Electrostatically controlled swelling and adsorption of polyelectrolyte brush-grafted nanoparticles to the solid/liquid interface.
Adsorption of 20 nm diameter silica nanoparticles grafted with a high density brush of the weak polymeric base poly(2-(dimethylamino)ethyl methacrylate) (SiO2-g-PDMAEMA) to the silica/aqueous interface was investigated using ellipsometry and streaming potential measurements. We measured SiO2-g-PDMAEMA adsorption to negatively charged silica surfaces in 1-100 mM sodium chloride solutions in the pH range 5-10 to investigate the role of electrostatics in the adsorption mechanism. In this system pH and ionic strength determine not only the charge density of the silica adsorption substrate but also the degree of ionization and swelling of the PDMAEMA brushes on the nanoparticles, resulting in nonmonotonic dependences of the extent of adsorption on pH and ionic strength. SiO2-g-PDMAEMA displays significantly different adsorption behavior from the linear PDMAEMA analogue, most notably in terms of a strongly hysteretic adsorption response to altered pH and a greater tendency to adsorb under weak surface attraction conditions that prevail at high pH.


Memory deficits associated with recreational use of "ecstasy" (MDMA).
Evidence from both animal, and human, studies suggests that repeated administration of 3,4-methylenedioxymethamphetamine (MDMA: "ecstasy") produces lasting decreases in serotonergic activity. Serotonin is believed to play a modulatory role in a variety of psychological processes, including learning and memory. There are recent reports that polydrug users, who have used ecstasy recreationally, exhibit selective impairments in memory. However, these studies did not compare ecstasy users with polydrug users who had not taken ecstasy, leaving open the possibility that the memory deficits may be associated with a history of use of other illicit drugs. The present study used the Rivermead Behavioural Memory test to investigate immediate and delayed recall in: 25 polydrug-users who had taken more than 20 tablets of ecstasy (MDMA group), 22 participants (polydrug controls) who had never taken ecstasy, but, otherwise has personal characteristics (e.g. age, gender, education, height, weight), and illicit drug use histories, that were generally not significantly different from those of the MDMA group, and 19 participants who had not used illicit drugs but who also had similar personal characteristics (non-drug controls). Participants in the MDMA group recalled significantly fewer ideas (approximately 75% of the number of ideas recalled by participants in either of the other two groups), in both immediate and delayed recall conditions. The two illicit drug-using groups did differ in their estimated IQ scores and their duration of use of LSD, but only the latter proved to be a statistically significant covariate, and the difference in recall performance between the MDMA and polydrug controls groups remained statistically significant when this variable was treated as a covariate. The present findings provide the first evidence that deficits in memory performance in recreational ecstasy users are primarily associated with past exposure to ecstasy, rather than with the other legal and illicit drugs consumed by these individuals, and are consistent with reduced serotonergic modulation of mnemonic function as a result of long-term neurotoxic effects of MDMA in humans.


Augmentation of HIV-specific T cell function by immediate treatment of hyperacute HIV-1 infection.
Sustained viremia after acute HIV infection is associated with profound CD4+ T cell loss and exhaustion of HIV-specific CD8+ T cell responses. To determine the impact of combination antiretroviral therapy (cART) on these processes, we examined the evolution of immune responses in acutely infected individuals initiating treatment before peak viremia. Immediate treatment of Fiebig stages I and II infection led to a rapid decline in viral load and diminished magnitude of HIV-specific (tetramer+) CD8+ T cell responses compared to untreated donors. There was a strong positive correlation between cumulative viral antigen exposure before full cART-induced suppression and immune responses measured by MHC class I tetramers, IFN-γ ELISPOT, and CD8+ T cell activation. HIV-specific CD8+ T responses of early treated individuals were characterized by increased CD127 and BCL-2 expression, greater in vitro IFN-γ secretion, and enhanced differentiation into effector memory (Tem) cells. Transcriptional analysis of tetramer+ CD8+ T cells from treated persons revealed reduced expression of genes associated with activation and apoptosis, with concurrent up-regulation of prosurvival genes including BCL-2, AXL, and SRC Early treatment also resulted in robust HIV-specific CD4+ T cell responses compared to untreated HIV-infected individuals. Our data show that limiting acute viremia results in enhanced functionality of HIV-specific CD4+ and CD8+ T cells, preserving key antiviral properties of these cells.


Pathogenicity Spectra and Screening for Resistance in Barley Against Tunisian Pyrenophora teres f. teres.
This work aimed to determine patterns of pathogenicity in Pyrenophora teres f. teres and to identify potentially effective resistance sources that could be used as breeding material to control net blotch in Tunisia. Extensive pathogenic variability was detected in 85 isolates of P. teres causing net blotch of barley in Tunisia. Based on unweighted pair-group method with arithmetic averaging clustering and mean disease rating scores, three distinct virulence groups were identified. The isolates were classified into 23 pathotypes. Pathogenic variability within the groups was higher than that between the groups, a finding that can guide a rational choice of isolates for screening lines as part of a breeding program. Conversely, studying the relationship between geographic and pathotypic structure allowed us to detect a significant isolation by distance pattern, suggesting a regular and gradual dispersal of the pathogen over this spatial scale. Using specific resistance properties of individual barley genotypes as virulence markers, all the differential barley genotypes were shown to be distinct, and no single source of resistance was totally effective against all isolates.


Absorption of Iron from Iron Chelate by Sunflower Roots.
Roots of decapitated sunflower plants absorbed iron from the ferric chelate of ethylenediamine di(o-hydroxyphenylacetic acid), leaving most of the acid in the nutrient solution. The chelating capacity of the nutrient solution increased as iron was absorbed by the plants. Most of the absorbed iron was found in the plant exudate.


Comparative in vitro and in vivo taste assessment of liquid praziquantel formulations.
The taste of pharmaceuticals strongly affects the compliance of patients. This study investigated the applicability of the electronic tongue and rodent brief-access taste aversion (BATA) model for the bitter compound praziquantel (PZQ) and taste masked liquid formulations for PZQ. In a comparative study maltodextrin (MD) Kleptose® linecaps 17 was selected as an alternative taste masking agent to two cyclodextrins; hydroxypropyl-beta-cyclodextrin (HP-β-CD) and sulfobutyl ether-beta-cyclodextrin (SBE-β-CD). A phase solubility study showed the highest affinity and solubilization capabilities for SBE-β-CD over HP-β-CD and MD, suggesting the highest taste masking ability for SBE-β-CD. No reliable results were achieved for PZQ with the Insent electronic tongue. Thus this system was not used for further evaluation of solutions with MD and CDs to confirm the results of the solubility study. In contrast the BATA model demonstrated conclusive responses for the aversiveness of PZQ. The concentration of PZQ inhibiting 50% of water lick numbers (called IC50 value) was 0.06mg/ml. In contrast to the phase solubility study, the MD enabled an equal taste masking effect in vivo in comparison to both CDs. Moreover HP-β-CD showed superior taste masking capabilities for PZQ compared to SBE-β-CD as the SBE-β-CD itself was less acceptable for the rodents than HP-β-CD. In conclusion, the BATA model was identified as a more efficient taste assessment tool for the pure PZQ and liquid formulations in contrast to the electronic tongue and the phase solubility study.


Effects of peroxynitrite on sarcoplasmic reticulum Ca2+ pump in pig coronary artery smooth muscle.
Peroxynitrite generated in arteries from superoxide and NO may damage Ca(2+) pumps. Here, we report the effects of peroxynitrite on ATP-dependent azide-insensitive uptake of Ca(2+) into pig coronary artery vesicular membrane fractions F2 [enriched in plasma membrane (PM)] and F3 [enriched in sarcoplasmic reticulum (SR)]. Membranes were pretreated with peroxynitrite and then with DTT to quench this agent. This pretreatment inhibited Ca(2+) uptake in a peroxynitrite concentration-dependent manner, but the effect was more severe in F3 than in F2. The inhibition was thus not overcome by excess DTT used to quench peroxynitrite and was not affected if catalase, SOD, or mannitol was added along with peroxynitrite. Such damage to the pump protein would be difficult to repair if produced during ischemia-reperfusion. The acylphosphates formed with ATP in F3 corresponded mainly to the SR Ca(2+) pump (110 kDa), but in F2 both PM (140 kDa) and 110-kDa bands were observed. Peroxynitrite treatment of F2 inhibited only the 110-kDa band. Inhibition of Ca(2+) uptake and acylphosphate formation from ATP correlated well in peroxynitrite-treated F3 samples. However, inhibition of acylphosphates from orthophosphate (reverse reaction of the pump) was slightly poorer. Peroxynitrite treatment also covalently cross-linked the pump protein, yielding no dimers but only larger oligomers. In contrast, cross-linking of the SR Ca(2+) pump in skeletal and cardiac muscles gives dimers as the first oligomers. Therefore, we speculate that SERCA2 has a different quaternary structure in the coronary artery smooth muscle.


High frequency of Smith autoantibodies in Omani patients with systemic lupus erythematosus.
This study was conducted to investigate the frequency and significance of some antinuclear autoantibodies in Omani patients with systemic lupus erythematosus (SLE). Anti-nuclear antibodies (ANA), anti-double stranded-DNA (anti-dsDNA), and anti-Smith (anti-Sm) autoantibodies were investigated in 60 Omani patients clinically diagnosed with SLE according to the American College of Rheumatology Criteria. The SLE group included 57 females and 3 males with an average age of 26 years. In addition, a group of 60 healthy Omanis (26 females and 34 males; average age 25 years) was used as a control. ANA patterns and autoantibody profile were assayed by indirect immunofluorescence assay using Hep-2 cells and liver/kidney/stomach tissue, respectively. Anti-dsDNA were examined by enzyme-linked immunosorbent assays; anti-Sm antibodies were measured by immunoblotting technique. Out of the 60 SLE patients, 59/60 (98.3%) were seropositive for ANA. Anti-dsDNA and anti-Sm each was detected in 50/60 (83.3%) of the Omani patients. The homogenous pattern of ANA was detected in 30/60 (50%) of patients, whereas the frequency of fine-speckled and coarse-speckled was 16/60 (26.7%) and 6/60 (10%), respectively. High titers (≥ 1:320) of ANA was detected in 56/60 (93.3%) of SLE patients. High titers of anti-Sm were detected in 22/60 (33.3%) of patients. High titers (>100 IU/ml) of anti-dsDNA were detected in 40/60 (66.7%) of patients. In the control group, ANA were detected in 8/60 (13.3%) but at low titers, whereas anti-dsDNA and anti-Sm were not detected in the healthy control group. This study shows that anti-Sm is as important as the anti-dsDNA for confirming the diagnosis of SLE and that anti-Sm occurs at a much higher frequency (83.3%) than that reported in other populations indicating the importance of this specific autoantibody for the diagnosis and possibly prognosis of Omani SLE patients.


