We present a new methodology for obtaining the static permittivity over wide ranges of temperatures, pressures, and compositions for use within an equation of state for mixed solvents containing salts. The static permittivity is calculated from a new extension of the framework developed by Onsager, Kirkwood, and Fröhlich to associating mixtures. Wertheim's association model as formulated in the statistical associating fluid theory is used to account for hydrogen-bonding molecules and ion-solvent association. Finally, we compare the Debye-Hückel Helmholtz energy obtained using an empirical model with the new physical model and show that the empirical models may introduce unphysical behavior in the equation of state.


CASSIS and SMIPS: promoter-based prediction of secondary metabolite gene clusters in eukaryotic genomes.
Secondary metabolites (SM) are structurally diverse natural products of high pharmaceutical importance. Genes involved in their biosynthesis are often organized in clusters, i.e., are co-localized and co-expressed. In silico cluster prediction in eukaryotic genomes remains problematic mainly due to the high variability of the clusters' content and lack of other distinguishing sequence features. We present Cluster Assignment by Islands of Sites (CASSIS), a method for SM cluster prediction in eukaryotic genomes, and Secondary Metabolites by InterProScan (SMIPS), a tool for genome-wide detection of SM key enzymes ('anchor' genes): polyketide synthases, non-ribosomal peptide synthetases and dimethylallyl tryptophan synthases. Unlike other tools based on protein similarity, CASSIS exploits the idea of co-regulation of the cluster genes, which assumes the existence of common regulatory patterns in the cluster promoters. The method searches for 'islands' of enriched cluster-specific motifs in the vicinity of anchor genes. It was validated in a series of cross-validation experiments and showed high sensitivity and specificity. CASSIS and SMIPS are freely available at https://sbi.hki-jena.de/cassis email@example.com or email@example.com Supplementary data are available at Bioinformatics online.


Regulatory T cells and organ transplantation.
Empirical studies attempting to explain tolerance to transplanted tissues have demonstrated a regulatory role for CD4+ T-cells. We here propose that regulatory T-cells mediating transplantion tolerance comprise two sets which can functionally complement each other. The CD4+CD25+ "natural regulator" arises in the thymus, and is preoccupied with self-antigens expressed at sites of inflammation. The second, comprising both CD4+CD25+ (FoxP3+) and CD4+CD25- Tr1-like cells are induced by persistent danger-free antigen in the periphery. The role of these cells is to moderate immune responses to prevent tissue destruction while allowing microbial elimination.


Fault Tree Analysis.
The purpose of this study was to use fault tree analysis to evaluate the adequacy of quality reporting programs in identifying root causes of postoperative bloodstream infection (BSI). A systematic review of the literature was used to construct a fault tree to evaluate 3 postoperative BSI reporting programs: National Surgical Quality Improvement Program (NSQIP), Centers for Medicare and Medicaid Services (CMS), and The Joint Commission (JC). The literature review revealed 699 eligible publications, 90 of which were used to create the fault tree containing 105 faults. A total of 14 identified faults are currently mandated for reporting to NSQIP, 5 to CMS, and 3 to JC; 2 or more programs require 4 identified faults. The fault tree identifies numerous contributing faults to postoperative BSI and reveals substantial variation in the requirements and ability of national quality data reporting programs to capture these potential faults. Efforts to prevent postoperative BSI require more comprehensive data collection to identify the root causes and develop high-reliability improvement strategies.


Out of the tropics: evolutionary dynamics of the latitudinal diversity gradient.
The evolutionary dynamics underlying the latitudinal gradient in biodiversity have been controversial for over a century. Using a spatially explicit approach that incorporates not only origination and extinction but immigration, a global analysis of genera and subgenera of marine bivalves over the past 11 million years supports an "out of the tropics" model, in which taxa preferentially originate in the tropics and expand toward the poles without losing their tropical presence. The tropics are thus both a cradle and a museum of biodiversity, contrary to the conceptual dichotomy dominant since 1974; a tropical diversity crisis would thus have profound evolutionary effects at all latitudes.


Quorum sensing in plant-pathogenic bacteria.
Quorum sensing (QS) allows bacteria to assess their local population density and/or physical confinement via the secretion and detection of small, diffusible signal molecules. This review describes how phytopathogenic bacteria have incorporated QS mechanisms into complex regulatory cascades that control genes for pathogenicity and colonization of host surfaces. Traits regulated by QS include the production of extracellular polysaccharides, degradative enzymes, antibiotics, siderophores, and pigments, as well as Hrp protein secretion, Ti plasmid transfer, motility, biofilm formation, and epiphytic fitness. Since QS regulatory systems are often required for pathogenesis, interference with QS signaling may offer a means of controlling bacterial diseases of plants. Several bacterial pathogens of plants that have been intensively studied and have revealed information of both fundamental and practical importance are reviewed here: Agrobacterium tumefaciens, Pantoea stewartii, Erwinia carotovora, Ralstonia solanacearum, Pseudomonas syringae, Pseudomonas aeruginosa, and Xanthomonas campestris.


Correlation between MET protein expression and MET gene copy number in a Caucasian cohort of non-small cell lung cancers according to the new IASLC/ATS/ERS classification.
MET pathway is a promising target in non-small cell lung cancers (NSCLC) requiring companion tests. The aim of this study was to compare MET expression/gene copy number in a Caucasian population of NSCLC patients.We analysed 201 NSCLC, with 141 adenocarcinomas classified according to 2011 IASLC recommendations, for MET expression by immunohistochemistry (IHC) and gene copy number (GCN) by silver in situ hybridisation (SISH) on tissue microarrays. Mutations in EGFR, KRAS, BRAF, HER2, PIK3CA genes and ALK rearrangements were determined.MET overexpression was observed in 44% and a high MET GCN (≥5 copies) in 14%. MET CGN was correlated with MET expression, regardless of IHC scores (p < 0.001) but only 31% of MET overexpressed cases were SISH positive. MET overexpression/GCN number was more frequent in ADC than the other types (p < 0.001), the highest in high grade (74%/34%) and sarcomatoid ADC (86%/43%). Mutations of current genes or ALK rearrangements were identified in overexpressed or amplified MET cases. MET overexpression was an independent prognostic factor for overall survival in non-smoker NSCLC in univariate (p = 0.01) and multivariate (p = 0.01) analyses.MET overexpression is more frequent than MET high GCN, particularly in high grade ADC, regardless of EGFR, KRAS, BRAF, HER2, PIK3CA and ALK status in NSCLC.