Intention to Read to Newborns Following a Brief Reading Promotion Intervention among Low-Income Pregnant Women.
Reading to children can increase word knowledge and success in school. The American Academy of Pediatrics recommends beginning reading at birth. However, children from low-income families are exposed to less words, including reading exposure, than children from high-income families. Pregnant women attending a community prenatal education program targeted at high-risk and low-income populations were recruited into this study. Participants completed a pre-survey, engaged with a brief educational intervention, then completed a matched post-survey. Surveys assessed perceived benefits, intended behaviors, and self-efficacy regarding reading to their child. Of 61 eligible participants, 54 (89%) completed the study. Participants reported being Black (33%), White (30%), Hispanic (28%), and other race (9%). Average gestational age at enrollment was 27 weeks (range 13 to 38 weeks). The average age of respondents was 26 years (SD = 7.2); 46% reported being pregnant for the first time. Following the intervention, no change in knowledge regarding benefits of reading was observed, however, baseline knowledge was high (58% - 94%). At post-test, significantly more women reported it was important to start reading to their child at birth (83% vs 56%; p < 0.001) and that they planned to start reading to their child at birth (70% vs 50%; p = 0.001). A brief educational intervention showed promise in increasing pregnant women's intentions to read to their children and should be considered in conjunction with other reading promotion programs. Follow-up to assess actual reading behavior is needed.


Sandarakinorhabdus limnophila gen. nov., sp. nov., a novel bacteriochlorophyll a-containing, obligately aerobic bacterium isolated from freshwater lakes.
Three strains (so36, so42T and wo26) representing a novel Gram-negative, obligately aerobic, bacteriochlorophyll a-containing species of the alpha-4 subgroup of the Proteobacteria were isolated from freshwater lakes using a high-throughput cultivation technique. The non-motile and slender rod-shaped cells formed orange-red-pigmented colonies. The main carotenoids were nostoxanthin and keto-nostoxanthin. According to the absorption spectrum, two different photosynthetic light-harvesting complexes, an LHI complex and a B800-830-type peripheral LHII complex, were present in the cells. The predominant fatty acids of strain so42T were hexadecenoic acid (16 : 1omega7c) and octadecenoic acid (18 : 1omega7c), whereas 17 : 1omega6c and 14 : 0 iso 2-OH were present in smaller amounts. The main polar lipids were phosphatidylethanolamine, phosphatidylglycerol, phosphatidylcholine, diphosphatidylglycerol, glycolipid and sphingoglycolipids. The major respiratory lipoquinone was ubiquinone-10, whereas ubiquinone-9 was present in smaller amounts. The three strains were cytochrome oxidase-negative and catalase-positive and formed alkaline and acid phosphatases. The strains grew chemoorganoheterotrophically in mineral media supplemented with various organic acids, amino acids or complex substrates such as peptone and yeast extract. The G+C content of the genomic DNA of strain so42T was 64.3 mol%. The three novel isolates contained the same 16S rRNA gene sequence. The 16S rRNA gene sequence similarity to the closest phylogenetic relative Sandaracinobacter sibiricus was only 92.8 %. Accordingly, the three strains represent a new genus and species, for which the name Sandarakinorhabdus limnophila gen. nov., sp. nov., is proposed, with strain so42T (=DSM 17366T = CECT 7086T) as the designated type strain.


Human brain slices for epilepsy research: Pitfalls, solutions and future challenges.
Increasingly, neuroscientists are taking the opportunity to use live human tissue obtained from elective neurosurgical procedures for electrophysiological studies in vitro. Access to this valuable resource permits unique studies into the network dynamics that contribute to the generation of pathological electrical activity in the human epileptic brain. Whilst this approach has provided insights into the mechanistic features of electrophysiological patterns associated with human epilepsy, it is not without technical and methodological challenges. This review outlines the main difficulties associated with working with epileptic human brain slices from the point of collection, through the stages of preparation, storage and recording. Moreover, it outlines the limitations, in terms of the nature of epileptic activity that can be observed in such tissue, in particular, the rarity of spontaneous ictal discharges, we discuss manipulations that can be utilised to induce such activity. In addition to discussing conventional electrophysiological techniques that are routinely employed in epileptic human brain slices, we review how imaging and multielectrode array recordings could provide novel insights into the network dynamics of human epileptogenesis. Acute studies in human brain slices are ultimately limited by the lifetime of the tissue so overcoming this issue provides increased opportunity for information gain. We review the literature with respect to organotypic culture techniques that may hold the key to prolonging the viability of this material. A combination of long-term culture techniques, viral transduction approaches and electrophysiology in human brain slices promotes the possibility of large scale monitoring and manipulation of neuronal activity in epileptic microcircuits.


The anteromedial thigh flap as a training model of a perforator flap in rat.
Perforator flap surgery is a complex surgery that is based on the use of a highly precise microsurgical technique that differs slightly from a conventional free flap, especially the intramuscular dissection of the pedicle. Herein, we report a new model of a perforator flap in rat, the anteromedial thigh flap, as a teaching model of a perforator flap. It is based on a constant musculocutaneous perforator that arises from the muscular vessels for the gracilis muscle. Twenty Wistar rats were used in this study. In 10 rats, an anatomical study was performed by means of anatomical dissection, Chinese ink injection, and microangiography studies, and in 10 rats, a flap transplantation study was carried out by means of transferring a pedicled perforator flap to the abdomen and monitoring its viability by direct inspection on the seventh day. Anatomical studies revealed a constant perforator that has an average length of pedicle up to 20 mm, an external diameter from 0.2 to 0.3 mm, and supplies blood to an area of approximately 3 x 3 cm of the anteromedial region of the thigh. In the flap studies, all the flaps survived on the seventh day after operation. The anteromedial thigh perforator flap is a reliable, reproducible inexpensive, replicates the handling of a perforator flap very closely, and has an easy method to record the outcomes by visual inspection, so we think that it is a useful tool as a teaching model for training a perforator flap in the preclinical setting.


Physiological concentration of atrial natriuretic peptide induces endothelial regeneration in vitro.
Both nitric oxide (NO) and natriuretic peptides produce apoptosis of vascular smooth muscle cells. However, there is evidence that NO induces endothelial cell proliferation, which suggests that there is a difference in the response of endothelial cells to natriuretic peptides. The purpose of this study was to investigate the effect of atrial natriuretic peptide (ANP) on human endothelial cell survival. ANP within the physiological concentration (10(-11) mol/l) induced a 52% increase in the number of human coronary arterial endothelial cells and a 63% increase in human umbilical vein endothelial cells at a low concentration of serum. The increase in cell numbers was blocked by pretreatment with RP8-CPT-cGMP (RP8), a cGMP-dependent protein kinase inhibitor, with wortmannin, an Akt/PKB inhibitor, and with PD-98059, an ERK1/2 inhibitor. In a Transwell migration test, ANP also increased the cell migration, and RP8, wortmannin, and PD-98059 blocked this increase. A wound healing assay was performed to examine the effects of ANP on regeneration in vitro. ANP increased both cell numbers and migration, but the effects were blocked by the above three kinase inhibitors. ANP increased the expression of phospho-Akt and of phospho-ERK1/2 within 1.5 h. These results suggest that ANP can potentiate endothelial regeneration by cGMP-dependent protein kinase stimulation and subsequent Akt and ERK1/2 activations.


Blockade of alpha-2 adrenergic receptors in the rostral ventrolateral medulla attenuates the sympathoinhibitory response to cocaine.
The purpose of this study was to determine whether neurons in the rostral ventrolateral medulla play a role in the sympathoinhibitory response elicited by i.v. administration of cocaine and, if so, to identify the type(s) of receptors involved. Adrenergic antagonists were microinjected bilaterally into the rostral ventrolateral medulla in pentobarbital-anesthetized rats in an attempt to block the decrease in sympathetic nerve discharge (SND) elicited by cocaine (1 mg/kg i.v.). After the bilateral microinjection of saline, cocaine elicited a -56 +/- 5% (mean +/- S.E.) decrease in SND lasting 36 +/- 3 min. Cocaine also increased arterial pressure (21 +/- 3 mm Hg). Prior microinjection of the alpha-2 adrenergic antagonist idazoxan (0.3, 3 or 10 nmol) did not alter the magnitude of the sympathoinhibitory response to cocaine; however, the duration of the response was significantly reduced by all 3 doses (range 21 +/- 3 to 11 +/- 2 min). Similarly, microinjection of the alpha-2 adrenergic antagonist piperoxan (10 nmol) decreased the duration (from 45 +/- 8 to 23 +/- 4 min), but not the magnitude of the sympathoinhibitory response. Microinjection of either the alpha-1 adrenergic antagonist terazosin (0.24 nmol) or the beta adrenergic receptor antagonist propranolol (2 nmol) did not attenuate the decrease in SND elicited by cocaine. The cocaine-mediated pressor response was not affected by any of the antagonist treatments. These data show that the decrease in SND elicited by cocaine is mediated centrally and involves, at least in part, the activation of alpha-2 adrenergic receptors in the rostral ventrolateral medulla.


Expression of inflammatory chemokines combined with local tumor destruction enhances tumor regression and long-term immunity.
Expression of chemokines within tumors can be used to recruit immature dendritic cells (DCs) for the initiation of antitumor T-cell responses. Here, we describe the chemokine receptor expression on murine bone marrow-derived immature DCs. On the basis of these receptor studies, we chose to express the chemokines CCL3 (Mip-1alpha) or CCL20 (Mip-3alpha) in tumors. We show that expression of these chemokines in the colorectal tumor model CMT93 significantly decreases tumorigenesis. This decrease is associated with an increase in CD8 T cells, natural killer cells, and Class II DCs in the tumor within the first 24 h. Furthermore, studies in immunodeficient mice show that both natural killer cells and T cells are required for this decrease in immunogenicity. CCL3 and CCL20 expression alone did not significantly inhibit the development of the B16 melanoma tumor. However, coexpression of the Herpes Simplex Virus thymidine kinase gene (HSVtk) and CCL20, cured large established tumors where HSVtk expression alone was not sufficient. Finally, coexpression of HSVtk with either CCL3 or CCL20 was able to significantly increase protection against subsequent tumor rechallenge.


Distribution of subpopulations of dendritic cells in peripheral blood of patients treated with exogenous thyrotropin.
Dendritic cells (DCs) play a major role as regulators of inflammatory events associated with thyroid pathology. The immunoregulatory function of DCs depends strongly on their subtype, as well as maturation and activation status. Numerous hormonal factors modulate the immune properties of DCs, however, little is known about effects exerted by the hypothalamus-pituitary-thyroid-axis. Recently, we have shown a direct regulatory influence of thyroid hormones (TH) on human DCs function. The aim of the present study was to analyze the effect of systemically administered thyrotropin (TSH) on human blood DCs ex vivo. Blood samples for the cytometric analysis of peripheral blood plasmacytoid and myeloid DCs subtypes were collected from patients subjected to total thyroidectomy because of differentiated thyroid carcinoma at 2 time points: (i) directly before the commencement of TSH administration and (ii) 5 days after first TSH injection. The whole blood quantitative and phenotypic analysis of plasmacytoid and myeloid DCs subtypes was performed by flow cytometry. Administration of TSH did not influence the percentage of plasmacytoid DCs in peripheral blood of study participants. Also the percentage of the two main myeloid DCs subpopulations - CD1c/BDCA1+ DCs and CD141/BDCA3+ DCs did not change significantly. TSH administration had no effect on the surface expression of CD86 - one of the major costimulatory molecules - neither in the whole peripheral blood mononuclear cell (PBMC) fraction nor in particular DCs subtypes. In the present study, we demonstrated no influence of systemic TSH administration on human peripheral blood DCs subtypes. These results are in accordance with our previous work suggesting the direct effect of TH on human DCs ex vivo.


[Irritable bowel syndrome: criteria and clinical view].
The syndrome diagnosis 'irritable bowel syndrome' (IBS) is often made on the basis of exclusion, but the question is how many diagnostic tests should be performed in order to establish this diagnosis with a degree of confidence. We present the diagnostic value of various IBS criteria for excluding IBS, based on a systematic review. The potential of the various criteria for distinguishing IBS from organic disease is extremely variable and disappointing. Patients fulfilling IBS criteria have, however, a lower risk of organic disease than patients with abdominal symptoms who do not fulfil the criteria. The same holds true for the diagnostic performance of individual alerting symptoms. These seem to be present frequently in IBS patients in whom there is no underlying organic bowel condition. An organic condition cannot be accurately excluded on the basis of symptom criteria. However, the low prior risk of organic conditions among patients who consult a primary care doctor and who meet IBS criteria argues against exhaustive diagnostic evaluation.


Adolescents' suicidal thinking and reluctance to consult general medical practitioners.
Appropriate help-seeking is widely recognized as a protective factor, and vital for early treatment and prevention of mental health problems during adolescence. General medical practitioners (GPs), that is, family doctors, provide a vital role in the identification of adolescents with mental health problems and the provision of treatment as well as access to other specialists in mental health care services. The current study examined the association between suicidal ideation and intentions to seek help from a GP for suicidal thoughts, emotional problems and physical health problems, using a sample of 590 Australian high school students that was 56.7% female and aged 13-18 years (M = 15.56 years, SD = .66 years). Higher levels of suicidal ideation and general psychological distress were related to lower intentions to seek help from a GP for suicidal and physical problems. The results suggest that even at subclinical levels, increases in suicidal ideation or psychological distress may lead to help avoidance. School personnel and other gatekeepers need to be aware of this trend in order to be more assertive in encouraging and supporting appropriate help-seeking for mental health problems. School health promotion programs should consider including information to explicitly address the help-negation process.


Immunometabolism in early and late stages of rheumatoid arthritis.
One of the fundamental traits of immune cells in rheumatoid arthritis (RA) is their ability to proliferate, a property shared with the joint-resident cells that form the synovial pannus. The building of biomass imposes high demands for energy and biosynthetic precursors, implicating metabolic control as a basic disease mechanism. During preclinical RA, when autoreactive T cells expand and immunological tolerance is broken, the main sites of disease are the secondary lymphoid tissues. Naive CD4+ T cells from patients with RA have a distinct metabolic signature, characterized by dampened glycolysis, low ATP levels and enhanced shunting of glucose into the pentose phosphate pathway. Equipped with high levels of NADPH and depleted of intracellular reactive oxygen species, such T cells hyperproliferate and acquire proinflammatory effector functions. During clinical RA, immune cells coexist with stromal cells in the acidic milieu of the inflamed joint. This microenvironment is rich in metabolic intermediates that are released into the extracellular space to shape cell-cell communication and the functional activity of tissue-resident cells. Increasing awareness of how metabolites regulate signalling pathways, guide post-translational modifications and condition the tissue microenvironment will help to connect environmental factors with the pathogenic behaviour of T cells in RA.


Efficient optical elements to generate intensity weighted spot arrays: design and fabrication.
We report on the design and fabrication of fully 2-D surface relief diffraction elements that can split a single collimated beam into many beams in an arbitrary intensity distribution. These splitters were designed by computer using simulated annealing, and made into phase gratings by electron-beam lithography followed by plasma etching into quartz glass. Both two and four phase level gratings have been fabricated, allowing a wide range of uniform and weighted spot patterns to be generated. These grating elements have a measured diffraction efficiency of over 74%, with the beam intensity ratios accurate to within 1% of their target values.


Marked differences in antidepressant use by race in an elderly community sample: 1986-1996.
Prescriptions of antidepressant medications have increased significantly over the past 15 years across the life cycle. One overall correlate of medication use in older adults is race, with African Americans using fewer medications than whites. Given the frequency of depressive symptoms among elderly populations, as well as the increased potential for adverse side effects from antidepressants, the relative contribution of race in the use of antidepressants is critical for determining well-designed studies. The authors analyzed data from a community-based cohort of elders followed for 10 years to determine the association of race to the use of antidepressants between 1986 and 1996, with control for known correlates of depression in late life. Information on antidepressant use and demographic and health characteristics were obtained from a stratified, probability-based sample of 4,162 elders (equally distributed between African American and white community-dwelling subjects) in the Piedmont region of North Carolina during four in-person interviews spanning 10 years. Descriptive statistics were calculated. Logistic regression was used for the final models. A total of 4.6% of whites and 2.3% of African Americans used antidepressants in 1986. Approximately 14.3% of whites and 5.0% of African Americans used antidepressants in 1996. In controlled analyses, the prevalence odds ratio for antidepressant use in whites, compared to African Americans, was 1. 76 in 1986 and 3.77 in 1996. African American elders are much less likely to take antidepressants, and the difference in use increased over the 10 years of the survey.


A C2HC zinc finger is essential for the RING-E2 interaction of the ubiquitin ligase RNF125.
The activity of RING ubiquitin ligases (E3s) depends on an interaction between the RING domain and ubiquitin conjugating enzymes (E2), but posttranslational events or additional structural elements, yet largely undefined, are frequently required to enhance or regulate activity. Here, we show for the ubiquitin ligase RNF125 that, in addition to the RING domain, a C2HC Zn finger (ZnF) is crucial for activity, and a short linker sequence (Li2(120-128)) enhances activity. The contribution of these regions was first shown with truncated proteins, and the essential role of the ZnF was confirmed with mutations at the Zn chelating Cys residues. Using NMR, we established that the C2HC ZnF/Li2(120-128) region is crucial for binding of the RING domain to the E2 UbcH5a. The partial X-ray structure of RNF125 revealed the presence of extensive intramolecular interactions between the RING and C2HC ZnF. A mutation at one of the contact residues in the C2HC ZnF, a highly conserved M112, resulted in the loss of ubiquitin ligase activity. Thus, we identified the structural basis for an essential role of the C2HC ZnF and conclude that this domain stabilizes the RING domain, and is therefore required for binding of RNF125 to an E2.


PERIODIC INDUCTION OF DEOXYRIBONUCLEASE ACTIVITY IN RELATION TO THE MITOTIC CYCLE.
The behavior of developing anthers has been studied with respect to deoxyribonuclease. This enzyme, in contrast to related hydrolytic ones, is sharply periodic in its activity. Whenever a pool of deoxyribosides appears in situ, it is preceded by the appearance of deoxyribonuclease. The duration of pool or enzyme does not exceed and is generally less than 12 hours, even though the life span of the cells concerned is of the order of 25 to 30 days. The significance of periodic enzyme induction is discussed in relation to cell morphogenesis.


The Productivity of Wh- Prompts in Child Forensic Interviews.
Child witnesses are often asked wh- prompts (what, how, why, who, when, where) in forensic interviews. However, little research has examined the ways in which children respond to different wh- prompts, and no previous research has investigated productivity differences among wh- prompts in investigative interviews. This study examined the use and productivity of wh- prompts in 95 transcripts of 4- to 13-year-olds alleging sexual abuse in child investigative interviews. What-how questions about actions elicited the most productive responses during both the rapport building and substantive phases. Future research and practitioner training should consider distinguishing among different wh- prompts.


Basolateral sorting of syntaxin 4 is dependent on its N-terminal domain and the AP1B clathrin adaptor, and required for the epithelial cell polarity.
Generation of epithelial cell polarity requires mechanisms to sort plasma membrane proteins to the apical and basolateral domains. Sorting involves incorporation into specific vesicular carriers and subsequent fusion to the correct target membranes mediated by specific SNARE proteins. In polarized epithelial cells, the SNARE protein syntaxin 4 localizes exclusively to the basolateral plasma membrane and plays an important role in basolateral trafficking pathways. However, the mechanism of basolateral targeting of syntaxin 4 itself has remained poorly understood. Here we show that newly synthesized syntaxin 4 is directly targeted to the basolateral plasma membrane in polarized Madin-Darby canine kidney (MDCK) cells. Basolateral targeting depends on a signal that is centered around residues 24-29 in the N-terminal domain of syntaxin 4. Furthermore, basolateral targeting of syntaxin 4 is dependent on the epithelial cell-specific clathrin adaptor AP1B. Disruption of the basolateral targeting signal of syntaxin 4 leads to non-polarized delivery to both the apical and basolateral surface, as well as partial intercellular retention in the trans-Golgi network. Importantly, disruption of the basolateral targeting signal of syntaxin 4 leads to the inability of MDCK cells to establish a polarized morphology which suggests that restriction of syntaxin 4 to the basolateral domain is required for epithelial cell polarity.