Stability and change in the mental health of New Zealand secondary school students 2007-2012: results from the national adolescent health surveys.
To describe the self-reported mental health of New Zealand secondary school students in 2012 and to investigate changes between 2007 and 2012. Nationally representative health and wellbeing surveys of students were completed in 2007 (n=9107) and 2012 (n=8500). Logistic regressions were used to examine the associations between mental health and changes over time. Prevalence data and adjusted odds ratios are presented. In 2012, approximately three-quarters (76.2%, 95% CI 74.8-77.5) of students reported good overall wellbeing. By contrast (also in 2012), some students reported self-harming (24.0%, 95% CI 22.7-25.4), depressive symptoms (12.8%, 95% CI 11.6-13.9), 2 weeks of low mood (31%, 95% CI 29.7-32.5), suicidal ideation (15.7%, 95% 14.5-17.0), and suicide attempts (4.5%, 95% CI 3.8-5.2). Between 2007 and 2012, there appeared to be slight increases in the proportions of students reporting an episode of low mood (OR 1.14, 95% CI 1.06-1.23, p=0.0009), depressive symptoms (OR 1.16, 95% CI 1.03-1.30, p=0.011), and using the Strengths and Difficulties Questionnaire - emotional symptoms (OR 1.38, 95% CI 1.23-1.54, p<0.0001), hyperactivity (OR 1.16, 95% CI 1.05-1.29, p=0.0051), and peer problems (OR 1.27, 95% CI 1.09-1.49, p=0.0022). The proportion of students aged 16 years or older reporting self-harm increased slightly between surveys, but there was little change for students aged 15 years or less (OR 1.29, 95% CI 1.15-1.44 and OR 1.10, 95% 0.98-1.23, respectively, p=0.0078). There were no changes in reported suicidal ideation and suicide attempts between 2007 and 2012. However, there has been an improvement in self-reported conduct problems since 2007 (OR 0.78, 95% CI 0.70-0.87, p<0.0001). The findings suggest a slight decline in aspects of self-reported mental health amongst New Zealand secondary school students between 2007 and 2012. There is a need for ongoing monitoring and for evidence-based, accessible interventions that prevent mental ill health and promote psychological wellbeing.


Photobiomodulation enhanced endogenous pain modulation in healthy volunteers.
To examine the effects of photobiomodulation (PBM) in healthy volunteers using photonic stimulation of acupuncture points on conditioned pain modulation (CPM), temporal summation of pain (TSP), and offset analgesia (OA), which reflect some aspects of endogenous pain modulation. We included 15 men and 15 women (age, 31.5 [27.3-37.0], body mass index, 25.7 [24.4-27.1], Fitzpatrick skin typing, II: 20, III: 8, IV: 2). CPM, TSP, and OA were evaluated after a sham procedure (control session) and after acupuncture point stimulation (LI4 and LI10 on the non-dominant forearm) using linear polarized near-infrared light irradiation (LPNILI; wavelengths peaked at approximately 1000 nm, output: 1.4 W/cm2, spot diameter: 10 mm, spot size: 1.02 cm2, maximum temperature: 40.5 °C, pulse width: 1 s, frequency: 0.2 Hz) (PBM session). Differences in CPM, TSP, and OA between the two sessions were evaluated by the paired t-test and Fisher's exact test (statistical significance: p < 0.05). Values indicate median [interquartile range]. LPNILI significantly increased CPM in all participants (control session: 12.1 [-4.5-37.4], PBM session: 23.9 [8.3-44.8], p < 0.05) and women (control session: 16.7 [-3.4-36.6], PBM session: 38.7 [24.6-52.1], p < 0.05). The CPM effect increment was significantly higher in women than in men (p = 0.0253). LPNILI decreased TSP in participants with higher TSP ratios (p = 0.0219) and increased OA in participants with lower OA scores (p = 0.0021). LPNILI enhanced endogenous pain modulation in healthy volunteers, particularly in women, as evaluated using CPM. CPM, TSP, and OA evaluations are potentially useful for discriminating PBM responders from non-responders.


Variations in Patterns of Utilization and Charges for the Care of Headache in North Carolina, 2000-2009: A Statewide Claims' Data Analysis.
The purpose of the study was to compare patterns of utilization and charges generated by medical doctors (MDs), doctors of chiropractic (DCs), and physical therapists (PTs) for the treatment of headache in North Carolina. Retrospective analysis of claims data from the North Carolina State Health Plan for Teachers and State Employees from 2000 to 2009. Data were extracted from Blue Cross Blue Shield of North Carolina for the North Carolina State Health Plan using International Classification of Diseases, Ninth Revision, diagnostic codes for headache. The claims were separated by individual provider type, combination of provider types, and referral patterns. The majority of patients and claims were in the MD-only or MD plus referral patterns. Chiropractic patterns represented less than 10% of patients. Care patterns with single-provider types and no referrals incurred the least charges on average for headache. When care did not include referral providers or services, MD with DC care was generally less expensive than MD care with PT. However, when combined with referral care, MD care with PT was generally less expensive. Compared with MD-only care, risk-adjusted charges (available 2006-2009) for patients in the middle risk quintile were significantly less for DC-only care. Utilization and expenditures for headache treatment increased from 2000 to 2009 across all provider groups. MD care represented the majority of total allowed charges in this study. MD care and DC care, alone or in combination, were overall the least expensive patterns of headache care. Risk-adjusted charges were significantly less for DC-only care.


Cardiac dysfunction caused by recombinant human C5A anaphylatoxin: mediation by histamine, adenosine and cyclooxygenase arachidonate metabolites.
We had found previously that complement-derived anaphylatoxins C3a and C5a function as mediators/modulators of cardiac immune hypersensitivity reactions. The purpose of this study was to determine the secondary mediators responsible for the cardiac effects of C5a. Recombinant human C5a (rhC5a) caused dose-dependent tachycardia, slowing of atrioventricular nodal conduction, a short lasting increase followed by a prolonged decrease in left ventricular contractility, and coronary vasoconstriction. These changes were associated with the release of histamine, thromboxane A2 and adenosine into the coronary effluent. Our data indicate that the positive inotropic and chronotropic effects of rhC5a are mediated by histamine release and consequent activation of H2-receptors, the coronary-vasoconstricting effect is due to thromboxane release and the negative dromotropic effect is associated with adenosine release. Furthermore, the decrease in contractility caused by rhC5a is likely to result from the H1-mediated negative inotropic effect of histamine compounded by the ischemic conditions created by the coronary vasoconstricting effects of thromboxane A2 and, perhaps, leukotrienes. Our findings demonstrate that C5a has marked cardiac effects at concentrations approximating those attained in vivo in a multitude of pathophysiological conditions in which complement is activated, including myocardial infarction. Thus, anaphylatoxins may play a role in the development of ischemic cardiac dysfunction.