[A case of squamous cell lung cancer in a nonsmoking female, successfully treated with docetaxel and cisplatin].
A 62-year-old nonsmoking female was admitted to our hospital in May, 1998 complaining of marked cough accompanied by repeated hemosputa. Chest X-ray and CT examinations revealed a large tumor, located adjacent to a cystic lesion in the left lower lung field, in association with a clearly recognizable swelling of the ipsilateral hilar as well as the mediastinal lymph nodes. Sputum cytology after bronchofiberscopy led to the diagnosis that the patient suffered from squamous cell lung cancer of Stage IIIA with bulky N2 (T2N2M0). Chemotherapy was selected as the most reasonable treatment for this patient. The new chemotherapeutic agent docetaxel (60 mg/m2) in combination with cisplatin (CDDP: 80 mg/m2) was tried, resulting in a remarkable reduction in tumor size by 60% after the initial course of chemotherapy was completed, which fulfilled the definition of a partial response (PR). Furthermore, after 4 courses of the chemotherapy, the hilar and mediastinal lymphadenopathy had conspicuously abated and only scar tissue was visible at the site where the lung cancer was thought to have originally developed. We herein report a case in which squamous cell lung cancer sprouted in a nonsmoking female, who was successfully treated by the combined chemotherapy of docetaxel and CDDP. The present case may suggest the efficacy of newly developed docetaxel in treating non-small cell lung cancer.


Towards a postponement of activities of daily living dependence and mobility limitations: Trends in healthy life years in old age in Sweden.
To investigate the development of healthy life expectancy from 65 years (HLE65) in Sweden in the period 1980-2011 using the health indicators activities of daily living (ADL) and mobility limitations within the framework of the postponement, compression and expansion theories. Sources of data for the HLE computations were Swedish national mortality statistics and the nationwide Swedish Surveys of Living Conditions, conducted biennially by Statistics Sweden since 1974. We used the Sullivan method for calculations of HLE and a decomposition into mortality and disability effects was made. Life expectancy at age 65 (LE65) increased by 3.1 years for women and 4.0 years for men from 1980-1985 to 2006-2011. HLE65 calculated according to ADL and mobility limitations increased more rapidly than LE65 for both men and women ( p<0.05). Our results for trends in the Swedish LE65 and HLE65, computed on the basis of ADL and mobility limitations and using the Swedish Surveys of Living Conditions study, are in line with the postponement hypothesis and there is also a tendency for compression. Thus the years with ADL dependence and mobility limitations are postponed to a higher age and the numbers of these years have decreased.


Changes in deposition of phytoplankton constituents in a Ca2+ polluted lake.
Systematic reductions in the deposition rate of organic C, N, P, and chlorophyll (Chl) are documented for Ca2+ polluted, culturally eutrophic, Onondaga Lake, NY, based on analyses of weekly sediment trap collections over the May-October interval for 10 years of the 1980-1992 period. Inputs of both nutrient-rich domestic waste and industrial salt waste (including Ca2+) decreased over this period. Constituent ratios of the collected sediment indicate phytoplankton biomass was the dominant source of the deposited organic C, N, and Chl. Substantial decreases in downward fluxes of these constituents occurred starting in 1987: 37, 42, 25, and 54%, on average, for organic C, N, P, and Chl, respectively. These reductions were driven primarily by the decreases in the lake's salinity and Ca2+ concentration, that resulted from the closure of a soda ash manufacturing facility (1986), rather than decreases in water column P concentrations from reductions in domestic waste loading. Three different mechanisms for the decreased deposition, related to the reductions in salinity and Ca2+ concentration, are considered: (i) decrease in coating of phytoplankton with CaCO3 precipitate, (ii) increased grazing of phytoplankton by large cladocerans, and (iii) decreases in coagulation of phytoplankton. The greater loss of phytoplankton biomass through deposition, driven by salt waste inputs from the industry, exacerbated the lake's problem of high primary production. This response is consistent with ecological theory for nutrient saturated phytoplankton growth but has not previously been demonstrated on a whole-lake basis.


[Anemia in public school first graders in the city of Maceió, Alagoas, Brazil].
A cross-sectional study was conducted in a representative sample of 426 randomly selected first graders (ages 6 to 10 years) from public schools in Maceió, State of Alagoas, Brazil. The aim was to determine the prevalence of anemia, as well as its association with growth retardation. Data were collected from May to July 2000, and determination of hemoglobin (HGB) employed an STKS Coulter counter. Two cut-off points were used to classify anemia, both established by the World Health Organization: HGB < 11.5g/dl and HGB < 12.0g/dl. The indicators height/age (H/A), weight/age (W/A), and weight/height (W/H) below -2.0 standard deviations from the NCHS reference were diagnosed as growth retardation. Prevalence of anemia was 9.9% when HGB < 11.5g/dl was used, and 25.4% when the cut-off point was HGB < 12.0g/dl. Growth retardation was detected in 6.2% of children according to H/A, 4.0% for W/A, and 3.0% for W/H. There was no statistically significant association between the variables in the study. These findings confirm results of previous surveys where prevalence of anemia was much higher than that of growth retardation. The severe consequences of anemia in this age group justify the implementation of broad public policies to overcome this nutritional deficiency.


A specifically designed aquatic exercise protocol to reduce chronic lower limb edema.
Objective Despite the fact that muscle pump activation is known to positively impact chronic lower limb edema, objective measurements of standardized exercises for venous-lymphatic rehab are lacking. The aim of this investigation is to determine the effectiveness of an addressed physical activity exploiting the advantages of an aquatic environment. Material and methods Thirty-two lower limbs of 16 patients affected by bilateral chronic leg swelling were included (12 females, 4 males). All the patients underwent a protocol of five sessions of physical exercises specifically conceived inside a pool. Volumetry, subcutaneous thickness, ankle range of motion and symptomatology were assessed as outcome measures. Results One week after the end of the protocol, the average reduction in lower limb volume was 303.13 ± 69.72 ml ( p = 0.00002) and 334.38 ± 62.50 ml ( p = 0.000003) in the right and left legs, respectively. Ankle range of motion and feeling of heaviness significantly improved. Conclusion A specifically designed aquatic protocol is able to positively impact chronic leg swelling offering a first line rehab for this medical condition.


Duration and timing of sensitivity related to bleaching.
Reports of sensitivity vary greatly from one study to another, probably because studies are small. Generally, only the percentage of subjects is reported. This study reports sensitivity using a large database. We investigated the source, duration, and timing of sensitivity during 14 days of active bleaching. One hundred and seventy-two people recorded sensitivity from any of the five sources on a daily basis. No one withdrew from the study because of sensitivity. Forty-seven percent of participants experienced sensitivity. Seventy-seven percent had sensitivity of 3 or fewer days. Temperature sensitivity tended to occur later in the 14-day bleaching cycle, and hot and cold sensitivity tended to occur together. There was great variability in sensitivity levels from person to person. Temperature sensitivity tended to occur later in the active phase of bleaching, whereas irritation of the tongue tended to occur earlier. The results from a large group of people are more likely to include a wide cross-section of the population sampled. This data provides practitioners with a better estimate of what their patients are likely to experience. It is estimated that, during 2 weeks of active bleaching, 77% of people will experience 3 or fewer days of sensitivity. On average, sensitivity is short-lived, thus making it is easy to underestimate the importance of discussing sensitivity with patients considering bleaching. However, for some, the duration of sensitivity is much greater and has a very negative impact on satisfaction.


Metabolic biomarkers related to energy metabolism in Saudi autistic children.
Energy metabolism is usually manipulated in many neurodegenerative diseases. Autism is considered a definable systemic disorder resulting in a number of diverse factors that may affect the brain development and functions both pre and post natal. The increased prevalence of autism will have enormous future public implications and has stimulated intense research into potential etiologic factors. This study aims to establish a connection between autism and the deterioration accompanied it, especially in the brain cognitive areas through a postulation of energy manipulation. The biochemical changes in activities of enzymes and pathways that participate in the production of ATP as the most important high-energy compound needed by the human brain were measured in Saudi autistic children. Na(+)/K(+)ATPase, ectonucleotidases (NTPDases) (ADPase and ATPase) and creatine kinase (CK), were assessed in plasma of 30 Saudi autistic patients and compared to 30 age-matching control samples. In addition, adenosine mono, di and trinucleotides (ATP, ADP, and AMP) were measured calorimetrically in the red blood cells of both groups and the adenylate energy charge (AEC) was calculated. Moreover, lactate concentration in plasma of both groups was monitored. The obtained data recorded 148.77% and 72.35% higher activities of Na(+)/K(+)ATPase and CK respectively in autistic patients which prove the impairment of energy metabolism in these children compared to age and sex matching healthy controls. While ADPase was significantly higher in autistic patients, ATPase were non-significantly elevated compared to control. In spite of the significant increase of Na(+)/K(+)ATPase activity in autistic patients, there was no significant difference in the levels of ATP, ADP, and AMP in both groups and the calculated AEC values were 0.814+/-0.094 and 0.806+/-0.081 for autistic and control groups respectively. The unchanged AEC value in autistic patients was easily correlated with the induced activity of CK and ADPase as two enzymes playing a critical role in the stabilization of AEC. Lactate as an important energy metabolite for the brain was significantly higher in autistic patients compared to control showing about 40% increase. The present study confirmed the impairment of energy metabolism in Saudi autistic patients which could be correlated to the oxidative stress previously recorded in the same investigated samples. The identification of biochemical markers related to autism would be advantageous for earlier clinical diagnosis and intervention.


Distinctive tics suppression network in Gilles de la Tourette syndrome distinguished from suppression of natural urges using multimodal imaging.
Gilles de la Tourette syndrome (GTS) is a neuropsychiatric disorder characterized by tics. A hallmark of GTS is the ability to voluntarily suppress tics. Our aim was to distinguish the neural circuits involved in the voluntary suppression of ocular tics in GTS patients from blink suppression in healthy subjects. Fifteen GTS patients and 22 healthy control subjects were included in a multimodal study using eye-tracker recordings during functional MRI (fMRI). The ability to suppress tics/blinks was compared both on subjective (self-rating) and objective (eye-tracker) performance. For fMRI analysis we used a novel designed performance-adapted block design analysis of tic/blink suppression and release based on eye-tracker monitoring. We found that the subjective self-reported ability to suppress tics or blinks showed no significant correlation with objective task performance. In GTS during successful suppression of tics, the dorsal anterior cingulate cortex and associated limbic areas showed increased activation. During successful suppression of eye blinks in healthy subjects, the right ventrolateral prefrontal cortex and supplementary and cingulate motor areas showed increased activation. These findings demonstrate that GTS patients use a characteristic limbic suppression strategy. In contrast, control subjects use the voluntary sensorimotor circuits and the classical 'stop' network to suppress natural urges. The employment of different neural suppression networks provides support for cognitive behavioral therapy in GTS.


Development and implementation of a paediatric rehabilitation care path for hard-to-reach families: a case report.
Service providers, policy makers and researchers are increasingly concerned with service provisions for hard-to-reach families. These are defined as families who are eligible for a service, but are difficult for service providers to identify or engage. In our setting, hard-to-reach families were those who missed appointments without prior notice, a problem that was inefficient for the organization, frustrating for clinicians and did not meet child or family needs. This case report describes the development of a care path to promote engagement with hard-to-reach families (MATCH: Making Alternative Therapy Choices Happen) and its adoption among clinicians within a community-based paediatric rehabilitation centre in Ontario, Canada. The care path was developed and implemented at a pilot site at KidsAbility Centre for Child Development (KidsAbility), which allowed us to tailor the care path using clinician input via questionnaires, and to monitor use of the care path. Following pilot implementation clinicians reported being satisfied with the approach and perceived improved child and family outcomes. The care path was expanded to four service sites using a Knowledge Brokering model. After training, clinicians reported a good understanding of the care path: 87% felt that they would have an opportunity to use it within six months, however only 68% felt ready to use it. Challenges to offering MATCH and continuing training preferences were investigated. The MATCH care path illustrates a practical application of the principles of best-practice for engaging hard-to-reach families, tailored for a specific paediatric rehabilitation setting. Continued research is planned to further define the hard-to-reach families within paediatric rehabilitation, determine how hard-to-reach families view engagement in services, and evaluate the effectiveness of MATCH implementation in reducing missed appointments and promoting family engagement in paediatric rehabilitation services.


A ferroelectric oxide made directly on silicon.
Metal oxide semiconductor field-effect transistors, formed using silicon dioxide and silicon, have undergone four decades of staggering technological advancement. With fundamental limits to this technology close at hand, alternatives to silicon dioxide are being pursued to enable new functionality and device architectures. We achieved ferroelectric functionality in intimate contact with silicon by growing coherently strained strontium titanate (SrTiO3) films via oxide molecular beam epitaxy in direct contact with silicon, with no interfacial silicon dioxide. We observed ferroelectricity in these ultrathin SrTiO3 layers by means of piezoresponse force microscopy. Stable ferroelectric nanodomains created in SrTiO3 were observed at temperatures as high as 400 kelvin.


Molecular characterization of Blastocystis species in Oregon identifies multiple subtypes.
The association of Blastocystis species infections with gastrointestinal symptoms in humans is clouded by the variable presentation of disease and multiple lineages of the parasite that can infect humans and other animals. It has long been suspected that certain subtypes of Blastocystis may be more or less pathogenic, be restricted to certain hosts, or have limits to their geographic distribution. In the state of Oregon, USA, Blastocystis spp. are the most commonly encountered parasites in fecal specimens submitted for diagnostic evaluation, yet the diversity of subtypes is unknown. In this study, fecal samples were collected from individuals experiencing symptoms associated with blastocystosis and analyzed by polymerase chain reaction for presence of the parasite and DNA sequenced for subtyping. Five of 19 individuals tested positive for the parasite, all of which were also positive by previous ova and parasitology examination. DNA sequencing of the small subunit ribosomal DNA and elongation factor 1 alpha gene followed by phylogenetic subtyping identified five unique subtypes, representing Blastocystis subtypes 1, 2, 3, 4, and 8. No symptoms were consistently associated with presence or absence of infection, although abdominal pain and fatigue were reported by all infected individuals. Multiple subtypes are indicative of multiple sources of infection, suggesting more extensive surveys are required to understand the transmission of this parasite.


Exercise economy does not change after acclimatization to moderate to very high altitude.
For more than 60 years, muscle mechanical efficiency has been thought to remain unchanged with acclimatization to high altitude. However, recent work has suggested that muscle mechanical efficiency may in fact be improved upon return from prolonged exposure to high altitude. The purpose of the present work is to resolve this apparent conflict in the literature. In a collaboration between four research centers, we have included data from independent high-altitude studies performed at varying altitudes and including a total of 153 subjects ranging from sea-level (SL) residents to high-altitude natives, and from sedentary to world-class athletes. In study A (n=109), living for 20-22 h/day at 2500 m combined with training between 1250 and 2800 m caused no differences in running economy at fixed speeds despite low typical error measurements. In study B, SL residents (n=8) sojourning for 8 weeks at 4100 m and residents native to this altitude (n=7) performed cycle ergometer exercise in ambient air and in acute normoxia. Muscle oxygen uptake and mechanical efficiency were unchanged between SL and acclimatization and between the two groups. In study C (n=20), during 21 days of exposure to 4300 m altitude, no changes in systemic or leg VO(2) were found during cycle ergometer exercise. However, at the substantially higher altitude of 5260 m decreases in submaximal VO(2) were found in nine subjects with acute hypoxic exposure, as well as after 9 weeks of acclimatization. As VO(2) was already reduced in acute hypoxia this suggests, at least in this condition, that the reduction is not related to anatomical or physiological adaptations to high altitude but to oxygen lack because of severe hypoxia altering substrate utilization. In conclusion, results from several, independent investigations indicate that exercise economy remains unchanged after acclimatization to high altitude.


Multi-locus phylogeny and taxonomy of Exserohilum.
Exserohilum includes a number of plant pathogenic, saprobic and clinically relevant fungi. Some of these species are of great importance in human activities, but the genus has never been revised in a phylogenetic framework. In this study, we revise Exserohilum based on available ex-type cultures from worldwide collections, observation of the holotypes and/or protologues, and additional isolates from diverse substrates and geographical origins. Based on nine nuclear loci, i.e., ITS, LSU, act, tub2, cam, gapdh, his, tef1 and rpb2, as well as phenotypic data, the genus and species boundaries are assessed for Exserohilum. Three species, i.e., E. novae-zelandiae, E. paspali and E. sorghicola, are excluded from the genus and reallocated in Sporidesmiella and Curvularia, respectively, whereas E. heteropogonicola and E. inaequale are confirmed as members of Curvularia. Exserohilum rostratum is revealed as conspecific with species previously described in Exserohilum such as E. antillanum, E. gedarefense, E. leptochloae, E. longirostratum, E. macginnisii and E. prolatum. Additionally, E. curvatum is revealed as synonym of E. holmii, and E. fusiforme of E. oryzicola. A total of 11 Exserohilum phylogenetic species are described, illustrated and discussed, including one novel taxon, E. corniculatum. The placements of 15 other doubtful species are discussed, and E. elongatum is validated.


Copper Transport Protein Antioxidant-1 Promotes Inflammatory Neovascularization via Chaperone and Transcription Factor Function.
Copper (Cu), an essential micronutrient, plays a fundamental role in inflammation and angiogenesis; however, its precise mechanism remains undefined. Here we uncover a novel role of Cu transport protein Antioxidant-1 (Atox1), which is originally appreciated as a Cu chaperone and recently discovered as a Cu-dependent transcription factor, in inflammatory neovascularization. Atox1 expression is upregulated in patients and mice with critical limb ischemia. Atox1-deficient mice show impaired limb perfusion recovery with reduced arteriogenesis, angiogenesis, and recruitment of inflammatory cells. In vivo intravital microscopy, bone marrow reconstitution, and Atox1 gene transfer in Atox1(-/-) mice show that Atox1 in endothelial cells (ECs) is essential for neovascularization and recruitment of inflammatory cells which release VEGF and TNFα. Mechanistically, Atox1-depleted ECs demonstrate that Cu chaperone function of Atox1 mediated through Cu transporter ATP7A is required for VEGF-induced angiogenesis via activation of Cu enzyme lysyl oxidase. Moreover, Atox1 functions as a Cu-dependent transcription factor for NADPH oxidase organizer p47phox, thereby increasing ROS-NFκB-VCAM-1/ICAM-1 expression and monocyte adhesion in ECs inflamed with TNFα in an ATP7A-independent manner. These findings demonstrate a novel linkage between Atox1 and NADPH oxidase involved in inflammatory neovascularization and suggest Atox1 as a potential therapeutic target for treatment of ischemic disease.


A prototypic modified risk tobacco product exhibits reduced effects on chemotaxis and transendothelial migration of monocytes compared with a reference cigarette.
Monocyte adhesion and migration to the subendothelial space represent critical steps in atherogenesis. Here, we investigated whether extracts from the aerosol of a prototypic modified risk tobacco product (pMRTP), based on heating rather than combusting tobacco, exhibited differential effects on the migratory behavior of monocytes compared with that from the reference cigarette, 3R4F. THP-1 cells, a monocytic cell line, and human coronary arterial endothelial cells (HCAECs) were used to investigate chemotaxis and transendothelial migration (TEM) of monocytes in conventional and impedance-based systems. THP-1 cells migrated through a monolayer of HCAECs in response to C-X-C motif ligand 12 (CXCL12), a chemokine involved in diverse cellular functions including chemotaxis and survival of stem cells. Treatment of THP-1 cells with extracts from 3R4F or pMRTP induced concentration-dependent increases in cytotoxicity (7-aminoactinomycin D), and inflammation (IL-8 and TNF-α). CXCL12-mediated chemotaxis and TEM were decreased in extract-treated THP-1 cells. Extracts from 3R4F were ~21 times more potent than those from pMRTP in all examined endpoints. Extracts from 3R4F and pMRTP induced concentration-dependent responses in assays of inflammation, cytotoxicity, chemotaxis, and TEM. Furthermore, our findings indicate that extracts from a pMRTP are significantly less cytotoxic and induce less inflammation than those from the reference cigarette, 3R4F.


Injection Site Reactions to Biologic Agents Used in Psoriasis and Psoriatic Arthritis.

Psoriasis is a chronic inflammatory cutaneous disease that affects 2-3% of the general population. Up to 30% of patients with psoriasis also develop psoriatic arthritis, a chronic inflammatory and progressive arthritis. Although their precise pathogeneses remain unclear, psoriasis and psoriatic arthritis involve altered expression of proinflammatory cytokines, including tumor necrosis factor-α, interleukin (IL)-12, IL-17, IL-22, and IL-23. The development of biologic agents that target these cytokines has greatly improved the treatment of psoriatic disease. Injection site reactions have been reported with many of these therapies. In this paper, we will present cases and review the literature on injection site reactions with the major biologic agents administered subcutaneously for the treatment of psoriasis and psoriatic arthritis.