Implementation of clinical practices to reduce return visits within 72 h to a paediatric emergency department.
Return visits to the paediatric emergency department (PED) are an important measure of quality of healthcare and are associated with patients' and parents'/guardians' satisfaction. Previous studies have been limited to describing characteristics and factors related to return visits. The objectives of this study were to develop new clinical practices to reduce return visits to the PED and to see whether implementation of these practices had the desired effect. This was a controlled before-and-after study. New clinical practices were developed by analysing data for patients visiting in 2011 (before) and by surveying emergency physicians and nurses in the PED. New clinical practices were implemented between 16 July and 4 November 2012 (after). The rate of return visits and admission rates after return visits were compared between matched periods in 2011 and 2012. We also investigated return visits at three independent hospitals to overcome the limitation of the intervention application to a single hospital. The new clinical practices included five protocols: set orders for common symptoms; management plans for patients at high risk of a return visit; a daily physician feedback system; protocolised discharge instructions; early planned visits to clinics. After implementation, the rate of return visits was reduced significantly, from 4.4% to 2.6% (p<0.01). The admission rate for return visits was also reduced, but not significantly so, from 22.3% to 17.5% (p=0.37). Return visits at the other hospitals were similar or significantly increased in 2012 compared with 2011. The development and implementation of clinical practices were effective in reducing return visits of paediatric patients to the ED.


Active movement restores veridical event-timing after tactile adaptation.
Growing evidence suggests that time in the subsecond range is tightly linked to sensory processing. Event-time can be distorted by sensory adaptation, and many temporal illusions can accompany action execution. In this study, we show that adaptation to tactile motion causes a strong contraction of the apparent duration of tactile stimuli. However, when subjects make a voluntary motor act before judging the duration, it annuls the adaptation-induced temporal distortion, reestablishing veridical event-time. The movement needs to be performed actively by the subject: passive movement of similar magnitude and dynamics has no effect on adaptation, showing that it is the motor commands themselves, rather than reafferent signals from body movement, which reset the adaptation for tactile duration. No other concomitant perceptual changes were reported (such as apparent speed or enhanced temporal discrimination), ruling out a generalized effect of body movement on somatosensory processing. We suggest that active movement resets timing mechanisms in preparation for the new scenario that the movement will cause, eliminating inappropriate biases in perceived time. Our brain seems to utilize the intention-to-move signals to retune its perceptual machinery appropriately, to prepare to extract new temporal information.


Natural killer cells and natural killer T cells in Lyme arthritis.
Natural killer (NK) and natural killer T (NKT) cells provide a first line of defense against infection. However, these cells have not yet been examined in patients with Lyme arthritis, a late disease manifestation. Lyme arthritis usually resolves with antibiotic treatment. However, some patients have persistent arthritis after spirochetal killing, which may result from excessive inflammation, immune dysregulation and infection-induced autoimmunity. We determined the frequencies and phenotypes of NK cells and invariant NKT (iNKT) cells in paired peripheral blood (PB) and synovial fluid (SF) samples from eight patients with antibiotic-responsive arthritis and fifteen patients with antibiotic-refractory arthritis using flow cytometry and cytokine analyses. In antibiotic-responsive patients, who were seen during active infection, high frequencies of CD56bright NK cells were found in SF, the inflammatory site, compared with PB (P <0.001); at both sites, a high percentage of cells expressed the activation receptor NKG2D and the chaperone CD94, a low percentage expressed inhibitory killer immunoglobulin-like receptors (KIR), and a high percentage produced IFN-γ. In antibiotic-refractory patients, who were usually evaluated near the conclusion of antibiotics when few if any live spirochetes remained, the phenotype of CD56bright cells in SF was similar to that in patients with antibiotic-responsive arthritis, but the frequency of these cells was significantly less (P = 0.05), and the frequencies of CD56dim NK cells tended to be higher. However, unlike typical NKdim cells, these cells produced large amounts of IFN-γ, suggesting that they were not serving a cytotoxic function. Lastly, iNKT cell frequencies in the SF of antibiotic-responsive patients were significantly greater compared with that of antibiotic-refractory patients where these cells were often absent (P = 0.003). In patients with antibiotic-responsive arthritis, the high percentage of activated, IFN-γ-producing CD56bright NK cells in SF and the presence of iNKT cells suggest that these cells still have a role in spirochetal killing late in the illness. In patients with antibiotic-refractory arthritis, the frequencies of IFN-γ-producing CD56bright and CD56dim NK cells remained high in SF, even after spirochetal killing, suggesting that these cells contribute to excessive inflammation and immune dysregulation in joints, and iNKT cells, which may have immunomodulatory effects, were often absent.


Automated Deployment of an Internet Protocol Telephony Service on Unmanned Aerial Vehicles Using Network Functions Virtualization.
The Network Function Virtualization (NFV) paradigm is one of the key enabling technologies in the development of the 5th generation of mobile networks. This technology aims to lessen the dependence on hardware in the provision of network functions and services by using virtualization techniques that allow the softwarization of those functionalities over an abstraction layer. In this context, there is increasing interest in exploring the potential of unmanned aerial vehicles (UAVs) to offer a flexible platform capable of enabling cost-effective NFV operations over delimited geographic areas. To demonstrate the practical feasibility of utilizing NFV technologies in UAV platforms, a protocol is presented to set up a functional NFV environment based on open source technologies, in which a set of small UAVs supply the computational resources that support the deployment of moderately complex network services. Then, the protocol details the different steps needed to support the automated deployment of an internet protocol (IP) telephony service over a network of interconnected UAVs, leveraging the capacities of the configured NFV environment. Experimentation results demonstrate the proper operation of the service after its deployment. Although the protocol focuses on a specific type of network service (i.e., IP telephony), the described steps may serve as a general guide to deploy other type of network services. On the other hand, the protocol description considers concrete equipment and software to set up the NFV environment (e.g., specific single board computers and open source software). The utilization of other hardware and software platforms may be feasible, although the specific configuration aspect of the NFV environment and the service deployment may present variations with respect to those described in the protocol.