J Drugs Dermatol. 2017;16(7):695-698.
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Feasibility of using a large amplitude movement therapy to improve ambulatory function in children with cerebral palsy.
Cerebral palsy (CP) is the most common cause of motor disability among children. Limited evidence exists regarding the efficacy of traditional rehabilitation strategies on improving ambulatory function in this population. The purpose of the study was to investigate the feasibility and short-term effects of a novel large amplitude movement therapy on ambulatory functions in children with CP. Temporal-spatial gait characteristics were examined before and after a single intervention session, replicated over five children. Five children with CP (7.0 ± 1.0 years); Gross Motor Function Classification System Levels I-II, participated. Baseline gait parameters were obtained as the participant walked across an instrumented walkway at self-selected and fast speeds. Children then participated in a 20-30 min intervention focused on making body and limb movements as large as possible with gait assessment repeated immediately. All children tolerated testing and therapy with no adverse effects. Outcomes after one intervention included: significantly greater stride velocity; reduced double support time; and greater stride length after training for three of the five participants. Results for this pilot study suggested that the large amplitude movement therapy was feasible for children with CP. There is a need for a larger scale study to determine if the protocol can be effective at an appropriate clinical dose.


L-2-oxothiazolidine-4-carboxylic acid attenuates oxidative stress and inflammation in retinal pigment epithelium.
Oxidant- and inflammation-induced damage to retinal pigment epithelial (RPE) cells is central to the pathogenesis of age-related macular degeneration (AMD). Thus, developing novel strategies to protect these cells is important. We reported previously on the robust antioxidant and therefore cell-protective effects of the cysteine pro-drug L-2-oxothiazolidine-4-carboxylic acid (OTC) in cultured human RPE cells. New reports citing a novel anti-inflammatory role for OTC in addition to the known glutathione-stimulating and antioxidant properties emerged recently; however, this role has not been evaluated in RPE cells or in intact retina. Given the crucial causative roles of oxidative stress and inflammation in AMD pathogenesis, knowing whether OTC might exhibit a similar benefit in this cell and tissue type has high clinical relevance; thus, we evaluated OTC in the present study. ARPE-19 and primary RPE cells isolated from wild-type, Gpr109a(-/-) , or Slc5a8(-/-) mouse eyes were exposed to TNF-α in the presence or absence of OTC, followed by analysis of IL-6 and Ccl2 expression with real-time quantitative polymerase chain reaction or enzyme-linked immunosorbent assay. Cellular and molecular markers of inflammation and oxidative stress (i.e., IL-1β, TGF-β, ABCG1, ABCA1, reduced glutathione, and dihydroethidium) were evaluated in Ccl2(-/-)/Cx3cr1(-/-) double knockout mice on rd8 background (DKO rd8) treated with OTC (10 mg/ml) in drinking water for a period of 5 months. OTC treatment significantly inhibited the expression and secretion of IL-6 and Ccl2 in TNF-α-stimulated ARPE-19 cells. Studies conducted using DKO rd8 animals treated with OTC in drinking water confirmed these findings. Cellular and molecular markers of inflammation were significantly suppressed in the retinas of the OTC-treated DKO rd8 animals. Subsequent in vitro and in vivo studies of the possible mechanism(s) to explain these actions revealed that although OTC is an agonist of the anti-inflammatory G-protein coupled receptor GPR109A and a transportable substrate of the sodium-coupled monocarboxylate transporter SMCT1 (SLC5A8), these properties may play a role but do not explain entirely the anti-inflammatory effects this compound elicits in cultured RPE cells and the intact mouse retina. This study represents, to our knowledge, the first report of the suppressive effects of OTC on inflammation in cultured RPE cells and on inflammation and oxidative stress in the retina in vivo.


On the continuous differentiability of inter-spike intervals of synaptically connected cortical spiking neurons in a neuronal network.
We derive conditions for continuous differentiability of inter-spike intervals (ISIs) of spiking neurons with respect to parameters (decision variables) of an external stimulating input current that drives a recurrent network of synaptically connected neurons. The dynamical behavior of individual neurons is represented by a class of discontinuous single-neuron models. We report here that ISIs of neurons in the network are continuously differentiable with respect to decision variables if (1) a continuously differentiable trajectory of the membrane potential exists between consecutive action potentials with respect to time and decision variables and (2) the partial derivative of the membrane potential of spiking neurons with respect to time is not equal to the partial derivative of their firing threshold with respect to time at the time of action potentials. Our theoretical results are supported by showing fulfillment of these conditions for a class of known bidimensional spiking neuron models.


Chronic sleep deprivation and gender-specific risk of depression in adolescents: a prospective population-based study.
Chronic exposure to sleep deprivation may increase the risk of depression in young people who are particularly vulnerable to changes in sleep and mental health. Sleep deprivation and incident depression may also differ by gender. We investigated the prospective association between cumulative sleep deprivation and subsequent levels of depressive symptomatology among adolescents from a gender perspective. A longitudinal study of 3071 young people in the British Columbia Adolescent Substance Use Survey (BASUS) cohort with three sleep time and two depression measures over 12 months (2011-12). Multivariable linear regression models with interaction terms estimated gender-specific associations between self-reported chronic sleep deprivation and changes in depressive symptomatology; post-estimation analysis calculated adjusted mean depression scores for each level of cumulative sleep deprivation. Cumulative sleep deprivation was associated with a monotonic increase in depression scores at follow-up in young women, but no consistent pattern was seen in young men. During follow-up, 15% of young women were chronically sleep deprived and 29% were depressed (CESD ≥24). Young women reporting chronic exposure to sleep deprivation had higher CESD scores at follow-up (21.50 points, [CI95 19.55-23.45]), than those reporting no history (16.59 [15.72-17.45]); that remained after multivariable adjustment (19.48 [17.59-21.38]). Results suggested that chronic sleep deprivation increases the risk of major depression among young women. Mental health promotion for young people should include relevant strategies to ensure young women can achieve recommended amounts of sleep.


Burden of Vaccine-Preventable Diseases-Measles, Tetanus, Diphtheria and Whooping Cough-in Iran: Findings from the GBD study 2010.
Vaccination has been one of the most successful and cost-effective public health interventions in the last century and has saved millions of lives. In 1984, the Expanded Program on Immunization (EPI) was launched in Iran as one of the main components of Primary Health Care (PHC). We aimed to investigate the burden of four vaccine-preventable diseases from 1990 to 2010 in Iran. GBD study 2010 includes death rates, Years of Life Lost (YLLs), Years Lived with Disability (YLDs) and Disability Adjusted Life Years (DALYs). YLLs is calculated through multiplying the number of deaths in each age group by a reference life expectancy for the same age group, while YLDs can be obtained from the prevalence of a disease multiplied by the disability weight (DW) for the same disease. The sum of these two indices yields DALYs. In the present study, we tried to produce new graphs and explain more about Iran results. We also describe the GBD study limitations. Regardless of gender differences, DALYs rates for measles at all ages were 86.1220 and 5.5703 per 100 000 in 1990 and 2010, respectively, indicating approximately 94% decrease in this disease. The maximum and minimum rates of deaths from whooping cough for males aged under 5 was 4.0674 and 0.2713 per 100 000 in 1990 and 2000, respectively, which shows 93% decline in whooping cough from in this period. This study demonstrated that vaccination has had a positive impact on the control of communicable diseases. But the results of this study have some limitations similar to GBD study which may pave the way for decision makers about other public health interventions. Moreover, since measuring the impact of various diseases on health plays an important role in public health, it can be an important step toward prioritization in health.


NOTCH1 pathway activation is an early hallmark of SCL T leukemogenesis.
The acquired activation of stem cell leukemia (SCL) during T lymphopoiesis is a common event in T-cell acute lymphoblastic leukemia (T-ALL). Here, we generated tamoxifen (TAM)-inducible transgenic mice (lck-ER(T2)-SCL) to study the consequences of acquired SCL activation during T-cell development. Aberrant activation of SCL in thymocytes resulted in the accumulation of immature CD4(+)CD8(+) (double-positive, DP) cells by preventing normal surface expression of the T-cell receptor alphabeta (TCRalphabeta) complex. SCL-induced immature DP cells were further characterized by up-regulated NOTCH1 and generated noncycling polyclonal CD8(+)TCRbeta(low) cells. The prevalence of these cells was SCL dependent because TAM withdrawal resulted in their disappearance. Furthermore, we observed that SCL activation led to a dramatic up-regulation of NOTCH1 target genes (Hes-1, Deltex1, and CD25) in thymocytes. Strikingly, NOTCH1 target gene up-regulation was already observed after short-term SCL induction, implying that enhanced NOTCH signaling is mediated by SCL and is not dependent on secondary genetic events. These data represent the basis for a novel pathway of SCL-induced leukemogenesis and provide a functional link between SCL and NOTCH1 during this process.


Physiological parameters for Prognosis in Abdominal Sepsis (PIPAS) Study: a WSES observational study.
Timing and adequacy of peritoneal source control are the most important pillars in the management of patients with acute peritonitis. Therefore, early prognostic evaluation of acute peritonitis is paramount to assess the severity and establish a prompt and appropriate treatment. The objectives of this study were to identify clinical and laboratory predictors for in-hospital mortality in patients with acute peritonitis and to develop a warning score system, based on easily recognizable and assessable variables, globally accepted. This worldwide multicentre observational study included 153 surgical departments across 56 countries over a 4-month study period between February 1, 2018, and May 31, 2018. A total of 3137 patients were included, with 1815 (57.9%) men and 1322 (42.1%) women, with a median age of 47 years (interquartile range [IQR] 28-66). The overall in-hospital mortality rate was 8.9%, with a median length of stay of 6 days (IQR 4-10). Using multivariable logistic regression, independent variables associated with in-hospital mortality were identified: age > 80 years, malignancy, severe cardiovascular disease, severe chronic kidney disease, respiratory rate ≥ 22 breaths/min, systolic blood pressure < 100 mmHg, AVPU responsiveness scale (voice and unresponsive), blood oxygen saturation level (SpO2) < 90% in air, platelet count < 50,000 cells/mm3, and lactate > 4 mmol/l. These variables were used to create the PIPAS Severity Score, a bedside early warning score for patients with acute peritonitis. The overall mortality was 2.9% for patients who had scores of 0-1, 22.7% for those who had scores of 2-3, 46.8% for those who had scores of 4-5, and 86.7% for those who have scores of 7-8. The simple PIPAS Severity Score can be used on a global level and can help clinicians to identify patients at high risk for treatment failure and mortality.