Potential role of nuclear factor kappaB and reactive oxygen species in cAMP and cytokine regulation of surfactant protein-A gene expression in lung type II cells.
The human surfactant protein-A2 (hSP-A2) gene is developmentally regulated, expressed in type II pneumonocytes, and induced by cAMP. cAMP induction of hSP-A2 expression is O2 dependent and mediated by increased phosphorylation, DNA binding, and transcriptional activation of thyroid transcription factor-1 (TTF-1). The TTF-1-binding element (TBE) at -175 bp contains a reverse-oriented nuclear factor-kappaB (NF-kappaB) binding site. IL-1 increased SP-A expression in lung type II cells and had additive stimulatory effects with cAMP. Nuclear extracts from cAMP- or IL-1-treated type II cells manifested increased binding to NF-kappaB consensus and TBE probes; cAMP and IL-1 had additive effects. Competitive and antibody supershift EMSA revealed that NF-kappaB and TTF-1 interact with TBE. IL-1 treatment of type II cells caused rapid (1 h) increases in nuclear levels of NF-kappaB (p50 and p65) and in binding to NF-kappaB and TBE probes; nuclear levels of TTF-1 were unaffected. Bt2cAMP increased binding to NF-kappaB and TBE probes more slowly; no changes in nuclear levels of p50, p65, or TTF-1 were evident, suggesting that IL-1 and cAMP act by different mechanisms. A role for endogenous NF-kappaB in cAMP and IL-1 regulation of SP-A was suggested by findings that dominant-negative forms of inhibitor of kappaB reduced binding of type II cell nuclear proteins to TBE and inhibited SP-A expression. In cotransfection assays, NF-kappaB and TTF-1 cooperatively interacted at TBE to stimulate SP-A promoter activity; this was further enhanced by IL-1. In coimmunoprecipitation assays using type II cell nuclear extracts, TTF-1 was found to interact with p65 in vivo. Finally, antioxidant inhibitors of NF-kappaB reduced type II cell nuclear protein binding to TBE and blocked stimulatory effects of cAMP on SP-A expression. This provides intriguing evidence that permissive effects of O2/reactive oxygen species on cAMP regulation of SP-A expression may be mediated by cooperative interactions of TTF-1 and NF-kappaB at the TBE.


Environmental effects of an impact-generated dust cloud: implications for the cretaceous-tertiary extinctions.
A model of the evolution and radiative effects of a debris cloud from a hypothesized impact event at the Cretaceous-Tertiary boundary suggests that the cloud could have reduced the amount of light at the earth's surface below that required for photosynthesis for several months and, for a somewhat shorter interval, even below that needed for many animals to see. For 6 months to 1 year, the surface would cool; the oceans would cool only a few degrees Celsius at most, but the continents might cool a maximum of 40 Kelvin. Extinctions in the ocean may have been caused primarily by the temporary cessation of photosynthesis, but those on land may have been primarily induced by a combination of lowered temperatures and reduced light.


Cross-lags and the unbiased estimation of life-history and demographic parameters.
Biological processes exhibit complex temporal dependencies due to the sequential nature of allocation decisions in organisms' life cycles, feedback loops and two-way causality. Consequently, longitudinal data often contain cross-lags: the predictor variable depends on the response variable of the previous time step. Although statisticians have warned that regression models that ignore such covariate endogeneity in time series are likely to be inappropriate, this has received relatively little attention in biology. Furthermore, the resulting degree of estimation bias remains largely unexplored. We use a graphical model and numerical simulations to understand why and how regression models that ignore cross-lags can be biased, and how this bias depends on the length and number of time series. Ecological and evolutionary examples are provided to illustrate that cross-lags may be more common than is typically appreciated and that they occur in functionally different ways. We show that routinely used regression models that ignore cross-lags are asymptotically unbiased. However, this offers little relief, as for most realistically feasible lengths of time-series conventional methods are biased. Furthermore, collecting time series on multiple subjects-such as populations, groups or individuals-does not help to overcome this bias when the analysis focusses on within-subject patterns (often the pattern of interest). Simulations, a literature search and a real-world empirical example together suggest that approaches that ignore cross-lags are likely biased in the direction opposite to the sign of the cross-lag (e.g. towards detecting density dependence of vital rates and against detecting life-history trade-offs and benefits of group living). Next, we show that multivariate (e.g. structural equation) models can dynamically account for cross-lags, and simultaneously address additional bias induced by measurement error, but only if the analysis considers multiple time series. We provide guidance on how to identify a cross-lag and subsequently specify it in a multivariate model, which can be far from trivial. Our tutorials with data and R code of the worked examples provide step-by-step instructions on how to perform such analyses. Our study offers insights into situations in which cross-lags can bias analysis of ecological and evolutionary time series and suggests that adopting dynamical models can be important, as this directly affects our understanding of population regulation, the evolution of life histories and cooperation, and possibly many other topics. Determining how strong estimation bias due to ignoring covariate endogeneity has been in the ecological literature requires further study, also because it may interact with other sources of bias.


Aging-Dependent Genetic Effects Associated to ADHD Predict Longitudinal Changes of Ventricular Volumes in Adulthood.
Attention-Deficit/Hyperactivity Disorder (ADHD) is a childhood-onset disorder that can persist into adult life. Most genetic studies have focused on investigating biological mechanisms of ADHD during childhood. However, little is known about whether genetic variants associated with ADHD influence structural brain changes throughout adulthood. Participant of the study were drawn from a population-based sample of 3,220 healthy individuals drawn from the Rotterdam Study, with at least two magnetic resonance imaging (MRI)-scans (8,468 scans) obtained every 3-4 years. We investigate associations of genetic single nucleotide polymorphisms (SNPs) that have previously been identified in genome-wide association studies for ADHD, and trajectories of global and subcortical brain structures in an adult population (aged 50 years and older), acquired through MRI. We also evaluated the existence of age-dependent effects of these genetic variants on trajectories of brain structures. These analyses were reproduced among individuals 70 years of age or older to further explore aging-dependent mechanisms. We additionally tested baseline associations using the first MRI-scan of the 3,220 individuals. We observed significant age-dependent effects on the rs212178 in trajectories of ventricular size (lateral ventricles, P= 4E-05; inferior lateral ventricles, P=3.8E-03; third ventricle, P=2.5E-03; fourth ventricle, P=5.5E-03). Specifically, carriers of the G allele, which was reported as protective for ADHD, had a smaller increase of ventricular size compared with homozygotes for the A allele in elder stages. Post hoc analysis on the subset of individuals older than 70 years of age reinforced these results (lateral ventricles, P=7.3E-05). In addition, the rs4916723, and the rs281324 displayed nominal significant age-dependent effects in trajectories of the amygdala volume (P=1.4E-03), and caudate volume (P=1.8E-03), respectively. To the best of our knowledge, this is the first study suggesting the involvement of protective genetic variants for ADHD on prevention of brain atrophy during adulthood.


Frozen shoulder: the effectiveness of conservative and surgical interventions--systematic review.
A variety of therapeutic interventions is available for restoring motion and diminishing pain in patients with frozen shoulder. An overview article concerning the evidence for the effectiveness of these interventions is lacking. To provide an evidence-based overview regarding the effectiveness of conservative and surgical interventions to treat the frozen shoulder. The Cochrane Library, PubMed, Embase, Cinahl and Pedro were searched for relevant systematic reviews and randomised clinical trials (RCTs). Two reviewers independently selected relevant studies, assessed the methodological quality and extracted data. A best-evidence synthesis was used to summarise the results. Five Cochrane reviews and 18 RCTs were included studying the effectiveness of oral medication, injection therapy, physiotherapy, acupuncture, arthrographic distension and suprascapular nerve block (SSNB). We found strong evidence for the effectiveness of steroid injections and laser therapy in short-term and moderate evidence for steroid injections in mid-term follow-up. Moderate evidence was found in favour of mobilisation techniques in the short and long term, for the effectiveness of arthrographic distension alone and as an addition to active physiotherapy in the short term, for the effectiveness of oral steroids compared with no treatment or placebo in the short term, and for the effectiveness of SSNB compared with acupuncture, placebo or steroid injections. For other commonly used interventions no or only limited evidence of effectiveness was found. Most of the included studies reported short-term results, whereas symptoms of frozen shoulder may last up to 4 years. High quality RCTs studying long-term results are clearly needed in this field.


The Incremental Multiresolution Matrix Factorization Algorithm.
Multiresolution analysis and matrix factorization are foundational tools in computer vision. In this work, we study the interface between these two distinct topics and obtain techniques to uncover hierarchical block structure in symmetric matrices - an important aspect in the success of many vision problems. Our new algorithm, the incremental multiresolution matrix factorization, uncovers such structure one feature at a time, and hence scales well to large matrices. We describe how this multiscale analysis goes much farther than what a direct "global" factorization of the data can identify. We evaluate the efficacy of the resulting factorizations for relative leveraging within regression tasks using medical imaging data. We also use the factorization on representations learned by popular deep networks, providing evidence of their ability to infer semantic relationships even when they are not explicitly trained to do so. We show that this algorithm can be used as an exploratory tool to improve the network architecture, and within numerous other settings in vision.


Women physicians in academic medicine: new insights from cohort studies.
I conducted a study to determine whether women who graduate from medical schools are more or less likely than their male counterparts to pursue full-time careers in academic medicine and to advance to the senior ranks of medical school faculties. The rates of advancement to the ranks of assistant, associate, and full professor for all U.S. medical school graduates from 1979 through 1993 and for all members of U.S. medical school faculties from 1979 through 1997 were studied. Cohorts were defined on the basis of the year of graduation from medical school, track (tenure or nontenure), and academic department. Within each cohort, the number of women who advanced to a senior rank was compared with the number that would be expected on the basis of parity between men and women, and 95 percent confidence intervals were calculated. Women were significantly more likely than men to pursue an academic career. During the study period, 634 more women became faculty members than expected. The numbers were higher in the older cohorts than in the younger cohorts. The numbers of women who advanced to the ranks of associate and full professor were significantly lower than the expected numbers. This was true for both tenure and nontenure tracks, even after adjustment for the department. A total of 334 fewer women advanced to associate professor than expected, and 44 fewer women advanced to full professor than expected. Disparities persist in the advancement of men and women on medical school faculties. However, the numbers of women physicians at all levels of academic medicine are increasing.


Confirming the efficacy of intravenous immunoglobulin in CIDP through minimum clinically important differences: shifting from statistical significance to clinical relevance.
The ICE trial demonstrated the efficacy of immune globulin intravenous (IGIV-C) over placebo in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). However, improving the interpretability of the results by analysing the minimum clinically important difference (MCID) had not been considered. To identify MCID thresholds of various outcome measures using different methods and to test treatment differences (IGIV-C vs placebo) using these thresholds. One anchor-based (Short Form-36 question 2) and three distribution-based (½ SD, 1 SE of measurement, and effect size) techniques were employed to identify MCID cut-offs for various impairments (electromyographic parameters, Medical Research Council (MRC) sum score, grip strength, inflammatory neuropathy cause and treatment (INCAT) sensory sum score), disability (INCAT scale score, Rotterdam handicap scale (RHS) score) and quality of life (SF-36). IGIV-C or placebo was administered every 3 weeks for up to 24 weeks to 117 CIDP patients. Patients who did not improve by ≥1 point on the INCAT scale received alternate treatment. The proportion of patients with results exceeding identified MCID thresholds was compared. Results MCID cut-offs for outcomes were determined using each method. For the INCAT disability scale (primary ICE-trial outcome), all MCID methods identified significantly more responders with IGIV-C than placebo. Significant differences favouring IGIV-C were also demonstrated for various nerve conduction parameters, MRC sum score, grip strength, RHS score and SF-36 physical component summary score. In addition to being statistically significant, all MCID analyses showed that CIDP improvements with IGIV-C are clinically meaningful. Consideration of MCID is recommended in future therapeutic trials. Trial Registration Number NCT00220740 (http://ClinicalTrials.gov).


The Evolution of Tau Phosphorylation and Interactions.
Tau is a neuronal microtubule-associated protein (MAP) that is involved in the regulation of axonal microtubule assembly. However, as a protein with intrinsically disordered regions (IDRs), tau also interacts with many other partners in addition to microtubules. Phosphorylation at selected sites modulates tau's various intracellular interactions and regulates the properties of IDRs. In Alzheimer's disease (AD) and other tauopathies, tau exhibits pathologically increased phosphorylation (hyperphosphorylation) at selected sites and aggregates into neurofibrillary tangles (NFTs). By bioinformatics means, we tested the hypothesis that the sequence of tau has changed during the vertebrate evolution in a way that novel interactions developed and also the phosphorylation pattern was affected, which made tau prone to the development of tauopathies. We report that distinct regions of tau show functional specialization in their molecular interactions. We found that tau's amino-terminal region, which is involved in biological processes related to "membrane organization" and "regulation of apoptosis," exhibited a strong evolutionary increase in protein disorder providing the basis for the development of novel interactions. We observed that the predicted phosphorylation sites have changed during evolution in a region-specific manner, and in some cases the overall number of phosphorylation sites increased owing to the formation of clusters of phosphorylatable residues. In contrast, disease-specific hyperphosphorylated sites remained highly conserved. The data indicate that novel, non-microtubule related tau interactions developed during evolution and suggest that the biological processes, which are mediated by these interactions, are of pathological relevance. Furthermore, the data indicate that predicted phosphorylation sites in some regions of tau, including a cluster of phosphorylatable residues in the alternatively spliced exon 2, have changed during evolution. In view of the "antagonistic pleiotropy hypothesis" it may be worth to take disease-associated phosphosites with low evolutionary conservation as relevant biomarkers into consideration.