Novel role of lipoxygenases in the inflammatory response: promotion of TNF mRNA decay by 15-hydroperoxyeicosatetraenoic acid in a monocytic cell line.
The metabolism of arachidonic acid via the lipoxygenase and cyclooxygenase pathways generates metabolites that regulate the inflammatory response. Although products of lipoxygenase are classically proinflammatory, recently it has been demonstrated that lipoxins, 15-hydroperoxyeicosatetraenoic acid (15-HPETE) and 15-hydroxyeicosatetraenoic acid exhibit anti-inflammatory activity. We now demonstrate for the first time that 15-HPETE regulates the production of the proinflammatory cytokine TNF posttranscriptionally by promoting degradation of LPS-induced TNFmRNA in a human monocytic cell line, Mono Mac 6. 15-HPETE causes a significant increase in the rate of TNF but not G3PDHmRNA degradation in the presence of the transcription inhibitor, actinomycin D. The decay of TNFmRNA is accelerated 1.7-fold, and its half-life is decreased by 57%. In view of its chemical and physical properties, we propose that 15-HPETE may function by destabilizing TNFmRNA by interaction with a trans-activating protein bound to the AU-rich element of TNFmRNA.


Cerebrospinal fluid macrophage biomarkers in amyotrophic lateral sclerosis.
The neurodegenerative disease, amyotrophic lateral sclerosis (ALS), is a heterogeneous clinical syndrome involving multiple molecular pathways. The development of biomarkers for use in therapeutic trials is a priority. We sought to use a high-throughput proteomic method to identify novel biomarkers in individual cerebrospinal fluid (CSF) samples. Liquid chromatography/tandem mass spectrometry with label-free quantification was used to identify CSF proteins using samples from a well-characterized longitudinal cohort comprising patients with ALS (n = 43), the upper motor neuron variant, primary lateral sclerosis (PLS; n = 6), and cross-sectional healthy (n = 20) and disease controls (Parkinsons' disease, n = 20; ALS mimic disorders, n = 12). Three macrophage-derived chitinases showed increased abundance in ALS: chitotriosidase (CHIT1), chitinase-3-like protein 1 (CHI3L1), and chitinase-3-like protein 2 (CHI3L2). Elevated CHI3L1 was common to ALS and PLS, whereas CHIT1 and CHI3L2 levels differed. Chitinase levels correlated with disease progression rate (CHIT1, r = 0.56, p < 0.001; CHI3L1, r = 0.31; p = 0.028; CHI3L2, r = 0.29, p = 0.044). CHIT1, CHI3L1, and CHI3L2 levels correlated with phosphorylated neurofilament heavy chain (pNFH; r = 0.62, p < 0.001; r = 0.49, p < 0.001; r = 0.41, p < 0.001). CHI3L1 levels, but not CHIT1 or CHI3L2, increased over time in those with low initial levels (gradient = 0.005 log abundance units/month, p = 0.001). High CHIT1 was associated with shortened survival (hazard ratio [HR] 2.84; p = 0.009). Inclusion of pNFH in survival models left only an association of pNFH and survival (HR 1.26; p = 0.019). Neuroinflammatory mechanisms have been consistently implicated through various experimental paradigms. These results support a key role for macrophage activity in ALS pathogenesis, offering novel target engagement and pharmacodynamic biomarkers for neuroinflammation-focused ALS therapy. Ann Neurol 2018;83:258-268.


Identification of novel mutations and sequence variants in the SOX2 and CHX10 genes in patients with anophthalmia/microphthalmia.
Mutations in the SOX2 and CHX10 genes have been reported in patients with anophthalmia and/or microphthalmia. In this study, we evaluated 34 anophthalmic/microphthalmic patient DNA samples (two sets of siblings included) for mutations and sequence variants in SOX2 and CHX10. Conformational sensitive gel electrophoresis (CSGE) was used for the initial SOX2 and CHX10 screening of 34 affected individuals (two sets of siblings), five unaffected family members, and 80 healthy controls. Patient samples containing heteroduplexes were selected for sequence analysis. Base pair changes in SOX2 and CHX10 were confirmed by sequencing bidirectionally in patient samples. Two novel heterozygous mutations and two sequence variants (one known) in SOX2 were identified in this cohort. Mutation c.310 G>T (p. Glu104X), found in one patient, was in the region encoding the high mobility group (HMG) DNA-binding domain and resulted in a change from glutamic acid to a stop codon. The second mutation, noted in two affected siblings, was a single nucleotide deletion c.549delC (p. Pro184ArgfsX19) in the region encoding the activation domain, resulting in a frameshift and premature termination of the coding sequence. The shortened protein products may result in the loss of function. In addition, a novel nucleotide substitution c.*557G>A was identified in the 3'-untranslated region in one patient. The relationship between the nucleotide change and the protein function is indeterminate. A known single nucleotide polymorphism (c. *469 C>A, SNP rs11915160) was also detected in 2 of the 34 patients. Screening of CHX10 identified two synonymous sequence variants, c.471 C>T (p.Ser157Ser, rs35435463) and c.579 G>A (p. Gln193Gln, novel SNP), and one non-synonymous sequence variant, c.871 G>A (p. Asp291Asn, novel SNP). The non-synonymous polymorphism was also present in healthy controls, suggesting non-causality. These results support the role of SOX2 in ocular development. Loss of SOX2 function results in severe eye malformation. CHX10 was not implicated with microphthalmia/anophthalmia in our patient cohort.


An effective repetitive training schedule to achieve skill proficiency using a novel robotic virtual reality simulator.
A robotic virtual reality simulator (Mimic dV-Trainer) can be a useful training method for the da Vinci surgical system. Herein, we investigate several repetitive training schedules and determine which is the most effective. A total of 30 medical students were enrolled and were divided into 3 groups according to the training schedule. Group 1 performed the task 1 hour daily for 4 consecutive days, group II performed the task on once per week for 1 hour for 4 consecutive weeks, and group III performed the task for 4 consecutive hours in 1 day. The effects of training were investigated by analyzing the number of repetitions and the time required to complete the "Tube 2" simulation task when the learning curve plateau was reached. The point at which participants reached a stable score was evaluated using the cumulative sum control graph. The average time to complete the task at the learning curve plateau was 150.3 seconds in group I, 171.9 seconds in group II, and 188.5 seconds in group III. The number of task repetitions required to reach the learning curve plateau was 45 repetitions in group I, 36 repetitions in group II, and 39 repetitions in group III. Therefore, there was continuous improvement in the time required to perform the task after 40 repetitions in group I only. There was a significant correlation between improvement in each trial interval and attempt, and the correlation coefficient (0.924) in group I was higher than that in group II (0.899) and group III (0.838). Daily 1-hour practice sessions performed for 4 consecutive days resulted in the best final score, continuous score improvement, and effective training while minimizing fatigue. This repetition schedule can be used for effectively training novices in future.


Immune responses to coiled coil supramolecular biomaterials.
Self-assembly has been increasingly utilized in recent years to create peptide-based biomaterials for 3D cell culture, tissue engineering, and regenerative medicine, but the molecular determinants of these materials' immunogenicity have remained largely unexplored. In this study, a set of molecules that self-assembled through coiled coil oligomerization was designed and synthesized, and immune responses against them were investigated in mice. Experimental groups spanned a range of oligomerization behaviors and included a peptide from the coiled coil region of mouse fibrin that did not form supramolecular structures, an engineered version of this peptide that formed coiled coil bundles, and a peptide-PEG-peptide triblock bioconjugate that formed coiled coil multimers and supramolecular aggregates. In mice, the native peptide and engineered peptide did not produce any detectable antibody response, and none of the materials elicited detectable peptide-specific T cell responses, as evidenced by the absence of IL-2 and interferon-gamma in cultures of peptide-challenged splenocytes or draining lymph node cells. However, specific antibody responses were elevated in mice injected with the multimerizing peptide-PEG-peptide. Minimal changes in secondary structure were observed between the engineered peptide and the triblock peptide-PEG-peptide, making it possible that the triblock's multimerization was responsible for this antibody response.


Activity of an antimicrobial peptide mimetic against planktonic and biofilm cultures of oral pathogens.
Antimicrobial peptides (AMPs) are naturally occurring, broad-spectrum antimicrobial agents that have recently been examined for their utility as therapeutic antibiotics. Unfortunately, they are expensive to produce and are often sensitive to protease digestion. To address this problem, we have examined the activity of a peptide mimetic whose design was based on the structure of magainin, exhibiting its amphiphilic structure. We demonstrate that this compound, meta-phenylene ethynylene (mPE), exhibits antimicrobial activity at nanomolar concentrations against a variety of bacterial and Candida species found in oral infections. Since Streptococcus mutans, an etiological agent of dental caries, colonizes the tooth surface and forms a biofilm, we quantified the activity of this compound against S. mutans growing under conditions that favor biofilm formation. Our results indicate that mPE can prevent the formation of a biofilm at nanomolar concentrations. Incubation with 5 nM mPE prevents further growth of the biofilm, and 100 nM mPE reduces viable bacteria in the biofilm by 3 logs. Structure-function analyses suggest that mPE inhibits the bioactivity of lipopolysaccharide and binds DNA at equimolar ratios, suggesting that it may act both as a membrane-active molecule, similar to magainin, and as an intracellular antibiotic, similar to other AMPs. We conclude that mPE and similar molecules display great potential for development as therapeutic antimicrobials.


Stochastic dynamics of cholera epidemics.
We describe the predictions of an analytically tractable stochastic model for cholera epidemics following a single initial outbreak. The exact model relies on a set of assumptions that may restrict the generality of the approach and yet provides a realm of powerful tools and results. Without resorting to the depletion of susceptible individuals, as usually assumed in deterministic susceptible-infected-recovered models, we show that a simple stochastic equation for the number of ill individuals provides a mechanism for the decay of the epidemics occurring on the typical time scale of seasonality. The model is shown to provide a reasonably accurate description of the empirical data of the 2000/2001 cholera epidemic which took place in the Kwa Zulu-Natal Province, South Africa, with possibly notable epidemiological implications.


Time to reconsider the role of ribavirin in Lassa fever.
Ribavirin is the only available Lassa fever treatment. The rationale for using ribavirin is based on one clinical study conducted in the early 1980s. However, reanalysis of previous unpublished data reveals that ribavirin may actually be harmful in some Lassa fever patients. An urgent reevaluation of ribavirin is therefore needed.


[Primary health care and urban dynamics in large cities in São Paulo State, Brazil].
The Baseline Studies on the Project for Expansion and Consolidation of the Family Health Strategy created primary health care indicators and models for the 62 municipalities with more than 100,000 inhabitants in São Paulo State, Brazil, and identified varying patterns for these indicators and models in relation to different urban dynamics in the State. The studies showed the need to reflect on health in relation to urban land use. The main objective was to gain a better understanding of how urban dynamics influence the health system's profile, organization, and operation, based on which it was possible to extract some hypotheses and discussions regarding how urbanization in São Paulo State creates challenges for the expansion and consolidation of primary health care and the Family Health Program in these municipalities.


CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment.
The efficacy of tamoxifen therapy for the treatment of breast cancer varies widely among individuals. Plasma concentrations of the active tamoxifen metabolite endoxifen are associated with the cytochrome P450 (CYP) 2D6 genotype. We examined the effects of concomitant use of selective serotonin reuptake inhibitor antidepressants, which are CYP2D6 enzyme inhibitors commonly prescribed to treat hot flashes in women who take tamoxifen, and genotypes for genes that encode tamoxifen-metabolizing enzymes on plasma concentrations of tamoxifen and its metabolites. Eighty patients with newly diagnosed with breast cancer who were beginning tamoxifen therapy (20 mg/day orally), 24 of whom were taking CYP2D6 inhibitors, were genotyped for common alleles of the CYP2D6, CYP2C9, CYP3A5, and sulfotransferase (SULT) 1A1 genes. Plasma concentrations of tamoxifen and its metabolites were measured after 1 and 4 months of tamoxifen therapy. Differences in plasma concentrations of tamoxifen and its metabolites between genotype groups were analyzed by the Wilcoxon rank sum test. All statistical tests were two-sided. Among all women, plasma endoxifen concentrations after 4 months of tamoxifen therapy were statistically significantly lower in subjects with a CYP2D6 homozygous variant genotype (20.0 nM, 95% confidence interval [CI] = 11.1 to 28.9 nM) or a heterozygous genotype (43.1 nM, 95% CI = 33.3 to 52.9 nM) than in those with a homozygous wild-type genotype (78.0 nM, 95%CI = 65.9 to 90.1 nM) (both P = .003). Among subjects who carried a homozygous wild-type genotype, the mean plasma endoxifen concentration for those who were using CYP2D6 inhibitors was 58% lower than that for those who were not (38.6 nM versus 91.4 nM, difference = -52.8 nM, 95% CI = -86.1 to -19.5 nM, P = .0025). The plasma endoxifen concentration was slightly reduced in women taking venlafaxine, a weak inhibitor of CYP2D6, whereas the plasma endoxifen concentration was reduced substantially in subjects who took paroxetine (a potent inhibitor of CYP2D6). Genetic variations of CYP2C9, CYP3A5, or SULT1A1 had no statistically significant associations with plasma concentrations of tamoxifen or its metabolites. Interactions between CYP2D6 polymorphisms and coadministered antidepressants and other drugs that are CYP2D6 inhibitors may be associated with altered tamoxifen activity.


Rainbow-enhanced forward and backward glory scattering.
When the refractive index m of a sphere is such that rainbows occur in the forward or backward direction, the glory scattering becomes exceptionally strong. A number of these refractive-index values have been determined from the geometry of ray paths. A physical-optics model of the scattering leads to an a(2)x(4/3) dependence in the scattered irradiance, where a is the radius of the sphere, and x = ka is the size parameter. Normal glory scattering gives an irradiance proportional to x. Mie theory computations illustrate the presence of rainbow glories at predicted m values and the x(4/3) irradiance factor. As in normal glory scattering, the rainbow-enhanced glory light contains a strong cross-polarized component. Experiments using single glass spheres immersed in liquids show the predicted cross-polarized scattering with a sensitive dependence on m.


A forward-looking review of seizure prediction.
Seizure prediction has made important advances over the last decade, with the recent demonstration that prospective seizure prediction is possible, though there remain significant obstacles to broader application. In this review, we will describe insights gained from long-term trials, with the aim of identifying research goals for the next decade. Unexpected results from these studies, including strong and highly individual relationships between spikes and seizures, diurnal patterns of seizure activity, and the coexistence of different seizure populations within individual patients exhibiting distinctive dynamics, have caused us to re-evaluate many prior assumptions in seizure prediction studies and suggest alternative strategies that could be employed in the search for algorithms providing greater clinical utility. Advances in analytical approaches, particularly deep-learning techniques, harbour great promise and in combination with less-invasive systems with sufficiently power-efficient computational capacity will bring broader clinical application within reach. We conclude the review with an exercise in wishful thinking, which asks what the ideal seizure prediction dataset would look like and how these data should be manipulated to maximize benefits for patients. The motivation for structuring the review in this way is to create a forward-looking, optimistic critique of the existing methodologies.


Applying Educational Theory and Best Practices to Solve Common Challenges of Simulation-based Procedural Training in Emergency Medicine.
Procedural competency is an essential prerequisite for the independent practice of emergency medicine. Multiple studies demonstrate that simulation-based procedural training (SBPT) is an effective method for acquiring and maintaining procedural competency and preferred over traditional paradigms ("see one, do one, teach one"). Although newer paradigms informing SBPT have emerged, educators often face circumstances that challenge and undermine their implementation. The goal of this paper is to identify and report on best practices and theory-supported solutions to some of these challenges as derived using a process of expert consensus building and reviews of the existing literature on SBPT. The Society for Academic Emergency Medicine (SAEM) Simulation Academy SBPT Workgroup convened approximately 8 months prior to the 2019 SAEM Annual Meeting to perform a review of the literature and participate in a consensus-building process to identify solutions (in the form of best practices and educational theory) to these challenges faced by educators engaging in SBPT. Thirteen distinct educational challenges to SBPT emerged from the expert group's primary literature reviews and consensus-building processes. Three domains emerged upon further analysis of the 13 challenges: learner, educator, and curriculum. Six challenges within the "learner" domain were selected for comprehensive discussion in this paper, as they were deemed representative of the most common and most significant threats to ideal SBPT. Each of the six challenges aligns with one of the following themes: 1) maximizing active learning, 2) maintaining learner engagement, 3) embracing learner diversity, 4) optimizing cognitive load, 5) promoting mindfulness and reflection, and 6) emphasizing deliberate practice for mastery learning. Over 20 "special treatments" for mitigating the impact of the 13 challenges were derived from the secondary literature search and consensus-building process prior to and during the preconference workshop; 11 of these that best address the six learner-centered challenges are explored, including implications for educators involved in SBPT. We propose multiple consensus-generated solutions (in the form of best practices and applied educational theory) that we believe are suitable and well aligned to overcome commonly encountered learner-centered challenges and threats to optimal SBPT.


Global comparison of warring groups in 2002-2007: fatalities from targeting civilians vs. fighting battles.
Warring groups that compete to dominate a civilian population confront contending behavioral options: target civilians or battle the enemy. We aimed to describe degrees to which combatant groups concentrated lethal behavior into intentionally targeting civilians as opposed to engaging in battle with opponents in contemporary armed conflict. We identified all 226 formally organized state and non-state groups (i.e. actors) that engaged in lethal armed conflict during 2002-2007: 43 state and 183 non-state. We summed civilians killed by an actor's intentional targeting with civilians and combatants killed in battles in which the actor was involved for total fatalities associated with each actor, indicating overall scale of armed conflict. We used a Civilian Targeting Index (CTI), defined as the proportion of total fatalities caused by intentional targeting of civilians, to measure the concentration of lethal behavior into civilian targeting. We report actor-specific findings and four significant trends: 1.) 61% of all 226 actors (95% CI 55% to 67%) refrained from targeting civilians. 2.) Logistic regression showed actors were more likely to have targeted civilians if conflict duration was three or more years rather than one year. 3.) In the 88 actors that targeted civilians, multiple regressions showed an inverse correlation between CTI values and the total number of fatalities. Conflict duration of three or more years was associated with lower CTI values than conflict duration of one year. 4.) When conflict scale and duration were accounted for, state and non-state actors did not differ. We describe civilian targeting by actors in prolonged conflict. We discuss comparable patterns found in nature and interdisciplinary research. Most warring groups in 2002-2007 did not target civilians. Warring groups that targeted civilians in small-scale, brief conflict concentrated more lethal behavior into targeting civilians, and less into battles, than groups in larger-scale, longer conflict.


Identification of benzo[a]pyrene-metabolizing bacteria in forest soils by using DNA-based stable-isotope probing.
DNA-based stable-isotope probing (DNA-SIP) was used in this study to investigate the uncultivated bacteria with benzo[a]pyrene (BaP) metabolism capacities in two Chinese forest soils (Mt. Maoer in Heilongjiang Province and Mt. Baicaowa in Hubei Province). We characterized three different phylotypes with responsibility for BaP degradation, none of which were previously reported as BaP-degrading microorganisms by SIP. In Mt. Maoer soil microcosms, the putative BaP degraders were classified as belonging to the genus Terrimonas (family Chitinophagaceae, order Sphingobacteriales), whereas Burkholderia spp. were the key BaP degraders in Mt. Baicaowa soils. The addition of metabolic salicylate significantly increased BaP degradation efficiency in Mt. Maoer soils, and the BaP-metabolizing bacteria shifted to the microorganisms in the family Oxalobacteraceae (genus unclassified). Meanwhile, salicylate addition did not change either BaP degradation or putative BaP degraders in Mt. Baicaowa. Polycyclic aromatic hydrocarbon ring-hydroxylating dioxygenase (PAH-RHD) genes were amplified, sequenced, and quantified in the DNA-SIP (13)C heavy fraction to further confirm the BaP metabolism. By illuminating the microbial diversity and salicylate additive effects on BaP degradation across different soils, the results increased our understanding of BaP natural attenuation and provided a possible approach to enhance the bioremediation of BaP-contaminated soils.


DC-ATLAS: a systems biology resource to dissect receptor specific signal transduction in dendritic cells.
The advent of Systems Biology has been accompanied by the blooming of pathway databases. Currently pathways are defined generically with respect to the organ or cell type where a reaction takes place. The cell type specificity of the reactions is the foundation of immunological research, and capturing this specificity is of paramount importance when using pathway-based analyses to decipher complex immunological datasets. Here, we present DC-ATLAS, a novel and versatile resource for the interpretation of high-throughput data generated perturbing the signaling network of dendritic cells (DCs). Pathways are annotated using a novel data model, the Biological Connection Markup Language (BCML), a SBGN-compliant data format developed to store the large amount of information collected. The application of DC-ATLAS to pathway-based analysis of the transcriptional program of DCs stimulated with agonists of the toll-like receptor family allows an integrated description of the flow of information from the cellular sensors to the functional outcome, capturing the temporal series of activation events by grouping sets of reactions that occur at different time points in well-defined functional modules. The initiative significantly improves our understanding of DC biology and regulatory networks. Developing a systems biology approach for immune system holds the promise of translating knowledge on the immune system into more successful immunotherapy strategies.