Prepartying promotes heightened risk in the college environment: an event-level report.
Due to the emergence of research literature examining the prepartying behavior of college students, the present study examines students' varying drinking rates, blood alcohol levels (BALs), and alcohol-related consequences during two drinking events - one involving prepartying and one devoid of prepartying. Two-hundred and thirty-eight student drinkers completed an online drinking assessment detailing their two most recent drinking occasions involving and not involving prepartying. Participants responded to a series of questions regarding quantities consumed on the drinking day and occurrence of alcohol-related consequences. While men did not differ in drinking or estimated BALs, between the two drinking days, female participants drank significantly more drinks and reached higher BALs on the prepartying drinking day. Both males and females reported increased experience of alcohol-related consequences on the prepartying drinking day. In analyzing the prepartying drinking day specifically, we found that while men drink more alcohol during prepartying, but both men and women reached similar BALs during the event. Also, amount consumed during prepartying related to further drinking throughout the evening. It appears that prepartying may influence women to reach comparable levels of intoxication and alcohol-related consequences as their male peers. Quick drinking during prepartying may raise BALs and lead to alcohol-related consequences particularly for female students.


Measuring lung function in airways diseases: current and emerging techniques.
Chronic airways diseases, including asthma, COPD and cystic fibrosis, cause significant morbidity and mortality and are associated with high healthcare expenditure, in the UK and worldwide. For patients with these conditions, improvements in clinical outcomes are likely to depend on the application of precision medicine, that is, the matching of the right treatment to the right patient at the right time. In this context, the identification and targeting of 'treatable traits' is an important priority in airways disease, both to ensure the appropriate use of existing treatments and to facilitate the development of new disease-modifying therapy. This requires not only better understanding of airway pathophysiology but also an enhanced ability to make physiological measurements of disease activity and lung function and, if we are to impact on the natural history of these diseases, reliable measures in early disease. In this article, we outline some of the key challenges faced by the respiratory community in the management of airways diseases, including early diagnosis, disease stratification and monitoring of therapeutic response. In this context, we review the advantages and limitations of routine physiological measurements of respiratory function including spirometry, body plethysmography and diffusing capacity and discuss less widely used methods such as forced oscillometry, inert gas washout and the multiple inert gas elimination technique. Finally, we highlight emerging technologies including imaging methods such as quantitative CT and hyperpolarised gas MRI as well as quantification of lung inhomogeneity using precise in-airway gas analysis and mathematical modelling. These emerging techniques have the potential to enhance existing measures in the assessment of airways diseases, may be particularly valuable in early disease, and should facilitate the efforts to deliver precision respiratory medicine.


Soil suppressiveness against the disease complex of the soybean cyst nematode and sudden death syndrome of soybean.
The ecology of the complex of soybean cyst nematode (SCN) and sudden death syndrome (SDS) of soybean was investigated under soybean monoculture in two field experiments from 2003 to 2007. Initially, susceptible soybean 'Spencer' was planted while inoculating Fusarium virguliforme into nonfumigated or preseason-fumigated plots (methyl bromide, MB, at 450 kg/ha), and SCN and SDS were monitored. In one field, SCN population densities declined in nonfumigated but increased in fumigated plots. After years of limited SDS in 2003 and 2004, SDS developed later in nonfumigated than fumigated plots. In 2006 in the greenhouse, nondisturbed or disturbed soil cores (10-cm diameter, 30-cm depth) from field plots received two two-level factors: (i) nonfumigated or fumigated (1,070 kg/ha MB); and (ii) noninoculated or inoculated with 9,000 second-stage juveniles of SCN. At harvest, nonfumigated cores from nonfumigated plots had fewer nematodes and less SDS regardless of disturbance or inoculation than the corresponding fumigated cores and any cores from fumigated plots. In the second field, SCN became detectable after 2003 during the monoculture in nonfumigated plots and lagged in fumigated plots; both treatments had low levels of SDS. Exploiting the suppressiveness of the first field could allow for biological control of SDS and SCN in soybean production.


Angiotensin-(1-7). A member of circulating angiotensin peptides.
We measured the concentrations of three principal products of the renin-angiotensin system and seven of their metabolites in the plasma of anesthetized normal dogs and in dogs 24 hours after bilateral nephrectomy. The levels of the angiotensin peptides were measured by high-performance liquid chromatography combined with radioimmunoassay using three specific antibodies that recognized different epitotes in the sequences of angiotensin I, angiotensin II, and angiotensin-(1-7). The analysis revealed that angiotensin-(1-7) is present in the plasma of intact (4.9 +/- 2.2 fmol/ml) and nephrectomized (0.5 +/- 0.5 fmol/ml) dogs. An intravenous injection of purified hog renin (0.01 Goldblatt unit/kg) increased plasma levels of angiotensin I, angiotensin II, and angiotensin-(1-7) both before and after nephrectomy. These changes were associated with parallel increases in the concentrations of fragments of the three parent peptides. Administration of MK-422 led to the disappearance of circulating angiotensin II and its fragments both before and after a second injection of the same dose of renin. In contrast, MK-422 augmented the plasma levels of both angiotensin I and angiotensin-(1-7). The concentrations of these two peptides, but not the blood pressure, were again augmented by a second injection of renin given after blockade of converting enzyme. These effects were observed both before and after bilateral nephrectomy. These findings show that angiotensin-(1-7) circulates in the blood of normal and nephrectomized dogs. In addition, we found that angiotensin-(1-7) is generated in the blood from the cleavage of angiotensin I through a pathway independent of converting enzyme (EC 220.127.116.11).


Small-molecule-mediated stabilization of familial amyotrophic lateral sclerosis-linked superoxide dismutase mutants against unfolding and aggregation.
Familial amyotrophic lateral sclerosis (FALS) is a fatal motor neuron disease that is caused by mutations in the gene encoding superoxide dismutase-type 1 (SOD1). The affected regions of the FALS brain are characterized by aggregated SOD1, and the mutations that destabilize SOD1 appear to promote its aggregation in vitro. Because dissociation of the native SOD1 dimer is required for its in vitro aggregation, we initiated an in silico screening program to find drug-like molecules that would stabilize the SOD1 dimer. A potential binding site for such molecules at the SOD1 dimer interface was identified, and its importance was validated by mutagenesis. About 1.5 million molecules from commercial databases were docked at the dimer interface. Of the 100 molecules with the highest predicted binding affinity, 15 significantly inhibited in vitro aggregation and denaturation of A4V, a FALS-linked variant of SOD1. In the presence of several of these molecules, A4V and other FALS-linked SOD1 mutants such as G93A and G85R behaved similarly to wild-type SOD1, suggesting that these compounds could be leads toward effective therapeutics against FALS.


Development of a questionnaire to assess sedentary time in older persons--a comparative study using accelerometry.
There is currently no validated questionnaire available to assess total sedentary time in older adults. Most studies only used TV viewing time as an indicator of sedentary time. The first aim of our study was to investigate the self-reported time spent by older persons on a set of sedentary activities, and to compare this with objective sedentary time measured by accelerometry. The second aim was to determine what set of self-reported sedentary activities should be used to validly rank people's total sedentary time. Finally we tested the reliability of our newly developed questionnaire using the best performing set of sedentary activities. The study sample included 83 men and women aged 65-92 y, a random sample of Longitudinal Aging Study Amsterdam participants, who completed a questionnaire including ten sedentary activities and wore an Actigraph GT3X accelerometer for 8 days. Spearman correlation coefficients were calculated to examine the association between self-reported time and objective sedentary time. The test-retest reliability was calculated using the intraclass correlation coefficient (ICC). Mean total self-reported sedentary time was 10.4 (SD 3.5) h/d and was not significantly different from mean total objective sedentary time (10.2 (1.2) h/d, p = 0.63). Total self-reported sedentary time on an average day (sum of ten activities) correlated moderately (Spearman's r = 0.35, p < 0.01) with total objective sedentary time. The correlation improved when using the sum of six activities (r = 0.46, p < 0.01), and was much higher than when using TV watching only (r = 0.22, p = 0.05). The test-retest reliability of the sum of six sedentary activities was 0.71 (95% CI 0.57-0.81). A questionnaire including six sedentary activities was moderately associated with accelerometry-derived sedentary time and can be used to reliably rank sedentary time in older persons.


Understanding conductivity anomalies in Cu(I)-based delafossite transparent conducting oxides: Theoretical insights.
The Cu(I)-based delafossite structure, Cu(I)M(III)O(2), can accommodate a wide range of rare earth and transition metal cations on the M(III) site. Substitutional doping of divalent ions for these trivalent metals is known to produce higher p-type conductivity than that occurring in the undoped materials. However, an explanation of the conductivity anomalies observed in these p-type materials, as the trivalent metal is varied, is still lacking. In this article, we examine the electronic structure of Cu(I)M(III)O(2) (M(III)=Al,Cr,Sc,Y) using density functional theory corrected for on-site Coulomb interactions in strongly correlated systems (GGA+U) and discuss the unusual experimental trends. The importance of covalent interactions between the M(III) cation and oxygen for improving conductivity in the delafossite structure is highlighted, with the covalency trends found to perfectly match the conductivity trends. We also show that calculating the natural band offsets and the effective masses of the valence band maxima is not an ideal method to classify the conduction properties of these ternary materials.


Early changes in emotional processing as a marker of clinical response to SSRI treatment in depression.
Antidepressant treatment reduces behavioural and neural markers of negative emotional bias early in treatment and has been proposed as a mechanism of antidepressant drug action. Here, we provide a critical test of this hypothesis by assessing whether neural markers of early emotional processing changes predict later clinical response in depression. Thirty-five unmedicated patients with major depression took the selective serotonin re-uptake inhibitor (SSRI), escitalopram (10 mg), over 6 weeks, and were classified as responders (22 patients) versus non-responders (13 patients), based on at least a 50% reduction in symptoms by the end of treatment. The neural response to fearful and happy emotional facial expressions was assessed before and after 7 days of treatment using functional magnetic resonance imaging. Changes in the neural response to these facial cues after 7 days of escitalopram were compared in patients as a function of later clinical response. A sample of healthy controls was also assessed. At baseline, depressed patients showed greater activation to fear versus happy faces than controls in the insula and dorsal anterior cingulate. Depressed patients who went on to respond to the SSRI had a greater reduction in neural activity to fearful versus happy facial expressions after just 7 days of escitalopram across a network of regions including the anterior cingulate, insula, amygdala and thalamus. Mediation analysis confirmed that the direct effect of neural change on symptom response was not mediated by initial changes in depressive symptoms. These results support the hypothesis that early changes in emotional processing with antidepressant treatment are the basis of later clinical improvement. As such, early correction of negative bias may be a key mechanism of antidepressant drug action and a potentially useful predictor of therapeutic response.


Drug discovery using chemical systems biology: identification of the protein-ligand binding network to explain the side effects of CETP inhibitors.
Systematic identification of protein-drug interaction networks is crucial to correlate complex modes of drug action to clinical indications. We introduce a novel computational strategy to identify protein-ligand binding profiles on a genome-wide scale and apply it to elucidating the molecular mechanisms associated with the adverse drug effects of Cholesteryl Ester Transfer Protein (CETP) inhibitors. CETP inhibitors are a new class of preventive therapies for the treatment of cardiovascular disease. However, clinical studies indicated that one CETP inhibitor, Torcetrapib, has deadly off-target effects as a result of hypertension, and hence it has been withdrawn from phase III clinical trials. We have identified a panel of off-targets for Torcetrapib and other CETP inhibitors from the human structural genome and map those targets to biological pathways via the literature. The predicted protein-ligand network is consistent with experimental results from multiple sources and reveals that the side-effect of CETP inhibitors is modulated through the combinatorial control of multiple interconnected pathways. Given that combinatorial control is a common phenomenon observed in many biological processes, our findings suggest that adverse drug effects might be minimized by fine-tuning multiple off-target interactions using single or multiple therapies. This work extends the scope of chemogenomics approaches and exemplifies the role that systems biology has in the future of drug discovery.


Repurposed molecules for antiepileptogenesis: Missing an opportunity to prevent epilepsy?
Prevention of epilepsy is a great unmet need. Acute central nervous system (CNS) insults such as traumatic brain injury (TBI), cerebrovascular accidents (CVA), and CNS infections account for 15%-20% of all epilepsy. Following TBI and CVA, there is a latency of days to years before epilepsy develops. This allows treatment to prevent or modify postinjury epilepsy. No such treatment exists. In animal models of acquired epilepsy, a number of medications in clinical use for diverse indications have been shown to have antiepileptogenic or disease-modifying effects, including medications with excellent side effect profiles. These include atorvastatin, ceftriaxone, losartan, isoflurane, N-acetylcysteine, and the antiseizure medications levetiracetam, brivaracetam, topiramate, gabapentin, pregabalin, vigabatrin, and eslicarbazepine acetate. In addition, there are preclinical antiepileptogenic data for anakinra, rapamycin, fingolimod, and erythropoietin, although these medications have potential for more serious side effects. However, except for vigabatrin, there have been almost no translation studies to prevent or modify epilepsy using these potentially "repurposable" medications. We may be missing an opportunity to develop preventive treatment for epilepsy by not evaluating these medications clinically. One reason for the lack of translation studies is that the preclinical data for most of these medications are disparate in terms of types of injury, models within different injury type, dosing, injury-treatment initiation latencies, treatment duration, and epilepsy outcome evaluation mode and duration. This makes it difficult to compare the relative strength of antiepileptogenic evidence across the molecules, and difficult to determine which drug(s) would be the best to evaluate clinically. Furthermore, most preclinical antiepileptogenic studies lack information needed for translation, such as dose-blood level relationship, brain target engagement, and dose-response, and many use treatment parameters that cannot be applied clinically, for example, treatment initiation before or at the time of injury and dosing higher than tolerated human equivalent dosing. Here, we review animal and human antiepileptogenic evidence for these medications. We highlight the gaps in our knowledge for each molecule that need to be filled in order to consider clinical translation, and we suggest a platform of preclinical antiepileptogenesis evaluation of potentially repurposable molecules or their combinations going forward.


Effect on attendance at breast cancer screening of adding a self administered questionnaire to the usual invitation to breast screening in southern England.
The primary aim of the research described in this paper was to ascertain whether inclusion of a self administered questionnaire with the usual invitation to routine breast screening affected screening uptake. Secondary aims included establishing appropriate questionnaire distribution and collection methods within the framework of the National Health Service Breast Screening Programme and optimisation of questionnaire design. Randomised study. Oxfordshire and West of London Breast Screening Units. 6400 women invited for routine screening mammography were individually randomised to receive either the usual breast screening invitation alone, or to receive the usual invitation accompanied by a self administered questionnaire, to be returned at the time of screening. Participants were then followed up and attendance rates at screening were compared between groups. Screening attendance rates were similar in women who did and did not receive a questionnaire (71% in each group). Of those who were sent a questionnaire and attended for screening, 77% returned a completed questionnaire. Screening uptake was not affected by the way in which the questionnaire was returned or by whether or not personal details and signed permission for follow up were requested. The inclusion of a self administered questionnaire accompanying the invitation to breast screening did not adversely affect screening uptake. A high proportion of women completed the questionnaire.


Hybrid wedge plasmon polariton waveguide with good fabrication-error-tolerance for ultra-deep-subwavelength mode confinement.
A novel hybrid plasmonic waveguide consisting of a high-index dielectric nanowire placed above a triangular metal wedge substrate is proposed and analyzed theoretically. The strong coupling between the wedge plasmon polariton and the dielectric nanowire mode results in both the ultra-tight confinement and low propagation loss. Compared to the previous studied hybrid surface plasmon polariton structures without the metal wedge substrate, stronger field enhancement in the low-index gap region as well as improved figure of merit (FOM) could be realized simultaneously. Results of the modal properties considering certain fabrication imperfections show that the proposed structure is also quite tolerant to these errors.


Alterations of the murine gut microbiome in allergic airway disease are independent of surfactant protein D.
SP-D is an important host defense lectin in innate immunity and SP-D deficient mice show several abnormal immune effects and are susceptible to allergen-induced airway disease. At the same time, host microbiome interactions play an important role in the development of allergic airway disease, and alterations to gut microbiota have been linked to airway disease through the gut-lung axis. Currently, it is unknown if the genotype (Sftpd-/- or Sftpd+/+) of the standard SP-D mouse model can affect the host microbiota to such an degree that it would overcome the cohousing effect on microbiota and interfere with the interpretation of immunological data from the model. Generally, little is known about the effect of the SP-D protein in itself and in combination with airway disease on the microbiota. In this study, we tested the hypothesis that microbiome composition would change with the lack of SP-D protein and presence of allergic airway disease in the widely used SP-D-deficient mouse model. We describe here for the first time the lung and gut microbiota of the SP-D mouse model with OVA induced allergic airway disease. After the challenge animals were killed and fecal samples were taken from the caecum and lungs were subjected to bronchoalveolar lavage for comparison of gut and lung microbiota by Illumina 16S rRNA gene sequencing. A significant community shift was observed in gut microbiota after challenge with OVA. However, the microbial communities were not significantly different between SP-D deficient and wild type mice from the same cages in either naïve or OVA treated animals. Wild type animals did however show the largest variation between mice. Our results show that the composition of the microbiota is not influenced by the SP-D deficient genotype under naïve or OVA induced airway disease. However, OVA sensitization and pulmonary challenge did alter the gut microbiota, supporting a bidirectional lung-gut crosstalk. Future mechanistic investigations of the influence of induced allergic airway disease on gut microbiota are warranted.


Benefits of sodium hexametaphosphate-containing chewing gum for extrinsic stain inhibition.
This study was designed to examine the ability of sodium hexametaphosphate delivered from a chewing gum to prevent extrinsic tooth stain formation. This study was a negative-controlled, randomized, two-period crossover design, with a 10-day washout period between treatments. The two treatments were a chewing gum containing 5.6% sodium hexametaphosphate and a negative control chewing gum. Eleven subjects who met study criteria were enrolled, and 10 completed the study over a two-week period. Each treatment period lasted approximately 48 hours and was separated by a washout period. After a dental prophylaxis, a digital image of the anterior teeth was taken to assess baseline stain. The three-day stain induction phase consisted of the patient using a 10 ml 0.2% chlorhexidine rinse for 60 seconds, followed by chewing two pellets/sticks of their assigned gum for five minutes and rinsing with 10 ml of cold tea solution for 60 seconds. No oral hygiene was permitted other than use of the test products. During both treatment periods, each subject followed the same regimen eight times, once per hour, throughout the day. On Days 2 and 3, the adjusted mean L* measurement was statistically significantly greater for the sodium hexametaphosphate gum than for the control gum. Moreover, nine of the 10 subjects had whiter teeth while on the experimental gum treatment at both Day 2 and Day 3. The results of this study support that sodium hexametaphosphate delivered from a chewing gum prevents dental stain formation and leads to a patient-desired whitening benefit.